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Efficacy and cost-effectiveness of therapist-guided internet cognitive behavioural therapy for paediatric anxiety disorders: a single-centre, single-blind, randomised controlled trial.

Background: Paediatric anxiety disorders are associated with substantial disability and long-term adverse consequences, but only a small proportion of affected children have access to evidence-based treatment. Internet-delivered cognitive behavioural therapy (ICBT) could help increase accessibility but needs further rigorous assessment. We aimed to assess the efficacy and cost-effectiveness of ICBT in the treatment of paediatric anxiety disorders. Methods: We did a single-blind randomised controlled trial in a clinical research unit within the Child and Adolescent Mental Health Services in Stockholm (Sweden). Eligible participants were children aged 8-12 years with a diagnosis of a principal anxiety disorder (seperation anxiety disorder, generalised anxiety disorder, specific phobia, social anxiety disorder, or panic disorder) of at least moderate severity. We randomly allocated participants (1:1) to ICBT or internet-delivered child-directed play, an active comparator aimed to improve parent-child relationships and increase a child's self-esteem without directly targeting anxiety. Block sizes for the randomisation varied between four and six and were generated using a computer random-number generator, and the allocation was concealed from the researchers by opaque sealed envelopes. Both treatment programmes comprised 12 modules presented over 12 weeks with weekly asynchronous online therapist support, and consisted of texts, films, illustrations, and exercises. The primary outcome was severity rating of the principal anxiety disorder 12-weeks post-treatment, via the Anxiety Disorder Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders-IV (a rating of at least 4 corresponds to meeting the criteria for the principal diagnosis), assessed by clinicians masked to treatment allocation. All participants were included in the primary analysis (intention-to-treat). This trial is registered at ClinicalTrials.gov, number NCT02350257. Findings: Between March 11, 2015, and Oct 21, 2016, 131 participants were recruited and allocated to either ICBT (n=66) or internet-delivered child-directed play (n=65). The clinician-assessed severity rating of the principal anxiety disorder improved significantly after the 12-weeks treatment period for participants in both ICBT (within-group effect size 1·22, 95% CI 0·78-1·65) and the active control (0·72, 0·44-1·00) groups. However, greater improvement was seen with ICBT than with the active control (estimated mean difference 0·79, 95% CI 0·42-1·16, p=0·002; between-group effect size 0·77, 95% CI 0·40-1·15). 29 (48%) participants in the ICBT group no longer had their principal diagnosis, compared to nine (15%) in the active control group (odds ratio 5·41, 95% CI 2·26 to 12·90, p<0·0001); the number needed to treat for ICBT to gain one additional participant in remission was three (95% CI 2·85 to 3·15). ICBT resulted in an average societal-cost saving of €493·05 (95% CI 477·17 to 508·92) per participant. No severe adverse events were reported. Interpretation: ICBT is an efficacious and cost-effective treatment for paediatric anxiety disorders that should be considered for implementation in routine clinical care. Funding: The Swedish Research Council for Health, Working Life and Welfare, and Stockholm County Council.

The Lancet. Child & adolescent health · randomised controlled trial · 51 citationsread the source →

Interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures.

Background: Achieving informed consent is a core clinical procedure and is required before any surgical or invasive procedure is undertaken.  However, it is a complex process which requires patients be provided with information which they can understand and retain, opportunity to consider their options, and to be able to express their opinions and ask questions.  There is evidence that at present some patients undergo procedures without informed consent being achieved. Objectives: To assess the effects on patients, clinicians and the healthcare system of interventions to promote informed consent for patients undergoing surgical and other invasive healthcare treatments and procedures. Search methods: We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2012), MEDLINE (OvidSP) (1950 to July 2011), EMBASE (OvidSP) (1980 to July 2011) and PsycINFO (OvidSP) (1806 to July 2011). We applied no language or date restrictions within the search. We also searched reference lists of included studies. Selection criteria: Randomised controlled trials and cluster randomised trials of interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures. We considered an intervention to be intended to promote informed consent when information delivery about the procedure was enhanced (either by providing more information or through, for example, using new written materials), or if more opportunity to consider or deliberate on the information was provided. Data collection and analysis: Two authors assessed the search output independently to identify potentially-relevant studies, selected studies for inclusion, and extracted data. We conducted a narrative synthesis of the included trials, and meta-analyses of outcomes where there were sufficient data. Main results: We included 65 randomised controlled trials from 12 countries involving patients undergoing a variety of procedures in hospitals. Nine thousand and twenty one patients were randomised and entered into these studies. Interventions used various designs and formats but the main data for results were from studies using written materials, audio-visual materials and decision aids. Some interventions were delivered before admission to hospital for the procedure while others were delivered on admission. Only one study attempted to measure the primary outcome, which was informed consent as a unified concept, but this study was at high risk of bias.  More commonly, studies measured secondary outcomes which were individual components of informed consent such as knowledge, anxiety, and satisfaction with the consent process.  Important but less commonly-measured outcomes were deliberation, decisional conflict, uptake of procedures and length of consultation. Meta-analyses showed statistically-significant improvements in knowledge when measured immediately after interventions (SMD 0.53 (95% CI 0.37 to 0.69) I(2) 73%), shortly afterwards (between 24 hours and 14 days) (SMD 0.68 (95% CI 0.42 to 0.93) I(2) 85%) and at a later date (15 days or more) (SMD 0.78 (95% CI 0.50 to 1.06) I(2) 82%). Satisfaction with decision making was also increased (SMD 2.25 (95% CI 1.36 to 3.15) I(2) 99%) and decisional conflict was reduced (SMD -1.80 (95% CI -3.46 to -0.14) I(2) 99%). No statistically-significant differences were found for generalised anxiety (SMD -0.11 (95% CI -0.35 to 0.13) I(2) 82%), anxiety with the consent process (SMD 0.01 (95% CI -0.21 to 0.23) I(2) 70%) and satisfaction with the consent process (SMD 0.12 (95% CI -0.09 to 0.32) I(2) 76%). Consultation length was increased in those studies with continuous data (mean increase 1.66 minutes (95% CI 0.82 to 2.50) I(2) 0%) and in the one study with non-parametric data (control 8.0 minutes versus intervention 11.9 minutes, interquartile range (IQR) of 4 to 11.9 and 7.2 to 15.0 respectively). There were limited data for other outcomes. In general, sensitivity analyses removing studies at high risk of bias made little difference to the overall results. Authors' conclusions: Informed consent is an important ethical and practical part of patient care.  We have identified efforts by researchers to investigate interventions which seek to improve information delivery and consideration of information to enhance informed consent.  The interventions used consistently improve patient knowledge, an important prerequisite for informed consent.  This is encouraging and these measures could be widely employed although we are not able to say with confidence which types of interventions are preferable. Our results should be interpreted with caution due to the high levels of heterogeneity associated with many of the main analyses although we believe there is broad evidence of beneficial outcomes for patients with the pragmatic application of interventions. Only one study attempted to measure informed consent as a unified concept.

The Cochrane database of systematic reviews · meta-analysis · 104 citationsread the source →

A randomized controlled trial of cognitive-behavioral treatment for posttraumatic stress disorder in severe mental illness.

A cognitive-behavioral therapy (CBT) program for posttraumatic stress disorder (PTSD) was developed to address its high prevalence in persons with severe mental illness receiving treatment at community mental health centers. CBT was compared with treatment as usual (TAU) in a randomized controlled trial with 108 clients with PTSD and either major mood disorder (85%) or schizophrenia or schizoaffective disorder (15%), of whom 25% also had borderline personality disorder. Eighty-one percent of clients assigned to CBT participated in the program. Intent-to-treat analyses showed that CBT clients improved significantly more than did clients in TAU at blinded posttreatment and 3- and 6-month follow-up assessments in PTSD symptoms, other symptoms, perceived health, negative trauma-related beliefs, knowledge about PTSD, and case manager working alliance. The effects of CBT on PTSD were strongest in clients with severe PTSD. Homework completion in CBT predicted greater reductions in symptoms. Changes in trauma-related beliefs in CBT mediated improvements in PTSD. The findings suggest that clients with severe mental illness and PTSD can benefit from CBT, despite severe symptoms, suicidal thinking, psychosis, and vulnerability to hospitalizations.

Journal of consulting and clinical psychology · randomised controlled trial · 195 citationsread the source →

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

Background: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. Findings: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). Interpretation: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. Funding: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

The Lancet. Oncology · randomised controlled trial · 1212 citationsread the source →

Long-term follow-up of internet-delivered exposure and mindfulness based treatment for irritable bowel syndrome.

We conducted a follow-up of a previously reported study of internet-delivered cognitive behavior therapy (CBT) for IBS, based on exposure and mindfulness exercises (Ljótsson et al. (2010). Internet-delivered exposure and mindfulness based therapy for irritable bowel syndrome - a randomized controlled trial. Behaviour Research and Therapy, 48, 531-539). Seventy-five participants from the original sample of 85 (88%) reported follow-up data at 15-18 months (mean 16.4 months) after completing treatment. The follow-up sample included participants from both the original study's treatment group and waiting list after it had been crossed over to treatment. Intention-to-treat analysis showed that treatment gains were maintained on all outcome measures, including IBS symptoms, quality of life, and anxiety related to gastrointestinal symptoms, with mainly large effect sizes (within-group Cohen's d=0.78-1.11). A total of fifty participants (59% of the total original sample; 52% of the original treatment group participants and 65% of the original waiting list participants) reported adequate relief of symptoms. Improvements at follow-up were more pronounced for the participants that had completed the full treatment and maintenance of improvement did not seem to be dependent on further treatment seeking. This study suggests that internet-delivered CBT based on exposure and mindfulness has long-term beneficial effects for IBS-patients.

Behaviour research and therapy · randomised controlled trial · 74 citationsread the source →

Placebo Effects on the Neurologic Pain Signature: A Meta-analysis of Individual Participant Functional Magnetic Resonance Imaging Data.

Importance: Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation. Objective: We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain. Data sources: Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations. Study selection: Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data. Data extraction and synthesis: Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. Main outcomes and measures: The main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. Results: We obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = -0.66 [95% CI, -0.80 to -0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = -0.08 [95% CI, -0.15 to -0.01]). Similarly, analyses restricted to studies with low risk of bias (g = -0.07 [95% CI, -0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = -0.22 [95% CI, -0.34 to -0.11]) indicated small effects, as well. Conclusions and relevance: Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.

JAMA neurology · meta-analysis · 131 citationsread the source →

Psychosocial interventions following self-harm in adults: a systematic review and meta-analysis.

Background: Self-harm (intentional acts of non-fatal self-poisoning or self-injury) is common, particularly in young adults aged 15-35 years, often repeated, and strongly associated with suicide. Effective aftercare of individuals who self-harm is therefore important. We have undertaken a Cochrane systematic review and meta-analysis of the effectiveness of psychosocial interventions for self-harm in adults. Methods: We searched five electronic databases (CCDANCTR-Studies and References, CENTRAL, MEDLINE, Embase, and PsycINFO) between Jan 1, 1998, and April 29, 2015, for randomised controlled trials of psychosocial interventions for adults after a recent (within 6 months) episode of self-harm. Most interventions were assessed in single trials. We report results for interventions for which at least three randomised controlled trials comparing interventions with treatment as usual have been published and hence might contribute to clinical guidance. The primary outcome was repetition of self-harm at the conclusion of treatment and at 6, 12, and 24 months' follow-up analysed, when available, with the intention-to-treat method; if this was not possible, we analysed with all available case data. Findings: We identified 29 non-overlapping randomised controlled trials with three independent trials of the same intervention. Cognitive-behavioural-based psychotherapy (CBT; comprising cognitive-behavioural and problem-solving therapy) was associated with fewer participants repeating self-harm at 6 months' (odds ratio 0·54, 95% CI 0·34-0·85; 12 trials; n=1317) and at 12 months' follow-up (0·80, 0·65-0·98; ten trials; n=2232). There were also significant improvements in the secondary outcomes of depression, hopelessness, suicidal ideation, and problem solving. Patients receiving dialectical behaviour therapy (in three trials) were not less likely to repeat self-harm compared with those provided with treatment as usual at 6 months (odds ratio [OR] 0·59, 95% CI 0·16-2·15; n=267, three trials) or at 12 months (0·36, 0·05-2·47; n=172, two trials). However, the secondary endpoint of frequency of self-harm was associated with a significant reduction with use of dialectical behaviour therapy (mean difference -18·82, 95% CI -36·68 to -0·95). Four trials each of case management (OR 0·78, 95% CI 0·47-1·30; n=1608) and sending regular postcards (OR 0·87, 95% CI 0·62-1·23; n=3277) did not reduce repetition of self-harm. Interpretation: CBT seems to be effective in patients after self-harm. Dialectical behaviour therapy did not reduce the proportion of patients repeating self-harm but did reduce the frequency of self-harm. However, aside from CBT, there were few trials of other promising interventions, precluding firm conclusions as to their effectiveness. Funding: National Institute for Health Research.

The lancet. Psychiatry · meta-analysis · 141 citationsread the source →

An Ecological Momentary Intervention for Smoking Cessation: Evaluation of Feasibility and Effectiveness.

Background: Despite substantial public health progress in reducing the prevalence of smoking in the United States overall, smoking among socioeconomically disadvantaged adults remains high. Objective: To determine the feasibility and preliminary effectiveness of a novel smartphone-based smoking cessation app designed for socioeconomically disadvantaged smokers. Methods: Participants were recruited from a safety-net hospital smoking cessation clinic in Dallas, Texas, and were followed for 13 weeks. All participants received standard smoking cessation clinic care (ie, group counseling and cessation pharmacotherapy) and a smartphone with a novel smoking cessation app (ie, Smart-T). The Smart-T app prompted 5 daily ecological momentary assessments (EMAs) for 3 weeks (ie, 1 week before cessation and 2 weeks after cessation). During the precessation period, EMAs were followed by messages that focused on planning and preparing for the quit attempt. During the postcessation period, participant responses to EMAs drove an algorithm that tailored messages to the current level of smoking lapse risk and currently present lapse triggers (eg, urge to smoke, stress). Smart-T offered additional intervention features on demand (eg, one-click access to the tobacco cessation quitline; "Quit Tips" on coping with urges to smoke, mood, and stress). Results: Participants (N=59) were 52.0 (SD 7.0) years old, 54% (32/59) female, and 53% (31/59) African American, and 70% (40/57) had annual household income less than US $16,000. Participants smoked 20.3 (SD 11.6) cigarettes per day and had been smoking for 31.6 (SD 10.9) years. Twelve weeks after the scheduled quit date, 20% (12/59) of all participants were biochemically confirmed abstinent. Participants responded to 87% of all prompted EMAs and received approximately 102 treatment messages over the 3-week EMA period. Most participants (83%, 49/59) used the on-demand app features. Individuals with greater nicotine dependence and minority race used the Quit Tips feature more than their counterparts. Greater use of the Quit Tips feature was linked to nonabstinence at the 2 (P=.02), 4 (P<.01), and 12 (P=.03) week follow-up visits. Most participants reported that they actually used or implemented the tailored app-generated messages and suggestions (83%, 49/59); the app-generated messages were helpful (97%, 57/59); they would like to use the app in the future if they were to lapse (97%, 57/59); and they would like to refer friends who smoke to use the Smart-T app (85%, 50/59). A minority of participants (15%, 9/59) reported that the number of daily assessments (ie, 5) was "too high." Conclusions: This novel just-in-time adaptive intervention delivered an intensive intervention (ie, 102 messages over a 3-week period), was well-liked, and was perceived as helpful and useful by socioeconomically disadvantaged adults who were seeking smoking cessation treatment. Smartphone apps may be used to increase treatment exposure and may ultimately reduce tobacco-related health disparities among socioeconomically disadvantaged adults.

