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Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols.

Purpose: To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Methods: Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, "Head Start" I and "Head Start" II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. Results: The 5-year event-free (EFS) and overall survival (OS) rates (+/-SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 +/- 11% and 70 +/- 10%, 64 +/- 13% and 79 +/- 11%, and 29 +/- 17% and 57 +/- 19%, respectively. The 5-year EFS and OS ( +/- SE) for patients with desmoplastic and classical medulloblastoma were 67 +/- 16% and 78 +/- 14%, and 42 +/- 14 and 67 +/- 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. Conclusion: This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality.

Pediatric blood & cancer · randomised controlled trial · 155 citationsread the source →

Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses.

Background: Tobacco smoking is the leading preventable cause of death and disease worldwide. Stopping smoking can reduce this harm and many people would like to stop. There are a number of medicines licenced to help people quit globally, and e-cigarettes are used for this purpose in many countries. Typically treatments work by reducing cravings to smoke, thus aiding initial abstinence and preventing relapse. More information on comparative effects of these treatments is needed to inform treatment decisions and policies. Objectives: To investigate the comparative benefits, harms and tolerability of different smoking cessation pharmacotherapies and e-cigarettes, when used to help people stop smoking tobacco. Search methods: We identified studies from recent updates of Cochrane Reviews investigating our interventions of interest. We updated the searches for each review using the Cochrane Tobacco Addiction Group (TAG) specialised register to 29 April 2022. Selection criteria: We included randomised controlled trials (RCTs), cluster-RCTs and factorial RCTs, which measured smoking cessation at six months or longer, recruited adults who smoked combustible cigarettes at enrolment (excluding pregnant people) and randomised them to approved pharmacotherapies and technologies used for smoking cessation worldwide (varenicline, cytisine, nortriptyline, bupropion, nicotine replacement therapy (NRT) and e-cigarettes) versus no pharmacological intervention, placebo (control) or another approved pharmacotherapy. Studies providing co-interventions (e.g. behavioural support) were eligible if the co-intervention was provided equally to study arms. Data collection and analysis: We followed standard Cochrane methods for screening, data extraction and risk of bias (RoB) assessment (using the RoB 1 tool). Primary outcome measures were smoking cessation at six months or longer, and the number of people reporting serious adverse events (SAEs). We also measured withdrawals due to treatment. We used Bayesian component network meta-analyses (cNMA) to examine intervention type, delivery mode, dose, duration, timing in relation to quit day and tapering of nicotine dose, using odds ratios (OR) and 95% credibility intervals (CrIs). We calculated an effect estimate for combination NRT using an additive model. We evaluated the influence of population and study characteristics, provision of behavioural support and control arm rates using meta-regression. We evaluated certainty using GRADE. Main results: Of our 332 eligible RCTs, 319 (835 study arms, 157,179 participants) provided sufficient data to be included in our cNMA. Of these, we judged 51 to be at low risk of bias overall, 104 at high risk and 164 at unclear risk, and 118 reported pharmaceutical or e-cigarette/tobacco industry funding. Removing studies at high risk of bias did not change our interpretation of the results. Benefits We found high-certainty evidence that nicotine e-cigarettes (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), varenicline (OR 2.33, 95% CrI 2.02 to 2.68; 67 RCTs, 16,430 participants) and cytisine (OR 2.21, 95% CrI 1.66 to 2.97; 7 RCTs, 3848 participants) were associated with higher quit rates than control. In absolute terms, this might lead to an additional eight (95% CrI 4 to 13), eight (95% CrI 6 to 10) and seven additional quitters per 100 (95% CrI 4 to 12), respectively. These interventions appeared to be more effective than the other interventions apart from combination NRT (patch and a fast-acting form of NRT), which had a lower point estimate (calculated additive effect) but overlapping 95% CrIs (OR 1.93, 95% CrI 1.61 to 2.34). There was also high-certainty evidence that nicotine patch alone (OR 1.37, 95% CrI 1.20 to 1.56; 105 RCTs, 37,319 participants), fast-acting NRT alone (OR 1.41, 95% CrI 1.29 to 1.55; 120 RCTs, 31,756 participants) and bupropion (OR 1.43, 95% CrI 1.26 to 1.62; 71 RCTs, 14,759 participants) were more effective than control, resulting in two (95% CrI 1 to 3), three (95% CrI 2 to 3) and three (95% CrI 2 to 4) additional quitters per 100 respectively. Nortriptyline is probably associated with higher quit rates than control (OR 1.35, 95% CrI 1.02 to 1.81; 10 RCTs, 1290 participants; moderate-certainty evidence), resulting in two (CrI 0 to 5) additional quitters per 100. Non-nicotine/placebo e-cigarettes (OR 1.16, 95% CrI 0.74 to 1.80; 8 RCTs, 1094 participants; low-certainty evidence), equating to one additional quitter (95% CrI -2 to 5), had point estimates favouring the intervention over control, but CrIs encompassed the potential for no difference and harm. There was low-certainty evidence that tapering the dose of NRT prior to stopping treatment may improve effectiveness; however, 95% CrIs also incorporated the null (OR 1.14, 95% CrI 1.00 to 1.29; 111 RCTs, 33,156 participants). This might lead to an additional one quitter per 100 (95% CrI 0 to 2). Harms There were insufficient data to include nortriptyline and non-nicotine EC in the final SAE model. Overall rates of SAEs for the remaining treatments were low (average 3%). Low-certainty evidence did not show a clear difference in the number of people reporting SAEs for nicotine e-cigarettes, varenicline, cytisine or NRT when compared to no pharmacotherapy/e-cigarettes or placebo. Bupropion may slightly increase rates of SAEs, although the CrI also incorporated no difference (moderate certainty). In absolute terms bupropion may cause one more person in 100 to experience an SAE (95% CrI 0 to 2). Authors' conclusions: The most effective interventions were nicotine e-cigarettes, varenicline and cytisine (all high certainty), as well as combination NRT (additive effect, certainty not rated). There was also high-certainty evidence for the effectiveness of nicotine patch, fast-acting NRT and bupropion. Less certain evidence of benefit was present for nortriptyline (moderate certainty), non-nicotine e-cigarettes and tapering of nicotine dose (both low certainty). There was moderate-certainty evidence that bupropion may slightly increase the frequency of SAEs, although there was also the possibility of no increased risk. There was no clear evidence that any other tested interventions increased SAEs. Overall, SAE data were sparse with very low numbers of SAEs, and so further evidence may change our interpretation and certainty. Future studies should report SAEs to strengthen certainty in this outcome. More head-to-head comparisons of the most effective interventions are needed, as are tests of combinations of these. Future work should unify data from behavioural and pharmacological interventions to inform approaches to combined support for smoking cessation.

The Cochrane database of systematic reviews · systematic review · 114 citationsread the source →

Defining the determinants of vaccine uptake and undervaccination in migrant populations in Europe to improve routine and COVID-19 vaccine uptake: a systematic review.

Understanding why some migrants in Europe are at risk of underimmunisation and show lower vaccination uptake for routine and COVID-19 vaccines is critical if we are to address vaccination inequities and meet the goals of WHO's new Immunisation Agenda 2030. We did a systematic review (PROSPERO: CRD42020219214) exploring barriers and facilitators of vaccine uptake (categorised using the 5As taxonomy: access, awareness, affordability, acceptance, activation) and sociodemographic determinants of undervaccination among migrants in the EU and European Economic Area, the UK, and Switzerland. We searched MEDLINE, CINAHL, and PsycINFO from 2000 to 2021 for primary research, with no restrictions on language. 5259 data sources were screened, with 67 studies included from 16 countries, representing 366 529 migrants. We identified multiple access barriers-including language, literacy, and communication barriers, practical and legal barriers to accessing and delivering vaccination services, and service barriers such as lack of specific guidelines and knowledge of health-care professionals-for key vaccines including measles-mumps-rubella, diphtheria-pertussis-tetanus, human papillomavirus, influenza, polio, and COVID-19 vaccines. Acceptance barriers were mostly reported in eastern European and Muslim migrants for human papillomavirus, measles, and influenza vaccines. We identified 23 significant determinants of undervaccination in migrants (p<0·05), including African origin, recent migration, and being a refugee or asylum seeker. We did not identify a strong overall association with gender or age. Tailored vaccination messaging, community outreach, and behavioural nudges facilitated uptake. Migrants' barriers to accessing health care are already well documented, and this Review confirms their role in limiting vaccine uptake. These findings hold immediate relevance to strengthening vaccination programmes in high-income countries, including for COVID-19, and suggest that tailored, culturally sensitive, and evidence-informed strategies, unambiguous public health messaging, and health system strengthening are needed to address access and acceptance barriers to vaccination in migrants and create opportunities and pathways for offering catch-up vaccinations to migrants.

The Lancet. Infectious diseases · systematic review · 165 citationsread the source →

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate.

Objective: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness. Design: Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence. Methods: HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF. Results: Thirty-five participants contributed to 33% (n = 23), 67% (n = 23) and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16) and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3 [95% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7- (4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119). Conclusion: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.

AIDS (London, England) · randomised controlled trial · 27 citationsread the source →

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.

Background: The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods: DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings: Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation: No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding: European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation: For the French translation of the abstract see Supplementary Materials section.

The Lancet. Infectious diseases · randomised controlled trial · 264 citationsread the source →

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective: To investigate the effect of psilocybin therapy in patients with MDD. Design, setting, and participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main outcomes and measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Trial registration: ClinicalTrials.gov Identifier: NCT03181529.

JAMA psychiatry · randomised controlled trial · 900 citationsread the source →

A randomized controlled trial of mindfulness meditation versus relaxation training: effects on distress, positive states of mind, rumination, and distraction.

Background: Although mindfulness meditation interventions have recently shown benefits for reducing stress in various populations, little is known about their relative efficacy compared with relaxation interventions. Purpose: This randomized controlled trial examines the effects of a 1-month mindfulness meditation versus somatic relaxation training as compared to a control group in 83 students (M age = 25; 16 men and 67 women) reporting distress. Method: Psychological distress, positive states of mind, distractive and ruminative thoughts and behaviors, and spiritual experience were measured, while controlling for social desirability. Results: Hierarchical linear modeling reveals that both meditation and relaxation groups experienced significant decreases in distress as well as increases in positive mood states over time, compared with the control group (p < .05 in all cases). There were no significant differences between meditation and relaxation on distress and positive mood states over time. Effect sizes for distress were large for both meditation and relaxation (Cohen's d = 1.36 and .91, respectively), whereas the meditation group showed a larger effect size for positive states of mind than relaxation (Cohen's d =.71 and .25, respectively). The meditation group also demonstrated significant pre-post decreases in both distractive and ruminative thoughts/behaviors compared with the control group (p < .04 in all cases; Cohen's d = .57 for rumination and .25 for distraction for the meditation group), with mediation models suggesting that mindfulness meditation's effects on reducing distress were partially mediated by reducing rumination. No significant effects were found for spiritual experience. Conclusions: The data suggest that compared with a no-treatment control, brief training in mindfulness meditation or somatic relaxation reduces distress and improves positive mood states. However, mindfulness meditation may be specific in its ability to reduce distractive and ruminative thoughts and behaviors, and this ability may provide a unique mechanism by which mindfulness meditation reduces distress.

Annals of behavioral medicine : a publication of the Society of Behavioral Medicine · randomised controlled trial · 507 citationsread the source →

Anxiety in youth with and without specific learning disorders: exploring the relationships with inhibitory control, perfectionism, and self-conscious emotions.

Introduction: Since early research on Specific Learning Disorders (SLD), their relationship with emotional issues have been recognized, although emotional factors have received less attention compared to the cognitive processes related with academic achievement. Methods: This study aimed to investigate mechanisms that may increase vulnerability to generalized and social anxiety in youth with SLD, compared to their non-diagnosed peers. We examined cognitive factors (inhibitory control), personality traits (self-oriented, socially prescribed perfectionism), and self-conscious emotions (shame, guilt). The sample included 134 individuals aged 10 to 16, divided into two groups: 67 with SLD and 67 without diagnoses, matched by age, sex, and IQ. Participants completed questionnaires on anxiety, perfectionism, and selfconscious emotions, alongside an inhibitory control task. Results: Findings revealed that those with SLD reported higher generalized and social anxiety, poorer inhibitory control, greater socially prescribed perfectionism, and more shame than nondiagnosed peers. Socially prescribed perfectionism was found to increase the risk of generalized anxiety in participants with SLD, while both socially prescribed perfectionism and shame were predictors of social anxiety across both groups. Finally, self-oriented perfectionism seemed to be associated with lower social anxiety in the SLD group. Discussion: These findings suggest that interventions should address risk and protective factors, focusing on reducing anxiety and fostering adaptive self-regulation strategies.

Frontiers in behavioral neuroscience · 1 citationsread the source →

The relevance of cognitive emotion regulation to psychotic symptoms - A systematic review and meta-analysis.

Numerous studies emphasise the pivotal role of negative affect in the formation and maintenance of positive symptoms, which moves emotion regulation (ER) as a contributing factor into focus. We systematically reviewed and meta-analysed case-control studies reporting cross-sectional, correlative and experimental data of ER strategies in patients with psychotic disorders. In total, 42 studies were eligible, providing data for 2498 subjects and 3381 healthy controls. Questionnaire-based cross-sectional data (k=39) indicated strongest effects for rumination (g=-0,67 [-0,85 to -0,48]), self-blaming (g=-0,56; [-0,76 to -0,37]) and distraction (g=0,55 [0,11 to 0,98]). Suppression was more frequently (g=-0,36 [-0,56 to -0,16]) and cognitive reappraisal less frequently used (g=0,41 [0,28 to 0,55]), but heterogeneity was high. Correlative data (k=6) supported the assumption of an association between maladaptive strategies and positive symptoms (r=0,34 [0,22 to 0,44]). Less evidence of group differences was found in the experimental studies (k=3). The findings support the notion that ER is markedly impaired in patients with psychotic disorders. However, future research will need to further clarify the extent to which difficulties continue to exist after controlling for context and emotion intensity. The large effects for rumination and self-blaming point to promising treatment targets but also raise questions concerning the specifity of findings.

Clinical psychology review · meta-analysis · 81 citationsread the source →

Integrated disease management interventions for patients with chronic obstructive pulmonary disease.

Background: People with chronic obstructive pulmonary disease (COPD) show considerable variation in symptoms, limitations, and well-being; this often complicates medical care. A multi-disciplinary and multi-component programme that addresses different elements of care could improve quality of life (QoL) and exercise tolerance, while reducing the number of exacerbations. Objectives: To compare the effectiveness of integrated disease management (IDM) programmes versus usual care for people with chronic obstructive pulmonary disease (COPD) in terms of health-related quality of life (QoL), exercise tolerance, and exacerbation-related outcomes. Search methods: We searched the Cochrane Airways Group Register of Trials, CENTRAL, MEDLINE, Embase, and CINAHL for potentially eligible studies. Searches were current as of September 2020. Selection criteria: Randomised controlled trials (RCTs) that compared IDM programmes for COPD versus usual care were included. Interventions consisted of multi-disciplinary (two or more healthcare providers) and multi-treatment (two or more components) IDM programmes of at least three months' duration. Data collection and analysis: Two review authors independently assessed trial quality and extracted data. If required, we contacted study authors to request additional data. We performed meta-analyses using random-effects modelling. We carried out sensitivity analyses for the quality of included studies and performed subgroup analyses based on setting, study design, dominant intervention components, and region. Main results: Along with 26 studies included in the 2013 Cochrane Review, we added 26 studies for this update, resulting in 52 studies involving 21,086 participants for inclusion in the meta-analysis. Follow-up periods ranged between 3 and 48 months and were classified as short-term (up to 6 months), medium-term (6 to 15 months), and long-term (longer than 15 months) follow-up. Studies were conducted in 19 different countries. The mean age of included participants was 67 years, and 66% were male. Participants were treated in all types of healthcare settings, including primary (n =15), secondary (n = 22), and tertiary care (n = 5), and combined primary and secondary care (n = 10). Overall, the level of certainty of evidence was moderate to high. We found that IDM probably improves health-related QoL as measured by St. George's Respiratory Questionnaire (SGRQ) total score at medium-term follow-up (mean difference (MD) -3.89, 95% confidence interval (CI) -6.16 to -1.63; 18 RCTs, 4321 participants; moderate-certainty evidence). A comparable effect was observed at short-term follow-up (MD -3.78, 95% CI -6.29 to -1.28; 16 RCTs, 1788 participants). However, the common effect did not exceed the minimum clinically important difference (MCID) of 4 points. There was no significant difference between IDM and control for long-term follow-up and for generic QoL. IDM probably also leads to a large improvement in maximum and functional exercise capacity, as measured by six-minute walking distance (6MWD), at medium-term follow-up (MD 44.69, 95% CI 24.01 to 65.37; 13 studies, 2071 participants; moderate-certainty evidence). The effect exceeded the MCID of 35 metres and was even greater at short-term (MD 52.26, 95% CI 32.39 to 72.74; 17 RCTs, 1390 participants) and long-term (MD 48.83, 95% CI 16.37 to 80.49; 6 RCTs, 7288 participants) follow-up. The number of participants with respiratory-related admissions was reduced from 324 per 1000 participants in the control group to 235 per 1000 participants in the IDM group (odds ratio (OR) 0.64, 95% CI 0.50 to 0.81; 15 RCTs, median follow-up 12 months, 4207 participants; high-certainty evidence). Likewise, IDM probably results in a reduction in emergency department (ED) visits (OR 0.69, 95%CI 0.50 to 0.93; 9 RCTs, median follow-up 12 months, 8791 participants; moderate-certainty evidence), a slight reduction in all-cause hospital admissions (OR 0.75, 95%CI 0.57 to 0.98; 10 RCTs, median follow-up 12 months, 9030 participants; moderate-certainty evidence), and fewer hospital days per person admitted (MD -2.27, 95% CI -3.98 to -0.56; 14 RCTs, median follow-up 12 months, 3563 participants; moderate-certainty evidence). Statistically significant improvement was noted on the Medical Research Council (MRC) Dyspnoea Scale at short- and medium-term follow-up but not at long-term follow-up. No differences between groups were reported for mortality, courses of antibiotics/prednisolone, dyspnoea, and depression and anxiety scores. Subgroup analysis of dominant intervention components and regions of study suggested context- and intervention-specific effects. However, some subgroup analyses were marked by considerable heterogeneity or included few studies. These results should therefore be interpreted with caution. Authors' conclusions: This review shows that IDM probably results in improvement in disease-specific QoL, exercise capacity, hospital admissions, and hospital days per person. Future research should evaluate which combination of IDM components and which intervention duration are most effective for IDM programmes, and should consider contextual determinants of implementation and treatment effect, including process-related outcomes, long-term follow-up, and cost-effectiveness analyses.

The Cochrane database of systematic reviews · meta-analysis · 48 citationsread the source →

Music interventions for acquired brain injury.

Background: Acquired brain injury (ABI) can result in impairments in motor function, language, cognition, and sensory processing, and in emotional disturbances, which can severely reduce a survivor's quality of life. Music interventions have been used in rehabilitation to stimulate brain functions involved in movement, cognition, speech, emotions, and sensory perceptions. An update of the systematic review published in 2010 was needed to gauge the efficacy of music interventions in rehabilitation for people with ABI. Objectives: To assess the effects of music interventions for functional outcomes in people with ABI. We expanded the criteria of our existing review to: 1) examine the efficacy of music interventions in addressing recovery in people with ABI including gait, upper extremity function, communication, mood and emotions, cognitive functioning, social skills, pain, behavioural outcomes, activities of daily living, and adverse events; 2) compare the efficacy of music interventions and standard care with a) standard care alone, b) standard care and placebo treatments, or c) standard care and other therapies; 3) compare the efficacy of different types of music interventions (music therapy delivered by trained music therapists versus music interventions delivered by other professionals). Search methods: We searched the Cochrane Stroke Group Trials Register (January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to June 2015), Embase (1980 to June 2015), CINAHL (1982 to June 2015), PsycINFO (1806 to June 2015), LILACS (1982 to January 2016), and AMED (1985 to June 2015). We handsearched music therapy journals and conference proceedings, searched dissertation and specialist music databases, trials and research registers, reference lists, and contacted relevant experts and music therapy associations to identify unpublished research. We imposed no language restriction. We performed the original search in 2009. Selection criteria: We included all randomised controlled trials and controlled clinical trials that compared music interventions and standard care with standard care alone or combined with other therapies. We examined studies that included people older than 16 years of age who had ABI of a non-degenerative nature and were participating in treatment programmes offered in hospital, outpatient, or community settings. We included studies in any language, published and unpublished. Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias of the included studies. We contacted trial researchers to obtain missing data or for additional information when necessary. Where possible, we presented results for continuous outcomes in meta-analyses using mean differences (MDs) and standardised mean differences (SMDs). We used post-test scores. In cases of significant baseline difference, we used change scores. We conducted a sensitivity analysis to assess the impact of the randomisation method. Main results: We identified 22 new studies for this update. The evidence for this update is based on 29 trials involving 775 participants. A music intervention known as rhythmic auditory stimulation may be beneficial for improving the following gait parameters after stroke. We found a reported increase in gait velocity of 11.34 metres per minute (95% confidence interval (CI) 8.40 to 14.28; 9 trials; 268 participants; P < 0.00001; moderate-quality evidence). Stride length of the affected side may also benefit, with a reported average of 0.12 metres more (95% CI 0.04 to 0.20; 5 trials; 129 participants; P = 0.003; moderate-quality evidence). We found a reported average improvement for general gait of 7.67 units on the Dynamic Gait Index (95% CI 5.67 to 9.67; 2 trials; 48 participants; P < 0.00001). There may also be an improvement in gait cadence, with a reported average increase of 10.77 steps per minute (95% CI 4.36 to 17.18; 7 trials; 223 participants; P = 0.001; low-quality evidence).Music interventions may be beneficial for improving the timing of upper extremity function after stroke as scored by a reduction of 1.08 seconds on the Wolf Motor Function Test (95% CI -1.69 to -0.47; 2 trials; 122 participants; very low-quality evidence).Music interventions may be beneficial for communication outcomes in people with aphasia following stroke. Overall, communication improved by 0.75 standard deviations in the intervention group, a moderate effect (95% CI 0.11 to 1.39; 3 trials; 67 participants; P = 0.02; very low-quality evidence). Naming was reported as improving by 9.79 units on the Aachen Aphasia Test (95% CI 1.37 to 18.21; 2 trials; 35 participants; P = 0.02). Music interventions may have a beneficial effect on speech repetition, reported as an average increase of 8.90 score on the Aachen Aphasia Test (95% CI 3.25 to 14.55; 2 trials; 35 participants; P = 0.002).There may be an improvement in quality of life following stroke using rhythmic auditory stimulation, reported at 0.89 standard deviations improvement on the Stroke Specific Quality of Life Scale, which is considered to be a large effect (95% CI 0.32 to 1.46; 2 trials; 53 participants; P = 0.002; low-quality evidence). We found no strong evidence for effects on memory and attention. Data were insufficient to examine the effect of music interventions on other outcomes. The majority of studies included in this review update presented a high risk of bias, therefore the quality of the evidence is low. Authors' conclusions: Music interventions may be beneficial for gait, the timing of upper extremity function, communication outcomes, and quality of life after stroke. These results are encouraging, but more high-quality randomised controlled trials are needed on all outcomes before recommendations can be made for clinical practice.