Journal of medical Internet research · 104 citationsread the source →

Multifactorial and multiple component interventions for preventing falls in older people living in the community.

Background: Falls and fall-related injuries are common, particularly in those aged over 65, with around one-third of older people living in the community falling at least once a year. Falls prevention interventions may comprise single component interventions (e.g. exercise), or involve combinations of two or more different types of intervention (e.g. exercise and medication review). Their delivery can broadly be divided into two main groups: 1) multifactorial interventions where component interventions differ based on individual assessment of risk; or 2) multiple component interventions where the same component interventions are provided to all people. Objectives: To assess the effects (benefits and harms) of multifactorial interventions and multiple component interventions for preventing falls in older people living in the community. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, trial registers and reference lists. Date of search: 12 June 2017. Selection criteria: Randomised controlled trials, individual or cluster, that evaluated the effects of multifactorial and multiple component interventions on falls in older people living in the community, compared with control (i.e. usual care (no change in usual activities) or attention control (social visits)) or exercise as a single intervention. Data collection and analysis: Two review authors independently selected studies, assessed risks of bias and extracted data. We calculated the rate ratio (RaR) with 95% confidence intervals (CIs) for rate of falls. For dichotomous outcomes we used risk ratios (RRs) and 95% CIs. For continuous outcomes, we used the standardised mean difference (SMD) with 95% CIs. We pooled data using the random-effects model. We used the GRADE approach to assess the quality of the evidence. Main results: We included 62 trials involving 19,935 older people living in the community. The median trial size was 248 participants. Most trials included more women than men. The mean ages in trials ranged from 62 to 85 years (median 77 years). Most trials (43 trials) reported follow-up of 12 months or over. We assessed most trials at unclear or high risk of bias in one or more domains. Forty-four trials assessed multifactorial interventions and 18 assessed multiple component interventions. (I2 not reported if = 0%).Multifactorial interventions versus usual care or attention controlThis comparison was made in 43 trials. Commonly-applied or recommended interventions after assessment of each participant's risk profile were exercise, environment or assistive technologies, medication review and psychological interventions. Multifactorial interventions may reduce the rate of falls compared with control: rate ratio (RaR) 0.77, 95% CI 0.67 to 0.87; 19 trials; 5853 participants; I2 = 88%; low-quality evidence. Thus if 1000 people were followed over one year, the number of falls may be 1784 (95% CI 1553 to 2016) after multifactorial intervention versus 2317 after usual care or attention control. There was low-quality evidence of little or no difference in the risks of: falling (i.e. people sustaining one or more fall) (RR 0.96, 95% CI 0.90 to 1.03; 29 trials; 9637 participants; I2 = 60%); recurrent falls (RR 0.87, 95% CI 0.74 to 1.03; 12 trials; 3368 participants; I2 = 53%); fall-related hospital admission (RR 1.00, 95% CI 0.92 to 1.07; 15 trials; 5227 participants); requiring medical attention (RR 0.91, 95% CI 0.75 to 1.10; 8 trials; 3078 participants). There is low-quality evidence that multifactorial interventions may reduce the risk of fall-related fractures (RR 0.73, 95% CI 0.53 to 1.01; 9 trials; 2850 participants) and may slightly improve health-related quality of life but not noticeably (SMD 0.19, 95% CI 0.03 to 0.35; 9 trials; 2373 participants; I2 = 70%). Of three trials reporting on adverse events, one found none, and two reported 12 participants with self-limiting musculoskeletal symptoms in total. Multifactorial interventions versus exerciseVery low-quality evidence from one small trial of 51 recently-discharged orthopaedic patients means that we are uncertain of the effects on rate of falls or risk of falling of multifactorial interventions versus exercise alone. Other fall-related outcomes were not assessed. Multiple component interventions versus usual care or attention controlThe 17 trials that make this comparison usually included exercise and another component, commonly education or home-hazard assessment. There is moderate-quality evidence that multiple interventions probably reduce the rate of falls (RaR 0.74, 95% CI 0.60 to 0.91; 6 trials; 1085 participants; I2 = 45%) and risk of falls (RR 0.82, 95% CI 0.74 to 0.90; 11 trials; 1980 participants). There is low-quality evidence that multiple interventions may reduce the risk of recurrent falls, although a small increase cannot be ruled out (RR 0.81, 95% CI 0.63 to 1.05; 4 trials; 662 participants). Very low-quality evidence means that we are uncertain of the effects of multiple component interventions on the risk of fall-related fractures (2 trials) or fall-related hospital admission (1 trial). There is low-quality evidence that multiple interventions may have little or no effect on the risk of requiring medical attention (RR 0.95, 95% CI 0.67 to 1.35; 1 trial; 291 participants); conversely they may slightly improve health-related quality of life (SMD 0.77, 95% CI 0.16 to 1.39; 4 trials; 391 participants; I2 = 88%). Of seven trials reporting on adverse events, five found none, and six minor adverse events were reported in two. Multiple component interventions versus exerciseThis comparison was tested in five trials. There is low-quality evidence of little or no difference between the two interventions in rate of falls (1 trial) and risk of falling (RR 0.93, 95% CI 0.78 to 1.10; 3 trials; 863 participants) and very low-quality evidence, meaning we are uncertain of the effects on hospital admission (1 trial). One trial reported two cases of minor joint pain. Other falls outcomes were not reported. Authors' conclusions: Multifactorial interventions may reduce the rate of falls compared with usual care or attention control. However, there may be little or no effect on other fall-related outcomes. Multiple component interventions, usually including exercise, may reduce the rate of falls and risk of falling compared with usual care or attention control.

The Cochrane database of systematic reviews · systematic review · 293 citationsread the source →

Exercise-based cardiac rehabilitation for coronary heart disease.

Background: Coronary heart disease (CHD) is the most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people living with CHD may need support to manage their symptoms and prognosis. Exercise-based cardiac rehabilitation (CR) aims to improve the health and outcomes of people with CHD. This is an update of a Cochrane Review previously published in 2016. Objectives: To assess the clinical effectiveness and cost-effectiveness of exercise-based CR (exercise training alone or in combination with psychosocial or educational interventions) compared with 'no exercise' control, on mortality, morbidity and health-related quality of life (HRQoL) in people with CHD. Search methods: We updated searches from the previous Cochrane Review, by searching CENTRAL, MEDLINE, Embase, and two other databases in September 2020. We also searched two clinical trials registers in June 2021. Selection criteria: We included randomised controlled trials (RCTs) of exercise-based interventions with at least six months' follow-up, compared with 'no exercise' control. The study population comprised adult men and women who have had a myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), or have angina pectoris, or coronary artery disease. Data collection and analysis: We screened all identified references, extracted data and assessed risk of bias according to Cochrane methods. We stratified meta-analysis by duration of follow-up: short-term (6 to 12 months); medium-term (> 12 to 36 months); and long-term ( > 3 years), and used meta-regression to explore potential treatment effect modifiers. We used GRADE for primary outcomes at 6 to 12 months (the most common follow-up time point).  MAIN RESULTS: This review included 85 trials which randomised 23,430 people with CHD. This latest update identified 22 new trials (7795 participants). The population included predominantly post-MI and post-revascularisation patients, with a mean age ranging from 47 to 77 years. In the last decade, the median percentage of women with CHD has increased from 11% to 17%, but females still account for a similarly small percentage of participants recruited overall ( < 15%). Twenty-one of the included trials were performed in low- and middle-income countries (LMICs). Overall trial reporting was poor, although there was evidence of an improvement in quality over the last decade. The median longest follow-up time was 12 months (range 6 months to 19 years). At short-term follow-up (6 to 12 months), exercise-based CR likely results in a slight reduction in all-cause mortality (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.73 to 1.04; 25 trials; moderate certainty evidence), a large reduction in MI (RR 0.72, 95% CI 0.55 to 0.93; 22 trials; number needed to treat for an additional beneficial outcome (NNTB) 75, 95% CI 47 to 298; high certainty evidence), and a large reduction in all-cause hospitalisation (RR 0.58, 95% CI 0.43 to 0.77; 14 trials;  NNTB 12, 95% CI 9 to 21; moderate certainty evidence). Exercise-based CR likely results in little to no difference in risk of cardiovascular mortality (RR 0.88, 95% CI 0.68 to 1.14; 15 trials; moderate certainty evidence), CABG (RR 0.99, 95% CI 0.78 to 1.27; 20 trials; high certainty evidence), and PCI (RR 0.86, 95% CI 0.63 to 1.19; 13 trials; moderate certainty evidence) up to 12 months' follow-up. We are uncertain about the effects of exercise-based CR on cardiovascular hospitalisation, with a wide confidence interval including considerable benefit as well as harm (RR 0.80, 95% CI 0.41 to 1.59; low certainty evidence). There was evidence of substantial heterogeneity across trials for cardiovascular hospitalisations (I2 = 53%), and of small study bias for all-cause hospitalisation, but not for all other outcomes. At medium-term follow-up, although there may be little to no difference in all-cause mortality (RR 0.90, 95% CI 0.80 to 1.02; 15 trials), MI (RR 1.07, 95% CI 0.91 to 1.27; 12 trials), PCI (RR 0.96, 95% CI 0.69 to 1.35; 6 trials), CABG (RR 0.97, 95% CI 0.77 to 1.23; 9 trials), and all-cause hospitalisation (RR 0.92, 95% CI 0.82 to 1.03; 9 trials), a large reduction in cardiovascular mortality was found (RR 0.77, 95% CI 0.63 to 0.93; 5 trials). Evidence is uncertain for difference in risk of cardiovascular hospitalisation (RR 0.92, 95% CI 0.76 to 1.12; 3 trials). At long-term follow-up, although there may be little to no difference in all-cause mortality (RR 0.91, 95% CI 0.75 to 1.10), exercise-based CR may result in a large reduction in cardiovascular mortality (RR 0.58, 95% CI 0.43 to 0.78; 8 trials) and MI (RR 0.67, 95% CI 0.50 to 0.90; 10 trials). Evidence is uncertain for CABG (RR 0.66, 95% CI 0.34 to 1.27; 4 trials), and PCI (RR 0.76, 95% CI 0.48 to 1.20; 3 trials). Meta-regression showed benefits in outcomes were independent of CHD case mix, type of CR, exercise dose, follow-up length, publication year, CR setting, study location, sample size or risk of bias. There was evidence that exercise-based CR may slightly increase HRQoL across several subscales (SF-36 mental component, physical functioning, physical performance, general health, vitality, social functioning and mental health scores) up to 12 months' follow-up; however, these may not be clinically important differences. The eight trial-based economic evaluation studies showed exercise-based CR to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years (QALYs). Authors' conclusions: This updated Cochrane Review supports the conclusions of the previous version, that exercise-based CR provides important benefits to people with CHD, including reduced risk of MI, a likely small reduction in all-cause mortality, and a large reduction in all-cause hospitalisation, along with associated healthcare costs, and improved HRQoL up to 12 months' follow-up. Over longer-term follow-up, benefits may include reductions in cardiovascular mortality and MI. In the last decade, trials were more likely to include females, and be undertaken in LMICs, increasing the generalisability of findings. Well-designed, adequately-reported RCTs of CR in people with CHD more representative of usual clinical practice are still needed. Trials should explicitly report clinical outcomes, including mortality and hospital admissions, and include validated HRQoL outcome measures, especially over longer-term follow-up, and assess costs and cost-effectiveness.

The Cochrane database of systematic reviews · systematic review · 330 citationsread the source →

Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis.

Background: Several interventions are available for management of obsessive-compulsive disorder in adults, but few studies have compared their relative efficacy in a single analysis. We aimed to simultaneously compare all available treatments using both direct and indirect data. Methods: In this systematic review and network meta-analysis, we searched the two controlled trials registers maintained by the Cochrane Collaboration Common Mental Disorders group for trials published up to Feb 16, 2016. We selected randomised controlled trials in which an active psychotherapeutic or pharmacological intervention had been used in adults with obsessive-compulsive disorder. We allowed all comorbidities except for schizophrenia or bipolar disorder. We excluded studies that focused exclusively on treatment-resistant patient populations defined within the same study. We extracted data from published reports. The primary outcome was symptom severity as measured by the Yale-Brown Obsessive Compulsive Scale. We report mean differences with 95% credible intervals compared with placebo. This study is registered with PROSPERO, number CRD42012002441. Findings: We identified 1480 articles in our search and included 53 articles (54 trials; 6652 participants) in the network meta-analysis. Behavioural therapy (mean difference -14·48 [95% credible interval -18·61 to -10·23]; 11 trials and 287 patients), cognitive therapy (-13·36 [-18·40 to -8·21]; six trials and 172 patients), behavioural therapy and clomipramine (-12·97 [-19·18 to -6·74]; one trial and 31 patients), cognitive behavioural therapy and fluvoxamine (-7·50 [-13·89 to -1·17]; one trial and six patients), cognitive behavioural therapy (-5·37 [-9·10 to -1·63]; nine trials and 231 patients), clomipramine (-4·72 [-6·85 to -2·60]; 13 trials and 831 patients), and all SSRIs (class effect -3·49 [95% credible interval -5·12 to -1·81]; 37 trials and 3158 patients) had greater effects than did drug placebo. Clomipramine was not better than were SSRIs (-1·23 [-3·41 to 0·94]). Psychotherapeutic interventions had a greater effect than did medications, but a serious limitation was that most psychotherapeutic trials included patients who were taking stable doses of antidepressants (12 [80%] of the 15 psychotherapy trials explicitly allowed antidepressants). Interpretation: A range of interventions is effective in the management of obsessive-compulsive disorder, but considerable uncertainty and limitations exist regarding their relative efficacy. Taking all the evidence into account, the combination of psychotherapeutic and psychopharmacological interventions is likely to be more effective than are psychotherapeutic interventions alone, at least in severe obsessive-compulsive disorder. Funding: National Institute for Health Research.

The lancet. Psychiatry · systematic review · 236 citationsread the source →

A randomized controlled trial evaluating an mHealth intervention for anger-related cognitions in misophonia.

Misophonia is a condition characterized by strong, aversive reactions to specific sounds produced by others, often manifesting as intense negative emotions like anger or rage in response to nearby noises. The present study aimed to evaluate the effectiveness of an mHealth app in reducing misophonia symptoms and related cognitions. In this study, 85 participants were randomly assigned to an immediate app use (iApp) or delayed app use (dApp) group and completed measures at baseline (T0), after 15 days of app use (T1 for iApp, T2 for dApp), and at 1-month follow-up (T3). Intention-to-treat analyses at T1 revealed significant interaction effects; compared with the dApp group, the iApp group exhibited lower misophonia symptoms on select measures (interaction effect sizes ranging from d = 0.06 to 0.52) as well as reductions in anger ruminations and anger-related metacognitions (interaction effect sizes of d = 0.47). Within-group analyses demonstrated substantial reductions in misophonia symptoms from baseline to follow-up (iApp: d = 0.62-1.51; dApp: d = 0.89-1.75) with similar decreases in anger-related outcomes (iApp: d = 0.89-0.92; dApp: d = 0.85-0.90). Mediation analyses, however, did not support an indirect effect of the intervention on misophonia symptoms via changes in rumination or anger-related metacognitions. mHealth applications show promise in alleviating misophonia symptoms and related cognitive processes. Further research is needed to elucidate the roles of anger rumination and metacognitions in misophonia.

Journal of affective disorders · randomised controlled trial · 3 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 →

Randomised clinical non-inferiority trial of breathing-based meditation and cognitive processing therapy for symptoms of post-traumatic stress disorder in military veterans.

Objective: Test whether Sudarshan Kriya Yoga (SKY) was non-inferior to cognitive processing therapy (CPT) for treating symptoms of post-traumatic stress disorder (PTSD) among veterans via a parallel randomised controlled non-inferiority trial. Setting: Outpatient Veterans Affairs healthcare centre. Participants: 85 veterans (75 men, 61% white, mean age 56.9) with symptoms of PTSD participated between October 2015 and March 2020: 59 participants completed the study. Interventions: SKY emphasises breathing routines and was delivered in group format in a 15-hour workshop followed by two 1-hour sessions per week for 5 weeks. CPT is an individual psychotherapy which emphasises shifting cognitive appraisals and was delivered in two 1-hour sessions per week for 6 weeks. Measures: The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). The secondary measures were the Beck Depression Inventory-II (BDI-II) and Positive and Negative Affect Scale (PANAS). Results: Mean PCL-C at baseline was 56.5 (±12.6). Intent-to-treat analyses showed that PCL-C scores were reduced at 6 weeks (end of treatment) relative to baseline (SKY, -5.6, d=0.41, n=41: CPT, -6.8, d=0.58, n=44). The between-treatment difference in change scores was within the non-inferiority margin of 10 points (-1.2, 95% CI -5.7 to 3.3), suggesting SKY was not inferior to CPT. SKY was also non-inferior at 1-month (CPT-SKY: -2.1, 95% CI -6.9 to 2.8) and 1-year (CPT-SKY: -1.8, 95% CI -6.6 to 2.9) assessments. SKY was also non-inferior to CPT on the BDI-II and PANAS at end of treatment and 1 month, but SKY was inferior to CPT on both BDI-II and PANAS at 1 year. Dropout rates were similar (SKY, 27%, CPT, 34%: OR=1.36, 95% CI 0.51 to 3.62, p=0.54). Conclusions: SKY may be non-inferior to CPT for treating symptoms of PTSD and merits further consideration as a treatment for PTSD. Trial registration number: NCT02366403.

BMJ open · randomised controlled trial · 15 citationsread the source →

Feedback-informed treatment versus usual psychological treatment for depression and anxiety: a multisite, open-label, cluster randomised controlled trial.

Background: Previous research suggests that the use of outcome feedback technology can enable psychological therapists to identify and resolve obstacles to clinical improvement. We aimed to assess the effectiveness of an outcome feedback quality assurance system applied in stepped care psychological services. Methods: This multisite, open-label, cluster randomised controlled trial was done at eight National Health Service (NHS) Trusts in England, involving therapists who were qualified to deliver evidence-based low-intensity or high-intensity psychological interventions. Adult patients (18 years or older) who accessed individual therapy with participating therapists were eligible for inclusion, except patients who accessed group therapies and those who attended less than two individual therapy sessions. Therapists were randomly assigned (1:1) to an outcome feedback intervention group or a treatment-as-usual control group by use of a computer-generated randomisation algorithm. The allocation of patients to therapists was quasi-random, whereby patients on waiting lists were allocated sequentially on the basis of therapist availability. All patients received low-intensity (less than eight sessions) or high-intensity (up to 20 sessions) psychological therapies for the duration of the 1-year study period. An automated computer algorithm alerted therapists in the outcome feedback group to patients who were not on track, and primed them to review these patients in clinical supervision. The primary outcome was symptom severity on validated depression (Patient Health Questionnaire-9 [PHQ-9]) and anxiety (Generalised Anxiety Disorder-7 [GAD-7]) measures after treatment of varying durations, which were compared between groups with multilevel modelling, controlling for cluster (therapist) effects. We used an intention-to-treat approach. This trial was prospectively registered with ISRCTN, number ISRCTN12459454. Findings: In total, 79 therapists were recruited to the study between Jan 8, 2016, and July 15, 2016, but two did not participate. Of these participants, 39 (51%) were randomly assigned to the outcome feedback group and 38 (49%) to the control group. Overall, 2233 patients were included in the trial (1176 [53%] were treated by therapists in the outcome feedback group, and 1057 [47%] by therapists in the control group). Patients classified as not on track had less severe symptoms after treatment if they were allocated to the outcome feedback group than those in the control group (PHQ-9 d=0·23, B=-1·03 [95% CI -1·84 to -0·23], p=0·012; GAD-7 d=0·19, B=-0·85 [-1·56 to -0·14], p=0·019). Interpretation: Supplementing psychological therapy with low-cost feedback technology can reduce symptom severity in patients at risk of poor response to treatment. This evidence supports the implementation of outcome feedback in stepped care psychological services. Funding: English NHS and Department of Health Sciences, University of York, York, UK.

The lancet. Psychiatry · randomised controlled trial · 86 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 →

The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.

Background: The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. Findings: Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). Interpretation: Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. Funding: National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

The lancet. Psychiatry · randomised controlled trial · 137 citationsread the source →

Yoga and compassion meditation program improve quality of life and self-compassion in family caregivers of Alzheimer's disease patients: A randomized controlled trial.

Aim: To investigate the effects of the practice of yoga in combination with compassion meditation on the quality of life, attention, vitality and self-compassion of family caregivers of patients with Alzheimer's disease. Methods: A total of 46 volunteers were randomly allocated to two groups, the yoga and compassion meditation program group (n = 25), and the control group (CG) that received no treatment (n = 21). The program lasted 8 weeks, and comprised three yoga and meditation practices per week, with each session lasting 1 h and 15 min. Quality of life, attention, vitality, and self-compassion scores were measured pre- and postintervention. Results: The yoga and compassion meditation program group showed statistically significant improvements (P < 0.05) on quality of life, attention, vitality and self-compassion scores as compared with the control group, which showed no statistical significant differences at the postintervention time-point. Conclusions: The findings of the present study suggest that an 8-week yoga and compassion meditation program can improve the quality of life, vitality, attention, and self-compassion of family caregivers of Alzheimer's disease patients. Geriatr Gerontol Int 2017; 17: 85-91.

Geriatrics & gerontology international · randomised controlled trial · 44 citationsread the source →

Smoking cessation for people with severe mental illness (SCIMITAR+): a pragmatic randomised controlled trial.

Background: People with severe mental illnesses such as schizophrenia are three times more likely to smoke than the wider population, contributing to widening health inequalities. Smoking remains the largest modifiable risk factor for this health inequality, but people with severe mental illness have not historically engaged with smoking cessation services. We aimed to test the effectiveness of a combined behavioural and pharmacological smoking cessation intervention targeted specifically at people with severe mental illness. Methods: In the smoking cessation intervention for severe mental illness (SCIMITAR+) trial, a pragmatic, randomised controlled study, we recruited heavy smokers with bipolar disorder or schizophrenia from 16 primary care and 21 community-based mental health sites in the UK. Participants were eligible if they were aged 18 years or older, and smoked at least five cigarettes per day. Exclusion criteria included substantial comorbid drug or alcohol problems and people who lacked capacity to consent at the time of recruitment. Using computer-generated random numbers, participants were randomly assigned (1:1) to a bespoke smoking cessation intervention or to usual care. Participants, mental health specialists, and primary care physicians were unmasked to assignment. The bespoke smoking cessation intervention consisted of behavioural support from a mental health smoking cessation practitioner and pharmacological aids for smoking cessation, with adaptations for people with severe mental illness-such as, extended pre-quit sessions, cut down to quit, and home visits. Access to pharmacotherapy was via primary care after discussion with the smoking cessation specialist. Under usual care participants were offered access to local smoking cessation services not specifically designed for people with severe mental illnesses. The primary endpoint was smoking cessation at 12 months ascertained via carbon monoxide measurements below 10 parts per million and self-reported cessation for the past 7 days. Secondary endpoints were biologically verified smoking cessation at 6 months; number of cigarettes smoked per day, Fagerström Test for Nicotine Dependence (FTND) and Motivation to Quit (MTQ) questionnaire; general and mental health functioning determined via the Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder-7 (GAD-7) questionnaire, and 12-Item Short Form Health Survey (SF-12); and body-mass index (BMI). This trial was registerd with the ISRCTN registry, number ISRCTN72955454, and is complete. Findings: Between Oct 7, 2015, and Dec 16, 2016, 526 eligible patients were randomly assigned to the bespoke smoking cessation intervention (n=265) or usual care (n=261). 309 (59%) participants were male, median age was 47·2 years (IQR 36·3-54·5), with high nicotine dependence (mean 24 cigarettes per day [SD 13·2]), and the most common severe mental disorders were schizophrenia or other psychotic illness (n=343 [65%]), bipolar disorder (n=115 [22%]), and schizoaffective disorder (n=66 [13%]). 234 (88%) of intervention participants engaged with the treatment programme and attended 6·4 (SD 3·5) quit smoking sessions, with an average duration of 39 min (SD 17; median 35 min, range 5-120). Verified quit data at 12 months were available for 219 (84%) of 261 usual care and 223 (84%) of 265 intervention participants. The proportion of participants who had quit at 12 months was higher in the intervention group than in the usual care group, but non-significantly (34 [15%] of 223 [13% of those assigned to group] vs 22 [10%] of 219 [8% of those assigned to group], risk difference 5·2%, 95% CI -1·0 to 11·4; odds ratio [OR] 1·6, 95% CI 0·9 to 2·9; p=0·10). The proportion of participants who quit at 6 months was significantly higher in the intervention group than in the usual care group (32 [14%] of 226 vs 14 [6%] of 217; risk difference 7·7%, 95% CI 2·1 to 13·3; OR 2·4, 95% CI 1·2 to 4·6; p=0·010). The incidence rate ratio for number of cigarettes smoked per day at 6 months was 0·90 (95% CI 0·80 to 1·01; p=0·079), and at 12 months was 1·00 (0·89 to 1·13; p=0·95). At both 6 months and 12 months, the intervention group was non-significantly favoured in the FTND (adjusted mean difference 6 months -0·18, 95% CI -0·53 to 0·17, p=0·32; and 12 months -0·01, -0·39 to 0·38, p=0·97) and MTQ questionnaire (adjusted mean difference 0·58, -0·01 to 1·17, p=0·056; and 12 months 0·64, 0·04 to 1·24, p=0·038). The PHQ-9 showed no difference between the groups (adjusted mean difference at 6 months 0·20, 95% CI -0·85 to 1·24 vs 12 months -0·12, -1·18 to 0·94). For the SF-12 survey, we saw evidence of improvement in physical health in the intervention group at 6 months (adjusted mean difference 1·75, 95% CI 0·21 to 3·28), but this difference was not evident at 12 months (0·59, -1·07 to 2·26); and we saw no difference in mental health between the groups at 6 or 12 months (adjusted mean difference at 6 months -0·73, 95% CI -2·82 to 1·36, and 12 months -0·41, -2·35 to 1·53). The GAD-7 questionnaire showed no difference between the groups (adjusted mean difference at 6 months -0·32 95% CI -1·26 to 0·62 vs 12 months -0·10, -1·05 to 0·86). No difference in BMI was seen between the groups (adjusted mean difference 6 months 0·16, 95% CI -0·54 to 0·85; 12 months 0·25, -0·62 to 1·13). Interpretation: This bespoke intervention is a candidate model of smoking cessation for clinicians and policy makers to address high prevalence of smoking. The incidence of quitting at 6 months shows that smoking cessation can be achieved, but the waning of this effect by 12 months means more effort is needed for sustained quitting. Funding: National Institute for Health Research Health Technology Assessment Programme.

The lancet. Psychiatry · randomised controlled trial · 134 citationsread the source →

Psychotherapy for depression in older veterans via telemedicine: a randomised, open-label, non-inferiority trial.

Background: Many older adults with major depression, particularly veterans, do not have access to evidence-based psychotherapy. Telemedicine could increase access to best-practice care for older adults facing barriers of mobility, stigma, and geographical isolation. We aimed to establish non-inferiority of behavioural activation therapy for major depression delivered via telemedicine to same-room care in largely male, older adult veterans. Methods: In this randomised, controlled, open-label, non-inferiority trial, we recruited veterans (aged ≥58 years) meeting DSM-IV criteria for major depressive disorder from the Ralph H Johnson Veterans Affairs Medical Center and four associated community outpatient-based clinics in the USA. We excluded actively psychotic or demented people, those with both suicidal ideation and clear intent, and those with substance dependence. The study coordinator randomly assigned participants (1:1; block size 2-6; stratified by race; computer-generated randomisation sequence by RGK) to eight sessions of behavioural activation for depression either via telemedicine or in the same room. The primary outcome was treatment response according to the Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI; defined as a 50% reduction in symptoms from baseline at 12 months), and Structured Clinical Interview for DSM-IV, clinician version (defined as no longer being diagnosed with major depressive disorder at 12 months follow-up), in the per-protocol population (those who completed at least four treatment sessions and for whom all outcome measurements were done). Those assessing outcomes were masked. The non-inferiority margin was 15%. This trial is registered with ClinicalTrials.gov, number NCT00324701. Findings: Between April 1, 2007, and July 31, 2011, we screened 780 patients, and the study coordinator randomly assigned participants to either telemedicine (120 [50%]) or same-room treatment (121 [50%]). We included 100 (83%) patients in the per-protocol analysis in the telemedicine group and 104 (86%) in the same-room group. Treatment response according to GDS did not differ significantly between the telemedicine (22 [22·45%, 90% CI 15·52-29·38] patients) and same-room (21 [20·39%, 90% CI 13·86-26·92]) groups, with an absolute difference of 2·06% (90% CI -7·46 to 11·58). Response according to BDI also did not differ significantly (telemedicine 19 [24·05%, 90% CI 16·14-31·96] patients; same room 19 [23·17%, 90% CI 15·51-30·83]), with an absolute difference of 0·88% (90% CI -10·13 to 11·89). Response on the Structured Clinical Interview for DSM-IV, clinician version, also did not differ significantly (39 [43·33%, 90% CI 34·74-51·93] patients in the telemedicine group and 46 [48·42%, 90% CI 39·99-56·85] in the same-room group), with a difference of -5·09% (-17·13 to 6·95; p=0·487). Results from the intention-to-treat population were similar. MEM analyses showed that no significant differences existed between treatment trajectories over time for BDI and GDS. The criteria for non-inferiority were met. We did not note any adverse events. Interpretation: Telemedicine-delivered psychotherapy for older adults with major depression is not inferior to same-room treatment. This finding shows that evidence-based psychotherapy can be delivered, without modification, via home-based telemedicine, and that this method can be used to overcome barriers to care associated with distance from and difficulty with attendance at in-person sessions in older adults. Funding: US Department of Veterans Affairs.

The lancet. Psychiatry · randomised controlled trial · 123 citationsread the source →

Effects of home visits by paraprofessionals and by nurses on children: follow-up of a randomized trial at ages 6 and 9 years.