The Cochrane database of systematic reviews · meta-analysis · 116 citationsread the source →

Cognitive behavioural therapy (CBT), third-wave CBT and interpersonal therapy (IPT) based interventions for preventing depression in children and adolescents.

Background: Depression is common in young people. It has a marked negative impact and is associated with self-harm and suicide. Preventing its onset would be an important advance in public health. This is an update of a Cochrane review that was last updated in 2011. Objectives: To determine whether evidence-based psychological interventions (including cognitive behavioural therapy (CBT), interpersonal therapy (IPT) and third wave CBT)) are effective in preventing the onset of depressive disorder in children and adolescents. Search methods: We searched the specialised register of the Cochrane Common Mental Disorders Group (CCMDCTR to 11 September 2015), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). We searched conference abstracts and reference lists of included trials and reviews, and contacted experts in the field. Selection criteria: We included randomised controlled trials of an evidence-based psychological prevention programme compared with any comparison control for young people aged 5 to 19 years, who did not currently meet diagnostic criteria for depression. Data collection and analysis: Two authors independently assessed trials for inclusion and rated their risk of bias. We adjusted sample sizes to take account of cluster designs and multiple comparisons. We contacted trial authors for additional information where needed. We assessed the quality of evidence for the primary outcomes using GRADE. Main results: We included 83 trials in this review. The majority of trials (67) were carried out in school settings with eight in colleges or universities, four in clinical settings, three in the community and four in mixed settings. Twenty-nine trials were carried out in unselected populations and 53 in targeted populations. For the primary outcome of depression diagnosis at medium-term follow-up (up to 12 months), there were 32 trials with 5965 participants and the risk of having a diagnosis of depression was reduced for participants receiving an intervention compared to those receiving no intervention (risk difference (RD) -0.03, 95% confidence interval (CI) -0.05 to -0.01; P value = 0.01). We rated this evidence as moderate quality according to the GRADE criteria. There were 70 trials (73 trial arms) with 13,829 participants that contributed to the analysis for the primary outcome of depression symptoms (self-rated) at the post-intervention time point, with results showing a small but statistically significant effect (standardised mean difference (SMD) -0.21, 95% CI -0.27 to -0.15; P value < 0.0001). This effect persisted to the short-term assessment point (up to three months) (SMD -0.31, 95% CI -0.45 to -0.17; P value < 0.0001; 16 studies; 1558 participants) and medium-term (4 to 12 months) assessment point (SMD -0.12, 95% CI -0.18 to -0.05; P value = 0.0002; 53 studies; 11,913 participants); however, the effect was no longer evident at the long-term follow-up. We rated this evidence as low to moderate quality according to the GRADE criteria. The evidence from this review is unclear with regard to whether the type of population modified the overall effects; there was statistically significant moderation of the overall effect for depression symptoms (P value = 0.0002), but not for depressive disorder (P value = 0.08). For trials implemented in universal populations there was no effect for depression diagnosis (RD -0.01, 95% CI -0.03 to 0.01) and a small effect for depression symptoms (SMD -0.11, 95% CI -0.17 to -0.05). For trials implemented in targeted populations there was a statistically significantly beneficial effect of intervention (depression diagnosis RD -0.04, 95% CI -0.07 to -0.01; depression symptoms SMD -0.32, 95% CI -0.42 to -0.23). Of note were the lack of attention placebo-controlled trials in targeted populations (none for depression diagnosis and four for depression symptoms). Among trials implemented in universal populations a number used an attention placebo comparison in which the intervention consistently showed no effect. Authors' conclusions: Overall the results show small positive benefits of depression prevention, for both the primary outcomes of self-rated depressive symptoms post-intervention and depression diagnosis up to 12 months (but not beyond). Estimates of numbers needed to treat to benefit (NNTB = 11) compare well with other public health interventions. However, the evidence was of moderate to low quality using the GRADE framework and the results were heterogeneous. Prevention programmes delivered to universal populations showed a sobering lack of effect when compared with an attention placebo control. Interventions delivered to targeted populations, particularly those selected on the basis of depression symptoms, had larger effect sizes, but these seldom used an attention placebo comparison and there are practical difficulties inherent in the implementation of targeted programmes. We conclude that there is still not enough evidence to support the implementation of depression prevention programmes. Future research should focus on current gaps in our knowledge. Given the relative lack of evidence for universal interventions compared with attention placebo controls and the poor results from well-conducted effectiveness trials of universal interventions, in our opinion any future such trials should test a depression prevention programme in an indicated targeted population using a credible attention placebo comparison group. Depressive disorder as the primary outcome should be measured over the longer term, as well as clinician-rated depression. Such a trial should consider scalability as well as the potential for the intervention to do harm.

The Cochrane database of systematic reviews · meta-analysis · 136 citationsread the source →

Treatment efficacy and effectiveness in adults with major depressive disorder and childhood trauma history: a systematic review and meta-analysis.

Background: Childhood trauma is a common and potent risk factor for developing major depressive disorder in adulthood, associated with earlier onset, more chronic or recurrent symptoms, and greater probability of having comorbidities. Some studies indicate that evidence-based pharmacotherapies and psychotherapies for adult depression might be less efficacious in patients with a history of childhood trauma than patients without childhood trauma, but findings are inconsistent. Therefore, we examined whether individuals with major depressive disorder, including chronic forms of depression, and a reported history of childhood trauma, had more severe depressive symptoms before treatment, had more unfavourable treatment outcomes following active treatments, and were less likely to benefit from active treatments relative to a control condition, compared with individuals with depression without childhood trauma. Methods: We did a comprehensive meta-analysis (PROSPERO CRD42020220139). Study selection combined the search of bibliographical databases (PubMed, PsycINFO, and Embase) from Nov 21, 2013, to March 16, 2020, and full-text randomised clinical trials (RCTs) identified from several sources (1966 up to 2016-19) to identify articles in English. RCTs and open trials comparing the efficacy or effectiveness of evidence-based pharmacotherapy, psychotherapy, or combination intervention for adult patients with depressive disorders and the presence or absence of childhood trauma were included. Two independent researchers extracted study characteristics. Group data for effect-size calculations were requested from study authors. The primary outcome was depression severity change from baseline to the end of the acute treatment phase, expressed as standardised effect size (Hedges' g). Meta-analyses were done using random-effects models. Findings: From 10 505 publications, 54 trials met the inclusion criteria, of which 29 (20 RCTs and nine open trials) contributed data of a maximum of 6830 participants (age range 18-85 years, male and female individuals and specific ethnicity data unavailable). More than half (4268 [62%] of 6830) of patients with major depressive disorder reported a history of childhood trauma. Despite having more severe depression at baseline (g=0·202, 95% CI 0·145 to 0·258, I2=0%), patients with childhood trauma benefitted from active treatment similarly to patients without childhood trauma history (treatment effect difference between groups g=0·016, -0·094 to 0·125, I2=44·3%), with no significant difference in active treatment effects (vs control condition) between individuals with and without childhood trauma (childhood trauma g=0·605, 0·294 to 0·916, I2=58·0%; no childhood trauma g=0·178, -0·195 to 0·552, I2=67·5%; between-group difference p=0·051), and similar dropout rates (risk ratio 1·063, 0·945 to 1·195, I2=0%). Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length, but differed by country (North American studies showed larger treatment effects for patients with childhood trauma; false discovery rate corrected p=0·0080). Most studies had a moderate to high risk of bias (21 [72%] of 29), but the sensitivity analysis in low-bias studies yielded similar findings to when all studies were included. Interpretation: Contrary to previous studies, we found evidence that the symptoms of patients with major depressive disorder and childhood trauma significantly improve after pharmacological and psychotherapeutic treatments, notwithstanding their higher severity of depressive symptoms. Evidence-based psychotherapy and pharmacotherapy should be offered to patients with major depressive disorder regardless of childhood trauma status. Funding: None.

The lancet. Psychiatry · meta-analysis · 65 citationsread the source →

Reduction in saturated fat intake for cardiovascular disease.

Background: Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. Objectives: To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. Search methods: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. Selection criteria: Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. Data collection and analysis: Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. Main results: We included 15 randomised controlled trials (RCTs) (16 comparisons, 56,675 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.70 to 0.98, 12 trials, 53,758 participants of whom 8% had a cardiovascular event, I² = 67%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 53. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. Authors' conclusions: The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

The Cochrane database of systematic reviews · meta-analysis · 98 citationsread the source →

Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis.

Background: Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents. Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841. Findings: From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis. Interpretation: Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. Funding: National Key Research and Development Program of China.

The lancet. Psychiatry · systematic review · 248 citationsread the source →

Effect of Varenicline Combined With Medical Management on Alcohol Use Disorder With Comorbid Cigarette Smoking: A Randomized Clinical Trial.

Importance: Individuals with alcohol use disorder have high rates of cigarette smoking. Varenicline tartrate, an approved treatment for smoking cessation, may reduce both drinking and smoking. Objectives: To test the efficacy of varenicline with medical management for patients with alcohol use disorder and comorbid smoking seeking alcohol treatment, and to evaluate the secondary effects on smoking abstinence. Design, setting, and participants: This phase 2, randomized, double-blind, parallel group, placebo-controlled trial was conducted at 2 outpatient clinics from September 19, 2012, to August 31, 2015. Eligible participants met alcohol-dependence criteria and reported heavy drinking (≥5 drinks for men and ≥4 drinks for women) 2 or more times per week and smoking 2 or more times per week; 131 participants were randomized to either varenicline or placebo stratified by sex and site. All analyses were of the intention-to-treat type. Data analysis was conducted from February 5, 2016, to September 29, 2017. Interventions: Varenicline tartrate, 1 mg twice daily, and matching placebo pills for 16 weeks. Medical management emphasized medication adherence for 4 weeks followed by support for changing drinking. Main outcomes and measures: Percentage of heavy drinking days (PHDD) weeks 9 to 16, no heavy drinking days (NHDD) weeks 9 to 16, and prolonged smoking abstinence weeks 13 to 16. Results: Of 131 participants, 39 (29.8%) were women and 92 (70.2%) were men, the mean (SD) age was 42.7 (11.7) years, and the race/ethnicity self-identified by most respondents was black (69 [52.7%]). Sixty-four participants were randomized to receive varenicline, and 67 to receive placebo. Mean change in PHDD between varenicline and placebo across sex and site was not significantly different. However, a significant treatment by sex by time interaction for PHDD (F1,106 = 4.66; P = .03) revealed that varenicline compared with placebo resulted in a larger decrease in log-transformed PHDD in men (least square [LS] mean difference in change from baseline, 0.54; 95% CI, -0.09 to 1.18; P = .09; Cohen d = 0.45) but a smaller decrease in women (LS mean difference, -0.69; 95% CI, -1.63 to 0.25; P = .15; Cohen d = -0.53). Thirteen of 45 men (29%) had NHDD taking varenicline compared with 3 of 47 men (6%) taking placebo (Cohen h = 0.64; 95% CI, 0.22-1.03), whereas 1 of 19 women (5%) had NHDD compared with 5 of 20 women (25%) taking placebo (Cohen h = -0.60; 95% CI, -1.21 to 0.04). Taking varenicline, 8 of 64 participants (13%) achieved prolonged smoking abstinence; no one (0 of 67) quit smoking taking placebo (P = .003; Cohen h = 0.72; 95% CI, 0.38-1.07). Conclusions and relevance: Varenicline with medical management resulted in decreased heavy drinking among men and increased smoking abstinence in the overall sample. Varenicline could be considered to promote improvements in men with these dual behavioral health risks. Trial registration: clinicaltrials.gov Identifier: NCT01553136.

JAMA psychiatry · randomised controlled trial · 77 citationsread the source →

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

Background: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. Methods: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. Findings: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. Interpretation: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. Funding: National Institute for Health Research, Health Technology Assessment programme.

The lancet. Psychiatry · randomised controlled trial · 192 citationsread the source →

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda.

Background: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. Methods: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. Findings: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0·668 for clinic facilitation and p=0·273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1·72, 95% CI 1·36-2·17; p<0·0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1·67, 1·29-2·14; p=0·0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. Interpretation: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

The lancet. HIV · randomised controlled trial · 65 citationsread the source →

Computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus.

Background: Diabetes is one of the commonest chronic medical conditions, affecting around 347 million adults worldwide. Structured patient education programmes reduce the risk of diabetes-related complications four-fold. Internet-based self-management programmes have been shown to be effective for a number of long-term conditions, but it is unclear what are the essential or effective components of such programmes. If computer-based self-management interventions improve outcomes in type 2 diabetes, they could potentially provide a cost-effective option for reducing the burdens placed on patients and healthcare systems by this long-term condition. Objectives: To assess the effects on health status and health-related quality of life of computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus. Search methods: We searched six electronic bibliographic databases for published articles and conference proceedings and three online databases for theses (all up to November 2011). Reference lists of relevant reports and reviews were also screened. Selection criteria: Randomised controlled trials of computer-based self-management interventions for adults with type 2 diabetes, i.e. computer-based software applications that respond to user input and aim to generate tailored content to improve one or more self-management domains through feedback, tailored advice, reinforcement and rewards, patient decision support, goal setting or reminders. Data collection and analysis: Two review authors independently screened the abstracts and extracted data. A taxonomy for behaviour change techniques was used to describe the active ingredients of the intervention. Main results: We identified 16 randomised controlled trials with 3578 participants that fitted our inclusion criteria. These studies included a wide spectrum of interventions covering clinic-based brief interventions, Internet-based interventions that could be used from home and mobile phone-based interventions. The mean age of participants was between 46 to 67 years old and mean time since diagnosis was 6 to 13 years. The duration of the interventions varied between 1 to 12 months. There were three reported deaths out of 3578 participants. Computer-based diabetes self-management interventions currently have limited effectiveness. They appear to have small benefits on glycaemic control (pooled effect on glycosylated haemoglobin A1c (HbA1c): -2.3 mmol/mol or -0.2% (95% confidence interval (CI) -0.4 to -0.1; P = 0.009; 2637 participants; 11 trials). The effect size on HbA1c was larger in the mobile phone subgroup (subgroup analysis: mean difference in HbA1c -5.5 mmol/mol or -0.5% (95% CI -0.7 to -0.3); P < 0.00001; 280 participants; three trials). Current interventions do not show adequate evidence for improving depression, health-related quality of life or weight. Four (out of 10) interventions showed beneficial effects on lipid profile. One participant withdrew because of anxiety but there were no other documented adverse effects. Two studies provided limited cost-effectiveness data - with one study suggesting costs per patient of less than $140 (in 1997) or 105 EURO and another study showed no change in health behaviour and resource utilisation. Authors' conclusions: Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control and the effect was larger in the mobile phone subgroup. There is no evidence to show benefits in other biological outcomes or any cognitive, behavioural or emotional outcomes.

The Cochrane database of systematic reviews · meta-analysis · 213 citationsread the source →

Cortisol response to stress in female youths exposed to childhood maltreatment: results of the youth mood project.

Background: Few studies have examined stress reactivity and its relationship to major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) among maltreated youth. We examined differences between maltreated and control participants in heart rate and cortisol resting and reactivity levels in response to a psychosocial stressor. Methods: We recruited 67 female youths aged 12 to 16 with no prior history of depression from child protection agencies and a control group of 25 youths matched on age and postal code. Child maltreatment was measured with two self-report instruments. Psychiatric status was assessed using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Results: Piecewise multilevel growth curve analysis was used to model group differences in resting and reactivity cortisol levels and heart rate in response to the Trier Social Stress Test (TSST). During the resting period, both the maltreated and control groups showed a similar decline in levels of cortisol. During the reactivity phase, youth in the control group showed an increase in cortisol levels following the TSST and a gradual flattening over time; maltreated youth exhibited an attenuated response. This blunted reactivity was not associated with current symptoms of MDD or PTSD. There were no group differences in resting and reactivity levels of heart rate. Conclusions: These findings provide further support for hypothalamic-pituitary-adrenal axis dysregulation among maltreated youth. Since the ability to respond to acute stressors by raising cortisol is important for health, these findings may assist in understanding the vulnerability of maltreated youth to experience physical and mental health problems.

Biological psychiatry · 190 citationsread the source →

Meditation or exercise for preventing acute respiratory infection: a randomized controlled trial.

Purpose: This study was designed to evaluate potential preventive effects of meditation or exercise on incidence, duration, and severity of acute respiratory infection (ARI) illness. Methods: Community-recruited adults aged 50 years and older were randomized to 1 of 3 study groups: 8-week training in mindfulness meditation, matched 8-week training in moderate-intensity sustained exercise, or observational control. The primary outcome was area-under-the-curve global illness severity during a single cold and influenza season, using the Wisconsin Upper Respiratory Symptom Survey (WURSS-24) to assess severity. Health care visits and days of missed work were counted. Nasal wash collected during ARI illness was assayed for neutrophils, interleukin-8, and viral nucleic acid. Results: Of 154 adults randomized into the study, 149 completed the trial (82% female, 94% white, mean age 59.3 ± 6.6 years). There were 27 ARI episodes and 257 days of ARI illness in the meditation group (n = 51), 26 episodes and 241 illness days in the exercise group (n = 47), and 40 episodes and 453 days in the control group (n = 51). Mean global severity was 144 for meditation, 248 for exercise, and 358 for control. Compared with control, global severity was significantly lower for meditation (P = .004). Both global severity and total days of illness (duration) trended toward being lower for the exercise group (P=.16 and P=.032, respectively), as did illness duration for the meditation group (P=.034). Adjusting for covariates using zero-inflated multivariate regression models gave similar results. There were 67 ARI-related days of-work missed in the control group, 32 in the exercise group (P = .041), and 16 in the meditation group (P <.001). Health care visits did not differ significantly. Viruses were identified in 54% of samples from meditation, 42% from exercise, and 54% from control groups. Neutrophil count and interleukin-8 levels were similar among intervention groups. Conclusions: Training in meditation or exercise may be effective in reducing ARI illness burden.

Annals of family medicine · randomised controlled trial · 91 citationsread the source →

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of <or=5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) (equivalent to <or=7 on the 17-item Hamilton Rating Scale for Depression [HRSD(17)]) defined remission; a QIDS-SR(16) total score of >or=11 (HRSD(17)>or=14) defined relapse. Results: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. Conclusions: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

The American journal of psychiatry · randomised controlled trial · 3740 citationsread the source →

Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial.

Context: There are few randomized controlled trials on the effectiveness of palliative care interventions to improve the care of patients with advanced cancer. Objective: To determine the effect of a nursing-led intervention on quality of life, symptom intensity, mood, and resource use in patients with advanced cancer. Design, setting, and participants: Randomized controlled trial conducted from November 2003 through May 2008 of 322 patients with advanced cancer in a rural, National Cancer Institute-designated comprehensive cancer center in New Hampshire and affiliated outreach clinics and a VA medical center in Vermont. Interventions: A multicomponent, psychoeducational intervention (Project ENABLE [Educate, Nurture, Advise, Before Life Ends]) conducted by advanced practice nurses consisting of 4 weekly educational sessions and monthly follow-up sessions until death or study completion (n = 161) vs usual care (n = 161). Main outcome measures: Quality of life was measured by the Functional Assessment of Chronic Illness Therapy for Palliative Care (score range, 0-184). Symptom intensity was measured by the Edmonton Symptom Assessment Scale (score range, 0-900). Mood was measured by the Center for Epidemiological Studies Depression Scale (range, 0-60). These measures were assessed at baseline, 1 month, and every 3 months until death or study completion. Intensity of service was measured as the number of days in the hospital and in the intensive care unit (ICU) and the number of emergency department visits recorded in the electronic medical record. Results: A total of 322 participants with cancer of the gastrointestinal tract (41%; 67 in the usual care group vs 66 in the intervention group), lung (36%; 58 vs 59), genitourinary tract (12%; 20 vs 19), and breast (10%; 16 vs 17) were randomized. The estimated treatment effects (intervention minus usual care) for all participants were a mean (SE) of 4.6 (2) for quality of life (P = .02), -27.8 (15) for symptom intensity (P = .06), and -1.8 (0.81) for depressed mood (P = .02). The estimated treatment effects in participants who died during the study were a mean (SE) of 8.6 (3.6) for quality of life (P = .02), -24.2 (20.5) for symptom intensity (P = .24), and -2.7 (1.2) for depressed mood (P = .03). Intensity of service did not differ between the 2 groups. Conclusion: Compared with participants receiving usual oncology care, those receiving a nurse-led, palliative care-focused intervention addressing physical, psychosocial, and care coordination provided concurrently with oncology care had higher scores for quality of life and mood, but did not have improvements in symptom intensity scores or reduced days in the hospital or ICU or emergency department visits. Trial registration: clinicaltrials.gov Identifier: NCT00253383.

JAMA · randomised controlled trial · 1314 citationsread the source →

Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial.

Background: Chronic fatigue syndrome is characterised by persistent fatigue and severe disability. Cognitive behavioural therapy seems to be a promising treatment, but its availability is restricted. We developed Fatigue In Teenagers on the interNET (FITNET), the first dedicated internet-based therapeutic program for adolescents with this disorder, and compared its effectiveness with that of usual care. Methods: Adolescents aged 12-18 years with chronic fatigue syndrome were assigned to FITNET or usual care in a 1:1 ratio at one tertiary treatment centre in the Netherlands by use of a computer-generated blocked randomisation allocation schedule. The study was open label. Primary outcomes were school attendance, fatigue severity, and physical functioning, and were assessed at 6 months with computerised questionnaires. Analysis was by intention to treat. Thereafter, all patients were offered FITNET if needed. This trial is registered, number ISRCTN59878666. Findings: 68 of 135 adolescents were assigned to FITNET and 67 to usual care, and 67 and 64, respectively, were analysed. FITNET was significantly more effective than was usual care for all dichotomised primary outcomes at 6 months-full school attendance (50 [75%] vs 10 [16%], relative risk 4·8, 95% CI 2·7-8·9; p<0·0001), absence of severe fatigue (57 [85%] vs 17 [27%], 3·2, 2·1-4·9; p<0·0001), and normal physical functioning (52 [78%] vs 13 [20%], 3·8, 2·3-6·3; p<0·0001). No serious adverse events were reported. Interpretation: FITNET offers a readily accessible and highly effective treatment for adolescents with chronic fatigue syndrome. The results of this study justify implementation on a broader scale. Funding: Netherlands Organisation for Health Research and Development.