Importance: The Nurse-Family Partnership delivered by nurses has been found to produce long-term effects on maternal and child health in replicated randomized trials. A persistent question is whether paraprofessional home visitors might produce comparable effects. Objective: To examine the impact of prenatal and infancy/toddler home visits by paraprofessionals and by nurses on child development at child ages 6 and 9 years. Design, setting, and participants: Randomized trial in public and private care settings in Denver, Colorado, of 735 low-income women and their first-born children (85% of the mothers were unmarried; 47% were Hispanic, 35% were non-Hispanic white, 15% were African American, and 3% were American Indian/Asian). Interventions: Home visits provided from pregnancy through child age 2 years delivered in one group by paraprofessionals and in the other by nurses. Main outcomes and measures: Reports of children's internalizing, externalizing, and total emotional/behavioral problems, and tests of children's language, intelligence, attention, attention dysfunction, visual attention/task switching, working memory, and academic achievement. We hypothesized that program effects on cognitive-related outcomes would be more pronounced among children born to mothers with low psychological resources. We report paraprofessional-control and nurse-control differences with P < .10 given similar effects in a previous trial, earlier effects in this trial, and limited statistical power. Results: There were no significant paraprofessional effects on emotional/behavioral problems, but paraprofessional-visited children born to mothers with low psychological resources compared with control group counterparts exhibited fewer errors in visual attention/task switching at age 9 years (effect size = -0.30, P = .08). There were no statistically significant paraprofessional effects on other primary outcomes. Nurse-visited children were less likely to be classified as having total emotional/behavioral problems at age 6 years (relative risk [RR] = 0.45, P = .08), internalizing problems at age 9 years (RR = 0.44, P = .08), and dysfunctional attention at age 9 years (RR = 0.34, P = .07). Nurse-visited children born to low-resource mothers compared with control-group counterparts had better receptive language averaged over ages 2, 4, and 6 years (effect size = 0.30, P = .01) and sustained attention averaged over ages 4, 6, and 9 years (effect size = 0.36, P = .006). There were no significant nurse effects on externalizing problems, intellectual functioning, and academic achievement. Conclusions and relevance: Children born to low-resource mothers visited by paraprofessionals exhibited improvement in visual attention/task switching. Nurse-visited children showed improved behavioral functioning, and those born to low-resource mothers benefited in language and attention but did not improve in intellectual functioning and academic achievement. Trial registration: clinicaltrials.gov Identifier: NCT00438282 and NCT00438594.

JAMA pediatrics · randomised controlled trial · 74 citationsread the source →

Hypnosis decreases presurgical distress in excisional breast biopsy patients.

Background: Excisional breast biopsy is associated with presurgical psychological distress. Such distress is emotionally taxing, and may have negative implications for postsurgical side effects and satisfaction with anesthesia. We investigated the ability of a brief hypnosis session to reduce presurgical psychological distress in excisional breast biopsy patients. Methods: Ninety patients presenting for excisional breast biopsy were randomly assigned to receive either a 15-minute presurgery hypnosis session (n = 49, mean age: 46.4 (95% CI: 42.3-50.4)) or a 15-minute presurgery attention control session (n = 41, mean age: 45.0 (95% CI: 40.8-49.2)). The hypnosis session involved suggestions for increased relaxation and decreased distress. The attention control session involved nondirective empathic listening. Presurgery distress was measured using visual analog scales (VAS) and the short version of the Profile of Mood States (SV-POMS). Data were analyzed using analysis of variance and chi2 procedures. Results: Groups did not differ in terms of the following: demographics (age, education, ethnicity, marital status, all P's > 0.28); medical variables (presurgery diagnosis, previous excisional biopsy, previous breast cancer, all P's > 0.11); or preintervention distress (SV-POMS P > 0.74) assessed on the day of surgery. Postintervention, and before surgery, patients in the hypnosis group had significantly lower mean values for presurgery VAS emotional upset (16.5 vs 38.2, P < 0.0001, d = .85), VAS depressed mood (6.6 vs 19.9, P < 0.02, d = .67), and SV-POMS anxiety (10.0 vs 5.0, P < 0.0001, d = 0.85); and significantly higher levels for VAS relaxation (75.7 vs 54.2, P < 0.001, d = -0.76) than attention controls. Conclusions: The study results indicate that a brief presurgery hypnosis intervention can be an effective means of controlling presurgical distress in women awaiting diagnostic breast cancer surgery.

Anesthesia and analgesia · randomised controlled trial · 52 citationsread the source →

Mothers, fathers, and toddlers: parental psychosocial functioning as a context for young children's sleep.

The aim of this study was to investigate the prospective relations between parental psychosocial functioning and toddlers' sleep consolidation. Investigators met with 85 families 3 times, when children were 15 months (Time 1 [T1]), 18 months (T2), and 2 years of age (T3). Mothers and fathers completed questionnaires pertaining to their parenting stress, marital satisfaction, and perceived social support at T1 or T2, and mothers completed child sleep diaries at T2 and T3. Results indicated that fathers' parenting stress and marital satisfaction, as well as mothers' perceived social support, were related in expected directions to children's subsequent sleep consolidation (T3), with or without controlling for prior sleep consolidation (T2). In addition, all these relations were moderated by family socioeconomic status (SES), such that links were stronger in lower SES homes.

Developmental psychology · 41 citationsread the source →

Similar Fecal Microbiota Signatures in Patients With Diarrhea-Predominant Irritable Bowel Syndrome and Patients With Depression.

Background & aims: Patients with irritable bowel syndrome (IBS) often have psychiatric comorbidities. Alterations in the intestinal microbiota have been associated with IBS and depression, but it is not clear if there is a microbial relationship between these disorders. We studied the profiles of fecal microbiota samples from patients with IBS, depression, or comorbidities of IBS and depression; we determined the relationships among these profiles and clinical and pathophysiological features of these disorders. Methods: We used 454 pyrosequencing to analyze fecal microbiota samples from 100 subjects (40 with diarrhea-predominant IBS [IBS-D], 15 with depression, 25 with comorbidities of IBS and depression, and 20 healthy individuals [controls]), recruited at Peking University. Abdominal and psychological symptoms were evaluated with validated questionnaires. Visceral sensitivity was evaluated using a barostat. Colonic mucosal inflammation was assayed by immunohistochemical analyses of sigmoid tissue biopsy specimens. Results: Fecal microbiota signatures were similar between patients with IBS-D and depression in that they were less diverse than samples from controls and had similar abundances of alterations. They were characterized by high proportions of Bacteroides (type I), Prevotella (type II), or nondominant microbiota (type III). Most patients with IBS-D or depression had type I or type II profiles (IBS-D had 85% type I and type II profiles, depression had 80% type I and type II profiles). Colon tissues from patients with type I or type II profiles had higher levels of inflammatory markers than colon tissues from patients with type III profiles. The level of colon inflammation correlated with the severity of IBS symptoms. Conclusions: Patients with IBS-D and depression have similar alterations in fecal microbiota; these might be related to the pathogenesis of these disorders. We identified 3 microbial profiles in patients that could indicate different subtypes of IBS and depression or be used as diagnostic biomarkers.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · cohort or longitudinal · 233 citationsread the source →

HIV combination prevention and declining orphanhood among adolescents, Rakai, Uganda, 2001-18: an observational community cohort study.

Background: Orphanhood increased markedly in the 1980s and 1990s in sub-Saharan Africa because of HIV-related mortality. Little is known about the contribution of HIV interventions, such as antiretroviral therapy (ART) and male medical circumcision, to more recent trends in orphanhood. In this study, we examined trends over time in maternal-only, paternal-only, and double orphanhood among adolescents before and after ART and male medical circumcision became widely available in the Rakai region of south-central Uganda. We sought to understand the association between adolescent orphanhood and HIV combination prevention (community-level ART use and prevalence of male medical circumcision). We hypothesised that increasing combination prevention, including greater use of ART and higher prevalence of male medical circumcision, would be associated with a lower probability of orphanhood. Methods: We examined the prevalence of orphanhood among adolescents aged 15-19 years, before and after roll-out of ART in mid-2004 and male medical circumcision in 2007, using data from 28 continuously followed communities within the Rakai Community Cohort Study. We used multinomial logistic regression with clustered SEs to estimate adjusted relative risk ratios (RRs) for maternal-only, paternal-only, and double orphanhood compared with non-orphanhood over 11 survey rounds between 2001 and 2018. Controlling for community HIV prevalence, household socioeconomic status, and adolescent age, we examined the association between community prevalence of ART use among people living with HIV and prevalence of male circumcision, including traditional circumcision. The primary outcome was orphanhood among adolescents aged 15-19 years. Findings: Orphanhood declined from 52% (920 of 1768 participants) in 2001-02 to 23% (592 of 2609 participants) by 2016-18 (p<0·0001), while double orphanhood declined from 20% (346 of 1768 participants) to 3% (86 of 2609 participants) (p<0·0001). Community prevalence of ART use among people living with HIV increased from 11% (105 of 945 participants) in 2005-06 to 78% (1163 of 1485 participants) in 2016-18. Male circumcision rates rose from 19% (147 of 790 participants) in 2005-06 to 65% (3535 of 5433 participants) in 2016-18. In the multinomial logistic regression model, a 10% increase in community prevalence of ART use was associated with a decrease in maternal orphanhood (adjusted relative RR 0·90, 95% CI 0·85-0·95) and double orphanhood (0·80, 0·75-0·85). In the post-ART era, a 10% increase in the community prevalence of male circumcision was associated with a decrease in paternal orphanhood (2005-18, adjusted relative RR 0·92, 0·87-0·97) and double orphanhood (0·91, 0·85-0·98). Interpretation: Widespread availability and uptake of HIV combination prevention was associated with marked reductions in orphanhood among adolescents. Reductions in orphanhood promise improved health and social outcomes for young people. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, and the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases.

The lancet. HIV · cohort or longitudinal · 5 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 →

Lifetime Risk and Risk Factors for Abdominal Aortic Aneurysm in a 24-Year Prospective Study: The ARIC Study (Atherosclerosis Risk in Communities).

Objective: Abdominal aortic aneurysm (AAA) is an important vascular disease in older adults, but data on lifetime risk of AAA are sparse. We examined lifetime risk of AAA in a community-based cohort and prospectively assessed the association between midlife cardiovascular risk factors and AAAs. Approach and results: In ARIC study (Atherosclerosis Risk in Communities), 15 792 participants were recruited at visit 1 in 1987 to 1989 and followed up through 2013. Longitudinal smoking status was defined using smoking behavior ascertained from visit 1 (1987-1989) to visit 4 (1996-1998). We followed up participants for incident, clinical AAAs using hospital discharge diagnoses, Medicare outpatient diagnoses, or death certificates through 2011 and identified 590 incident AAAs. An abdominal ultrasound was conducted in 2011 to 2013 in 5911 surviving participants, and 75 asymptomatic AAAs were identified. We estimated the lifetime risk of AAA from the index age 45 years through 85 years of age. At age 45, the lifetime risk for AAA was 5.6% (95% confidence interval, 4.8-6.1) and was higher in men (8.2%) and current smokers (10.5%). Smokers who quit smoking between visit 1 and visit 4 had a 29% lower AAA lifetime risk compared with continuous smokers but had a higher risk than pre-visit 1 quitters. The lifetime risk of rupture or medical intervention was 1.6% (95% confidence interval, 1.2-1.8). Smoking, white race, male sex, greater height, and greater low-density lipoprotein or total cholesterol were associated with an increased risk of clinical AAA and asymptomatic AAA. Conclusions: At least 1 in 9 middle-aged current smokers developed AAA in their lifetime. Smoking cessation reduced the lifetime risk of AAA.

Arteriosclerosis, thrombosis, and vascular biology · cohort or longitudinal · 115 citationsread the source →

Availability, use of, and satisfaction with green space, and children's mental wellbeing at age 4 years in a multicultural, deprived, urban area: results from the Born in Bradford cohort study.

Background: It is unknown whether the quantity or quality of green space is more important for mental wellbeing. We aimed to explore associations between availability of, satisfaction with, and use of green space and mental wellbeing among children aged 4 years in a multi-ethnic sample. Methods: We did a 4-year follow-up assessment of participants in the Born in Bradford longitudinal cohort study, which recruited children and mothers at the city's main maternity unit from 2007 to 2011. The primary outcome was parent-reported mental wellbeing for children aged 4 years, assessed with the standardised Strengths and Difficulties Questionnaire. Total, internalising, and externalising behavioural difficulties and prosocial behaviour scales were computed (with higher scores indicating greater difficulties or more prosocial behaviour). Residential green space around participants' home addresses and distance to major green spaces were computed with the normalised difference vegetation index (NDVI). A subsample of participants completed additional questionnaires on measures of satisfaction with, and use of, local green spaces. Multiple regressions examined associations between green space and children's mental wellbeing and explored moderation by ethnicity (white British vs south Asian) and socioeconomic status. Findings: Between Oct 1, 2012, and June 30, 2015, 2594 mothers attended a follow-up appointment during which they completed a detailed questionnaire assessing the health of their child. 1519 (58%) participants were of south Asian origin, 740 (29%) of white British origin, and 333 (13%) of another ethnicity. Data on ethnicity were missing for two participants. 832 (32%) of 2594 participants completed additional questionnaires. Ethnicity moderated associations between residential green space and mental wellbeing (p<0·05 for total and internalising difficulties). After adjusting for all relevant variables, more green space was associated with fewer internalising behavioural difficulties (mean NDVI 100 m: β -2·35 [95% CI -4·20 to -0·50]; 300 m: -3·15 [-5·18 to -1·13]; 500 m: -2·85 [-4·91 to -0·80]) and with fewer total behavioural difficulties (100 m: -4·27 [-7·65 to -0·90]; 300 m: -5·22 [-8·91 to -1·54]; 500 m: -4·82 [-8·57 to -1·07]) only for south Asian children across all three buffer zones. In the subsample of participants, the effect of NDVI on wellbeing was rendered non-significant after controlling for satisfaction with, and use of, green space. Among south Asian children, satisfaction with green space was significantly associated with fewer total behavioural difficulties across all three buffer zones (β -0·59 [95% CI -1·11 to -0·07]), fewer internalising behavioural difficulties within 100 m (-0·28 [95% CI -0·56 to -0·003]) and 300 m buffer zones (-0·28 [-0·56 to -0·002]), and greater prosocial behaviour across all three buffer zones (0·20 [0·02 to 0·38]); no such associations were observed among white British children. Interpretation: Positive effects of green space on wellbeing differ by ethnicity. Satisfaction with the quality of green space appears to be a more important predictor of wellbeing than does quantity of green space. Public health professionals and urban planners need to focus on both quality and quantity of urban green spaces to promote health, particularly among ethnic minority groups. Funding: European Community's Seventh Framework Programme.

The Lancet. Planetary health · 61 citationsread the source →

The role of spirituality and religious coping in the quality of life of patients with advanced cancer receiving palliative radiation therapy.

Objectives: National palliative care guidelines outline spiritual care as a domain of palliative care, yet patients' religiousness and/or spirituality (R/S) are underappreciated in the palliative oncology setting. Among patients with advanced cancer receiving palliative radiation therapy (RT), this study aims to characterize patient spirituality, religiousness, and religious coping; examine the relationships of these variables to quality of life (QOL); and assess patients' perceptions of spiritual care in the cancer care setting. Methods: This is a multisite, cross-sectional survey of 69 patients with advanced cancer (response rate = 73%) receiving palliative RT. Scripted interviews assessed patient spirituality, religiousness, religious coping, QOL (McGill QOL Questionnaire), and perceptions of the importance of attention to spiritual needs by health providers. Multivariable models assessed the relationships of patient spirituality and R/S coping to patient QOL, controlling for other significant predictors of QOL. Results: Most participants (84%) indicated reliance on R/S beliefs to cope with cancer. Patient spirituality and religious coping were associated with improved QOL in multivariable analyses (β = 10.57, P < .001 and β = 1.28, P = .01, respectively). Most patients considered attention to spiritual concerns an important part of cancer care by physicians (87%) and nurses (85%). Limitations: Limitations include a small sample size, a cross-sectional study design, and a limited proportion of nonwhite participants (15%) from one US region. Conclusion: Patients receiving palliative RT rely on R/S beliefs to cope with advanced cancer. Furthermore, spirituality and religious coping are contributors to better QOL. These findings highlight the importance of spiritual care in advanced cancer care.

The journal of supportive oncology · cohort or longitudinal · 146 citationsread the source →

The subsyndromal phenomenology of borderline personality disorder: a 10-year follow-up study.

Objective: The purpose of this study was to characterize the course of 24 symptoms of borderline personality disorder in terms of time to remission. Method: The borderline psychopathology of 362 patients with personality disorders, all recruited during inpatient stays, was assessed using two semistructured interviews of proven reliability. Of these, 290 patients met DSM-III-R criteria as well as Revised Diagnostic Interview for Borderlines criteria for borderline personality disorder, and 72 met DSM-III-R criteria for another axis II disorder. Over 85% of the patients were reinterviewed at five distinct 2-year follow-up waves by interviewers blind to all previously collected information. Results: Among borderline patients, 12 of the 24 symptoms studied showed patterns of sharp decline over time and were reported at 10-year follow-up by less than 15% of the patients who reported them at baseline. The other 12 symptoms showed patterns of substantial but less dramatic decline over the follow-up period. Symptoms reflecting core areas of impulsivity (e.g., self-mutilation and suicide efforts) and active attempts to manage interpersonal difficulties (e.g., problems with demandingness/entitlement and serious treatment regressions) seemed to resolve the most quickly. In contrast, affective symptoms reflecting areas of chronic dysphoria (e.g., anger and loneliness/emptiness) and interpersonal symptoms reflecting abandonment and dependency issues (e.g., intolerance of aloneness and counterdependency problems) seemed to be the most stable. Conclusions: The results suggest that borderline personality disorder may consist of both symptoms that are manifestations of acute illness and symptoms that represent more enduring aspects of the disorder.

The American journal of psychiatry · cohort or longitudinal · 211 citationsread the source →

Beneficial effects of breast milk in the neonatal intensive care unit on the developmental outcome of extremely low birth weight infants at 18 months of age.

Objective: Beneficial effects of breast milk on cognitive skills and behavior ratings have been demonstrated previously in term and very low birth weight infants. Extremely low birth weight infants are known to be at increased risk for developmental and behavior morbidities. The benefits of breast milk that is ingested in the NICU by extremely low birth weight infants on development and behavior have not been evaluated previously. Methods: Nutrition data including enteral and parenteral feeds were collected prospectively, and follow-up assessments of 1035 extremely low birth weight infants at 18 months' corrected age were completed at 15 sites that were participants in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial between October 14, 1999, and June 25, 2001. Total volume of breast milk feeds (mL/kg per day) during hospitalization was calculated. Neonatal characteristics and morbidities, interim history, and neurodevelopmental and growth outcomes at 18 to 22 months' corrected age were assessed. Results: There were 775 (74.9%) infants in the breast milk and 260 (25.1%) infants in the no breast milk group. Infants in the breast milk group were similar to those in the no breast milk group in every neonatal characteristic and morbidity, including number of days of hospitalization. Mean age of first day of breast milk for the breast milk infants was 9.3 +/- 9 days. Infants in the breast milk group began to ingest non-breast milk formula later (22.8 vs 7.3 days) compared with the non-breast milk group. Age at achieving full enteral feeds was similar between the breast milk and non-breast milk groups (29.0 +/- 18 vs 27.4 +/- 15). Energy intakes of 107.5 kg/day and 105.9 kg/day during the hospitalization did not differ between the breast milk and non-breast milk groups, respectively. At discharge, 30.6% of infants in the breast milk group still were receiving breast milk. Mothers in the breast milk group were significantly more likely to be white (42% vs 27%), be married (50% vs 30%), have a college degree (22% vs 6%), and have private health insurance (34% vs 18%) compared with the no breast milk group. Mothers who were black, had a low household income (< or = dollar 20000), or had higher parity were less likely to provide breast milk feeds. The analysis of outcomes between the any human milk and no human milk groups were adjusted for maternal age, maternal education, marital status, race/ethnicity, and the other standard covariates. Children in the breast milk group were more likely to have a Bayley Mental Development Index > or = 85, higher mean Bayley Psychomotor Development Index, and higher Bayley Behavior Rating Scale percentile scores for orientation/engagement, motor regulation, and total score. There were no differences in the rates of moderate to severe cerebral palsy or blindness or hearing impairment between the 2 study groups. There were no differences in the mean weight (10.4 kg vs 10.4 kg), length (80.5 cm vs 80.5 cm), or head circumference (46.8 cm vs 46.6 cm) for the breast milk and no breast milk groups, respectively, at 18 months. Multivariate analyses, adjusting for confounders, confirmed a significant independent association of breast milk on all 4 primary outcomes: the mean Bayley (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and incidence of rehospitalization). For every 10-mL/kg per day increase in breast milk ingestion, the Mental Development Index increased by 0.53 points, the Psychomotor Development Index increased by 0.63 points, the Behavior Rating Scale percentile score increased by 0.82 points, and the likelihood of rehospitalization decreased by 6%. In an effort to identify a threshold effect of breast milk on Bayley Mental Development Index and Psychomotor Development Index scores and Behavior Rating Scale percentile scores, the mean volume of breast milk per kilogram per day during the hospitalization was calculated, and infants in the breast milk group were divided into quintiles of breast milk ingestion adjusted for confounders. Overall, the differences across the feeding quintiles of Mental Development Index and Psychomotor Development Index were significant. There was a 14.0% difference in Behavior Rating Scale scores between the lowest and highest quintiles. For the outcomes (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and Rehospitalization <1 year), only the values for the >80th percentile quintile of breast milk feeding were significantly different from the no breast milk values. In our adjusted regression analyses, every 10 mL/kg per day breast milk contributed 0.53 points to the Bayley Mental Development Index; therefore, the impact of breast milk ingestion during the hospitalization for infants in the highest quintile (110 mL/kg per day) on the Bayley Mental Development Index would be 10 x 0.53, or 5.3 points. Conclusions: An increase of 5 points potentially would optimize outcomes and decrease costs by decreasing the number of very low birth weight children who require special education services. The societal implications of a 5-point potential difference (one third of an SD) in IQ are substantial. The potential long-term benefit of receiving breast milk in the NICU for extremely low birth weight infants may be to optimize cognitive potential and reduce the need for early intervention and special education services.

Pediatrics · cohort or longitudinal · 344 citationsread the source →

Diagnosis and Management of Infertility: A Review.

Importance: In the US, approximately 12.7% of reproductive age women seek treatment for infertility each year. This review summarizes current evidence regarding diagnosis and treatment of infertility. Observations: Infertility is defined as the failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse. Approximately 85% of infertile couples have an identifiable cause. The most common causes of infertility are ovulatory dysfunction, male factor infertility, and tubal disease. The remaining 15% of infertile couples have "unexplained infertility." Lifestyle and environmental factors, such as smoking and obesity, can adversely affect fertility. Ovulatory disorders account for approximately 25% of infertility diagnoses; 70% of women with anovulation have polycystic ovary syndrome. Infertility can also be a marker of an underlying chronic disease associated with infertility. Clomiphene citrate, aromatase inhibitors such as letrozole, and gonadotropins are used to induce ovulation or for ovarian stimulation during in vitro fertilization (IVF) cycles. Adverse effects of gonadotropins include multiple pregnancy (up to 36% of cycles, depending on specific therapy) and ovarian hyperstimulation syndrome (1%-5% of cycles), consisting of ascites, electrolyte imbalance, and hypercoagulability. For individuals presenting with anovulation, ovulation induction with timed intercourse is often the appropriate initial treatment choice. For couples with unexplained infertility, endometriosis, or mild male factor infertility, an initial 3 to 4 cycles of ovarian stimulation may be pursued; IVF should be considered if these approaches do not result in pregnancy. Because female fecundity declines with age, this factor should guide decision-making. Immediate IVF may be considered as a first-line treatment strategy in women older than 38 to 40 years. IVF is also indicated in cases of severe male factor infertility or untreated bilateral tubal factor. Conclusions and relevance: Approximately 1 in 8 women aged 15 to 49 years receive infertility services. Although success rates vary by age and diagnosis, accurate diagnosis and effective therapy along with shared decision-making can facilitate achievement of fertility goals in many couples treated for infertility.

JAMA · review · 849 citationsread the source →

The longitudinal integrated database for health insurance and labour market studies (LISA) and its use in medical research.

Education, income, and occupation are factors known to affect health and disease. In this review we describe the Swedish Longitudinal Integrated Database for Health Insurance and Labour Market Studies (LISA, Longitudinell Integrationsdatabas för Sjukförsäkrings- och Arbetsmarknadsstudier). LISA covers the adult Swedish population aged ≥ 16 years registered on December 31 each year since 1990 (since 2010 individuals aged ≥ 15 years). The database was launched in response to rising levels of sick leave in the country. Participation in Swedish government-administered registers such as LISA is compulsory, and hence selection bias is minimized. The LISA database allows researchers to identify individuals who do not work because of injury, disease, or rehabilitation. It contains data on sick leave and disability pension based on calendar year. LISA also includes information on unemployment benefits, disposable income, social welfare payments, civil status, and migration. During 2000-2017, an average of 97,000 individuals immigrated to Sweden each year. This corresponds to about 1% of the Swedish population (10 million people in 2017). Data on occupation have a completeness of 95%. Income data consist primarily of income from employment, capital, and allowances, including parental allowance. In Sweden, work force participation is around 80% (2017: overall: 79.1%; men 80.3% and women 77.9%). Education data are available in > 98% of all individuals aged 25-64 years, with an estimated accuracy for highest attained level of education of 85%. Some information on civil status, income, education, and employment before 1990 can be obtained through the Population and Housing Census data (FoB, Folk- och bostadsräkningen).

European journal of epidemiology · review · 942 citationsread the source →

Fostering cardiovascular health at work - case study from Senegal.

Background: Of the 15 million annual premature deaths from non-communicable diseases (NCDs), 85% occur in low- and middle-income countries (LMICs). Affecting individuals in the prime of their lives, NCDs impose severe economic damage to economies and businesses, owing to the high mortality and morbidity within the workforce. The Novartis Foundation urban health initiative, Better Hearts Better Cities, was designed to improve cardiovascular health in Dakar, Senegal through a combination of interventions including a workplace health program. In this study, we describe the labor policy environment in Senegal and the outcomes of a Novartis Foundation-supported multisector workplace health coalition bringing together volunteering private companies. Methods: A mixed method design was applied between April 2018 and February 2020 to evaluate the workplace health program as a case study. Qualitative methods included a desk review of documents relevant to the Senegalese employment context and work environment and in-depth interviews with eight key informants including human resource representatives and physicians working in the participating companies. Quantitative methods involved an analysis of workplace health program indicators, including data on diagnosis, treatment and control of hypertension in employees, provided by the coalition companies, and a cost estimate of NCD-related ill-health as compared to the investment needed for hypertension screening and awareness raising events. Results: Senegal has a legal and regulatory system that ensures employee protection, supports social security benefits, and promotes health and hygiene in companies. The Dakar Workplace Health Coalition comprised 18 companies, with a range of staff between 300 and 4'220, covering 36'268 employees in total. Interviews suggested that the main enablers for workplace program success were strong leadership support within the company and a central coordination mechanism for the program. The main barrier to monitor progress and outcomes was the reluctance of companies to share data. Four companies provided aggregated anonymized cohort data, documenting a total of 21'392 hypertension screenings and an increasing trend in blood pressure control (from 34% in Q4 2018 to 39% in Q2 2019) in employees who received antihypertensive treatment. Conclusion: Evidence on workplace health and wellness programs in Africa is scarce. This study highlights how private sector companies can play a significant role in improving cardiovascular population health in LMICs.