Lancet (London, England) · randomised controlled trial · 140 citationsread the source →

Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock.

Objective: Intensive care unit admission is associated with muscle wasting and impaired physical function. We investigated the effect of early transcutaneous electrical muscle stimulation on quadriceps muscle volume in patients with septic shock. Design: Randomized interventional study using a single-legged exercise design with the contralateral leg serving as a paired control. Setting: A mixed 18-bed intensive care unit at a tertiary care university hospital. Patients: Eight adult male intensive care unit patients with septic shock included within 72 hrs of diagnosis. Interventions: After randomization of the quadriceps muscles, transcutaneous electrical muscle stimulation was applied on the intervention side for 7 consecutive days and for 60 mins per day. All patients underwent computed tomographic scans of both thighs immediately before and after the 7-day treatment period. The quadriceps muscle was manually delineated on the computed tomography slices, and muscle volumes were calculated after three-dimensional reconstruction. Measurements and main results: Median age and Acute Physiology and Chronic Health Evaluation II score were 67 years (interquartile range, 64-72 years) and 25 (interquartile range, 20-29), respectively. During the 7-day study period, the volume of the quadriceps muscle on the control thigh decreased by 16% (4-21%, p=.03) corresponding to a rate of 2.3% per day. The volume of the stimulated muscle decreased by 20% (3-25%, p=.04) corresponding to a rate of 2.9% per day (p=.12 for the difference in decrease). There was no difference in muscle volume between the stimulated and nonstimulated thigh at baseline (p=.10) or at day 7 (p=.12). The charge delivered to the muscle tissue per training session (0.82 [0.66-1.18] coulomb) correlated with the maximum sequential organ failure assessment score. Conclusions: We observed a marked decrease in quadriceps volume within the first week of intensive care for septic shock. This loss of muscle mass was unaffected by transcutaneous electrical muscle stimulation applied for 60 mins per day for 7 days.

Critical care medicine · randomised controlled trial · 88 citationsread the source →

Long-term trends in child maltreatment in England and Wales, 1858-2016: an observational, time-series analysis.

Background: It is unclear whether child maltreatment is increasing or decreasing in England and Wales. More evidence is needed, from multiple sources and over longer periods of time, to explore trends in child maltreatment. We investigated whether the annual incidence of child maltreatment has changed over time, using official record data and time-series methods to establish long-term trends. Methods: In this observational time-series analysis, we used six data sources (Government records for child mortality, police-recorded child homicides, crimes against children, child protection, and children in care; and NSPCC data) to estimate the incidence of child maltreatment in England and Wales and examine long-term trends. We included nationally representative data that could estimate the incidence of child maltreatment for more than 25 years. Our primary outcomes were the number of victims (age <20 years) or perpetrators (age >16 years) of child maltreatment per 12-month period in England, including or excluding Wales. We fitted Poisson regression models with year as the exposure and the number of victims or perpetrators of child maltreatment as the outcome (adjusted for population age-structure and size). When a linear trend was not appropriate, we fitted generalised additive models with penalised splines to visualise trends. Findings: The incidence of child mortality by homicide or assault decreased by 90% (2·7 per 100 000 children) between 1858 and 2016 and the incidence of people guilty of child cruelty or neglect decreased by 83% (6·7 per 100 000 adults) between 1893 and 2016, whereas child protection registrations increased by 182% (328·7 per 100 000 children) between 1988 and 2016. Crimes against children and children entering care increased between 2000 and 2016. In 2016, 40 children died by homicide, with twice as many adolescent (15-19 years) deaths than infant (age <1 year) deaths. In 2016, 67 700 children were placed on the child protection register and neglect and emotional abuse were the most common reasons. Interpretation: Although long-term trends have decreased, child maltreatment remains a major public health problem in England and Wales. Further research is needed to establish whether adolescents are a particularly vulnerable age group and whether neglect and emotional abuse are increasing. Future child protection policies and practices should respond to these areas of growing need. Funding: Andrew W Mellon Foundation and Clarendon through The Oxford Research Centre in the Humanities, Oxford.

The Lancet. Public health · cohort or longitudinal · 22 citationsread the source →

What Are the Minimal and Substantial Improvements in the HOOS and KOOS and JR Versions After Total Joint Replacement?

Background: Patient-reported outcome measures (PROMs) are a gold standard for measuring therapeutic outcomes in research. Extending their use to inform clinical care decisions, determine the appropriateness of therapeutic choices, and assess healthcare quality is attractive but will require our professional community to establish valid estimates of minimal and substantial clinical improvements. Questions/purposes: The purposes of this study were (1) to assess the validity of estimates for the minimal clinically important difference (MCID) calculated using distribution- and anchor-based methods by determining whether they exceed the minimal detectable change (MDC) for the Hip Disability and Osteoarthritis Outcome Score (HOOS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) domains, the HOOS, joint replacement (JR) and the KOOS, JR among patients who underwent THA or TKA; (2) to determine substantial clinical benefit thresholds for the HOOS and KOOS domains, the HOOS, JR, and the KOOS, JR among patients who underwent THA or TKA; and (3) to assess the proportions of patients who underwent THA or TKA who achieved an MCID for the HOOS and KOOS domains, HOOS, JR, and KOOS, JR based on distribution-based and anchor-based methods as well as the percentages of patients who achieved substantial clinical benefit using the anchor-based method. Methods: Medicare patients enrolled in our institutional joint replacement registry who subsequently underwent THA (n = 2323) or TKA (n = 2630) between 2007 and 2012 completed HOOS or KOOS preoperatively and 2 years postoperatively. Short-form joint replacement (JR) versions of each PROM were derived from the full PROMs. Of all eligible patients, 78% (3161 of 4080) of THAs and 74% of TKAs (3815 of 5156) consented to join the registry and completed a baseline survey, 88% (2796 of 3161) of THAs and 85% (3230 of 3815) of TKAs were eligible for followup survey administration, and 83% of THAs (2323 of 2796) and 81% (2630 of 3230) of TKAs returned 2-year surveys. For each HOOS domain, KOOS domain, HOOS, JR, and KOOS, JR, we calculated the calibration variation of the instrument (MDC) with confidence intervals (CIs) reflecting 80% (MDC80), 90% (MDC90), and 95% (MDC95) certainty; we calculated the smallest difference joint health patients might detect (MCID) using distribution- and anchor-based approaches and the difference that can be considered a large improvement in joint health (substantial clinical benefit) using an anchor-based approach. Results: Patients undergoing THA were 57% female with a mean (± SD) age of 73 ± 6 years, whereas patients undergoing TKA were 63% female with a mean age of 74 ± 6 years. Depending on the CI chosen for the MDC, values ranged from 7 to 16 for the HOOS and KOOS domains and the JRs. The MCIDs ranged from 6 to 9 for the distribution-based approach and 7 to 36 for the anchor-based approach. All HOOS and KOOS domains and all JR scores are scores from 0 (worst joint health) to 100 (best joint health). The MCIDs calculated using the distribution-based approach were not valid, because they were lower than the MDC for all HOOS/KOOS domains and both JRs at every confidence level. The anchor-based receiver operating characteristic approach, on the other hand, resulted in MCIDs exceeding MDC80 for seven of eight HOOS/KOOS domains and MDC95 for both JR scores. For all domains and JR versions, substantial clinical benefits ranged from 15 to 36, exceeding MDC95 in all domains and JR scores. Across HOOS and KOOS domains as well as the JR, the proportion of patients undergoing THA who achieved an MCID ranged from 77% to 95% with the distribution-based method and from 67% to 96% using the anchor-based method. The proportion achieving substantial clinical benefit ranged from 67% to 85%. Conclusions: The MDC and MCID differ greatly based on assumptions and methods used. The MCID anchor-based approach had superior construct and face validity compared with the MCID distribution-based approach, which never exceeded even small MDCs. Achieving consensus about standard definitions of meaningful improvement will be necessary to maximize utility of these PROMs to inform clinical care or performance measurement. Level of evidence: Level III, diagnostic study.

Clinical orthopaedics and related research · cohort or longitudinal · 400 citationsread the source →

The Effectiveness of Online Cognitive Behavioral Treatment in Routine Clinical Practice

CONTEXT: Randomized controlled trails have identified online cognitive behavioral therapy as an efficacious intervention in the management of common mental health disorders. OBJECTIVE: To assess the effectiveness of online CBT for different mental disorders in routine clinical practice. DESIGN: An uncontrolled before-after study, with measurements at baseline, posttest, 6-week follow-up, and 1-year follow-up. PARTICIPANTS & SETTING: 1500 adult patients (female: 67%; mean age: 40 years) with a GP referral for psychotherapy were treated at a Dutch online mental health clinic for symptoms of depression (n = 413), panic disorder (n = 139), posttraumatic stress (n = 478), or burnout (n = 470). INTERVENTIONS: Manualized, web-based, therapist-assisted CBT, of which the efficacy was previously demonstrated in a series of controlled trials. Standardized duration of treatment varied from 5 weeks (online CBT for Posttraumatic stress) to 16 weeks (online CBT for Depression). MAIN OUTCOME MEASURES: Validated self-report questionnaires of specific and general psychopathology, including the Beck Depression Inventory, the Impact of Event Scale, the Panic Disorder Severity Scale-Self Report, the Oldenburg Burnout Inventory, and the Depression Anxiety Stress Scales. RESULTS: Treatment adherence was 71% (n = 1071). Study attrition was 21% at posttest, 33% at 6-week FU and 65% at 1-year FU. Mixed-model repeated measures regression identified large short-term reductions in all measures of primary symptoms (d = 1.9±0.2 to d = 1.2±0.2; P<.001), which sustained up to one year after treatment. At posttest, rates of reliable improvement and recovery were 71% and 52% in the completer sample (full sample: 55%/40%). Patient satisfaction was high. CONCLUSIONS: Results suggest that online therapist-assisted CBT may be as effective in routine practice as it is in clinical trials. Although pre-treatment withdrawal and long-term outcomes require further study, results warrant continued implementation of online CBT.

PLoS ONE · clinical trial · 175 citationsread the source →

Dialectical behaviour therapy for adolescents: a comparison of 16-week and 24-week programmes delivered in a public community setting.

Background: Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. Previous studies have reported on varying lengths of treatment, however, and optimal treatment duration has not yet been identified. While the treatment developers initially proposed a 16-week programme, they have more recently recommended an extension to 24 weeks. This study compares outcomes for adolescents and parent/guardians who participated in 16- and 24-week DBT-A programmes in a community setting. Methods: Eighty-four adolescents and 100 parent/guardians participated in 16-week DBT-A, while 68 adolescents and 67 parent/guardians participated in the 24-week programme. Outcome measures for adolescents included the presence and frequency of self-harm, suicidal ideation and depression; and for parents were burden, grief and parental stress. Outcomes were assessed at pre- and postintervention. Linear mixed-effects models were used to estimate the treatment duration effect (24-week vs. 16-week) utilising all available data at pre- and postintervention. Results: Data analyses showed a reduction in the presence and frequency of self-harm at postintervention for adolescents in both programmes. Both adolescent and parent participants in the 16- and 24-week programmes also showed changes indicating significant improvement on all self-report outcome measures (p < .05). A treatment duration effect was identified with adolescents in the 24-week programme reporting greater gains on measures of suicidal ideation and depression (p < .05). However, drop-out rates were higher for the 24-week programme. Conclusions: The findings of the current study indicate that 24-week DBT-A may have additional benefits in comparison to 16-week DBT-A in terms of further reductions in suicidal ideation and depression. Given the nature of this study, it was not possible to explore a potential time effect, however, so these results should be interpreted with caution. Further research will assist in determining an optimal programme duration of DBT-A.

Child and adolescent mental health · 10 citationsread the source →

Evaluation of Parental Dental Fear and Anxiety (DFA) on Adolescent Dental Treatment

INTRODUCTION Dental anxiety is a negative state of mind of a dental patient, which is shown to be excessive and unreasonable.[1] Dental fear is a normal emotional response to particularly alarming stimuli in situations related to dental treatment.[1] Dental fear and anxiety (DFA) are often used together to describe different types of fear experienced in the dental environment.[2] American Academy of Pediatrics divides adolescents into three age groups: early 11–14 years, middle 15–17 years, and late 18–21 years.[3] Five specific pathways for DFA were seen in adolescent dental patients. One of which being the parental pathway plays an important role in the transmission of fear hindering their child’s dental treatment.[4] Parental DFA is usually an excessive perturbing of the things that could go wrong in child’s oral health and is an important factor that has an impact on adolescents receiving dental treatment and maintenance of their oral health. It is necessary to recognize and know how parental DFA affects the dental treatment of adolescents. Thus, this review aimed at evaluating the parental influence of DFA on dental treatment of adolescents. MATERIALS AND METHODS DATA EXTRACTION AND LITERATURE SEARCH STRATEGY A broad search of literature published between 2005 and 2021 from electronic databases through Scopus, PubMed, Google Scholar, and Web of Science was performed. These studies were conducted in different countries as mentioned in Table 1. This review article includes eight cross-sectional studies, three longitudinal studies, and one descriptive study. The age group of children included ranged from 10 to 19 years. Table 1: Summary study design, data collection, dental fear and anxiety assessment scales used analysis, and interpretation of reviewed articlesThe search was carried out using the following keywords: dental anxiety, parental dental anxiety, adolescent, and dental treatment. The terms used to formulate the search strategies were parent OR mother OR father AND dental fear OR dental anxiety AND adolescent AND dental treatment. Data extracted were independently reviewed and disagreements were solved by discussion. A flowchart representing the method of article selection for the review is shown in Figure 1.Figure 1: Flowchart representing the method of article selectionINCLUSION CRITERIA We included the studies in which parental dental anxiety was a major criterion affecting different dental health conditions. Articles referring to adolescents (10–19 years) facing different oral health problems were also included in the study. EXCLUSION CRITERIA Abstracts that were not giving relevant data, data from unpublished articles, parental dental anxiety in medically compromised and specially challenged adolescents, and articles that did not include the adolescent age group were excluded from the study. RESULTS Approximately 83 publications were found related. Screening identified 10 articles that fulfilled the criteria of inclusion; full-text versions were retrieved and their references were screened for further relevant articles. Checking the subreference list, another two relevant articles were found. Thus, 12 articles were considered for this review that met the final inclusion criteria. Of 12 articles reviewed, 8 studies[56789101112] used validated assessment scales as mentioned by authors for measuring parental DFA. The authors have not specified the validation of assessment scales used for the other four studies.[13141516] The various DFA assessment scales used in the reviewed articles are mentioned in Table 2. Summary study design, data collection, analysis, and interpretation of reviewed articles are mentioned in Table 1.Table 2: Tabular representation of dental fear and anxiety assessment scales usedDISCUSSION Dental anxiety being primarily a negative parental factor was found to affect children from assessing regular dental care. Among the reviewed articles based on the outcome, we found that three articles explained about a relationship between parental DFA and adolescent dental treatment,[67,13] and the remaining nine articles explained about the correlation between parental DFA scores with adolescent DFA scores.[6891011,13141516] No significant association was observed between parental DFA and adolescent DFA scores in two of the studies,[78] whereas two studies showed positive association only during early adolescence.[914] Other five studies showed a significant positive correlation of parental DFA with their children’s dental anxiety,[10111215,16] of which three studies also suggested fathers as mediating role in transmission of DFA to their children.[1011,15] RELATIONSHIP BETWEEN PARENTAL DENTAL FEAR AND ANXIETY AND ADOLESCENT DENTAL TREATMENT Adolescent dental treatment utilization mainly depends on parental/caretaker’s decision-making and their dental care obtaining habits. In childhood and even adolescence, this becomes very crucial for the development of good oral health behavior like regular visits to the dentist and preventive dental care.[17] Another postulated process is “social learning” wherein, media, friends, and relatives portray dentists in negative light or image leading to formation of DFA. These processes of information transmission and vicarious experience lead to negative portrayal of dentists and pessimistic expectations about the dentist’s role. All these predispose to DFA.[18] The absence of anxiety among parents would have a positive influence on a child.[19] Parental dental anxiety along with family income, economic stability, parental oral health literacy, and oral health practices is found to be a few factors that affect adolescent’s oral health-related quality of life (QOL).[202122] Dental anxiety being primarily a negative parental factor was found to affect children from accessing regular dental care, whereas parental self-dental utilization being a positive parental factor showed a positive impact on a child’s dental utilization.[23] Parents with higher anxiety levels were found to start brushing their children’s teeth at an earlier age; hence, a significant correlation was found between parent’s anxiety levels and the age at which the child starts to brush.[24] Dental health status of children was found to be better with more a positive attitude of parents toward dentistry.[25] Among the articles reviewed, two articles were found to have parental DFA during fixed orthodontic treatment of the adolescents which included the use of extraoral appliances. These two studies used different anxiety measurement scales for assessing parental DFA before and during the treatment procedures.[513] Poorer QOL is seen in families of adolescents with malocclusion as compared with the families of adolescents without any occlusal variation; the impact may have effects on parental or guardian’s emotions.[26] Both of the studies assessed state and trait dental anxiety of parents (STAI scale). State anxiety is transient, fluctuates, and varies in intensity. Trait anxiety is a personality trait; it is stable with time.[2728] The result showed that parent’s trait anxiety levels did not change during orthodontic treatment.[513] State anxiety was found to be within normal range and changed according to intensity of pressure.[13] There was an incidence of high levels of state anxiety and depression in both parents and patients under treatment with extra oral orthodontic appliances after 1 year of active treatment. Among patients waiting for orthodontic treatment and among their parents no statistically significant differences were noted in their trait anxiety levels.[5] The extra oral appliances had a negative effect on patient’s and parent’s anxiety levels which might indirectly affect the ongoing dental treatment. It was therefore recommended for clinicians to have alternate treatment modalities in mind to address this challenge.[5] Apart from orthodontic treatment, adolescents are also found commonly with traumatic dental injuries (TDIs) involving dentine/pulp or fracture of the root. A family’s QOL in such conditions was assessed using the family impact scale (FIS). This scale had four subscales, in which parental emotion was one of the subscales assessed. Parental emotion had a significant negative impact on the severity of TDI and severe untreated TDI of an adolescent can be a source of family distress.[629,30] EVIDENCE OF ASSOCIATION OF DENTAL FEAR AND ANXIETY BETWEEN PARENTS AND THEIR ADOLESCENTS Previous studies have shown that parents exhibit an influence on their children’s DFA through modeling and information.[31] The DFA experienced in childhood may lead into adulthood causing a predictor for dental treatment avoidance in adulthood.[3233] Among the reviewed articles, we found a correlation between the parental dental DFA scores with their adolescent’s DFA scores. Parent’s DFA and children’s DFA were assessed using the same dental anxiety measuring scale in nine of the studies,[6891011,13141516] and three studies[57,12] used different scales to measure anxiety levels in parents and children’s. Two of the studies showed no significant association between the anxiety level of adolescents and that of their parents.[78] One of the studies suggested that when a child reached adolescence, parental DFA does not directly contribute to child DFA. Other factors such as the presence of a sibling and family structure (single-parent family, nuclear) are found to play a significant role.[7] Lending support to the former findings, there was no relation between anxiety levels of adolescents (12–17 years) and that of their parents, whereas in the same study a positive association was found when the child is 8–11 years of age.[8] Two studies suggested a positive association in early adolescence.[914] In one of these two studies, mother’s and adolescents dental fear scores had a significant association at the age of 12 years and 18 years in given treatment scenarios such as “feeling about having their teeth scraped and polished, having teeth drilled and having an injection in gum,” whereas there was no significant association between dental fear scores of mother’s and adolescence at 15 years of age.[9] In another study reviewed, in early adolescence (11–12 years), there was a statistically significant association between parental and adolescent dental fear but in mid-adolescence (15–16 years) there was only an association with parental dental fear with their daughters.[14] It was found in the Finnish population, by eliminating dental fear among 30 years and elderly population, 41% of irregular attendees could become regular attenders.[34] In contrast, other five studies showed a significant positive correlation of parental DFA with their children’s dental anxiety.[10111215,16] Fearful parents of adolescents of age (11–16 years) assumed that their child had fear irrespective of whether the child had fear or not.[16] Three of these studies, where parental DFA was assessed in both the parents, suggested that the father also has a mediating role in the transmission of DFA to the children of age group 11–17 years,[10] 7–15 years,[11] and 7–12 years,[15] respectively. Father’s DFA is one of the best predictors of adolescence DFA[1035] and it is also found that child’s dental anxiety is best predicted by the parent’s fear of pain.[12] Previous studies have suggested that children experience fear and anxiety in their early life due to a lack of cognitive ability without having a clear perception of fearful situation and have been influenced by their parent’s fear and anxiety.[36] It is still unclear of the association of DFA between parents and late adolescents.[9] It was found that limited studies were found in the area of adolescent oral health. In the available literature, definite assessment methods were not used to assess the anxiety levels among parents. Furthermore, studies focused on late adolescence are indicated to establish the changes in oral health due to parental DFA. Adolescence is the transitional phase between childhood and adulthood and is a crucial period where they develop decision-making and independence; this has an impact on dental treatment-seeking behavior. The influence of parental dental anxiety might worsen the scenario. Parental DFA is seen to have a direct impact on the treatment itself.[56,20] Previously reviewed articles show a strong association of parental DFA and child’s DFA below 8 years of age.[37] In this study, we found parental DFA showed a positive association with their adolescent’s DFA, which thus hinders their dental treatment. There is a need to give attention to psychological parameters before and during the treatment of both parents and adolescents. Therefore, identifying parental dental anxiety prior to the treatment and intervention helps to reduce or eliminate DFA in children and further improves their dental treatment utilization. This study adds value in sensitizing dental professionals toward addressing parental concerns while treating adolescents and recommendations for appropriate implementations in teaching curricula and policies regarding the same. There is more potential to understand the background of parental DFA in single parents and in mother and father alone and also the factors that made them vulnerable. Parental education/counselling regarding various dental treatment procedures using appropriate methods such as focus group discussion will help to reduce DFA among the parental populations. ACKNOWLEDGEMENT We thank Health Sciences Library, Manipal Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India and Department of Psychiatry, Kasturba Medical College and Hospital, Manipal, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India. FINANCIAL SUPPORT AND SPONSORSHIP This study was self-funded. CONFLICTS OF INTEREST There are no conflicts of interest. AUTHORS CONTRIBUTIONS Idea and conceptualization: Ramprasad Vasthare. Literature search: Thrisha Hegde, Bhavyashri P. Manuscript writing: Thrisha Hegde, Bhavyashri P, Ramprasad Vasthare, Karthik M, Ravindra Munoli. Editing of the review: Ramprasad Vasthare, Thrisha Hegde, Bhavyashri P, Karthik M, Ravindra Munoli. Intellectual inputs: Ramprasad Vasthare, Ravindra Munoli, Karthik M. ETHICAL POLICY AND INSTITUTIONAL REVIEW BOARD STATEMENT Not applicable as this was a narrative review. PATIENT DECLARATION OF CONSENT Not applicable. DATA AVAILABILITY STATEMENT Data of literature search is available on appropriate request to the corresponding author.