BMC public health · 6 citationsread the source →

Menstrual Disorders

After reading this article, readers should be able to:The onset of menstruation in young women is a milestone with personal, cultural, and medical ramifications. Menarche heralds the onset of fertility, which can be cause for both celebration and trepidation for the patient, her family, and clinicians. It behooves both general and specialist pediatricians to be comfortable discussing what is normal and what is not normal about menstruation. Young women who have special health-care needs and their families deserve particular attention. Both the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists encourage pediatricians to think of menstruation as a “vital sign” for women. (1)(2) Irregular, absent, or overly painful periods should be evaluated, closely monitored, and managed proactively. In both the evaluation and treatment of menstrual disorders, it is critical to keep in mind the patient’s perspective on her symptoms. It is extremely valuable to hear from the patient what her expectations of menses are, and where she has derived these expectations. In conditions ranging from polycystic ovary syndrome (PCOS) to endometriosis, the patient’s quality of life has been shown to be much more strongly linked to her own perception of her symptoms than to her doctors’ assessment of their severity. Periods perceived as heavy, painful, or abnormal can be a significant cause of school absence and decreased work productivity. What many patients and families desire as much as relief from menses or menstrual pain is predictability. Setting realistic expectations from the onset of medical treatment goes a long way in improving quality of life. The presence of menses can be a challenge to the families of young women who have special health-care needs, and particular sensitivity is warranted. The onset of menstruation may raise what can be uncomfortable questions about fertility and sexual activity (voluntary or otherwise) for the families of these young women. Patients and families appreciate and deserve the opportunity to talk openly about these subjects. The median age of menarche in the United States is 12.4 years, with African-American girls experiencing menarche slightly earlier on average than non-Hispanic white and Mexican-American girls, as determined in the third National Health and Nutrition Evaluation Survey. (3) The usual sequence of events leading up to menarche includes thelarche (Tanner [sexual maturation rating] stage 2 breast development) at a median age of 10.2 years and pubarche (Tanner stage 2 pubic hair) at a median age of 11.6 years, but recent studies have revealed that girls are developing breasts and pubic hair earlier than in past generations although the age of menarche has remained more constant. (4) Some girls, particularly African-American girls, may experience pubarche before thelarche. Early pubarche, especially accompanied by obesity and insulin resistance, is associated with later development of PCOS.The definition of precocious puberty remains controversial because of mixed data about how ethnicity and adiposity affect development. Generally, the presence of breast development or pubic hair before age 8 years is considered precocious, although girls whose BMI is greater than 85% or who are African-American or Mexican-American may have earlier development. In one study, 27% of African-American girls had signs of pubertal development at age 7 years, compared with 7% of white girls. (5) Menarche occurring after age 14.1 years occurs in only 5% of girls in the United States; the definition of primary amenorrhea is failure to achieve menarche by age 15 years. Failure to progress from thelarche to menarche within 3 years is also cause for concern. It was thought previously that hypothalamic axis immaturity in the first gynecologic year was common, and therefore menstrual irregularity was to be expected. More current data indicate that even in the first gynecologic year, amenorrhea for more than 3 months is uncommon in healthy girls in the United States and should be investigated if there are other issues apparent, or if the pattern persists into the second year. A normal menstrual cycle (counting from the first day of one menstrual period to the first day of menses of the next cycle) is 21 to 35 days in adults but has a slightly wider range of normal in adolescents during the first 2 years after menarche. A normal period lasts from 3 to 7 days. Bleeding lasting 8 or more days is considered prolonged. The menstrual cycle is divided commonly into three phases: follicular (proliferative), ovulation, and luteal (secretory) (Figure). The follicular phase may vary in length, but the luteal phase is 14 days during normal ovulatory cycles. Ovulation is the event that defines regular cycles and triggers the prostaglandin cascade, which is associated with primary dysmenorrhea. Gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus is pulsatile and stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH), which stimulates follicle growth in the ovary. A dominant follicle in the ovary secretes increasing amounts of estrogen, which causes the endometrial lining to proliferate. A feedback loop develops in which increasing amounts of estrogen result in decreasing LH and FSH levels; but above a certain estrogen level, the negative feedback is reversed and LH release from the pituitary is stimulated. This “LH surge” triggers ovulation. After ovulation, the remaining follicular cells in the ovary luteinize and become the corpus luteum. This corpus luteum secretes estrogen and progesterone, which has the effect of stabilizing the endometrium and causing differentiation into glandular tissue to produce the spongy lining needed for implantation of a fertilized ovum. If fertilization and implantation do not occur, human chorionic gonadotropin is not produced, and the corpus luteum involutes. The withdrawal of progesterone (and estrogen) levels derived from the corpus luteum is the trigger for the shedding of the endometrial lining, or menses. In anovulatory girls, menstrual periods occur from a proliferative endometrium because of waxing and waning of estrogen levels. Primary amenorrhea is clinically defined as the lack of menses by the age of 15 years or by more than 3 years after the onset of secondary sexual development. Lack of any secondary sexual characteristics by age 13 years also is abnormal and should be investigated. Secondary amenorrhea is defined as 3 months of amenorrhea after the achievement of menarche. Underlying conditions may overlap in primary and secondary amenorrhea (Table 1). Careful history and physical examination are crucial to diagnosis. It cannot be overstated, however, that a sensitive pregnancy test must be part of the initial evaluation of any patient with amenorrhea, regardless of the reported sexual history. Besides pregnancy, disordered eating patterns and weight changes are among the most common reasons for amenorrhea. Review of a growth chart is important in considering the possible causes. The differential diagnosis of primary amenorrhea includes genital tract abnormalities, as well as endocrine causes (which also may cause secondary amenorrhea), including hypothalamic/pituitary, ovarian, thyroid, or adrenal abnormalities. The assessment of the patient should include a detailed history and physical examination, laboratory testing, and radiologic imaging in some cases. The patient and parent should be asked about a past medical history of chronic illness, tempo of any pubertal development, weight gain or loss, exercise habits, and stressors. Family history should focus on any potential endocrine disorders in first-order relatives, including thyroid disease, diabetes, PCOS, and infertility. The parent should be asked also about any family history of constitutional delay of menses. Sexual history should be obtained confidentially, because pregnancy is a rare but possible cause of primary amenorrhea and the most common cause of secondary amenorrhea. Social stressors may contribute to primary or secondary amenorrhea, and asking about academic pressure, family conflict, mood disorders, body image, and eating behaviors is important. Clinicians should ask about history of medication use, including any antipsychotic medication, contraceptive use (adolescents often forget or deny use unless asked specifically), and illicit drug use. The review of systems should include discussion of acne or unwanted hair growth, weight changes, mood changes, disordered eating attitudes and behavior, change in bowel habits, abdominal pain, headaches, visual changes, galactorrhea, and vaginal discharge. The review of a growth chart identifies patients who are overweight or underweight for height. Girls who are overweight for height and not growing appropriately are more likely to have an endocrinopathy (hypothyroidism, Cushing syndrome), whereas patients underweight for height may have a deficit of calories (eating disorder or bowel disease such as inflammatory bowel disease or celiac disease).The patient who has exceptionally short stature (final height predicted to be less than 5 ft in the patient who has normal parental heights), with or without other features such as webbed neck, widely spaced nipples, shield chest, and high arched palate, and primary amenorrhea raises concerns about Turner syndrome (45,X) or mosaicism (46,XX/45,X). Consultation with a geneticist or endocrinologist may be warranted. Physical examination should include assessment of height, weight, and BMI in addition to routine vital signs. The clinician should examine the patient’s skin thoroughly. Peripheral visual fields should be checked by confrontation and the fundi examined. The clinician should test for, or at least ask about, the presence of smell (anosmia is associated with Kallmann syndrome). The thyroid gland should be palpated for enlargement. Tanner staging should be recorded and tracked over time, and breast examination should verify whether there is any galactorrhea. Abdominal palpation should be performed to detect constipation or the presence of any masses. An external genital evaluation should be performed to detect clitoromegaly (clitoral glans wider than 0.5 cm) and patency of the introitus. All that is necessary for an internal examination in virginal patients may be passage of a saline moistened cotton-tip swab to assess the depth of the vagina (7–8 cm is average for a postpubertal young woman). If there is any question of an anatomic abnormality, pelvic ultrasonography should be performed at a center experienced with prepubertal patients. The range of congenital abnormalities includes external anomalies such as imperforate hymen and transverse vaginal septum with normal müllerian structures, as well as müllerian anomalies such as uterine and vaginal agenesis. Appropriate and consistent visual examination of the vaginal introitus in the newborn and at health maintenance visits should prevent the late diagnosis of imperforate hymen. Early detection can help avoid the “classic” presentation of imperforate hymen in a postpubertal young woman: cyclic abdominal pain, midline abdominal mass, and purplish bulging seen at the introitus of the vagina (a hematocolpos, which may be remarkably large). Such late-found gynecologic in an or as to a the patient is as a vaginal septum but may be to because the external examination may A swab cannot be a normal in the presence of a transverse but a high septum may not be without or pelvic occurs as an and is associated with other müllerian syndrome includes vaginal uterine and as external examination, the vaginal in a Girls with puberty at the usual tempo because have normal but do not menarche. have normal can have by fertilization of the in and a women with syndrome are but their do not to in the usual have levels of with but do not have body hair and do have breast development to to are müllerian which of the and have external which most patients to have after puberty because of the of are of in which patients as with vaginal are able to a vagina with the use of with and The young must be able to whether she to if at which age she to there are such as bowel and other the are vaginal and the for and such as at may a needed of and for girls with and other rare girls with primary amenorrhea to tract the evaluation is to that for girls who experience secondary amenorrhea. pregnancy is a common cause for secondary amenorrhea, the first test to is a sensitive pregnancy The next are to levels of thyroid stimulating hormone or and laboratory to include levels of and and to for and pelvic levels should only be if the laboratory is to high quality levels of FSH indicate whereas levels indicate and the most common cause is most to Turner Turner syndrome with puberty and primary amenorrhea, but secondary amenorrhea is especially in patients with a causes of include and or as well as may be associated with other such as adrenal thyroid disease, celiac disease, and that the hypothalamus or the pituitary gland is the of the The most common cause of is hypothalamic amenorrhea, but this is a and a diagnosis of including levels of and is as well as for eating disorders and for celiac may on the it is important to ask patients about the of headaches, visual changes, and galactorrhea, and to for on The most common pituitary is a A also can with growth and amenorrhea, as can pituitary by and with and amenorrhea to hypothalamic Kallmann syndrome as amenorrhea with Kallmann syndrome is a disorder of do not to the the also do not hypothalamic amenorrhea, or secondary amenorrhea to of in which anatomic or disease is can be by weight loss, or This may result in a estrogen which young women at for failure to achieve This disorder is but not associated with underweight and with eating Secondary amenorrhea may significant weight in and weight gain the where menses is for of menses. patients who are also may experience are at for developing the of amenorrhea, and of can withdrawal but has not been shown to be at increasing in or in with of is investigated because has been to of menses. of and and estrogen have in weight gain in most has been shown to have and significant on of the for young women with hypothalamic amenorrhea who do not or not their should be for assessment to a a health and a health-care who are well in eating disorders and is the most common endocrinopathy in young some that the up to of American women of Young women with with amenorrhea or and signs of including and are but not are three of for diagnosis of the National of Health the and the The National of Health include patients with anovulatory menses and or of with or without polycystic on in other congenital adrenal and thyroid have been The and also include patients who experience normal menses but have or and also polycystic on use one of these with or for includes and levels to other disorders, as well as levels of (a normal a in most patients with and patients with a first to congenital adrenal and evaluation for a is warranted. ultrasonography may be a to laboratory testing, although the should be performed in a center with In the of of or other such as and may be and with an endocrinologist is In rare of high levels with genital studies should be considered to is associated with abnormal LH and secretion in the in from the and adrenal as well as to of the endometrial lining, the initial presentation of may be as as uterine is associated with insulin in more than one of patients and is an for later development of and the are that patients who have and an BMI should and an test to 2 of periods of estrogen and endometrial from women with also are at of endometrial This can be detection and treatment to more regular endometrial including exercise and weight can menstrual in some treatment for includes three cyclic use of to withdrawal use of or vaginal to and hormone and use of to insulin levels and hormone is important to the potential of these are the for young women who do not desire a pregnancy and with and use is particularly for with ovulation, this drug should not be the in Some young women to use both often is as an treatment to on the hair follicle in girls with use as is not because it is and causes menstrual irregularity unless in with an vaginal is reported commonly during must what is normal in to assess patients A normal period lasts 3 to 7 days. Bleeding that lasts 8 days or is considered The normal menses in adolescents may be 21 and days in young although 21 to 35 days is more a of and and patients that have however, it is important to ask whether that is in or associated with pain, because these symptoms have that both patients and their can as well as the of vaginal it is important to of regardless of the history differential diagnosis of abnormal vaginal is (Table The uterine has been by uterine uterine to and to a delay in maturation of the negative feedback loop estrogen levels FSH This delay in a proliferative endometrium with uterine is the most common cause of abnormal in but it is a diagnosis of and the differential diagnosis also should include pregnancy such as pregnancy and disorders, pelvic and such as and thyroid the patient with abnormal vaginal it is important to the of pregnancy because pregnancy with such as pregnancy, can be life All patients should be asked whether have had or but pregnancy should be obtained because patients may the of Patients who have had should be asked about contraceptive use and about history of any and should be for and by of pediatricians should have a for these for because the of is high in patient’s menstrual history can help other Patients should be asked about the of menarche and the pattern of that patients who have had from the of initial a disorder such as disease is more cycles accompanied by symptoms and ovulatory but is of a cycles anovulatory which may be to an endocrinopathy such as or a that causes hypothalamic amenorrhea. anatomic disease to must be or associated with use of review of symptoms should include questions about weight changes, exercise habits, headaches, visual changes, chronic illness, bowel habits, and symptoms patients may with vaginal Family history of during and and should be Patients should be asked (and about contraceptive use, including Clinicians also should ask about antipsychotic and that may cause and and other which may examination should include vital signs for with Young women may be remarkably of and signs other than or should examine the skin for and of as well as or to The thyroid gland should be of the should in the and progress for a uterine that and examination is for patients to for and pelvic inflammatory In virginal patients who have or in assessment can be managed by external genital examination with passage of a cotton-tip swab to assess vaginal as well as pelvic should of a pregnancy test and a including and and In both the initial evaluation and in for girls who have normal and the of in the is a sensitive of and can more about the tempo of or of laboratory may be on the and of the patients with from menarche or at any time, studies including time, and are patients with amenorrhea or for should be by and as well as levels for girls with signs of on girls with pain or a pelvic mass, abdominal ultrasonography also is of abnormal vaginal is on the of in addition to of any The treatment of vaginal in is is All treatment of vaginal in must include although this can be during the presentation and general of treatment is to the endometrium by estrogen for initial and for endometrial The most and in most is treatment by (Table withdrawal of estrogen or may trigger treatment for months is warranted. for conditions to abnormal such as PCOS, is necessary as adolescents who have to the use of estrogen, such as a history of with or chronic illness, of abnormal with cyclic often is although more may be an in some by is in some but because of the initial withdrawal often occurs at 3 before amenorrhea is this use is than use in an such as with the of and or these may be an in some adolescents with with a is is common in young women and occurs in the of or is pain that occurs in the absence of pelvic disease, whereas secondary is secondary to a is more common than secondary but should be with on history and examination that should to a diagnosis other than in the second or third gynecologic year, more may be reported in the or The pain may be associated with or The symptoms are by prostaglandin and secretion in the after an ovulatory in uterine and of pain such as and an necessary for prostaglandin are commonly to and have been shown to be in It is important to that not on this and is much less for the treatment of primary for and have not been shown to be may result in significant school absence and and treatment is warranted. If of (Table do not symptoms after to three a of may be menstrual pain by and by the endometrial not occur and the endometrial lining is the of is In cycle by 7 may be to menses. Young women with often including and and such as and should therefore ask about before a patient has primary the clinician should possible causes of secondary Patients who to experience significant pain 3 to months of use have a of of endometrial tissue the and should be to a for is the only way to endometriosis, but often it is to this in include pelvic pain or that occurs and pain associated with vaginal of which may be associated with pelvic Clinicians should have a for for and and a and examination to for pelvic inflammatory examination also may of an may menstrual pain pregnancy is because adolescents may in pregnancy for a adolescents who have from menarche that genital tract abnormalities with should be as well as causes of pelvic pain not associated with menstrual are the of this women with special health-care needs and their families may particular with to normal menstruation as well as menstrual the patient’s concerns should be and It is important that not that young women with or are not to to sexual activity should be and openly with have about their to and deserve the opportunity to these menses may cause of for girls with or menses cause and some conditions may be or by menstrual to or more should be and to the American of Obstetricians and Gynecologists on menstrual for adolescents with amenorrhea may be to and some patients and families may that it is to that is but than that is and may a in pain and as may or in or young women with the potential of with estrogen use should be although the is contraceptive may have a associated of also may be of use in these patients to the potential of with as well as weight gain that may long lasting and and can result in amenorrhea but a of as do and both may and endometrial are more likely to result in amenorrhea but be only in to for her with review of the as well as and for their this