Journal of International Society of Preventive and Community Dentistry · review · 16 citationsread the source →

Developmental Coordination Disorder

For the last 100 years, poor motor coordination in children has been recognized as a developmental problem.1 As early as 1937, these children were classified as “clumsy.”1 Since then, other terms such as “motorically awkward,” “motor impaired,” and “physically awkward” have been used to describe these children, and the terms “developmental apraxia” and “perceptual motor difficulties” have been used to characterize this developmental problem.2,3 Since the 1994 International Consensus Conference on Children and Clumsiness, the term “developmental coordination disorder” (DCD) has been used to describe the condition of children with motor incoordination.1,4 The purpose of this article is to provide the following information about DCD: (1) definition, (2) prevalence, (3) etiology, (4) discussion regarding the difficulties in classifying these children, (5) common characteristics, (6) long-term prognosis, and (7) brief review of treatment approaches. Developmental coordination disorder, a chronic and usually permanent condition found in children, is characterized by motor impairment that interferes with the child's activities of daily living and academic achievement.3,5 In order for a child to be diagnosed with DCD, these motor impairments must negatively affect some other aspect of his or her life.6 Impairment alone, however, does not qualify a child for the diagnosis of DCD; the motor impairment must not be caused by or have the symptoms of an identifiable neurological problem.2,5 That is, the child must not have any disturbances of muscle tone (ataxia or spasticity), sensory loss, or involuntary movements. If mental retardation is present, the testable IQ of the child must be greater than 70 and the motor impairments must be greater than what would normally be expected for children with mental retardation.5 Finally, a child diagnosed with DCD must not meet the criteria for a diagnosis of pervasive developmental disorder.6 Developmental coordination disorder appears to be a fairly common disorder of childhood and is usually identified in children between 6 and 12 years of age. Ten years ago, researchers7,8 estimated that DCD occurred in 10% to 19% of school-aged children. With a more precise definition of DCD, the current prevalence is estimated to be between 5% and 8% of all school-aged children,5,9–11 with more boys than girls (2:1) being diagnosed with DCD.12 This difference may reflect higher referral rates for boys, because the behavior of boys with motor incoordination may be more difficult to manage at home and in the classroom.8 In addition, a higher incidence of DCD may be found among children with a history of prenatal or perinatal difficulties.3 Due to the heterogeneity of DCD, finding its cause has been difficult.3 Several theories speculate that the etiology of DCD is part of the continuum of cerebral palsy5,13; is secondary to prenatal, perinatal, or neonatal insult3; or is secondary to neuronal damage at the cellular level in the neurotransmitter or receptor systems.14 Hadders-Algra14 based her view that DCD is a result of damage at the cellular level on evidence that cerebral palsy is often caused by prenatal damage that cannot be identified by current diagnostic techniques. Developmental coordination disorder, a chronic and usually permanent condition found in children, is characterized by motor impairment that interferes with the child’s activities of daily living. Although both standard and nonstandard functional tests are available to identify the specific disabilities experienced by a child with DCD, relating the observed disabilities to the primary impairment(s) or any possible neuropathology is not easily accomplished. The problems experienced by children with DCD are believed to emanate from abnormalities in neurotransmitter or receptor systems rather than from damage to specific groups of neurons or brain regions.15 Children's difficulties with coordination can result from a combination of one or more impairments in proprioception, motor programming, timing, or sequencing of muscle activity. A number of theories have evolved in an attempt to shed light on the specific neuronal processing deficits that contribute to DCD. Current models used to explain the neural regulation of posture and movement during development can serve as a basis for the examination and management of individuals with DCD. Using these models, many of the deficits of motor control observed in these children can be described. A variety of theoretical models exist to explain the role of the nervous system in motor development. Forty years ago, the primitive reflex model was a generally accepted theory used to explain how the brain regulates early motor behavior.16 As development proceeded, the higher centers exerted increasing control over the lower reflexes.16 These earlier models were based on a hierarchy of motor control in which higher centers were capable of planning and executing a motor plan without external or internal feedback from lower centers of the central nervous system (CNS). The more recently proposed systems model suggests a more complex interaction among various levels of the CNS. In the systems model, sensory feedback is interpreted by the CNS, and the appropriate movement strategy is selected based on current experience, the state of the internal and external environment, and memory of similar movements. Edelman's neuronal group selection theory includes aspects of both of these models and proposes that functional groups of neurons exist at all levels of the CNS.17 These neuronal groups are determined by evolution, but their functional integrity is dependent on afferent information produced by movement and experience.17 In this regard, these genetically determined collections of interconnected neurons (neuronal groups) in both cortical and subcortical structures serve as an early repertoire for motor behavior or receipt of specific sensory information.14,17,18 According to neuronal group selection theory, motor development proceeds in 2 phases.15 The first, the phase of primary variability, is characterized by crude and erratic motor activity that does not require sensory information for its initiation or guidance. These self-generated movements give rise to afferent (visual, kinesthetic) inputs that reinforce more specific synaptic connections within each group. An intermediate period in which effective patterns are selected is followed by the secondary variability phase. In this phase, sensory and motor factors interact to establish the intercellular connections that produce the specific and complex muscle contraction patterns that characterize coordinated, goal-directed movement. Reciprocal connections between groups subserving movements in various body parts and representing different parts of visual space are reinforced with each repetition of a particular function. As the more efficient movement patterns are practiced, the appropriate synaptic circuits are reinforced and subsequently established.14,17,19,20 The literature includes a wide variation in terminology and criteria to describe DCD. This variation has made studying the causes of DCD and developing treatment approaches for the child with DCD difficult. In their analysis of clinical trial data, Macnab et al21 identified 5 different subtype profiles of DCD. The first subtype included children with better gross motor than fine motor skills, although both were still below normal while standing balance and visual-perceptual skills were both within normal ranges. Compared with children of the same age with DCD, children in the second subtype scored high on measures of upper-limb speed and dexterity, visuomotor integration, and visual-perception skills, but they demonstrated poor performance on measures of kinesthetic ability (accuracy in discriminating movement and position of the upper limbs) and balance. Children in subtype 3 demonstrated the greatest overall motor involvement and were the only subtype to have difficulty with both kinesthetic and visual skills. Compared with their peers with DCD, children in subtype 4 performed well on kinesthetic tasks but demonstrated poor performance on tasks requiring visual and dexterity skills. Children in subtype 5 demonstrated poor performance on measurements of running speed and agility compared with their peers with DCD; however, they performed well relative to their peers with DCD in the tasks involving visual-perception skills. The development of different classification systems for DCD may have been influenced by the design of motor tests.21 For example, items testing one motor skill may be influenced by a related motor skill (eg, ball-throwing skills cannot be separated from visuomotor skills). In addition, a test may have an over-representation of one skill that could unduly influence the child's performance on the test. For example, having a greater number of items testing gross motor rather than fine motor skills could either positively or negatively influence a child's score, depending on the child's specific strengths and weaknesses. Another difficulty in interpreting the literature on DCD is the lack of inclusion criteria. Geuze et al22 reviewed 164 publications on the study of DCD and found that only 60% of the studies had objective inclusion criteria. Because of this lack of inclusion criteria, Geuze et al recommended that a child scoring below the 15th percentile on standardized tests of motor skills and having an IQ score above 69 would qualify for a diagnosis of DCD. The inconsistency among standardized motor tests used to identify children with DCD is another problem. In one study,5 the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) and the Movement Assessment Battery for Children (M-ABC) were administered to 157 children with DCD and 155 children with no motor difficulties; the test results were in agreement 82% (kappa=.62) of the time in distinguishing children who had DCD from children who did not have DCD. This is considered a substantial level of agreement.23 In a study of 202 children (101 with DCD and 101 without DCD), the BOTMP and M-ABC agreed only 67% of the time (kappa=.41), which was considered a moderate level of agreement.24 Because the BOTMP and the M-ABC are 2 of the most commonly used tests for identifying children with DCD, the potential lack of agreement by these tests in identifying children who have DCD is a concern. Two primary factors may explain the difference in outcomes between the BOTMP and M-ABC when used to identify children with DCD.24 First, the BOTMP allows the tester to verbally prompt and correct the child during the testing procedure, allowing the child who is dependent on more external controls to do better on the BOTMP. The BOTMP tends to under-identify children with DCD. Second, the M-ABC requires more careful instruction on the part of the examiner and allows more opportunities for the examinee to practice, but does not allow any verbal or physical prompting by the examiner. Children with attention problems may have more difficulty with the careful instructions for the M-ABC. Another difficulty in classifying children with DCD is the overlap with other disorders. Approximately 41% of children with attention-deficit/hyperactivity disorder (ADHD) and 56% of children with learning disabilities also have DCD.5,21 Further confusing the classification scheme is that the terms “developmental coordination disorder,” for which no identifiable organic brain damage is present, and “apraxia,” which is caused by identifiable brain damage, have been used interchangeably.3 Children with DCD may have a wide range of dysfunctions. These dysfunctions can be grouped into 3 areas: gross motor, fine motor, and psychosocial. Many children with DCD have neurological soft signs such as hypotonia, persistence of primitive reflexes, and immature balance reactions that interfere with gross motor development.5,25 These children also may demonstrate an awkward running pattern, fall frequently, drop items, and have difficulty imitating body positions and following 2- to 3-step motor commands.8 Because of their gross motor problems, children with DCD also perform poorly in sporting events,2 possibly due, in part, to their slow reaction and movement times.7 Their decreased participation in sports may result in decreased muscle force.8 Difficulty with handwriting or drawing often is the first identifiable sign of a fine motor problem and is the most frequently mentioned motor problem experienced by children with DCD. Children with DCD frequently have difficulty planning and executing other fine motor skills such as gripping and dressing.26–29 Unfortunately, children with DCD may experience problems not limited to fine or gross motor areas. These children also may experience psychosocial problems at school. Children with DCD may have learning disabilities or reading problems and may be at increased risk for lower intelligence.5,8 They may act out in class more than other children,13 may be the class clown, and may exhibit less socially desirable means of gaining recognition and friends.8 Adolescents with DCD have been found to have fewer friends, and they have more feelings of low self-worth and more anxiety than peers without DCD and younger children with DCD.30 Historically, parents have been told not to worry about their child's clumsiness because the child will outgrow the problem.31 However, current researchers in the area of DCD report that the children do not outgrow clumsiness and that, without intervention, they will not improve.1,8,12,27,31 Losse et al31 tested 17 children aged 6 years and retested them at age 16 years. The children with motor difficulties at 6 years of age continued to exhibit problems at 16 years of age. In another study,32 818 children with DCD were tested for reading comprehension at age 7 years and then again at age 10 years. A positive correlation in poor reading comprehension existed for children with DCD at 7 and 10 years of age. A follow-up study was conducted on 22-year-old individuals (N=55) who at age 7 years had either DCD or attention-deficit/hyperactivity disorder (ADHD), or both.33 The children with DCD and those with both DCD and ADHD had poorer outcomes than their similarly aged peers without DCD and children with ADHD only. The children with DCD and those with both DCD and ADHD were found to have had more criminal offenses, more incidences of substance abuse and other psychiatric disorders, and lower levels of schooling. Treatment approaches used by occupational therapists and physical therapists can be broadly categorized into either bottom-up or top-down approaches (Tab. 1).10,12,34–36 Bottom-up approaches are based on hierarchical theories of motor control. These theories tend to explain the remediation of motor dysfunction through activation of higher levels of neuronal functioning in a child. The bottom-up approaches frequently used in managing children with DCD are sensory integration, the process-oriented treatment approach, and perceptual motor training.34 Summary of Bottom-Up Versus Top-Down Approaches Summary of Bottom-Up Versus Top-Down Approaches In sensory integration therapy, the child is provided sensory stimulation designed to promote motor development and higher cortical learning. A child undergoing sensory integration therapy may show some gains in motor development, but these gains often do not generalize to functional skills.34 Kinesthesia (the perception of one's own body parts, weight, and movement) is integral to the acquisition of motor skills in process-oriented treatment approaches. Therapeutic intervention with process-oriented treatment is based on specifically designed kinesthetic training activities. As described by Laszlo and Bairstow,37 this approach has an inherent reward system built into it through its use of positive reinforcement, presentation of desirable activities within the capabilities of the child, and judicious progression of the level of difficulty. The usefulness of the process-oriented treatment approach has been the subject of considerable study.9,10,37,38 Sims and colleagues35 suggested that much of the success of this approach can be attributed to a strong motivation effect, fostered by positive feedback and a sense of self-competence. Perceptual motor training, an eclectic approach, offers the child with DCD a wide range of motor experiences along with ample opportunities to practice these skills. Often, in outcome studies, children who receive perceptual motor training are compared with children who receive either sensory integration therapy or process-oriented treatment. Children perceptual motor training have been found to demonstrate motor to or greater than those of children either sensory integration therapy or process-oriented perceptual motor training, process-oriented may promote learning through positive feedback and reinforcement, these do not and to the that top-down approaches approaches use a approach to motor skill development and have been influenced by the systems approach to motor learning and control. This approach suggests that motor skills from an interaction of many both internal and external to the approaches also the in which motor behavior intervention and approaches or are the 2 most commonly intervention on of a The theoretical for intervention in a child's motor performance is the result of learning on a specific Motor tasks are into with each and then to the Children with this approach have demonstrated gains in motor skills.34 approaches to motor development problem The approach strategy the to to the and perform the well did plan The child verbal to the to motor learning. In this approach, the as a by the child out how to his or her motor performance on various motor intervention, the results of studies of approaches are In one 10 children with DCD who were with a approach to motor development were compared with 10 children who were with a bottom-up The children were for and groups on various standardized motor tests 10 treatment However, children in the approach group motor skill and to better than children who were the bottom-up and the approach both provide repetition and practice of specific motor skills, and the approach has the of problem The greater success of top-down when compared with bottom-up be a result of the top-down inclusion of both and motor learning with for attention to and memory as the child in activities. The results of these studies, in to outcome measures of the different approaches in children with DCD, would that approaches that systems theory on sensory information being only part of the and motor learning theory be most effective for these 2 a brief of clinical the of various treatment approaches used with children with of Treatment Approaches for Children With Developmental approach to daily occupational performance treatment approach treatment group integration, perceptual motor, gross and fine motor integration Assessment Battery for Test of Motor Test of for of Motor and of of Treatment Approaches for Children With Developmental approach to daily occupational performance treatment approach treatment group integration, perceptual motor, gross and fine motor integration Assessment Battery for Test of Motor Test of for of Motor and of The neuronal group selection theory can provide a for interpreting the in outcomes among the various approaches. children with moderate to cerebral palsy have a limited repertoire of primary neuronal which children with DCD are believed to experience difficulty at the level of secondary variability, that is, in and the most efficient and effective for a normal development, experience a primary role in the neuronal group selection that the for and According to the neuronal group selection theory, this of motor skill during the of secondary variability as a result of of neuronal selection of specific neurons within each repetition of synaptic within and among neuronal and sensory synaptic which act in and cortical and subcortical and following to a variety of motor of these connections is dependent on sensory Bottom-up approaches such as sensory integration, process-oriented and perceptual motor training sensory experience, with less on processing and motor Although an intervention based on information processing may provide the experience to the most effective neuronal bottom-up approaches may not provide for motor practice of and goal-directed tasks in order to reinforce and establish these approaches less on the specific impairments to decreased coordination and more on the of that is, the among a number of structures and systems and the within which the is Treatment based on a top-down approach that provide the child the to in problem while afferent subcortical structures the feedback and to identify and the most efficient movement for the Because integration, internal of motor and appropriate motor at the level of secondary the on sensory rather than factors by the bottom-up approaches in part, be for the observed in outcomes following treatment. A number of motor learning theories have been proposed in an attempt to explain the through which are into more complex According to the motor control and learning theory proposed by and motor circuits that the and following long-term these and functioning neuronal circuits through practice, the child is to motor into more complex movements. and proposed 2 to such the first of which on sensory to neuronal is during the second that the to the specific motor tasks through the and involving the and in the first of learning requires attention and The motor then in the of learning through repetition and top-down approaches meet both of these bottom-up approaches information processing only. the and of the neural in children with DCD is a not Motor control are complex and on functioning of and motor only are children with DCD a group in terms of functional disabilities the specific of the problems observed can from one child to the Because of these an approach to the management of children with DCD is Developmental coordination disorder is a complex disorder 5% to of school-aged children. intervention, these children will to exhibit poor motor skills and show deficits in other as for may (1) the most appropriate level of intervention (2) which produce results that generalize to the and provide long-term in motor (3) what have on the child's motor and (4) motor skills to the that to the

Physical Therapy · review · 472 citationsread the source →

The Potential Role of Bio Extra Virgin Olive Oil (BEVOO) in Recovery from HPV 16-Induced Tonsil Cancer: An Exploratory Case Study.

The human papillomavirus type 16 (HPV 16) is a high-risk human papillomavirus strain commonly associated with oropharyngeal cancers, including lymph node involvement. The treatment for HPV 16-related tonsil cancer, commonly involving surgery, radiation, and chemotherapy, presents significant challenges. Complications such as oral mucositis, xerostomia, dysphagia, dysgeusia, hypogeusia, impaired gustatory function, and significant weight loss frequently arise, leading to reduced nutritional intake, impaired healing, and recovery progression. These challenges underscore the need for supportive interventions to enhance rehabilitation and the post-recovery period, improve treatment tolerance, and maintain quality of life. Objective: This single-subject study examines a 67-year-old male patient diagnosed with a T1N3b (small primary tumor with advanced lump node involvement) associated with HPV 16 positivity, indicating a virus-associated oncogenesis. Methods: The patient underwent radiation therapy and chemotherapy, leading to treatment-associated side effects. After having dietary drinks for daily nourishment, the patient routinely incorporated oral bio extra virgin olive oil (BEVOO) to cope with indicated challenges. Results: Body composition and metabolic parameters showed treatment-induced declines, followed by substantial but not complete recovery during follow-up examination. Visual Analog Scale (VAS) scores reflected gradual improvements in dysphagia, xerostomia, mucositis, and subtle but ongoing enhancement of the dysgeusia, gustatory perception, and oral palatability. The BEVOO supplementation and mindfulness were associated with positive recovery trends. Additional variables could have impacted the outcomes, preceding and throughout treatment, including the patient's cognitive and somatic health, environmental conditions, dietary habits, individual attitudes toward recovery, physical activity, and patient way of life. Conclusions: These results emphasize the need for additional research employing a comprehensive, multi-factorial framework that accounts for the complex interplay of physiological, psycho-social, and environmental contributors. More extensive, more diverse studies are essential to confirm these observations and substantiate the role of BEVOO as a supportive intervention in cancer recovery.

Healthcare (Basel, Switzerland) · case reportread the source →

Examining risk and crisis communications of government agencies and stakeholders during early-stages of COVID-19 on Twitter.

During COVID-19, social media has played an important role for public health agencies and government stakeholders (i.e. actors) to disseminate information regarding situations, risks, and personal protective action inhibiting disease spread. However, there have been notable insufficient, incongruent, and inconsistent communications regarding the pandemic and its risks, which was especially salient at the early stages of the outbreak. Sufficiency, congruence and consistency in health risk communication have important implications for effective health safety instruction as well as critical content interpretability and recall. It also impacts individual- and community-level responses to information. This research employs text mining techniques and dynamic network analysis to investigate the actors' risk and crisis communication on Twitter regarding message types, communication sufficiency, timeliness, congruence, consistency and coordination. We studied 13,598 pandemic-relevant tweets posted over January to April from 67 federal and state-level agencies and stakeholders in the U.S. The study annotates 16 categories of message types, analyzes their appearances and evolutions. The research then identifies inconsistencies and incongruencies on four critical topics and examines spatial disparities, timeliness, and sufficiency across actors and message types in communicating COVID-19. The network analysis also reveals increased communication coordination over time. The findings provide unprecedented insight of Twitter COVID-19 information dissemination which may help to inform public health agencies and governmental stakeholders future risk and crisis communication strategies related to global hazards in digital environments.

Computers in human behavior · 79 citationsread the source →

People Have Mixed Reactions to Both Physiological and Psychological Explanations of Disproportionate Pain.

Background: There are two general frameworks that conceptualize pain that is more intense or persistent than expected based on measurable pathologic findings: the psychological (unhelpful thoughts and emotions) and the physiological (purported nervous system dysfunction, such as central sensitization). Some clinicians believe people will be more receptive to a physiological conceptualization. Prior quantitative research demonstrated that carefully crafted psychological explanations are rated similarly to crafted physiological explanations, with relatively mixed reactions. This qualitative study was undertaken in parallel with that quantitative study to help develop effective communication and treatment strategies by identifying specific thoughts and feelings (themes) regarding the physiological and psychological conceptualizations of disproportionate pain that make people more or less comfortable considering comprehensive, biopsychosocial treatment approaches. Question/purpose: What themes arise in patient thoughts and feelings regarding physiological and psychological conceptualizations of pain that is more intense or persistent than expected? Methods: We sought to understand the experience of considering pain as a biopsychosocial experience (phenomenology approach) by studying the thoughts and feelings that arise as people seeking care for arm and back pain engage with physiological and psychological conceptualizations of pain that is more intense or persistent than one would expect based on the pathology. We recruited 29 patients presenting for upper extremity or back pain specialty care at one of two urban offices, intentionally recruiting people of various ages, genders, backgrounds, socioeconomic status, as well as type and duration of pain (purposive sampling). The 29 patients included 18 women and 11 men (16 married, 15 non-White, 20 with arm pain) with a median (interquartile range) age of 62 years (42 to 67). The interviews were conducted by a trained woman orthopaedic surgeon interviewer using a semistructured interview guide soliciting participants' thoughts and feelings about a physiological explanation (nerves in the central nervous system stuck in the on position can make pain more intense) and a psychological explanation (unhelpful thoughts and feelings of distress can make pain more intense) for pain more intense or persistent than expected. The interviews were transcribed and themes were identified as the data were collected. Based on current experimental evidence, including what is known about the physiological effects of thoughts, feelings, and context (placebo/nocebo effects), we assumed an underlying physiological basis for pain that is variably experienced and expressed (mixed postpositive/interpretive approach). Themes were identified in the interview transcripts systematically by two coders and then discussed with the entire research team to arrive at consensus. We stopped enrolling patients when the authors agreed that additional themes did not arise in five consecutive interviews. Results: The following themes and interpretations were derived from the analysis: Neither the physiological nor the psychological explanation for disproportionate pain (1) avoided the stigma associated with mental health, (2) was consistently understood, (3) provided a consistent sense of control, (4) consistently provided hope, and (5) represented the stress and emotion of disproportionate or persistent pain. The physiological explanation also generated mixed reactions regarding whether or not it: (1) was a useful point of conversation, (2) was reassuring or frightening, and (3) supported physiological or psychological treatments. The psychological explanation made some people feel worse. Conclusion: People have mixed reactions to both physiological and psychological explanations of disproportionate pain. As such, without direction on content, communication might be most effective by focusing on relational aspects, such as emotional connection and trust. Clinical relevance: Although there is room to improve the content of strategies for explaining more pain than expected to patients, our findings extend the discoveries of others in highlighting the need for tailored relational communication strategies that prioritize feeling heard, validated, and accompanied.

Clinical orthopaedics and related research · 17 citationsread the source →

Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data.

Background: Although the long-term health effects of COVID-19 are increasingly recognised, the societal restrictions during the COVID-19 pandemic hold the potential for considerable detriment to cognitive and mental health, particularly because major dementia risk factors-such as those related to exercise and dietary habits-were affected during this period. We used longitudinal data from the PROTECT study to evaluate the effect of the pandemic on cognition in older adults in the UK. Methods: For this longitudinal analysis, we used computerised neuropsychology data from individuals aged 50 years and older participating in the PROTECT study in the UK. Data were collected from the same participants before the COVID-19 pandemic (March 1, 2019-Feb 29, 2020) and during its first (March 1, 2020-Feb 28, 2021) and second (March 1, 2021-Feb 28, 2022) years. We compared cognition across the three time periods using a linear mixed-effects model. Subgroup analyses were conducted in people with mild cognitive impairment and in people who reported a history of COVID-19, and an exploratory regression analysis identified factors associated with changes in cognitive trajectory. Findings: Pre-pandemic data were included for 3142 participants, of whom 1696 (54·0%) were women and 1446 (46·0%) were men, with a mean age of 67·5 years (SD 9·6, range 50-96). Significant worsening of executive function and working memory was observed in the first year of the pandemic across the whole cohort (effect size 0·15 [95% CI 0·12-0·17] for executive function and 0·51 [0·49-0·53] for working memory), in people with mild cognitive impairment (0·13 [0·07-0·20] and 0·40 [0·36-0·47]), and in people with a history of COVID-19 (0·24 [0·16-0·31] and 0·46 [0·39-0·53]). Worsening of working memory was sustained across the whole cohort in the second year of the pandemic (0·47; 0·44-0·49). Regression analysis indicated that cognitive decline was significantly associated with reduced exercise (p=0·0049; executive function) and increased alcohol use (p=0·049; working memory) across the whole cohort, as well as depression (p=0·011; working memory) in those with a history of COVID-19 and loneliness (p=0·0038; working memory) in those with mild cognitive impairment. In the second year of the pandemic, reduced exercise continued to affect executive function across the whole cohort, and associations were sustained between worsening working memory and increased alcohol use (p=0·0040), loneliness (p=0·042), and depression (p=0·014) in those with mild cognitive impairment, and reduced exercise (p=0·0029), loneliness (p=0·031) and depression (p=0·036) in those with a history of COVID-19. Interpretation: The COVID-19 pandemic resulted in a significant worsening of cognition in older adults, associated with changes in known dementia risk factors. The sustained decline in cognition highlights the need for public health interventions to mitigate the risk of dementia-particularly in people with mild cognitive impairment, in whom conversion to dementia within 5 years is a substantial risk. Long-term intervention for people with a history of COVID-19 should be considered to support cognitive health. Funding: National Institute for Health and Care Research.

The lancet. Healthy longevity · 43 citationsread the source →

Determinants of health-related lifestyles among university students.

Aims: The aim of this study was to investigate students' health-related lifestyles and to identify barriers and social determinants of healthier lifestyles. Methods: An online survey, two focus groups and three in-depth interviews across 2014/2015. A stratified by school size and random sample ( n = 468) of university students answered a 67-item questionnaire comprising six scales: Rapid Assessment of Physical Activity, Rapid Eating and Activity Assessment for Patients-Short Version, CAGE, Fagerström Test for Nicotine Dependence, Warwick-Edinburgh Mental Wellbeing Scale short version, and ad hoc scale for drug use/misuse. Stratified by gender, χ2 tests were run to test associations/estimate risks and three multivariate Logistic Regression models were adjusted. A thematic approach guided the analysis of qualitative data. Results: A total of 60% of the respondents were insufficiently physically active, 47% had an unbalanced diet and 30% had low mental wellbeing. Alcohol drinkers versus abstinent were almost equally distributed. A total of 42% of alcohol drinkers reported getting drunk at least once a month. Smokers accounted for 16% of the respondents. Identified risk factors for suboptimal physical activity were as follows: being a woman, not using the university gym and smoking. Risk factors for unbalanced diet were low mental wellbeing and drug use. Poor mental wellbeing was predicted by unbalanced diet, not feeling like shopping and cooking frequently, and a lack of help-seeking behaviour in cases of distress. Qualitative analysis revealed seven thematic categories: transition to new life, university environment and systems, finances, academic pressure, health promotion on campus and recommendations. Conclusion: This study provides robust evidence that the health-related lifestyles of the student population are worrying and suggests that the trend in chronic diseases associated with unhealthy lifestyles sustained over years might be unlikely to change in future generations. University students' health-related lifestyle is a concern. Nine out of the identified 10 predictors of problematic physical activity, nutrition and mental wellbeing, were environmental/societal or institutional barriers. Universities must expand corporate responsibilities to include the promotion of health as part of their core values.

Perspectives in public health · 105 citationsread the source →

Combat sports and wellbeing: advancing health and inclusion in athletes and practitioners. An opinion paper

Historically, combat sports have been predominantly conceptualized within the framework of elite competition, emphasizing physical aptitude, technical proficiency, and strategic execution (1-3). Despite their traditional and peculiar constitutions and developments, disciplines such as judo, karate, taekwondo, wrestling, fencing, boxing, and mixed martial arts have commonly been associated with high-performance athletes striving for competitive excellence on national and international stages (1, 4-6). However, contemporary discourse increasingly recognizes their expansive role in contributing to physical and psychological well-being, and social inclusion of the practitioners (7, 8). This paradigmatic shift underscores the capacity of combat sports to function as inclusive and accessible modalities for fostering multidimensional health benefits across diverse populations, including individuals with disabilities and other marginalized groups (9-13).The interdisciplinary exploration of physical activity and health highlights the intricate interrelationship between structured sports engagement and holistic well-being (14). Whilst conventional team and individual sports have long been acknowledged for their physiological and psychosocial benefits, combat sports exhibit distinct characteristics that might amplify these advantages (15, 16). Within combat sports, the synergistic interplay of rigorous physical conditioning, the cognitive engagement, adherence to rules, competition dynamics, respect, externalizing emotions regulation, are intertwined with pedagogical and philosophical values, thus presenting a unique framework for enhancing psychological resilience, cognitive adaptability, and emotional control. Consequently, the systematic practice of combat sports has been increasingly examined as a way of promoting mental health, stress modulation, and social cohesion (17, 18).The inclusive nature of many combat sports programmes further accentuates their relevance in dismantling stereotypes, facilitating integration, and fostering equity and social integration (19-21). In fact, they demonstrated significant adaptability to accommodate individuals with disabilities (e.g., physical impairments, developmental, emotional, intellectual disorders), thereby ensuring equitable access and fostering empowerment (9, 22). Adapted judo, para-taekwondo, and other modified combat disciplines provide individuals with disabilities a structured platform to engage in physical activity, cultivate self-efficacy, and develop meaningful social connections within a supportive and adaptive environment (23). From a public health perspective, the integration of combat sports within community-based health initiatives offers a compelling opportunity to engage populations that may not traditionally participate in structured physical activity programmes (7, 8, 19). The distinctive accessibility of combat sports, which cater to practitioners of all skill levels (e.g., from novices to elite athletes) sets them apart from many other sports. While their structured progression, adaptability, and emphasis on holistic development make them a viable option for lifelong and intergenerational participation (19, 24, 25), the mentorship and pedagogical frameworks cultivate positive role modeling, discipline, and intrinsic motivation, which are integral for sustaining long-term adherence to health-promoting behaviors (8).Furthermore, the intersection between combat sports and mental health has increasingly emerged as a focal point within academic and clinical research (17) with empirical evidence suggesting an association between participation and enhanced self-regulation and self-efficacy, and reduction in anxiety and depressive symptomatology (8, 26, 27). In necessitating sustained focus, adaptability, and emotional equilibrium, combat sports inherently require cognitive and affective demands, which align closely with established psychological frameworks that underpin mental well-being (28, 29). Moreover, the integration of mindfulness techniques, stress management strategies, and resilience-building paradigms within combat sports training substantiates their potential as a non-pharmacological intervention for addressing various mental health challenges (e.g., autism spectrum and oppositional defiant disorders) (30, 31).Despite these advantages, the discourse surrounding combat sports and well-being necessitates a critical examination of inherent risks and potential challenges. Issues related to injury risk, hypercompetitive environments, eating disorders, sexual harassment, and the psychological stressors associated with high-intensity training warrant careful scrutiny (32-36). The implementation of evidence-based injury prevention protocols, the establishment of ethically responsible coaching methodologies, and the promotion of safe training environments are imperative to ensure that the benefits of combat sports are maximized while minimizing adverse outcomes. Against this backdrop, this opinion paper seeks to examine the role of combat sports in advancing health and social inclusion among athletes and practitioners. Through a synthesis of contemporary empirical findings, theoretical paradigms, and applied insights, this paper aims to contribute to the evolving discourse on the potential of combat sports as a catalyst for holistic well-being. By delineating the multidimensional impact of combat sports on physical, psychological, and social health, this paper endeavors to underscore their transformative potential as an instrument for fostering individual and community well-being within different populations. DiscussionWhilst an expanding body of research and an evolution in scholarly discourse is recognizing the combat sports’ broader implications for holistic well-being (30, 37), a rigorous evaluation of the investigation methodologies, the validity of hypotheses, and the translational potential of recent findings is necessary to contextualize their significance within the sports and public health sciences, considering their strengths, weaknesses, opportunities, and threats (Figure 1).----------------------------------------ADD FIGURE 1 ABOUT HERE----------------------------------------Empirical evidence robustly shows the positive impact of combat sports on physical fitness, motor coordination, and cardiovascular health (3, 38). These benefits are attributed to the high-intensity, intermittent nature of combat sports training, which enhances aerobic and anaerobic endurance, muscular strength, and neuromuscular control (39). However, concerns regarding injury risk, particularly in striking and contact-intensive disciplines such as boxing, taekwondo, and mixed martial arts, necessitate continued research into injury mitigation strategies, particularly those targeting concussion and repetitive head trauma (6, 35, 40, 41). Moreover, many combat sports have developed styles with reduced or simulated contact to minimize injury risk. For example, the French "boxe éducative" emphasizing technique and control, penalizing any violent behaviors (42) and the value and application of kata (i.e., forms; prearranged, pattern practices) to learning and adopting judo technique in a safe way educating the athlete culturally, to enrich her/him as a person (43).Beyond physical health, recent studies highlight the psychological benefits of combat sports, including reductions in anxiety and depression and improvements in self-efficacy, emotional regulation, resilience, and stress management (27, 44-47). Therefore, combat sports-based interventions for individuals with mental health conditions have yielded promising outcomes (23). Despite these encouraging findings, variability in study designs, participant demographics, and intervention protocols limits their external validity, underscoring the need for further rigorously controlled investigations. Furthermore, some authors claimed that combat sport athletes might present symptoms of low energy availability and high anxiety levels associated with competition- and injury-related psychological stressors, deficits in executive functions and neuropsychological impairments associated with occurrence of concussions, disordered eating and eating disorders associated with weight-loss, and might suffer offensive, frightening, hostile, degrading, humiliating experiences, or sexual harassment, which urge safeguarding actions (32-36).The role of combat sports in fostering social inclusion has gained empirical support, particularly in programmes aimed at individuals with disabilities and marginalized communities (25, 48). For instance, a recent systematic review shows that judo interventions adapted for intellectual disabilities help improve social integration and self-perception and enhance participants' quality of life (49). The development of para-combat sports demonstrates enhanced physical and motor abilities while providing psychosocial benefits to various populations with different disabilities, promoting social integration, self-perception, and community belonging (50, 51). However, longitudinal research is needed to assess the long-term retention rates and sustainability of these benefits. Furthermore, there is a need of studies focused on the most appropriate adapted rules to achieve a fairer competition for ensuring a sense of success in individuals with physical, emotional, mental, hearing or visual impairments participating in adapted sports competitions at local, national, and international levels. Methodological approaches in combat sports research encompass experimental, longitudinal, qualitative, and systematic review designs. While randomized controlled trials remain the gold standard for establishing causality, their application in combat sports research is constrained by ethical concerns, logistical challenges, and the inherently dynamic nature of training environments (52, 53). Consequently, many studies rely on observational designs, which, despite their value in identifying associations, are susceptible to confounding variables and biases (24, 54).Qualitative methodologies have provided critical insights into the lived experiences of combat sports practitioners, offering perspectives on psychological and social dimensions that are often overlooked in quantitative studies (28). Ethnographic research has been particularly instrumental in elucidating the role of combat sports in shaping identity, discipline, and personal development (55). However, limitations in reproducibility and generalizability highlight the need for mixed-methods approaches to generate a more comprehensive understanding of combat sports' impact (25, 56).Additionally, the incorporation of biometric and neurocognitive assessments, such as heart rate variability analysis, functional MRI, and salivary cortisol measurements, has advanced our understanding of the physiological and psychological mechanisms underlying combat sports participation (47, 57, 58). Despite their objective precision, these techniques often face challenges related to cost, accessibility, and limited sample sizes, necessitating the development of scalable and cost-effective methodologies for broader research application. Finally, recent studies show that virtual reality (VR) technology and digital platforms are increasingly becoming part of combat sports training methods. Due to COVID-19 restrictions, martial arts schools and organizations implemented hybrid or online training models, which allowed athletes to stay engaged. VR boxing programmes provide users with virtual sparring simulations to enhance their motor skills without needing physical interaction. Initial results indicate that VR training enhances response behavior in karate athletes (59). Digital adaptations offer great potential, especially for people with limited mobility or remote locations. However, further studies are necessary to prove their enduring effects on physical health and psychological and social aspects (59-61).Strengths and Weaknesses of Scientific HypothesesThe hypothesis that combat sports confer multidimensional health benefits is strongly supported by empirical evidence spanning physiological, psychological, and social domains (8, 62-64). The integration of physical exertion, cognitive engagement, and structured discipline inherent in combat sports aligns with established theories of exercise psychology, neuroplasticity, and social identity formation (65, 66). This multidimensional perspective provides a robust theoretical foundation for advocating combat sports as a health-promoting activity. Nevertheless, several limitations warrant consideration. The heterogeneity of disciplines, which vary highly in intensity, contact level, and training methodologies, is often inadequately addressed in research, leading to overgeneralized conclusions (17, 39). Often underexamined, individual differences in personality, motivation, and previous trauma history may strongly moderate the psychological outcomes of combat sports participation (35, 67, 68).Additionally, a research focus is needed on concerns regarding the potential for adverse psychological effects (e.g., anxiety, depression, disordered eating behaviors, burnout, and decreased self-esteem), particularly in competitive environments where performance pressure, extreme weight-cutting practices, and aggressive coaching styles are prevalent (69, 70). Indeed, a balanced perspective that considers both benefits and risks is essential for the development of evidence-based recommendations (10, 71).Future DirectionsTo enhance the field, future research should prioritize well-structured longitudinal studies that assess the long-term impact of combat sports participation on physical, psychological, and social health. Standardization of outcome measures, intervention protocols, and participant demographics would facilitate cross-study comparisons and strengthen the reliability of findings (72, 73). Moreover, interdisciplinary collaborations incorporating sports science, psychology, and sociology could provide a more holistic perspective on combat sports' broader implications on practitioners (74).From a policy perspective, to yield valuable insights into combat sports’ practical applications research should investigate their efficacy within public health, educational, and rehabilitation initiatives, particularly for underserved and vulnerable populations (23, 75, 76).Furthermore, while safety remains a primary concern, advancements in protective equipment, training methodologies, education for athletes, coaches, referees and tournament directors, and regulatory frameworks should be continually evaluated to optimize benefits while mitigating risks (40, 41, 58, 77, 78). Ethical considerations, particularly concerning athlete well-being and inclusive participation, should remain a central focus in both research and practical implementation (17, 34, 36).Therefore, key research challenges to be addressed are: 1. Injury risk and safety: a need for injury prevention strategies, especially for concussions and head trauma in striking sports. 2. Psychological wellbeing: risks of stress, anxiety, burnout, and negative self-perception in competitive environments. 3. Inclusion and accessibility: a need for more research on long-term social and psychological benefits for marginalized groups and individuals with disabilities. 4. Methodological limitations: lack of standardized protocols, variability in study designs, and limited reproducibility of findings. 5. Ethical and regulatory issues: concerns over coaching practices, extreme weight-cutting, and athlete wellbeing in high-pressure environments. 6. Technological innovations: more research required on the effectiveness of VR and digital training tools in combat sports. 7. Public health and policy: exploration of combat sports' role in health initiatives, rehabilitation, and educational programs. ConclusionThe evolving discourse on combat sports highlights their potential as a multidimensional tool for well-being promotion. While a substantial body of evidence supports their benefits, a critical examination of methodological limitations, scientific hypotheses, and practical applications is essential for further refine our understanding and enhance their effectiveness. Finally, this article makes a significant contribution not only to the field of martial arts but also to public health and sports psychology. Its interdisciplinary approach calls for scientific collaboration and methodological rigor, reinforces the need for evidence-based policies and can serve as a valuable guide for researchers and policymakers looking to integrate combat sports into strategies for promoting health and social inclusion.

Frontiers in Psychology · 12 citationsread the source →

Using social risk factors to predict allostatic biotypes of depression: A latent profile and multinomial regression analysis.

Objective: Major depression is often difficult to treat, particularly among individuals exposed to psychosocial risks like childhood maltreatment, loneliness, and recent stress. These experiences may lead to biological dysregulation consistent with allostatic load theory. This study explored whether distinct biological profiles among adults with depression are associated with specific psychosocial and health-related factors. Method: Data were drawn from the Midlife in the United States study (MIDUS), including 367 participants with clinically significant depressive symptoms (CES-D ≥ 16). Latent profile analysis identified biological profiles based on 23 biomarkers across seven systems: inflammation, glucose, sympathetic and parasympathetic nervous systems, HPA-axis, cardiovascular, and lipids. Multinomial regression models examined associations between profile membership and psychosocial (childhood maltreatment, loneliness, recent stress), health (alcohol use, smoking, exercise), and demographic variables (sex, race/ethnicity, age, education). Results: A five-profile solution best fit the data: High Inflammation & Glucose (n = 74), Low PNS (n = 83), High PNS (n = 73), Healthy Depression (n = 67), and High HPA-Axis (n = 70). Childhood maltreatment significantly predicted membership in the High Inflammation & Glucose and Low PNS profiles compared to the Healthy Depression group, even after controlling for health behaviors and demographics. Loneliness and recent stress were not significant predictors. Conclusion: Childhood maltreatment is a predictor of biological dysregulation in depression, differentially predicting profiles characterized by inflammatory and metabolic vs parasympathetic functioning. These may represent different vulnerability pathways from social experiences to depressive illness. Incorporating measurement strategies specific to these pathways may aide in selecting treatment options for people who have depression and a history of childhood maltreatment.

Brain, behavior, and immunityread the source →

Socioeconomic inequalities in adolescent health 2002-2010: a time-series analysis of 34 countries participating in the Health Behaviour in School-aged Children study.

Background: Information about trends in adolescent health inequalities is scarce, especially at an international level. We examined secular trends in socioeconomic inequality in five domains of adolescent health and the association of socioeconomic inequality with national wealth and income inequality. Methods: We undertook a time-series analysis of data from the Health Behaviour in School-aged Children study, in which cross-sectional surveys were done in 34 North American and European countries in 2002, 2006, and 2010 (pooled n 492,788). We used individual data for socioeconomic status (Health Behaviour in School-aged Children Family Affluence Scale) and health (days of physical activity per week, body-mass index Z score [zBMI], frequency of psychological and physical symptoms on 0-5 scale, and life satisfaction scored 0-10 on the Cantril ladder) to examine trends in health and socioeconomic inequalities in health. We also investigated whether international differences in health and health inequalities were associated with per person income and income inequality. Findings: From 2002 to 2010, average levels of physical activity (3·90 to 4·08 days per week; p<0·0001), body mass (zBMI -0·08 to 0·03; p<0·0001), and physical symptoms (3·06 to 3·20, p<0·0001), and life satisfaction (7·58 to 7·61; p=0·0034) slightly increased. Inequalities between socioeconomic groups increased in physical activity (-0·79 to -0·83 days per week difference between most and least affluent groups; p=0·0008), zBMI (0·15 to 0·18; p<0·0001), and psychological (0·58 to 0·67; p=0·0360) and physical (0·21 to 0·26; p=0·0018) symptoms. Only in life satisfaction did health inequality fall during this period (-0·98 to -0·95; p=0·0198). Internationally, the higher the per person income, the better and more equal health was in terms of physical activity (0·06 days per SD increase in income; p<0·0001), psychological symptoms (-0·09; p<0·0001), and life satisfaction (0·08; p<0·0001). However, higher income inequality uniquely related to fewer days of physical activity (-0·05 days; p=0·0295), higher zBMI (0·06; p<0·0001), more psychological (0·18; p<0·0001) and physical (0·16; p<0·0001) symptoms, and larger health inequalities between socioeconomic groups in psychological (0·13; p=0·0080) and physical (0·07; p=0·0022) symptoms, and life satisfaction (-0·10; p=0·0092). Interpretation: Socioeconomic inequality has increased in many domains of adolescent health. These trends coincide with unequal distribution of income between rich and poor people. Widening gaps in adolescent health could predict future inequalities in adult health and need urgent policy action. Funding: Canadian Institutes of Health Research.