Pediatrics in Review · review · 23 citationsread the source →

Omega‐3 fatty acids in colorectal cancer prevention

Colon cancer, which is the fourth most common cancer in the world, is one of the leading causes of cancer death in both men and women in the United States, Canada, Northern and Western Europe, Australia and New Zealand.1, 2 It is markedly less frequent in Asia, Africa and South America.1, 2 Therefore, it is a major public health problem. Migrant and temporal trend studies suggest that colon cancer is determined largely by environmental exposures, especially nutritional habits.1 Marked international differences in the incidence and mortality of colon cancer and increase of risk in populations migrating from low- to high-risk areas such as from Japan, China and the Philippines to the United States within 1 or 2 generations suggest that environmental factors, specifically dietary habits, rather than the genetic factors play an important role in the etiology of this cancer. This upward trend in incidences of colon cancer among Japanese immigrants in Hawaii and California compared to Japanese in Japan stimulated epidemiologists to investigate the reasons for this increase. Although the relationship between nutrition and cancer is complex and sometimes perplexing to nutritionists and to those who visualize carcinogenesis in terms of a specific carcinogen, it should be recognized that nutritional factors and diet may relate to cancer risk in several ways; first, food additives, contaminants, a particular dietary component, or products formed during food preparation may act as carcinogens, cocarcinogens and/or promoters; second, nutrient deficiencies and excesses may lead to biochemical/molecular alterations that may promote neoplastic processes; third, changes in the intake of selected macronutrients may induce metabolic, biochemical and molecular abnormalities that enhance cancer risk; and fourth, certain dietary constituents act as anticarcinogens or chemopreventives. During the last 3 decades, substantial progress has been made in understanding the relationship between dietary constituents and colon cancer risk. Fish oils are unique because they contain high levels of polyunsaturated omega-3 fatty acids (n-3 PUFAs) that are not present in vegetable oils or in saturated fats. Omega-3 fatty acids that are present in fish oil include docosahexaenoic acid (DHA; C22:6), eicosapentaenoic acid (EPA; C20:5) and docosapentaenoic acid (DPA; C22:5). Vegetable oils including corn oil and safflower oil contain high levels of linoleic acid (LA; C18:2). LA has the terminal double-bond 6 carbon atoms from the terminal (omega) methyl group of fatty acid, whereas DHA has the terminal double-bond 3 carbon atoms from the terminal (omega) methyl group of fatty acid (Fig. 1). Chemical structures of omega-3 and omega-6 fatty acids. Nutritional epidemiologic studies have provided evidence that dietary factors are important determinants of colorectal cancer in different populations worldwide. Cancer statistics in Japan for 2001 published by the Foundation for Promotion of Cancer Research indicate that there is an upward trend in age-adjusted mortality rates for colon cancer from 1955 to 1999.3 According to this report, the death rates due to colon cancer in Japanese men and women in 1955 were 2.9 and 3.0, respectively, whereas they increased to 14.7 and 9.8 in 1999. This upward trend in death rates due to colon cancer is mainly attributable to Westernization of Japanese food habits.3, 4 In addition, the report by the Foundation for Promotion of Cancer Research provided the data on the time trends in food consumption, which show increased dietary intakes of animal fat and meat and decreased consumption of whole grains from 1960 to 1999. For example, animal fat consumption in 1960 was about 25 g/day (per capita), whereas in 1999 it increased to about 58 g/day. Meat intake was increased from 19 to 78 g/day (per capita), whereas grain consumption decreased from 453 to 245 g/day during these years.3 The importance of types of dietary fat differing in fatty acid composition rather than total fat cannot be discounted because several preclinical studies using well-established colon cancer models strongly supported the notion that the colon tumor-promoting effect of dietary fat or lack of such effect depends on its fatty acid composition.5 A recent report by an expert panel assembled by the American Institute for Cancer Research/World Cancer Research Fund came to the scientific consensus that evidence for an association between the intake of saturated fat and/or animal fat and colon cancer risk is very strong.6 Continuing population studies revealed that diets particularly high in total fat, especially animal fat, are generally associated with increased risk of developing colon cancer, whereas high dietary fish oil or fish reduces this risk.7, 8 A recent ecologic study suggests that mortality data for colorectal cancer in 22 European countries, the United States and Canada correlate with the consumption of animal fat.7 That eating a diet rich in n-3 PUFAs may decrease the risk of colorectal cancer has been hypothesized in relation to fish and fish oil.7 Caygill and Hill et al.8 reported an inverse correlation between fish and fish oil consumption and colorectal cancer when expressed as a proportion of total or animal fat. This inverse relationship was significant for both male and female colorectal cancer, whether the intakes were in the current period or 10 years or 23 years before cancer mortality, It is noteworthy that these effects were only observed in countries with a high (> 85 g/caput/day) animal fat intake.8 Also, Mediterranean diet rich in olive oil and fish is associated with a low risk of colorectal cancer.9 On the basis of epidemiologic evidence, it is reasonable to suggest that diets high in saturated fats increase the risk of colorectal cancer, whereas diets high in fish and fish oil rich in n-3 PUFAs reduce the risk. Animal models have contributed significantly to understanding of the carcinogenesis process and to study the multiple environmental factors against the pathogenesis of colon cancer.10 Several studies have utilized these relevant animal models to investigate the modulation of colon carcinogenesis by nutritional and chemopreventive agents. These animal models include induction of colon tumors in rats by administration of aromatic amines such as 3,2′-dimethyl-4-aminobi-phenyl (DMBA); derivatives and analogs of cycacin, such as methylazoxymethanol (MAM), 1,2-dimethyl-hydrazine (DMH) and azoxymethane (AOM) in rats and mice of selected strains; direct-acting carcinogens of the type of alkylureas, such as methylnitrosourea (MNU) or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG); and heterocyclic amines such as 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The spectrum of epithelial lesions induced in the colon by these agents is similar to various types of neoplastic lesions observed in the colorectum of humans. Azoxymethane (AOM), which is a potent inducer of carcinomas of the large intestine in various strains of male and female rats, has been used extensively by many investigators to induce colon tumors and to study the effects of nutritional factors and chemopreventive agents in colon carcinogenesis.10, 11, 12, 13, 14, 15, 16, 17 Colons of Fischer (F344) rats treated with AOM seem to have light and electron microscopic morphology as well as histochemical properties that are quite similar to that of humans and the biologic behavior of AOM-induced rat colon carcinomas is similar to that of human colon carcinomas.10, 18 Other characteristics of the human disease process reflected in the AOM rat model are the occurrence of both adenomas and adenocarcinomas.18 Also, aberrant crypt foci (ACF), which are recognized as early appearing preneoplastic lesions, develop in experimentally induced colon carcinogenesis in laboratory rodents as well as in the colonic mucosa of patients with colon cancer.19, 20 Recently, β-catenin-accumulated crypts were identified in the colonic mucosa at the early stages of AOM-induced colon carcinogenesis and are considered as early-appearing preneoplastic lesions.21 Therefore, ACF are now regarded as putative preneoplastic lesions for colon cancers and are used as biomarkers to evaluate potential chemopreventive agents against colon carcinogenesis.22 AOM treatment also induces oncogene mutations at codon 12 of K- and H-ras and increases in the expression of the ras family of protooncogenes have been causally associated with colon tumor development.23, 24 Enhanced ras oncogene expression has been observed in a variety of human colon tumors.25 AOM-induced colon tumors also demonstrate enhanced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression similar to human colon tumors.13, 26 Mutations in the tumor suppressor gene, APC, are known to be early events in the colon cancer process in humans and have been identified in patients with familial adenomatous polyposis, who have germline mutation in one of the APC alleles, and in sporadic colorectal cancer.27, 28 Evidence in humans thus implicates the APC suppressor gene as causal in large bowel carcinogenesis. Recent studies indicating the presence of APC mutation in AOM-induced colon tumors in rats strengthens the concept that these models are appropriate for human colon cancer studies.29 It has been increasingly apparent that β-catenin signaling pathway is closely associated with the development of colon cancer.30 Also, frequent mutations in the β-catenin gene are confirmed in AOM-induced colon tumors in rodent models.30 it has been that the expression of β-catenin is with the of colon of of of adenomas and ACF and several molecular between human colon tumors and AOM-induced colon it is that the AOM model and induced colon models to be appropriate colon cancer Recent progress in the of molecular carcinogenesis has identified multiple molecular for the and nutritional modulation of colon cancer. The multiple which a mutation codon of the APC gene from a to a is markedly different from that of patients with familial adenomatous in which adenomas are in the colon and whereas in adenomas are in the intestine and in the mice also develop at an early These are potential of and models for agents for potential chemopreventive properties against colon carcinogenesis. The development of for of colorectal cancer by dietary has been markedly by the of relevant laboratory animal including colon cancer the neoplastic process that in humans. and evidence from preclinical studies have provided evidence that not only the also types of dietary fat differing in fatty acid composition are important factors in effect of this nutrient in colon tumor in laboratory and those of have that diets high in and corn oil in the significantly increased induced colon carcinogenesis in and rats as compared to diets low in these studies in laboratory also demonstrate that male rats diets or corn oil rich in PUFAs were to colon carcinogenesis compared with those diets or corn et that dietary n-3 PUFAs methylazoxymethanol of areas of and colon whereas PUFAs enhance colon in In a recent et reported a effect of dietary fish oil against AOM-induced colon carcinogenesis in male dietary fish oil significantly colon tumors as compared to high corn oil In addition, colon tumor by fish oil diet was associated with levels of in the colon compared with corn oil These studies provided evidence in preclinical models that diets high of saturated fat of animal or PUFAs a colon effect than diets low in such fatty whereas diets high in n-3 PUFAs such effect studies in laboratory have the effects of high dietary corn oil and safflower oil rich in olive oil high in fatty acid acid, oil high in fatty acids such as acid and fish oil during the of AOM-induced colon carcinogenesis in male diets high corn oil or safflower oil a incidence of colon tumors than those diets low in fat diets high in olive oil or fish oil such colon The effects of different types of fat on colon carcinogenesis during suggest that fatty acid composition is one of the factors in colon tumor by a dietary fat and that the of types and of dietary fat is during the of In this it is to that in a 2 of patients with colonic dietary fish oil have in in the colonic progress has been made with to the relationship between dietary fat intake and colon cancer risk in that of the tumor-promoting effects of diets rich in PUFAs and saturated fatty acids and lack of such effects by n-3 it should be recognized that among the of dietary fat, animal fat with its fatty acid is by the most important to about to the Western dietary fat intake in the United States and Canada and Western countries, colon cancer rates are of a of and polyunsaturated A recent in mice that high dietary fat composition of the diet lesions in the colon of In of the of in colon cancer and because of potential properties of n-3 have a study to the effects of diets that contain rich in saturated fatty acids and to with the effects of fish oil during the different stages of colon carcinogenesis in male preneoplastic lesions, were in the diets for 23 and which are putative preneoplastic lesions in the were observed at high in the colonic mucosa of patients with colon and of rats and mice treated with colon ACF and are to be biomarkers of the effects of agents carcinogenesis in the ACF were observed in the of the diet a significantly of compared with those the corn oil or fish oil diet at time The incidence of aberrant foci was also in the diet group than in the or diet that administration of the diet significantly the and of preneoplastic lesions in the whereas the diet the of such Also, dietary significantly increased colon tumor incidence and when compared with the or rats the diet incidence of colonic compared with incidences of and in rats the and Also, the of was significantly in the diet as compared to those the the diet fat in the of fish induced tumors than diet the of total fat from This that both the type and the of fatty acids in the diet play a role in colon carcinogenesis. In evidence from preclinical studies is with the epidemiologic The of dietary n-3 PUFAs including DHA and against colon carcinogenesis has also been in rodent et reported that administration of of DHA a for 4 and 12 significantly AOM-induced ACF in the et also reported that administration of 1 of DHA a for significantly AOM-induced colon tumor specifically in the and colon in male et compared dietary at LA at or LA at against AOM-induced colon carcinogenesis in male The indicate that the rats a significantly colon tumor incidence and than those the LA of tumors that the rats on diet and than those on the LA Also, the of in the colon tumors of LA diet group was than that in the colon tumors of the diet These suggest that its effect the modulation of in colon Several potential have been for colon cancer of types of dietary fat. Several studies indicate that diets high in saturated fatty acids and and PUFAs oil or safflower increase the of colonic including acid and acid, whereas dietary fish oil high in n-3 PUFAs such epidemiologic studies that populations who are on Western diet and at high risk for colon cancer high levels of acids have been to in a similar to induce and a in and act as in colon these suggest that acids that are by types of dietary fat may be important for in relation to colon tumor in by et dietary PUFAs may and n-3 PUFAs may against colon carcinogenesis by and/or levels of AOM-induced were in fish rats as compared to those corn oil rich in et and et have also that fish oil an increase in in the colon compared with corn It is reasonable to that one of the by which n-3 PUFAs against colon carcinogenesis is in by the of and by the of colonic Also, of fish oil or n-3 fatty acid increased and DHA levels in the of at the of fatty It has been that of colon carcinogenesis by DHA is the of a of a large of n-3 PUFAs effects in the colon the of of the are factors that and are studies to indicate that inducible nitric oxide synthase which is at the is in human colon and in induced colon tumors of laboratory animal data also indicate that the of by is to carcinogenesis process and induces lesions, thus in and in the by family of also These data suggest a role for in tumor and in laboratory indicate that acid induces in with specific expression that one of the by which tumor including acids may an increase in expression of pathway that colon It is known that the fatty acid composition of is to in laboratory indicate that levels of dietary fish oil in rats increased the omega-3 fatty DHA and in the colonic at the of omega-6 PUFAs such as linoleic acid and acid, the that the DHA and of fish oil the of by acid and linoleic acid in the Therefore, the types of dietary fat the fatty acid composition of colonic It is well that acid and of its including play an important role in the signaling pathway associated with and gene increase promote and of which are in tumor The by which n-3 PUFAs colon carcinogenesis are in of an important role in colon and who have in the of of rat epithelial have that of lead to the of high intake of saturated fat and omega-6 PUFAs acid from and levels of have been observed in human colon tumors and induced colon tumors in rodent and human colon levels of that are by Northern Recent have a between the potential of APC mutations and by that of the gene reduces the of tumors in mice for an by than evidence a role for from which show a in colon tumors in rodents with Recent studies in laboratory have provided evidence that an diet AOM-induced expression of and from acid in colon tumors of rats, whereas the diet the levels of In this administration of the diet of in the colon significantly levels than the corn oil diet or the diet 28 indicating This suggests that of the modulation of may be important for the of n-3 PUFAs to colon Also, colon tumors of the diet a than was observed in the colon tumors of rats the The of these studies indicating that of in the tumors of the diet in to the diet and the tumor the that of lead to the of In colon the levels of may be to by and induction of and thus tumor A major that to be is which signaling are in of the These not only a between dietary fatty and of colon also molecular for colon cancer by which n-3 PUFAs colon carcinogenesis. The potential and molecular events by n-3 PUFAs against colon carcinogenesis. The of molecular events by n-3 PUFAs include including and specific and factors including that and dietary n-3 PUFAs by with the and of modulation of thus Recent studies from laboratory have that high dietary PUFAs enhance of including that have been or in colon tumor whereas diet n-3 PUFAs to the of these a gene family of that play in signaling events and are in and include several with unique to the from the et reported that chemopreventive of dietary fish oil is associated with the alterations in colonic a that is by PUFAs may the of the which a of It is that several have been to in The a of ras that is to the of in the of of are in the etiology of human colon It is also known that of from to is by a of closely including which is by It that of ras association of and neoplastic of in laboratory have provided data to indicate that high dietary PUFAs increases expression in colonic whereas high dietary n-3 PUFAs to by with and of the modulation of thus Several have against in both and laboratory animal in have the of in and of colon cancer. of is with the development of certain of has also been to induce an effect that with and have that expression of was in colon tumors of rats than in colon Colon tumors from rats the diet high levels of PUFAs very low levels of whereas the tumors from the diet high of n-3 PUFAs not of These correlate with colon tumor incidences by dietary n-3 and It that modulation of a significant role in n-3 colon tumor and studies in laboratory have that DHA of colon cancer in and induces also the effects of DHA on the genetic of human colon cancer at the using in gene expression due to DHA treatment was observed to be in the multiple signaling in the of and of DHA on and induction of were by an increase in the of several of family of and of such as and of several of these and factors the of the chemopreventive of DHA and important n-3 PUFAs present in fish oil and thus colon cancer. Also, of these and factors provided several expressed biologic many of which suggest as molecular for by chemopreventive including nutritional is a major of and mortality in patients with cancer, including colorectal cancer. Several studies have provided evidence for effects of fish oil administration in cancer during Omega-3 fatty acids have been to have effects on in cancer in patients with cancer is to and is associated with a time and of A fish nutritional has the potential to be a and of a fish oil preparation of and and a preparation in patients with 85 The of of the of which in the of of cancer patients and death from attributable to of of in cancer by and this may be one of the for of tumor Also, fish oil at a of during In on the basis of epidemiologic evidence from ecologic and it is reasonable to suggest that diets high in saturated fats increase the risk of colorectal cancer, whereas diets high in n-3 PUFAs not increase its risk. The studies both epidemiologic and evidence for the effects of diets rich in n-3 in the of colorectal cancer. Also, recent demonstrate effects of fish oil administration in cancer and during and studies have provided evidence that colon tumor-promoting effect of dietary fat depends on its fatty acid that the composition of dietary fatty acids is to colon cancer risk than is the total of fat. studies also demonstrate that a diet high in including saturated fats of animal as well as high dietary PUFAs a potential to promote colon than of a diet on of fat n-3 Although the by which diets high in saturated fats as those in Western and PUFAs promote colon carcinogenesis are not the studies thus indicate that increased levels of colonic modulation of the on and the expression of by the types of dietary fat, especially may play a role in colon carcinogenesis. studies are to the role of n-3 PUFAs on the modulation of that are in colon and types of cancer. The of is to decrease the and mortality from colorectal cancer. and those of suggest that nutritional has the potential to be a major of colorectal cancer especially in the are and in n-3 PUFAs be before they are for cancer Although there are data to indicate and n-3 PUFAs should be for of colorectal cancer, levels of dietary n-3 PUFAs should be with the on epidemiologic studies of disease as by several These studies suggest that fish or as as g/day of fish the risk of Although a dietary for n-3 PUFAs not there is a that consumption of of fish in on the epidemiologic studies may also reduce the risk of colorectal cancer. et has that the of PUFAs to n-3 PUFAs may be important for The risk for and several types of cancer among Mediterranean and Western European populations may at in be on the basis of to n-3 of and 10 in on preclinical and epidemiologic studies on and et for a in the intake of linoleic acid and increase in the intake of n-3 PUFAs that a of 2 be for of and that this is in Western countries for of and and This may well be for the of colorectal cancer in the consumption of and is also for those in Western countries to reduce the risk of colorectal cancer. In the of colorectal cancer in omega-3 fatty acids are in and of be It should be recognized that with nutritional and/or diet may not be for of colorectal cancer in patients such as those with and sporadic colon This to colon cancer is of importance as have not been in the high incidence or low of colorectal cancer. by diet as to the with chemopreventive agents that or the development of those which with and progress to and is an for of colon cancer in these high-risk This is important when chemopreventive agents demonstrate significant may effects at It is certain that colon cancer be a significant of and in high-risk by molecular that or the process of carcinogenesis. there is a to in patients with sporadic colon using the n-3 diets in with a chemopreventive to the of events leading to The for preparation of the and studies on n-3 PUFAs in colon cancer are supported by the Cancer Institute and