Lancet (London, England) · 301 citationsread the source →

Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.

Background: Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods: We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings: In 2019, there were 12·2 million (95% UI 11·0-13·6) incident cases of stroke, 101 million (93·2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6·55 million (6·00-7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8-12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1-6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0-73·0), prevalent strokes increased by 85·0% (83·0-88·0), deaths from stroke increased by 43·0% (31·0-55·0), and DALYs due to stroke increased by 32·0% (22·0-42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0-18·0), mortality decreased by 36·0% (31·0-42·0), prevalence decreased by 6·0% (5·0-7·0), and DALYs decreased by 36·0% (31·0-42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0-24·0) and incidence rates increased by 15·0% (12·0-18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5-3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5-3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57-8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97-3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01-1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7-90·8] DALYs or 55·5% [48·2-62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3-48·6] DALYs or 24·3% [15·7-33·2]), high fasting plasma glucose (28·9 million [19·8-41·5] DALYs or 20·2% [13·8-29·1]), ambient particulate matter pollution (28·7 million [23·4-33·4] DALYs or 20·1% [16·6-23·0]), and smoking (25·3 million [22·6-28·2] DALYs or 17·6% [16·4-19·0]). Interpretation: The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding: Bill & Melinda Gates Foundation.

The Lancet. Neurology · 5441 citationsread the source →

Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers.

Importance: Despite epidemic rates of addiction and death from prescription opioids in the United States, suggesting the importance of providing alternatives to opioids in the treatment of pain, little is known regarding how payers' coverage policies may facilitate or impede access to such treatments. Objective: To examine coverage policies for 5 nonpharmacologic approaches commonly used to treat acute or chronic low back pain among commercial and Medicare Advantage insurance plans, plus an additional 6 treatments among Medicaid plans. Design, setting, and participants: Cross-sectional study of 15 commercial, 15 Medicaid, and 15 Medicare Advantage health plans for the 2017 calendar year in 16 states representing more than half of the US population. Interviews were conducted with 43 senior medical and pharmacy health plan executives from representative plans. Main outcomes and measures: Medical necessity and coverage status for the treatments examined, as well as the use of utilization management tools and cost-sharing magnitude and structure. Results: Commercial and Medicare insurers consistently regarded physical and occupational therapy as medically necessary, but policies varied for other therapies examined. Payers most commonly covered physical therapy (98% [44 of 45 plans]), occupational therapy (96% [43 of 45 plans]), and chiropractic care (89% [40 of 45 plans]), while transcutaneous electrical nerve stimulation (67% [10 of 15 plans]) and steroid injections (60% [9 of 15 plans]) were the most commonly covered among the therapies examined for Medicaid plans only. Despite evidence in the literature to support use of acupuncture and psychological interventions, these therapies were either not covered by plans examined (67% of all plans [30 of 45] did not cover acupuncture) or lacked information about coverage (80% of Medicaid plans [12 of 15] lacked information about coverage of psychological interventions). Utilization management tools, such as prior authorization, were common, but criteria varied greatly with respect to which conditions and what quantity and duration of services were covered. Interviewees represented 6 Medicaid managed care organizations, 2 Medicare Advantage or Part D plans, 9 commercial plans, and 3 trade organizations (eg, Blue Cross Blue Shield Association). Interviews with plan executives indicated a low level of integration between the coverage decision-making processes for pharmacologic and nonpharmacologic therapies for chronic pain. Conclusions and relevance: Wide variation in coverage of nonpharmacologic treatments for low back pain may be driven by the absence of best practices, the administrative complexities of developing and revising coverage policies, and payers' economic incentives. Such variation suggests an important opportunity to improve the accessibility of services, reduce opioid use, and ultimately improve the quality of care for individuals with chronic, noncancer pain while alleviating the burden of opioid addiction and overdose.

JAMA network open · 127 citationsread the source →

Association of Sex and Age With Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI Study.

Importance: Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients. Objective: To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI. Design, setting, and participants: The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021. Exposures: Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls. Main outcomes and measures: Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales). Results: A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate-corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate-corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02). Conclusions and relevance: This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.

JAMA network open · 130 citationsread the source →

Go Where the Students Are: A Comparison of the Use of Social Networking Sites Between Medical Students and Medical Educators.

Background: Medical education has grown beyond the boundaries of the classroom, and social media is seen as the bridge between informal and formal learning as it keeps students highly engaged with educational content outside the classroom. Objective: The purpose of this study is to explore the perceptions of medical educators and medical students regarding the use of social media for educational purposes. Methods: Both groups (medical educators and students) were invited to take a survey. The surveys consisted of 29 questions, including Likert-style, multiple choice, yes/no, ranking, and short answer questions. The survey forms and statistics were built using Google Drive analytics with the free Spanning Stats module. To compare between professors and students, results were exported to a Microsoft Office Excel spreadsheet (Microsoft Corp, Redmond, WA). The study protocol was approved by The Ottawa Health Science Network Research Ethics Board (OHSN-REB:20140680-01H). Results: The overall response rate to the survey was 40.9% (63/154) for students, and 36% (72/200) for medical educators. The majority of educators (79%, 57/72) and students (100.0%, 63/63) had presence on social networking sites (SNSs). Only (33% 19/57) of educators used SNSs with their students, the most used sites were Facebook (52%, 10/19) and Twitter (47%, 9/19), followed by LinkedIn (21%, 4/19), Google+ (16%, 3/19),YouTube (11%, 2/19), and blogs (11%, 2/19). Facebook (100%, 63/63), YouTube (43%, 27/63), Twitter (31%, 20/63), and Instagram (30%, 19/63) were the sites most commonly used by students. The educators used SNSs mainly to post opinions (86%, 49/57), share videos (81%, 46/57), chat (71%, 41/57), engage in medical education (68%, 40/57), take surveys (24%, 14/57), and play games (5%, 3/57). On the other hand, students used SNSs mainly to chat with friends (94%, 59/63), for medical education purposes (67%, 42/63), to share videos (62%, 39/63), to post opinions (49%, 31/63), to take surveys (11%, 7/63), and to play games (6%, 4/63). Most educators (67%, 38/57) do not use social media in their education Although most of the educators (89%, 17/19) and students (73%, 46/63) found the use of social media time-effective, that it offered an inviting atmosphere (89%, 17/19 and 70%, 44/63), and that it enhanced the learning experience (95%, 18/19 and 70%, 44/63), both groups stated that they had colleagues who refused to use social media. The detractors' concerns included privacy issues (47%, 18/38), time-wasting (34%, 13/38), distraction (21%, 8/38), and that these media might not be suitable for education (11%, 4/38). When it came to using SNSs with the students, the educators most often used SNSs to post articles (42%, 8/19), explanatory comments (31%, 6/19), and videos (27%, 5/19).While students preferred the following posts : Quizzes (87% 55/63), revision files (82% 52/63) and explanatory comments (29% 21/63). Conclusions: Although social media continue to grow, some educators find that they do not offer suitable modes of learning. However, it is important to acknowledge that there are persistent differences in technology adoption and use along gender, racial, and socioeconomic lines; this is often referred to as the "digital divide". The current study shows that students prefer certain posts like quizzes and revision files, while educators are focused on posting videos, articles, and explanatory comments. Medical educators are encouraged to focus on the students in a way to minimize the gap between learners and educators. It will remain our responsibility as educators to focuson the student, use SNSs at their fullest, and integrate them into traditional Web-based management systems and into existingcurricula to best benefit the students.

JMIR medical education · 49 citationsread the source →

Outcomes in people with eating disorders: a transdiagnostic and disorder-specific systematic review, meta-analysis and multivariable meta-regression analysis.

Eating disorders (EDs) are known to be associated with high mortality and often chronic and severe course, but a recent comprehensive systematic review of their outcomes is currently missing. In the present systematic review and meta-analysis, we examined cohort studies and clinical trials published between 1980 and 2021 that reported, for DSM/ICD-defined EDs, overall ED outcomes (i.e., recovery, improvement and relapse, all-cause and ED-related hospitalization, and chronicity); the same outcomes related to purging, binge eating and body weight status; as well as mortality. We included 415 studies (N=88,372, mean age: 25.7±6.9 years, females: 72.4%, mean follow-up: 38.3±76.5 months), conducted in persons with anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), other specified feeding and eating disorders (OSFED), and/or mixed EDs, from all continents except Africa. In all EDs pooled together, overall recovery occurred in 46% of patients (95% CI: 44-49, n=283, mean follow-up: 44.9±62.8 months, no significant ED-group difference). The recovery rate was 42% at <2 years, 43% at 2 to <4 years, 54% at 4 to <6 years, 59% at 6 to <8 years, 64% at 8 to <10 years, and 67% at ≥10 years. Overall chronicity occurred in 25% of patients (95% CI: 23-29, n=170, mean follow-up: 59.3±71.2 months, no significant ED-group difference). The chronicity rate was 33% at <2 years, 40% at 2 to <4 years, 23% at 4 to <6 years, 25% at 6 to <8 years, 12% at 8 to <10 years, and 18% at ≥10 years. Mortality occurred in 0.4% of patients (95% CI: 0.2-0.7, n=214, mean follow-up: 72.2±117.7 months, no significant ED-group difference). Considering observational studies, the mortality rate was 5.2 deaths/1,000 person-years (95% CI: 4.4-6.1, n=167, mean follow-up: 88.7±120.5 months; significant difference among EDs: p<0.01, range: from 8.2 for mixed ED to 3.4 for BN). Hospitalization occurred in 26% of patients (95% CI: 18-36, n=18, mean follow-up: 43.2±41.6 months; significant difference among EDs: p<0.001, range: from 32% for AN to 4% for BN). Regarding diagnostic migration, 8% of patients with AN migrated to BN and 16% to OSFED; 2% of patients with BN migrated to AN, 5% to BED, and 19% to OSFED; 9% of patients with BED migrated to BN and 19% to OSFED; 7% of patients with OSFED migrated to AN and 10% to BN. Children/adolescents had more favorable outcomes across and within EDs than adults. Self-injurious behaviors were associated with lower recovery rates in pooled EDs. A higher socio-demographic index moderated lower recovery and higher chronicity in AN across countries. Specific treatments associated with higher recovery rates were family-based therapy, cognitive-behavioral therapy (CBT), psychodynamic therapy, and nutritional interventions for AN; self-help, CBT, dialectical behavioral therapy (DBT), psychodynamic therapy, nutritional and pharmacological treatments for BN; CBT, nutritional and pharmacological interventions, and DBT for BED; and CBT and psychodynamic therapy for OSFED. In AN, pharmacological treatment was associated with lower recovery, and waiting list with higher mortality. These results should inform future research, clinical practice and health service organization for persons with EDs.

World psychiatry : official journal of the World Psychiatric Association (WPA) · 148 citationsread the source →

Roles of cyberbullying, sleep, and physical activity in mediating the effects of social media use on mental health and wellbeing among young people in England: a secondary analysis of longitudinal data.

Background: There is growing concern about the potential associations between social media use and mental health and wellbeing in young people. We explored associations between the frequency of social media use and later mental health and wellbeing in adolescents, and how these effects might be mediated. Methods: We did secondary analyses of publicly available data from the Our Futures study, a nationally representative, longitudinal study of 12 866 young people from age 13 years to 16 years in England. The exposure considered was the frequency of social media use (from weekly or less to very frequent [multiple times daily]) at wave 1 (participants aged 13-14 years) through wave 3 of the study (participants aged 15-16 years). Outcomes were mental health at wave 2 (with high 12-item General Health Questionnaire [GHQ12] scores [≥3] indicating psychological distress), and wellbeing at wave 3 (life satisfaction, feeling life is worthwhile, happiness, and anxiety, rated from 1 to 10 by participants). Analyses were adjusted for a minimal sufficient confounding structure, and were done separately for boys and girls. Cyberbullying, sleep adequacy, and physical activity were assessed as potential mediators of the effects. Findings: Very frequent use of social media increased from wave 1 to wave 3: from 34·4% (95% CI 32·4-36·4) to 61·9% (60·3-63·6) in boys, and 51·4% (49·5-53·3) to 75·4% (73·8-76·9) in girls. Very frequent social media use in wave 1 predicted a high GHQ12 score at wave 2 among girls (adjusted odds ratio [OR] 1·31 [95% CI 1·06-1·63], p=0·014; N=4429) and boys (1·67 [1·24-2·26], p=0·0009; N=4379). Persistent very frequent social media use across waves 1 and 2 predicted lower wellbeing among girls only (adjusted ORs 0·86 [0·74-0·99], N=3753, p=0·039 for life satisfaction; 0·80 [0·70-0·92], N=3831, p=0·0013 for happiness; 1·28 [1·11-1·48], N=3745, p=0·0007 for anxiety). Adjustment for cyberbullying, sleep, and physical activity attenuated the associations of social media use with GHQ12 high score (proportion mediated 58·2%), life satisfaction (80·1%), happiness (47·7%), and anxiety (32·4%) in girls, such that these associations (except for anxiety) were no longer significant; however, the association with GHQ12 high score among boys remained significant, being mediated only 12·1% by these factors. Interpretation: Mental health harms related to very frequent social media use in girls might be due to a combination of exposure to cyberbullying or displacement of sleep or physical activity, whereas other mechanisms appear to be operative in boys. Interventions to promote mental health should include efforts to prevent or increase resilience to cyberbullying and ensure adequate sleep and physical activity in young people. Funding: None.

The Lancet. Child & adolescent health · 131 citationsread the source →

Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes

Chronic illness can result in chronicity of clinical practice. As we have moved away from prescribing classical antipsychotics and tricyclic antidepressants, issues remain with the use of atypical antipsychotics and second-generation antidepressants that need to be addressed, namely, iatrogenic discontinuation syndromes and supersensitivity psychiatric symptoms. An optimal maintenance drug treatment consists of regular attempts to reduce the dose by finding a minimal therapeutic dose, regularly asking the question of when to reduce or withdraw treatment and for which patients, and moreover, why it is difficult to decrease a given drug treatment. Recently, Falloon [1] proposed that maintenance pharmacotherapy in schizophrenia will depend on finally finding minimally effective doses through ‘extensive training in stress management’. In the long-term treatment of major depression, Fava [2] has hypothesized that antidepressants can aggravate the course of depressive illness. Lambert [3] recently suggested that ‘antipsychotic-switching syndromes’, which include discontinuation syndromes, are a ‘major barrier’ to adjusting antipsychotic treatment. In this paper, we propose that to achieve optimal maintenance treatment with antipsychotics, and to reduce or withdraw antipsychotics effectively, we must distinguish syndromes associated with discontinuing antipsychotics, such as supersensitivity psychosis, from true relapse. While the prevalence and incidence of drug-induced movement disorder(s) (DIMD) has continuously decreased with atypical antipsychotics, DIMD persist as do psychiatric and psychiatric-like symptoms associated with DIMD, and these must also be identified and evaluated. Persistent DIMD have been found to be a predictor of the later emergence of tardive dyskinesia (TD) and supersensitivity psychosis [4]. At present, we need to determine the relative risk of iatrogenic discontinuation syndromes, DIMD and DIMD psychiatric symptoms resulting from atypical antipsychotics. Although atypical antipsychotics are now most commonly prescribed, a debate has emerged on the differences between classical and atypical antipsychotics following the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [5]. The question that comes to the forefront is why recent studies are no longer finding well-established differences between these two generations in terms of efficacy and DIMD. Reasons to explain why recent schizophrenia studies have found reduced drug and placebo differences were examined at the International Society for CNS Clinical Trials and Methodology Annual Mid-Year Conference [6]. While the fact must be considered that patients included in recent studies have less severe illness with symptoms that are better controlled than in past studies (likely due to earlier treatment), the issue that psychiatric symptoms specific to schizophrenia are not being adequately measured nor differentiated from psychiatric and psychiatric-like symptoms associated with DIMD is crucial to answering this question. For example, it is hard to believe that in a recent review of psychomotor slowing in schizophrenia, the authors, when evaluating its effect on measurement and treatment research to improve cognition in schizophrenia (MATRICS), nearly completely ignored the influence of akinesia and DIMD on neuropsychological tests in schizophrenia and the importance of accurate DIMD measurements [7]. As we pursue this ongoing discussion, we recommend the discontinuation of all classical antipsychotics due to their neurotoxic association with a high prevalence of DIMD and increases in basal ganglia volumes [8], and now address how to prescribe atypical antipsychotics most effectively, by taking into account DIMD-associated psychiatric symptoms and iatrogenic discontinuation syndromes. The first widely prescribed atypical antipsychotic, risperidone, was first approved in Canada in 1993 following the publication of the Canadian Multicenter Risperidone Study, which reported clear advantages of risperidone over haloperidol and the placebo, and significantly less appearance of DIMD with risperidone than haloperidol [9]. DIMD includes the 4 types of movement disorders induced by antipsychotics: parkinsonism, dystonia, dyskinesia and akathisia [10]. These findings were confirmed by the American Risperidone Study [11] and several other studies reporting greater efficacy of risperidone over classical antipsychotics in terms of cost-efficiency [12] and the clinical management of patients with schizophrenia [13,14,15,16,17]. However, the CATIE study [5] challenged these results. The CATIE study found that of the 4 atypical antipsychotics studied, olanzapine was the only atypical to be more efficacious than the classical antipsychotic perphenazine, and to be highly superior to risperidone for discontinuation of treatment, due to lack of efficacy [5]. Olanzapine is known to produce less DIMD compared to risperidone, therefore one would expect psychiatric symptoms caused by DIMD to be less frequent with olanzapine than risperidone. The expected higher rate of DIMD-induced emergent psychiatric symptoms associated with risperidone would explain the CATIE results, showing risperidone to be significantly less efficacious than olanzapine [5], despite risperidone being known to be at least as efficacious as olanzapine for true schizophrenic symptoms. Furthermore, the rating scales used to measure DIMD did not find the well-established differences between the 5 antipsychotics for DIMD rates [5]. Thus, we propose that DIMD and DIMD-induced psychiatric symptoms were confounded with true schizophrenic symptoms in the CATIE study. DIMD-associated psychiatric symptoms could be classified into 3 types: (1) emergent psychiatric symptoms caused by DIMD, such as akinesia inducing depression, akathisia inducing anxiety; (2) iatrogenic psychiatric-like symptoms resulting from confounding DIMD with psychiatric symptoms, such as akinesia confounded with psychomotor retardation, akathisia with agitation; (3) supersensitivity psychosis symptoms associated with DIMD. In the CATIE study, quetiapine (mean dose = 543.4 mg/day), which shares a low rate of DIMD with olanzapine, was also found to be significantly less efficacious compared to olanzapine, but in contrast to risperidone, this lack of efficacy could be due to psychiatric symptoms related to supersensitivity psychosis explained by quetiapine’s loose binding properties at the D2 receptor [18]. Patients taking quetiapine had a completion rate of 18% out of 329 patients, whereas in our 3-year prospective study of quetiapine monotherapy with a lower mean dose of 487 mg/day (thus less likely to develop therapeutic tolerance), the completion rate was 21.7% out of 23 patients; 6 of 7 patients who relapsed, after a minimum 3 months of stabilized quetiapine treatment, met the criteria for supersensitivity psychosis [19]. Without distinguishing these DIMD-associated psychiatric symptoms from symptoms due to the original illness, the major impact of atypical antipsychotics is on the reduction of DIMD and TD [10, 20,] and their beneficial effects on psychosis are masked by DIMD emergent psychiatric symptoms, including supersensitivity psychosis. We will review 4 multicenter trials, which include a total of 14,497 patients, to illustrate how psychiatric and schizophrenic symptoms are confounded with DIMD-associated psychiatric symptoms.TD epidemiology has changed significantly since the introduction of atypical antipsychotics, with a constant decline in its prevalence [10]. TD, classified as a DIMD, is a hyperkinetic, involuntary and purposeless movement disorder [10, 20]. Considered as the most significant side effect of classical antipsychotics, TD has been associated with antipsychotics and gastrointestinal neuroleptics, and usually occurs after several years of treatment. Persistent TD can also occur after short-term exposure to classical antipsychotics and gastrointestinal neuroleptics even at low doses and for as few as 2 months [8,21,22,23], while reversible and withdrawal dyskinesias share properties with levodopa-induced dyskinesia [24]. We conducted several epidemiological studies of TD [4,25,26,27] and in 1975, using the National Institute of Mental Health (NIMH) psychopharmacology criteria, we found a 31% prevalence of TD in 261 outpatients with schizophrenia [25]. We also evaluated these patients according to the Schooler and Kane research diagnostic criteria and found a 22% prevalence of TD. This variability of findings related to defining criteria complicates comparisons across studies [10]. In a 5-year follow-up study of 169 of the same patients [4, 25], 45% met the research diagnostic criteria for TD. In 1975, 131 of the 261 patients did not meet the research diagnostic for TD, and in 1980 treatment-emergent TD was found in 46 of the patients who did not have it in 1975, for a 5-year cumulative incidence rate of 35% and a mean annual incidence rate of 8.4%. When corrected for remissions, the mean annual incidence rate decreased to 2.9%. This incidence rate, which includes both patients who developed and remitted from TD over time, is similar to results found by other studies during the same time period [28, 29]. The cumulative incidence of treatment-emergent TD in the study by Kane et al. [29] was 12% after 4 years and 40% after 8 years of neuroleptic exposure, which is similar to our finding of an annual incidence rate (corrected for remissions) of 3% for classical antipsychotics. In a study carried out in 130 lithium-treated affective disorder patients previously, but less, exposed to antipsychotics, we found a TD prevalence of 9.2% [26], which was a quarter of the incidence reported in our previous studies on patients with schizophrenia who had greater exposure to antipsychotics. In this time period of classical antipsychotics, 2 meta-analyses (including mostly patients with schizophrenia) reported mean TD prevalences of 23% [30] and 20% [31]. In view of the fact that 58% of patients treated with classical antipsychotics will develop treatment-emergent TD after 10–15 years of treatment [4], and the known beneficial neuroprotective effects of atypical antipsychotics on TD [32] and on increased basal ganglia volumes induced by classical antipsychotics [8], we recommend the discontinuation of all classical antipsychotics due to their neurotoxic effects. In the time period of both classical and atypical antipsychotics, the following multicenter studies (n = 3,753) evaluated the incidence and prevalence of TD, using the same definitions, Extrapyramidal Symptom Rating Scale [20] and training videotapes as in the previous time period. In the first study, an annual TD incidence of 0.68% was reported prospectively in 725 patients with schizophrenia, treated with the long-acting injectable atypical antipsychotic risperidone [27, 33]. Treatment-emergent TD was found in 12 of 587 patients without dyskinesia at the baseline [33]; however, expert case assessment determined 7 cases (1.19%) of withdrawal dyskinesia (3 cases resolved, 4 cases unchanged), 1 case (0.17%) of reversible dyskinesia and 4 cases (0.68%) of persistent treatment-emergent TD. Of the patients with baseline dyskinesia, 28.4% improved, no longer met TD criteria and maintained this response [33]. This annual treatment-emergent TD incidence of 0.68% with atypical antipsychotics is only 22% of the annual incidence of 3% reported with classical antipsychotics [4]. In the second study, the Schizophrenia International Suicide Prevention Trial (67 centers in 11 countries) [34], 980 patients with schizophrenia, or schizoaffective disorders, taking an atypical alone (25.6%), a classical alone (31.5%) or both a classical and an atypical antipsychotic (42.9%) were included from March 19, 1998, to February 14, 1999, and TD was found at the baseline in 115 (12%) patients [27, 35]. Thus, after 10 years in the time period of both classical and atypical antipsychotics, the overall prevalence of TD decreased by at least twofold compared to our previous 1979–1988 studies with classical antipsychotics [4, 25], using the same definitions, Extrapyramidal Symptom Rating Scale and training videotapes. In the third study (baseline data from three Ris-Consta multicenter studies) [27, 36] carried out 1 year later, 2,048 patients were included from March 21, 1999, to December 15, 2000, and TD was found at the baseline in 209 patients (10.2%), using the same methodology. This study showed a further decrease in the prevalence of TD after an additional year of atypical use. This changing epidemiology of TD with atypical antipsychotics is confirmed by Correll et al. [37] in a systematic review of 1-year prospective studies with atypical antipsychotics, and by Jeste et al. [38] in a 1-year study of elderly patients treated with risperidone. In conclusion, following the introduction of atypical antipsychotics, the prevalence and incidence of TD have significantly decreased. However, the risk for TD still exists with both atypical and classical antipsychotics, and there is a need for continued surveillance of emerging cases of TD in patients taking antipsychotics [39], especially as the current debate continues on the differences in efficacy between these two generations of antipsychotics following results from studies such as the CATIE [5, 39]. Furthermore, Kane [39] has pointed out that newly trained clinicians using mostly atypical antipsychotics may not have had the same exposure to TD as previously trained clinicians.A high prevalence of all 4 types of DIMD (parkinsonism, dystonia, dyskinesia and akathisia) remains. In the Schizophrenia International Suicide Prevention Trial (n = 980), a prevalence of 57.5% of DIMD (n = 551 patients) was found [27, 35]. In the Ris-Consta studies (n = 2,048) [27, 36], 970 patients (47.4%) had DIMD at the baseline, which consisted of 778 patients with parkinsonism (38.0%), 285 patients with akathisia (14%) and 209 patients with TD (10.2%). Thus, nearly 1 patient out of 2 had a definite DIMD in this time period of classical and atypical antipsychotics. In addition, DIMD have been consistently associated with significant psychiatric symptoms as measured by the positive and negative syndrome scale (PANSS) [40, 41]. In the InterSept study (n = 980), which included patients with schizophrenia and schizoaffective disorder who were at risk of suicide, suicidality was associated at baseline with DIMD, parkinsonism, TD and akathisia, and depression was associated with TD and akathisia [27, 35]. Based on these results, we recommend routinely assessing DIMD in patients with schizophrenia with suicidal and depressive symptoms. In the Ris-Consta studies (n = 2,048), baseline DIMD were also significantly associated with the PANSS total score, positive, negative and anxiety/depression symptoms [27, 36]. Greater anxiety and depression were seen in patients with severer DIMD, akathisia and parkinsonism. Higher PANSS negative symptom rating was associated with parkinsonism and higher PANSS total scores were associated with akathisia. In this time period, these last two studies (n = 3,028) show that DIMD persists with atypical antipsychotics, and that patients with DIMD have significantly higher PANSS scores compared to patients without DIMD.These results are in agreement with findings from 2 other multicenter studies: the American CATIE study [5] and the European Schizophrenia Outpatient Health Outcomes (SOHO) study [42]. In the CATIE baseline data, patients with TD (n = 212) were found to have significantly more psychopathology than patients without TD (n = 1,098) as measured by the PANSS total score and PANSS general psychopathology subscale [43]. In the 3-year prospective SOHO study, emergent cases of TD were associated with greater overall psychopathology. An increase in clinical global impression overall symptom severity was longitudinally associated with cases of TD in patients without TD at the baseline (n = The SOHO and the CATIE studies have also examined other for TD. the CATIE and SOHO studies found that other DIMD were associated with TD the CATIE study showed that patients with TD had more parkinsonism akathisia while the SOHO study found that baseline symptoms TD our findings in a prospective study of TD [4]. In to reporting that the incidence of TD was lower in patients taking atypical compared to classical antipsychotics after 6 months the SOHO study showed that the incidence of TD was associated with the incidence of of drug-induced in is crucial to that there is a of DIMD with atypical antipsychotics, which are not and confounded with psychiatric symptoms rating scales used routinely in clinical to DIMD do not DIMD from psychiatric symptoms from the 4 multicenter (n = 14,497 patients) into this the CATIE the [27, the Ris-Consta [27, 36] and the SOHO studies have all confirmed the association of DIMD with psychiatric symptoms. most of the studies included in this measure psychiatric symptoms according to the we propose the following of PANSS psychiatric symptoms associated with emergent psychiatric symptoms caused by DIMD, such as depression and suicidality example, akinesia is known to produce depression, psychomotor and suicidal while akathisia psychomotor and suicidal and TD is also associated with suicidal iatrogenic psychiatric-like symptoms resulting from confounding and DIMD with psychiatric symptoms, such as confounding and with and retardation, akathisia with anxiety and and and dyskinesias with and schizophrenic psychiatric schizophrenic symptoms associated with DIMD caused by supersensitivity psychosis, which we are now to first reported drug-induced associated with TD a in and increased receptor after long-term treatment with classical antipsychotics, and we this supersensitivity psychosis. We that TD and supersensitivity psychosis with the decrease or withdrawal of an antipsychotic, given risk not and at the same The debate continues on how to most withdraw antipsychotic [1] and and psychiatric syndromes associated with types of syndromes have been with the discontinuation of (1) withdrawal syndromes and major (2) syndromes anxiety and which have been reported with and (3) supersensitivity syndromes such as TD and supersensitivity psychosis These discontinuation syndromes all produce psychiatric symptoms that can be confounded with true of the original illness. In a recent review of the on psychosis the importance of between antipsychotic withdrawal effects related to the course of the original illness and drug-induced effects such as supersensitivity psychosis. due to the discontinuation of a drug can be differentiated from the course of original illness and more long-term maintenance treatment could be reduced and in patients The long-term maintenance with second-generation antidepressants and of a major depressive disorder is of the in and during long-term maintenance treatment. The has also recently been to produce a persistent disorder following withdrawal to be related to supersensitivity When discontinuing antipsychotics and antidepressants, the of supersensitivity syndromes and other iatrogenic discontinuation syndromes must be to high doses or of outpatients and with schizophrenia treated with a classical antipsychotic treatment also included 1 but no antidepressants, no and no showed a prevalence of 22% for supersensitivity psychosis The prevalence of TD using Schooler and Kane criteria, was that found for supersensitivity psychosis. cases of supersensitivity psychosis increased the prevalence of supersensitivity psychosis to psychosis was associated with a higher maintenance dose of classical antipsychotics, high and schizophrenia with a The higher antipsychotic dose and higher associated with supersensitivity psychosis to the of supersensitivity and these results that lower doses of antipsychotics could the appearance of supersensitivity psychosis. In this study, there was no found between TD and supersensitivity psychosis, due to TD being associated with schizophrenia and supersensitivity psychosis with higher antipsychotic dose was not to be a risk for TD, whereas increased was associated with TD but not associated with supersensitivity psychosis. is that most patients in this study were treated with which has a high for the D2 which could to both a high incidence of supersensitivity psychosis and DIMD as the drug is known to produce a high incidence of symptoms psychosis, in its masked and withdrawal is known to occur 6 following the decrease or withdrawal of an antipsychotic or 3 months for a long-acting injectable We have proposed that TD and supersensitivity psychosis can result from the of in the caused by following in D2 with high for The of supersensitivity psychosis and TD share can both occur after long-term use of antipsychotics and can and difficult to with of the antipsychotic stress both TD and supersensitivity psychosis and both can be by and by and TD was to be the predictor of supersensitivity psychosis in our and follow-up study of supersensitivity psychosis [4, TD and supersensitivity psychosis may or may not occur in the same time but TD is associated with supersensitivity psychosis when it occurs during withdrawal of antipsychotics These two supersensitivity syndromes have been difficult to study due to the fact that antipsychotics can their appearance further with supersensitivity psychosis is that symptoms the original illness and true however, supersensitivity psychosis can be as it more after of the antipsychotic than true occurs with high doses of antipsychotics and not with antipsychotic treatment and therapeutic to antipsychotic treatment after drug response time, as therapeutic there is further of supersensitivity and further syndromes, TD, can (1) or (2) persistent or (3) reversible or symptoms can persist for several months or years and can still be reversible or When persistent and supersensitivity symptoms symptoms, being severer than the original symptoms, but these supersensitivity symptoms persist in contrast to symptoms and may include symptoms atypical antipsychotics, it has been proposed that supersensitivity psychosis occurs more with antipsychotics with from the D2 receptor The 2 atypical antipsychotics most associated with supersensitivity psychosis are quetiapine and which both have loose binding properties at the D2 receptor An additional which and severe in the withdrawal of is its effect as an receptor Thus, for the withdrawal would be by the receptor following of at this drug in the of the a and psychosis results cases of supersensitivity psychosis have also been reported with olanzapine psychosis was found to be associated with quetiapine in our 3-year study of quetiapine in 23 outpatients with schizophrenia and schizoaffective disorder who had previously been treated with classical antipsychotics risperidone, and had symptoms and of side effects [19]. As in our of the CATIE study, 7 patients after a minimum of 3 months of stabilized treatment and 6 of these patients met the criteria for supersensitivity psychosis [19]. the 11 of patients with baseline TD relapsed, the that TD to supersensitivity psychosis and have been to be efficacious in of patients with supersensitivity psychosis We also recommend the use of in supersensitivity and anxiety disorder induced by the discontinuation of the An can be used in with an antipsychotic or an in to more decrease or withdraw these and find the minimal therapeutic dose for patients who still need long-term treatment. a minimal therapeutic dose with an has an additional for a drug olanzapine, as the dose will significant side In in the of Mental Health psychiatric 35% of patients with a of schizophrenia and For severe cases of schizophrenia, the use of or is in to drug to antipsychotic While is less than or it is superior to for anxiety and the of optimal minimal maintenance drug treatment. proposed the beneficial results of treatment in schizophrenia is their effect We have also related their beneficial effects to an of a We recommend treatment as a first for from treatment, can also be prescribed as with as it has a In a and that and had than other in addition, emerging that may improve DIMD has also been to be effective as an to antipsychotic monotherapy in patients with schizophrenia who treatment We that of cases of schizophrenia can be related to supersensitivity psychosis. In patients for maintenance treatment is a minimal therapeutic dose can be with the use of an that will patients from antipsychotic or conclusion, DIMD-induced psychiatric symptoms and supersensitivity syndromes will to to results such as found in the CATIE study which show that olanzapine is the only atypical antipsychotic more efficacious than a classical The proposed for psychiatric and psychiatric-like symptoms associated with DIMD may to the of all classical antipsychotics and the use of higher doses and longer than of atypical antipsychotics. research is in to develop to distinguish between true and iatrogenic discontinuation syndromes and to to more withdraw antipsychotics and antidepressants by and supersensitivity syndromes, for the antipsychotics and quetiapine and for the may to further of DIMD, TD and supersensitivity psychosis as we to more differences in the of As most of antipsychotics and second-generation antidepressants are not routinely or for more differences in drug will also to prescribe minimal therapeutic doses of antipsychotics and antidepressants for greater efficacy and better in the maintenance has and the last 3 years from and

Psychotherapy and Psychosomatics · editorial or comment · 168 citationsread the source →

PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Major depressive disorder (MDD) is a common and costly disorder which is usually associated with severe and persistent symptoms leading to important social role impairment and increased mortality 1,2. It is one of the most important causes of disability worldwide 3. The high rate of inadequate treatment of the disorder remains a serious concern 1. This review is aimed at summarizing the solid evidence on the etiology and pathophysiology of MDD that is likely relevant for clinical psychiatry. Neurobiological findings are regarded as solid when they are consistent and convergent, i.e., they have been confirmed by several studies using the same method and fit into results from studies using different methodological approaches. Family, twin, and adoption studies provide very solid and consistent evidence that MDD is a familial disorder and that this familiality is mostly or entirely due to genetic factors 4. This important finding suggests that parental social behavior and other familial environmental risk factors are not as important in the pathogenesis of MDD as previously assumed and should not be the major focus of the treatment of the disorder. The above-mentioned studies consistently show that the influence of genetic factors is around 30–40% 4. Non-genetic factors, explaining the remaining 60–70% of the variance in susceptibility to MDD, are individual-specific environmental effects (including measurement error effects and gene-environment interactions). These effects are mostly adverse events in childhood and ongoing or recent stress due to interpersonal adversities, including childhood sexual abuse, other lifetime trauma, low social support, marital problems, and divorce 5,6. These results suggest that there is a huge potential in the prevention of MDD by means of psychosocial interventions (e.g., in schools, at workplace). In addition, these results mirror the clinical practice of empirically validated psychotherapies to treat depression 7,8,9, including interpersonal, psychodynamic and cognitive behavioral psychotherapies and cognitive behavioural analysis system of psychotherapy, which all focus directly or indirectly on interpersonal difficulties and skills. This does not exclude the fact that unidentified non-genetic, non-psychosocial risk factors may also play important roles in some patients (e.g., climatic change, medical conditions). Stress sensitivity in depression is partly gender-specific. While men and women are, in general, equally sensitive to the depressogenic effects of stressful life events, their responses vary depending upon the type of stressor. Specifically, men are more likely to have depressive episodes following divorce, separation, and work difficulties, whereas women are more sensitive to events in their proximal social network, such as difficulty getting along with an individual, serious illness, or death 10. These findings point to the importance of gender-sensitive psychosocial approaches in the prevention and treatment of MDD. In contrast to the very solid evidence from epidemiological studies on broad risk factor domains, there is no solid evidence for specific genes and specific gene-by-environment interactions in the pathogenesis of MDD. Genome-wide association studies have indicated that many genes with small effects are involved in complex diseases, increasing the difficulty in identifying such genes 11. While there has been progress in the search for risk genes for several complex diseases despite this methodological problem 12, psychiatric conditions have turned out to be very resistant to robust gene identification. For example, based on a community-based prospective study, it has been proposed that a specific genetic variation in the promoter region of the serotonin transporter (a target of antidepressant drugs) interacts with stressful life events in the pathogenesis of depression 13. Although there is high clinical and neurobiological plausibility of this interaction, a recent meta-analysis yielded no evidence that the serotonin transporter gene alone or in interaction with psychological stress was associated with the risk of depression 14. The limited success of genetic studies of depression has been related to use of current classification schemas including ICD-10 and DSM-IV. These diagnostic manuals are based on clusters of symptoms and characteristics of clinical course that do not necessarily describe homogenous disorders but instead reflect common final pathways of different pathophysiolgical processes 15,16. The clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of MDD. Corticotropin-releasing hormone (CRH) is released from the hypothalamus in response to the perception of psychological stress by cortical brain regions. This hormone induces the secretion of pituitary corticotropin, which stimulates the adrenal gland to release cortisol into the plasma. The physiologic response to stress is partly gender-specific: women show generally greater stress responsiveness than men, which is consistent with the greater incidence of major depression in women 17. Moreover, men show greater cortisol responses to achievement challenges, whereas women show greater cortisol responses to social rejection challenges 18. Although MDD is considered as a stress disorder, most subjects treated for MDD have no evidence of dysfunctions of the hypothalamic-pituitary-adrenal axis (HPA) 19. However, some subjects with MDD do show abnormalities of that axis and of the extrahypothalamic CRH system 20. Altered stress hormone secretion appeared to be most prominent in depressed subjects with a history of childhood trauma 21. Elevated cortisol may act as a mediator between major depression and its physical long-term consequences such as coronary heart disease, type II diabetes, and osteoporosis 22. The importance of HPA axis dysfunction for the efficacy of antidepressants is a matter of debate 23. This axis is regulated through a dual system of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Decreased limbic GR receptor function 24,25 and increased functional activity of the MR system 26 suggest an imbalance in the MR/GR ratio in stress-related conditions such as MDD. Epigenetic regulation of the glucocorticoid receptors has been associated with childhood abuse 27. Such environmental programming of gene expression may represent one possible mechanism that links early life stress to abnormal HPA axis function and increased risk of MDD in adults. While the CRH stimulation test (dex/CRH test) 28 is a sensitive measure of the HPA axis dysfunction in depression, the specificity of this test for MDD is low. However, non-suppression in the dex/CRH test has consistently predicted increased risk for depressive relapse during clinical remission 23. Additionally, the measurement of waking salivary cortisol concentration has been shown to be a simple and sensitive test for HPA axis hyperactivity in depression 29. Hypercortisolemia is almost exclusively found in subjects with severe and psychotic depression, in whom glucocorticoid antagonists may have some therapeutic effect 30. There is convergent evidence for CRH to play a major role in the pathogenesis of certain types of depression. Levels of CRH in the cerebrospinal fluid are elevated in some depressed subjects 31. Post-mortem studies reported an increased number of CRH secreting neurons in limbic brain regions in depression 32, likely reflecting a compensatory response to increased CRH concentrations 33. In addition, CRH produces a number of physiological and behavioral alterations that resemble the symptoms of major depression, including decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations 34. There is also preliminary evidence that CRH1 receptor antagonists reduce symptoms of depression and anxiety 35. “Sickness behavior” as a result of an activation of the inflammatory response system shares many symptoms with depression, including fatigue, anhedonia, psychomotor retardation, and cognitive impairment. Sickness is mediated by pro-inflammatory cytokines such as interleukin-1α, tumor necrosis factor-α, and interleukin-6, which activate the HPA axis and impair the central serotonin system 36. The prevalence of depression as an unwanted effect of recombinant interferons is around 30% 37. In animals, blocking pro-inflammatory cytokine-mediated signaling produces antidepressant-like effects 38. Clinical data suggest that cytokines may play a role in the pathophysiology of a subgroup of depressed subjects, particularly those with comorbid physical conditions 36. The antidepressant enhancing effect of acetylsalicylic acid 39 points to the possible clinical relevance of psychoneuroimmunology in clinical depression research. Taken together, the laboratory tests with the highest potential to be clinically useful in the care of depressed individuals are based on abnormalities of the neuroendocrine and neuroimmune systems. Despite the large amount of basic science data suggesting that the HPA axis is importantly involved in the pathophysiology of depression, the effect of pharmacological modulation of this neuroendocrine system as antidepressant therapy has been disappointing. The link between childhood trauma and a permanently altered physiologic stress system points to the use of specific psychotherapies in the treatment of depressed patients with a history of early life trauma 40. Most of the serotonergic, noradrenergic and dopaminergic neurons are located in midbrain and brainstem nuclei and project to large areas of the entire brain. This anatomy suggests that monoaminergic systems are involved in the regulation of a broad range of brain functions, including mood, attention, reward processing, sleep, appetite, and cognition. Almost every compound that inhibits monoamine reuptake, leading to an increased concentration of monoamines in the synaptic cleft, has been proven to be a clinically effective antidepressant 19. Inhibiting the enzyme monoamine oxidase, which induces an increased availability of monoamines in presynaptic neurons, also has antidepressant effects. These observations led to the pharmacologically most relevant theory of depression, referred to as the monoamine-deficiency hypothesis. The monoamine-deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of the neurotransmitters serotonin, norepinephrine or dopamine in the central nervous system. Serotonin is the most extensively studied neurotransmitter in depression. The most direct evidence for an abnormally reduced function of central serotonergic system comes from studies using tryptophan depletion, which reduces central serotonin synthesis. Such a reduction leads to the development of depressive symptoms in subjects at increased risk of depression (subjects with MDD in full remission, healthy subjects with a family history of depression) 41,42, possibly mediated by increased brain metabolism in the ventromedial prefrontal cortex and subcortical brain regions 42. Experimentally reduced central serotonin has been associated with mood congruent memory bias, altered reward-related behaviors, and disruption of inhibitory affective processing 16, all of which add to the clinical plausibility of the serotonin deficiency hypothesis. There is also evidence for abnormalities of serotonin receptors in depression, with the most solid evidence pointing to the serotonin-1A receptor, which regulates serotonin function. Decreased availability of this receptor has been found in multiple brain areas of patients with MDD 43, although this abnormality is not highly specific for MDD and has been found in patients with panic disorder 44 and temporal lobe epilepsy 45, possibly contributing to the considerable comorbidity among these conditions. However, there is no explanation for the mechanism of serotonin loss in depressed patients, and studies of serotonin metabolites in plasma, urine and cerebrospinal fluid, as well as post-mortem research on the serotonergic system in depression, have yielded inconsistent results. There is preliminary evidence that an increased availability of the brain monoamine oxidase, which metabolizes serotonin, may cause serotonin deficiency 46. In addition, loss-of-function mutations in the gene coding for the brain-specific enzyme tryptophan hydroxylase-2 may explain the loss of serotonin production as a rare risk factor for depression 47. Dysfunction of the central noradrenergic system has been hypothesized to play a role in the pathophysiology of MDD, based upon evidence of decreased norepinephrine metabolism, increased activity of tyrosine hydroxylase, and decreased density of norepinephrine transporter in the locus coeruleus in depressed patients 48. In addition, decreased neuronal counts in the locus coeruleus, increased alpha-2 adrenergic receptor density, and decreased alpha-1 adrenergic receptor density have been found in the brains of depressed suicide victims post-mortem 49. Since there is no method to selectively deplete central norepinephrine and no imaging tool to study the central norepinephrine system, solid evidence for abnormalities of this system in depression is lacking. While the classical theories of the neurobiology of depression mainly focused on serotonin and norepinephrine, there is increasing interest in the role of dopamine 50. Dopamine reuptake inhibitors (e.g., nomifensine) and dopamine receptor agonists (e.g., pramipexole) had antidepressant effects in placebo-controlled studies of MDD 51. In the cerebrospinal fluid and jugular vein plasma, levels of dopamine metabolites were consistently reduced in depression, suggesting decreased dopamine turnover 52. Striatal dopamine transporter binding and dopamine uptake were reduced in MDD, consistent with a reduction in dopamine neurotransmission 53. Degeneration of dopamine projections to the striatum in Parkinson's disease was associated with a major depressive syndrome in about one half of cases, which usually preceded the appearance of motor signs 54. Experimentally reduced dopaminergic transmission into the accumbens has been associated with anhedonic symptoms and performance deficits on a reward processing task in subjects at increased risk of depression 55,56. These findings are consistent with the clinical observation that depressed patients have a blunted reaction to positive reinforcers and an abnormal response to negative feedback 57. Almost all established antidepressants target the monoamine systems 58. However, full and partial resistance to these drugs and their delayed onset of action suggest that dysfunctions of monoaminergic neurotransmitter systems found in MDD represent the downstream effects of other, more primary abnormalities. Despite this limitation, the monoamine-deficiency hypothesis has proved to be the most clinically relevant neurobiological theory of depression. New findings on the role of dopamine in depression emphasize the scientific potential of this theory, and promising reports of antidepressant effects of drugs that modulate the dopaminergic system (e.g., pramipexole, modafinil) in difficult-to-treat depression underline its clinical relevance 51,59. Although many historical attempts to localize mental functions have failed, they have considerably contributed to a modern neuroscientific understanding of mental disorders 60. The development of neuroimaging techniques has opened up the potential to investigate structural and functional abnormalities in living depressed patients. Unfortunately, the diversity of imaging techniques used, the relatively small and heterogeneous study samples studied, and the limited overlap of results across imaging paradigms 61 make it difficult to reliably identify neuronal regions or networks with consistently abnormal structure or function in MDD. Functional imaging studies have provided the most limited overlap of findings. This may be due to methodological limitations and/or the complexity of neurocircuitry involved in MDD. A recent meta-analytic study found the best evidence for abnormal brain activity in MDD in lateral frontal and temporal cortices, insula, and cerebellum. In these brain regions activity was decreased at rest, they showed a relative lack of activation during induction of negative emotions, and an increase in activity following treatment with serotonin reuptake inhibitors. Opposite changes may exist in ventromedial frontal areas, striatum and possibly other subcortical brain regions 61. More solid evidence has been provided by structural imaging and post-mortem studies. A recent meta-analytic study on brain volume abnormalities in MDD revealed relatively large volume reductions in the ventromedial prefrontal cortex, particularly in the left anterior cingulate and in the orbitofrontal cortex. Moderate volume reductions were found in the lateral prefrontal cortex, hippocampus and striatum 62. Post-mortem studies consistently identified a reduction in glia cell density in dorsal, orbital and subgenual prefrontal cortices, as well as in the amygdala 63,64. Overall, functional, structural and post-mortem studies suggest that structural and functional abnormalities in the left subgenual cingulate cortex are the most solid neuroanatomical finding in MDD. Volume reduction in this region was found early in illness and in young adults at high familial risk for MDD 65, suggesting a primary neurobiological abnormality associated with the etiology of the illness. Humans with lesions that include the subgenual prefrontal cortex showed abnormal autonomic responses to social stimuli 66, and rats with left-sided lesions in this region had increased sympathetic arousal and corticosterone responses to restraint stress 67. Most importantly, chronic deep brain stimulation to reduce the potentially elevated activity in the subgenual cingulated cortex produced clinical benefits in patients with treatment-resistant depression 68. In summary, despite the considerable heterogeneity of findings from neuroimaging studies, there is convergent evidence for the presence of abnormalities in the subgenual prefrontal cortex in some patients with MDD. Neuroanatomical research in depression is of great clinical interest, since novel antidepressant treatments such as deep brain stimulation can target specific brain regions. In addition, there are promising leads for neuroimaging findings to predict the likelihood of responses to specific treatments 69. Risk factors for depressive episodes change during the course of the illness. The first depressive episode is usually “reactive”, i.e., triggered by important psychosocial stressors, while subsequent episodes become increasingly “endogenous”, i.e., triggered by minor stressors or occurring spontaneously 70. There is consistent evidence that the volume loss of the hippocampus and other brain regions is related to the duration of depression 71, suggesting that untreated depression leads to hippocampal volume loss, possibly resulting in increased stress sensitivity 72 and increased risk of recurrence 73. Glucocorticoid neurotoxicity, glutamatergic toxicity, decreased neurotrophic factors, and decreased neurogenesis have been proposed as possible mechanisms explaining brain volume loss in depression. There is no solid evidence on of these since there are no imaging to directly and neurotrophic processes in neurotrophic factor has considerable Specifically, studies have shown between and in hippocampal as well as expression of following antidepressant treatment The clinician should be aware of the potentially effect of depression and treat depressed patients as early and as A of studies consistently showed reductions in acid concentrations in the prefrontal and cortex in depression This may reflect stress since psychological stress to presynaptic of prefrontal neurotransmission low concentration may reflect reduction in the density and of In addition, chronic stress may reduce receptor possibly through changes in evidence of the hypothesis of depression the lack of effects of drugs on depressive symptoms and prefrontal concentration in subjects with MDD of evidence suggest a dysfunction of the neurotransmitter system in a of the receptor produced and large antidepressant effects in patients with treatment-resistant MDD inhibitors of release (e.g., antidepressant abnormal levels were found in depressed subjects as by and there is evidence for abnormal signaling in post-mortem Since is the major neurotransmitter involved in almost every brain the of the specific role of in depression (e.g., there are promising leads that the receptor is involved in MDD and are diagnostic for MDD, suggesting regulation in depressed patients. In addition, some depressive symptoms may show psychomotor of of positive and negative and a subgroup of patients with MDD may have a disorder In healthy young subjects, changes in the of the had specific effects on subsequent mood In depressed patients, of can have antidepressant on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of The and of the neurobiological of depression are in 1. The many theories of depression and the relatively low response rate of all antidepressant treatments a hypothesis of and suggest that depression is a clinically and heterogeneous disorder. This research on of the response to therapeutic interventions using such as neuroimaging and neuroendocrine tests in with for with to stress sensitivity and antidepressant The of of therapeutic will for the development of that has the potential to interventions and to up pathways in the of novel therapeutic approaches.

World Psychiatry · editorial or comment · 607 citationsread the source →

Exceptional longevity in men: modifiable factors associated with survival and function to age 90 years.

Background: Prospective data on nongenetic determinants of exceptional longevity are limited, and information on long-lived men and their functional status is particularly sparse. We examined modifiable factors associated with a life span of 90 or more years and late-life function in men. Methods: In this prospective cohort study of 2357 healthy men (mean age, 72 years) within the Physicians' Health Study (1981-2006), biological and lifestyle factors and comorbid conditions were assessed by self-report with baseline and annual questionnaires. Mortality and incidence of major diseases were confirmed by medical record review. Late-life function was assessed 16 years after baseline by the Medical Outcomes Study 36-Item Short-Form Health Survey. Results: A total of 970 men (41%) survived to at least age 90 years. Smoking was associated with increased risk of mortality before age 90 years (hazard ratio [HR]; 2.10; 95% confidence interval [CI], 1.75-2.51), and similar associations were observed with diabetes (HR, 1.86; 95% CI, 1.52-2.26), obesity (HR, 1.44; 95% CI, 1.10-1.90), and hypertension (HR, 1.28; 95% CI, 1.15-1.43). Regular exercise was associated with a nearly 30% lower mortality risk (HR, 0.72; 95% CI, 0.62-0.83). The probability of a 90-year life span at age 70 years was 54% in the absence of smoking, diabetes, obesity, hypertension, or sedentary lifestyle. It ranged from 36% to 22% with 2 adverse factors and was negligible (4%) with 5. Compared with nonsurvivors, men with exceptional longevity had a healthier lifestyle (67% vs 53% had <or=1 adverse factor), had a lower incidence of chronic diseases, and were 3 to 5 years older at disease onset. They had better late-life physical function (mean +/- SD score [maximum 100], 73 +/- 23 vs 62 +/- 30; P < .001) and mental well-being (mean score, 84 +/- 14 vs 81 +/- 17; P = .03). More than 68% (vs 45%) rated their late-life health as excellent or very good, and less than 8% (vs 22%) reported fair or poor health (P < .001 for trend). Regular exercise was associated with significantly better-and smoking and overweight with significantly worse-late-life physical function. Smoking also was associated with a significant decrement in mental function. Conclusion: Modifiable healthy behaviors during early elderly years, including smoking abstinence, weight management, blood pressure control, and regular exercise, are associated not only with enhanced life span in men but also with good health and function during older age.

Archives of internal medicine · editorial or comment · 143 citationsread the source →

Is failure to meet spiritual needs associated with cancer patients' perceptions of quality of care and their satisfaction with care?

Purpose: Few studies regarding patients' views about spirituality and health care have included patients with cancer who reside in the urban, northeastern United States. Even fewer have investigated the relationship between patients' spiritual needs and perceptions of quality and satisfaction with care. Patients and methods: Outpatients (N = 369) completed a questionnaire at the Saint Vincent's Comprehensive Cancer Center in New York, NY. The instrument included the Quality of End-of-Life Care and Satisfaction with Treatment quality-of-care scale and questions about spiritual and religious beliefs and needs. Results: The participants' mean age was 58 years; 65% were female; 67% were white; 65% were college educated; and 32% had breast cancer. Forty-seven percent were Catholic; 19% were Jewish; 16% were Protestant; and 6% were atheist or agnostic. Sixty-six percent reported that they were spiritual but not religious. Only 29% attended religious services at least once per week. Seventy-three percent reported at least one spiritual need; 58% thought it appropriate for physicians to inquire about their spiritual needs. Eighteen percent reported that their spiritual needs were not being met. Only 6% reported that any staff members had inquired about their spiritual needs (0.9% of inquiries by physicians). Patients who reported that their spiritual needs were not being met gave lower ratings of the quality of care (P = .009) and reported lower satisfaction with care (P = .006). Conclusion: Most patients had spiritual needs. A slight majority thought it appropriate to be asked about these needs, although fewer thought this compared with reports in other settings. Few had their spiritual needs addressed by the staff. Patients whose spiritual needs were not met reported lower ratings of quality and satisfaction with care.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 194 citationsread the source →

The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study.

NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH's Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48% rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5%) and only 16 completed it (50%), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80% completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73-1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54-0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial.

Journal of neuro-oncology · 47 citationsread the source →

The adult galactosemic phenotype.

Background: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. Methods: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. Results: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. Conclusions: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Journal of inherited metabolic disease · 134 citationsread the source →

An outbreak of measles in an undervaccinated community.

Measles is readily spread to susceptible individuals, but is no longer endemic in the United States. In March 2011, measles was confirmed in a Minnesota child without travel abroad. This was the first identified case-patient of an outbreak. An investigation was initiated to determine the source, prevent transmission, and examine measles-mumps-rubella (MMR) vaccine coverage in the affected community. Investigation and response included case-patient follow-up, post-exposure prophylaxis, voluntary isolation and quarantine, and early MMR vaccine for non-immune shelter residents >6 months and <12 months of age. Vaccine coverage was assessed by using immunization information system records. Outreach to the affected community included education and support from public health, health care, and community and spiritual leaders. Twenty-one measles cases were identified. The median age was 12 months (range, 4 months to 51 years) and 14 (67%) were hospitalized (range of stay, 2-7 days). The source was a 30-month-old US-born child of Somali descent infected while visiting Kenya. Measles spread in several settings, and over 3000 individuals were exposed. Sixteen case-patients were unvaccinated; 9 of the 16 were age-eligible: 7 of the 9 had safety concerns and 6 were of Somali descent. MMR vaccine coverage among Somali children declined significantly from 2004 through 2010 starting at 91.1% in 2004 and reaching 54.0% in 2010 (χ(2) for linear trend 553.79; P < .001). This was the largest measles outbreak in Minnesota in 20 years, and aggressive response likely prevented additional transmission. Measles outbreaks can occur if undervaccinated subpopulations exist. Misunderstandings about vaccine safety must be effectively addressed.

Pediatrics · 70 citationsread the source →

Spirituality, religiosity, and spiritual pain among caregivers of patients with advanced cancer.

Background: Caregivers of patients with advanced cancer often face physical, social, and emotional distress as well as spiritual pain. Limited research has focused on the spiritual aspects of caregivers' suffering in the palliative care setting. Methods: We interviewed 43 caregivers of patients with advanced cancer in our palliative care outpatient clinic. We determined demographic characteristics, religious affiliation, and relationship to the patient. Levels of spirituality, religiosity, and spiritual pain were self-reported using numeric rating scales (0 = lowest; 10 = highest). The participants completed various validated questionnaires to assess sleep disturbances, psychosocial distress, coping skills, and quality of life (QOL). Results: The median age was 52 years (range, 21-83); 29 (67%) were women, 34 (78%) were white, 7 (17%) were African American, and 2 (5%) were Hispanic; 39 (91%) were Christian, 1 (2%) was Jewish, and 1 (2%) was agnostic; 37 (86%) were married; 18 (42%) were working full time; and 25 (58%) were spouses. All considered themselves spiritual, and 98% considered themselves religious, with median scores of 8 (interquartile range, 6-10) and 8 (interquartile range, 4-9), respectively. All the caregivers reported that spirituality and religiosity helped them cope with their loved one's illness, and many reported that spirituality and religiosity had a positive impact on their loved one's physical (58%) and emotional (76%) symptoms. Spiritual pain was reported by 23 (58%), with a median score of 5 (interquartile range, 2-8). Caregivers with spiritual pain had higher levels of anxiety (median 10 vs 4; P = .002), depression (6 vs 2; P = .006), and denial (3 vs 2; P = .01); more behavioral disengagement (3 vs 2; P = 0.011) more dysfunctional coping strategies (19 vs 16; P < .001) and worse QOL (70 vs 51; P < .001) than those who did not have spiritual pain. Conclusions: The majority of caregivers of patients with advanced cancer considered themselves spiritual and religious. Despite this, there is high prevalence of spiritual pain in this population. Caregivers with spiritual pain experienced worse psychological distress and worse QOL. These findings support the importance of spiritual assessment of and spiritual support for caregivers in this setting.

The American journal of hospice & palliative care · 65 citationsread the source →

Frequency and relevance of psychoeducation in psychiatric diagnoses: results of two surveys five years apart in German-speaking European countries.

Background: Psychoeducation has been shown to reduce relapse rates in several psychiatric disorders. Studies investigating for which psychiatric diagnoses psychoeducation is offered and assessing its perceived relevance compared to other interventions are lacking. Methods: A two-part questionnaire addressing these questions was sent to the heads of all psychiatric hospitals in Germany, Austria and Switzerland. Results were compared with those from a similar survey 5 years earlier. Results: 289 of 500 (58%) institutions responded. Significantly (p = 0,02) more institutions (93%) offer any type of psychoeducation as compared to 5 years before (86%). Psychoeducation is mainly offered for schizophrenia (86%) and depression (67%) and less frequently for anxiety disorders (18%) and substance abuse (17%). For the following specific diagnoses it is offered by less than 10% of the institutions: Personality disorder, bipolar disorder, posttraumatic stress disorder, dementia, obsessive compulsive disorder, sleeping disorders, eating disorders, schizophrenia plus substance abuse, pain, attention deficit hyperactivity disorder and early psychosis. 25% offer diagnosis-unspecific psychoeducation. 'Pharmacotherapy' (99%), 'basic occupational therapy' (95%) and 'psychoeducation for patients' (93%) were the therapies being most often, 'light therapy' (24%) and 'sleep deprivation' (16%) the therapies being least often perceived as relevant by the respondents when asked about the value of different interventions offered in their hospitals. Art therapy (61%) and psychoanalytically oriented psychotherapy (59%), two therapies with a smaller evidence base than light therapy or sleep deprivation, were perceived as relevant by more than the half of the respondents. Conclusion: Psychoeducation for patients is considered relevant and offered frequently in German-speaking countries, however, mostly only for schizophrenia and depression. The ranking of the perceived relevance of different treatment options suggests that the evidence base is not considered crucial for determining their relevance.

BMC psychiatry · 13 citationsread the source →

STAR*D: revising conventional wisdom.

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study used a series of sequenced, randomized treatment trials following a first and, if needed, subsequent treatment steps to define the tolerability and effectiveness of various options in both acute and longer term treatment. Adult outpatients (n=4041) with nonpsychotic major depressive disorder, substantial chronic and recurrent depression, and co-morbid psychiatric and general medical conditions were enrolled in 41 representative primary and specialty care settings. About one-third of participants remitted in first step treatment with citalopram, 50% of these within 6 weeks. Poorer outcomes were associated with minority status, socioeconomic disadvantage, more axis I and III co-morbid disorders, lower function and quality of life, and anxious and melancholic features. In step 2 medication switch, there were no significant differences in remission among within-class, out-of-class or dual-action agents: sertraline (27%), bupropion-sustained release (26%) and venlafaxine-extended release (25%). In step 2 medication augmentation of citalopram, there was no significant difference in remission between bupropion-sustained release (39%) and buspirone (33%), although participants using bupropion-sustained release had greater symptom reduction and better tolerability. There were no significant differences in remission in step 2 between cognitive therapy and medication treatment in either the switch (31% vs 27%) or augmentation (31% vs 33%) strategies, although participants in cognitive therapy augmentation had a longer time to remission than those in medication augmentation (55 vs 40 days). In step 3, there were no differences in remission between a switch to mirtazapine (8%) or nortriptyline (12%), or between augmentation with lithium (13%) or T(3) (triiodothyronine, liothyronine) [25%], although more participants discontinued lithium due to adverse effects than discontinued T(3). In the fourth step, there was no difference in remission between tranylcypromine (14%) or venlafaxine-extended release plus mirtazapine (16%), although the combination treatment had fewer adverse effects and had the advantages of not requiring a washout period or diet restrictions. Participants requiring more than two well delivered treatments may be characterized as treatment resistant given the substantially lower remission rates after that point. Treatment resistance was associated with more concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity and melancholic or anxious features. However, if participants remained in treatment for up to four steps, about 67% reached remission. Times to remission were not substantially longer for later treatment steps. The importance of reaching remission is highlighted by the lower relapse rates in naturalistic follow-up for participants entering in remission compared with those entering with response but not remission (step 1: 34% vs 59%; step 2: 47% vs 68%; step 3: 42% vs 76%; step 4: 50% vs 83%). Clinical decision making based on the itemized measurement of symptoms and adverse effects at each treatment visit was feasible in STAR*D's real world settings and resulted in adequate dosages and durations of treatment that generally exceeded those typically found in practice settings. Although switch and augmentation strategies could not be directly compared due to the equipoise stratified randomized design, the higher remission rates at step 2 with medication augmentation are intriguing and merit further study.

CNS drugs · 236 citationsread the source →

2014 Alzheimer's disease facts and figures.

This report discusses the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, costs of care, and overall effect on caregivers and society. It also examines the impact of AD on women compared with men. An estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million are age 65 years or older. By mid-century, fueled in large part by the baby boom generation, the number of people living with AD in the United States is projected to grow by about 9 million. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million. In 2010, official death certificates recorded 83,494 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans aged 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting from AD increased 68%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2014, an estimated 700,000 older Americans will die with AD, and many of them will die from complications caused by AD. In 2013, more than 15 million family members and other unpaid caregivers provided an estimated 17.7 billion hours of care to people with AD and other dementias, a contribution valued at more than $220 billion. Average per-person Medicare payments for services to beneficiaries aged 65 years and older with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2014 for health care, long-term care, and hospice services for people aged 65 years and older with dementia are expected to be $214 billion. AD takes a stronger toll on women than men. More women than men develop the disease, and women are more likely than men to be informal caregivers for someone with AD or another dementia. As caregiving responsibilities become more time consuming and burdensome or extend for prolonged durations, women assume an even greater share of the caregiving burden. For every man who spends 21 to more than 60 hours per week as a caregiver, there are 2.1 women. For every man who lives with the care recipient and provides around-the-clock care, there are 2.5 women. In addition, for every man who has provided caregiving assistance for more than 5 years, there are 2.3 women.

Alzheimer's & dementia : the journal of the Alzheimer's Association · 685 citationsread the source →

Microsurgical denervation of the spermatic cord for chronic orchialgia: long-term results from a single center.

Purpose: We assessed the long-term efficacy, complications and patient perceptions of microsurgical denervation of the spermatic cord in the treatment of chronic orchialgia. Materials and methods: Microsurgical denervation of the spermatic cord was performed on 95 testicular units in 79 men (mean age 40.3 years, mean duration of pain 62 months, 16 bilateral) for chronic orchialgia. Conservative management failed in all, and patients were evaluated with an extensive medical history and physical examination. To be a candidate for microsurgical denervation of the spermatic cord each man would have responded either completely or partially to spermatic cord block (greater than 50% decrease in pain) and had no identifiable reversible etiology. Postoperative pain rating scales (0 to 10) were used to determine efficacy. Results: Mean followup was 20.3 months (range 1 to 102 months) and complete, durable relief was noted in 67 (71%) testicular units, partial relief in 17 (17%), and unchanged in 11 (12%). No patients reported worse pain. Complications included testicular atrophy without hypogonadism in 2 patients, superficial wound infection in 2, hydrocele in 2 and an incisional hematoma in 1. Conclusions: Microsurgical denervation of the spermatic cord is a minimally invasive, effective and durable management option for treatment of chronic orchialgia refractory to medical management, preserving the physiological function and psychological role of the testes.

The Journal of urology · 78 citationsread the source →