International Journal of Cancer · review · 65 citationsread the source →

The Management of Preoperative Anxiety in Children: An Update

Anxiety in children undergoing surgery is characterized by subjective feelings of tension, apprehension, nervousness, and worry that may be expressed in various forms (1). Postoperative maladaptive behaviors, such as new onset enuresis, feeding difficulties, apathy and withdrawal, and sleep disturbances, may also result from anxiety before surgery. In fact, studies have indicated that up to 60% of all children undergoing surgery may present with negative behavioral changes at 2 wk postoperatively (1,2). Variables such as age, temperament, and anxiety of the child and parent in the preoperative holding area have been identified as predictors for these behavioral changes (1). Extreme anxiety during induction of anesthesia is also associated with an increase of these postoperative negative behavioral changes (3). In addition to behavioral manifestations, preoperative anxiety activates the human stress response, leading to increased serum cortisol, epinephrine, and natural killer cell activity (4,5). This stress response can be activated by many different noxious stimuli including fear, anxiety, pain, cold, major surgery, and infection. The main components of the stress system are the corticotropin-releasing hormone and the locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the hypothalamic pituitary-adrenal axis and the limbs of the autonomic system (5). There is also evidence for a bidirectional communication between the neuroendocrine system and the immune system. Stress activates the hypothalamic pituitary-adrenal axis, increases circulating glucocorticoids, and is associated with alterations of immune function and susceptibility to infection and neoplastic disease (6). The human response to surgical stress is characterized by a series of hormonal, immunological, and metabolic changes that together constitute the global surgical stress response (7,8). This perioperative response is considered a homeostatic mechanism for adapting to the perioperative injury. The effects of the surgical stress response, however, may be detrimental: neuroendocrine hormones (e.g., cortisol, catecholamines) and cytokines (e.g., interleukin-6) provoke a negative nitrogen balance and catabolism, delay wound healing, and cause postoperative immunosuppression (7,8). Children are particularly vulnerable to the global surgical stress response because of limited energy reserves, larger brain masses, and obligatory glucose requirements (9). Because acute psychological stress, such as preoperative anxiety, is associated with immediate stress hormone release, the contribution of perioperative psychological factors to the global perioperative stress response cannot be ignored. In adults, increased preoperative anxiety is associated with poor postoperative behavioral and clinical recovery (10,11). As an indicator of the importance of preoperative anxiety, a panel of 72 anesthesiologists recently ranked various anesthesia low-morbidity clinical outcomes based on importance and frequency. The five clinical outcomes with the highest combined score were incisional pain, nausea, vomiting, preoperative anxiety, and discomfort from IV insertion (12). Thus, consensus is evident among anesthesiologists about the need to treat anxiety before surgery. In a modern epidemiological framework, diseases can be characterized in terms of risk factors, interventions, and outcomes. In this update, we will review preoperative anxiety in children using this conceptual framework (Fig. 1).Figure 1: Conceptual framework of perioperative anxiety. Revised from (72).The Psychobiology of Separation Learning to cope with separation from a parent is necessary for a child’s normal development (13). Separation experiences such as going to school facilitate normal psychological development and personality organization. Other separation experiences, such as perioperative separation, may precipitate confusion and anxiety. Between these two extremes, there are many separation experiences with varying degrees of psychobiological stress. In the first weeks of life, infants are able to discriminate among people, but will accept care and comfort from adults other than their parents (14). By 3 mo of age, however, infants begin to respond differently to familiar and unfamiliar people. Older infants smile more at familiar people and may even try to engage their attention (14). Separation anxiety usually begins at 7–8 mo of age and peaks around 1 yr of age. In part, separation anxiety represents the infant’s acquisition of new cognitive abilities and object permanence. The intensity of separation anxiety declines with age, largely because of increasing cognitive abilities and memory capacity. Frequently, however, the increase in abilities does not immunize toddlers and preschoolers against the stress and distress of separations. The extent to which separation is traumatic or evokes adaptive responses reflects an individual child’s developmental age, parenting experiences, genetic endowment, and environmental stability. For children with biologically based vulnerabilities, such as a sensitivity to novelty and transitions, even expected separations may impose a greater degree of stress than for less sensitive children (13). How parents help the child mediate a separation experience play a crucial role in the child’s acute and long-term responses. In the extreme, the parent may be unable to mediate the experience for the child because of limitations such as severe anxiety. How well children have been cared for up to the time of the separation also influences their response to the stressor. Children deprived of attention in the home are at increased risk for stress in response to separations. Thus, the extent to which separations evoke adaptive responses reflects an individual child’s genetics, personality, parenting, and previous life experiences. Preoperative Anxiety: Identification Identifying risk factors for development of preoperative anxiety is important, as more resources can be directed toward vulnerable children. Children 1–5 yr old are at the highest risk for developing extreme anxiety (1). This is not surprising considering the psychobiology of separation anxiety. Children who are shy or inhibited and those who have a high intelligence quotient and lack good adaptive abilities are also at increased risk (15). Previous surgery or hospitalization and poor response to visits to the pediatrician’s office are also predictors for the development of preoperative anxiety. Finally, parental anxiety has been identified as a predictor for increased child’s anxiety. Preoperative Anxiety: Behavioral Modalities Preoperative Preparation Programs Most studies suggest that preoperative preparation programs reduce anxiety and enhance coping in children (16). These behavioral preparation programs have evolved significantly over recent decades. In the 1960s, preparation programs were designed to provide an orientation tour and narrative information and facilitate trust between the hospital staff, the child, and the parent (16). In the 1970s, modeling techniques were developed where children indirectly experienced the perioperative course by role rehearsal using dolls or by viewing a video (17). These modeling techniques were augmented in the late 1980s with child life preparation and the teaching of coping skills (17). Currently, development of coping skills is considered the most effective preoperative preparation intervention, followed by modeling, play therapy, operating room tour, and printed material (18). Although experts favor teaching of coping skills, most preparation programs in the United States consist of an orientation tour and printed information (18). Although coping preparation has been associated with reduction of anxiety in the preoperative holding area, no differences were found among the various preparation programs during induction, in the recovery room period, or postoperatively (19). Thus, the cost-effectiveness of child life specialists may or may not be justified by an associated reduction in preoperative anxiety. Psychological preparation programs should be tailored to individual needs such as age, developmental stage, and previous experience (20). The priority of the age criterion relates to both the anxiety such exposure might generate and the length of time over which children can cope with anticipation. In addition, timing of the program before surgery is an important variable (20). Children aged ≥6 yr benefit most if they participate in a preparation program ≥5 days before surgery and benefit least if the program is given only 1 day before surgery. This phenomenon is related to the way that children in this age group process new information. Finally, a child who has previously undergone surgery or has been hospitalized may develop an exaggerated emotional response to an information-based preparation program (20). As increased parental anxiety results in increased child’s anxiety (1), there is a need for interventions that are designed specifically for parents. Cassady et al. (21) demonstrated that parental preoperative anxiety decreased after viewing an educational videotape. We suggest that more parental interventions need to be developed and that a child’s anxiety should be evaluated as an outcome. Preoperative Anxiety: Behavioral Modalities Parental Presence during Induction of Anesthesia. Parents and children prefer to stay together during medical procedures such as immunizations, dental treatment, and induction of anesthesia (22). Some data indicate, however, that parental presence during induction of anesthesia (PPIA) is allowed in 26% of US hospitals and is encouraged in only 8% of hospitals (23). In contrast, 28% of hospitals have no formal hospital policy and parental presence is against hospital policy for 32% of hospitals in the US. The smallest use of this induction technique was reported in the South-Central region and the highest in the Northwest and the Northeast (23). Interestingly, anesthesiologists from Great Britain (GB) encourage PPIA significantly more than anesthesiologists from the US (23,24). The reasons for these differences may include the use of different induction techniques, less concern about legal ramifications in GB, and a stronger demand for parental presence in GB. Economic issues such as operating room (OR) efficiency, infrastructure issues, lack of induction rooms and patchy preoperative educational programs, probably limit the availability of PPIA in the US. Potential benefits from PPIA include reducing the need for preoperative sedatives and avoiding the fear and anxiety that may occur on separation to the OR. Other benefits, such as increasing the child’s compliance during induction, remain controversial. Objections to PPIA include concern about disruption of the OR routine, crowded ORs, and a possible adverse reaction of parents. In addition, increased parental anxiety can increase a child’s anxiety, prolong anesthetic induction, and place additional stress on the anesthesiologist. Although early observational studies suggested reduced anxiety if parents were present during induction (25), more recent randomized controlled trials indicate that routine parental presence is not beneficial (26–28). One study demonstrated that only children >4 yr of age, those who have a “calm” baseline personality, or those who have a parent with a “calm” baseline personality benefit from this intervention (26). When interpreting the results of these studies, however, it should be noted that the design of a randomized controlled study does not reflect the practice of all anesthesiologists. When data of survey studies are reviewed (23,24), it is noticed that most anesthesiologists use either PPIA or sedative premedication to treat preoperative anxiety. When sedative premedications were directly compared with PPIA, however, it was found that children receiving oral midazolam were significantly less anxious and more compliant during the induction process (27). A recent study examined whether a combination of PPIA and oral midazolam is more effective than oral midazolam alone (28). The investigators found that PPIA has no additive anxiolytic effects for children who received oral midazolam preoperatively. Parents who accompany their sedated children into the ORs, however, are significantly less anxious and more satisfied both with the separation process and with the overall anesthetic, nursing and surgical care provided (28). PPIA is also associated with important legal implications. Lewyn (29) described a case in which a mother was invited to accompany her son into an emergency treatment room. According to the court, the mother fainted and suffered an injury to the head. In its verdict the Illinois Supreme Court stated that a hospital, which allows a nonpatient to accompany a patient during treatment, does not have a duty to protect the nonpatient from fainting. However, if medical personnel invite the nonpatient to participate in the treatment, then the hospital has a legal responsibility toward the nonpatient. Interestingly, some hospitals in the US now require the parents to sign a written informed consent acknowledging the risk of being present during induction of anesthesia. We believe that future research interests should shift towards an emphasis on what parents actually do during induction of anesthesia, rather than simply on their presence. Allowing a parent into an OR without significant preparation may be counterproductive because some parent behaviors, such as criticism and commands, are associated with increased distress. Effective methods of training such as parental preparation programs can be developed for enhancing the effects of PPIA. Preoperative Anxiety: Pharmacological Modalities The reported rate of use of pharmacological modalities for the treatment of preoperative anxiety in the US varies widely among age groups and geographical locations (24). Premedicant sedative drugs are least often used with children <3 yr of age and most often used with adults <65 yr of age (25% vs 75%). Currently, the most commonly used sedative premedicant in the preoperative holding area is midazolam (85%), followed by ketamine (4%), transmucosal fentanyl (3%), and meperidine (2%) (Fig. 2). TABLETABLE The majority of children in the US are premedicated via the oral route (80%), followed by the intranasal route (8%), the IM route (6%), and the rectal route (3%).Figure 2: Types of premedicants used in the preoperative holding area (23).Table 1: Premedications Administered by the Oral RouteTable 2: Premedications Administered Transmucosally and RectallyMidazolam. Midazolam is a short-acting benzodiazepine that is very lipophilic at physiologic pH, which accounts for its rapid onset of action. Davis et al. (30) has demonstrated that intranasally administered midazolam in a dosage of 0.2–0.3 mg/kg in patients undergoing myringotomies led to satisfactory separation from parents and a satisfactory induction over 70% of the time and did not prolong recovery time and hospital discharge time. Midazolam administered intranasally is effective in reducing anxiety in children within 10–12 min (31). A major drawback of intranasally administered midazolam, however, is that at least 50% of children cry on administration because it transiently irritates the nasal passages. Midazolam can also be given as a nasal spray, which is effective in reducing procedural anxiety in children undergoing cancer therapy (32). Midazolam can be administrated sublingually at the same dosage as intranasally. Although sublingual administration of midazolam is associated with a decreased incidence of crying (18%), it may be difficult to prevent small children from either swallowing the midazolam or spitting it out immediately (33). Rectal administration of midazolam in doses of 0.5–1.0 mg/kg effectively reduces the anxiety of children before induction of anesthesia (34). Although the incidence of hiccups after IV midazolam is <2%, the incidence noted that in a recent study involving rectally administered midazolam was more than 20%(34). The investigators had no explanation as to the increased rate of hiccups other than the young age of the children, but they found that the hiccups were easily treated by ethyl chloride nasal spray (34). Orally administered midazolam (0.5 mg/kg) has been shown to significantly reduce preoperative anxiety in young children (27,28). Orally administered midazolam can be given in a dosage of 0.25 mg to 1.0 mg/kg up to total dose of 20 mg depending on the of surgery and the anxiety of the A and and midazolam in a of 2 in et al. examined different doses of the midazolam and found that 0.25 mg/kg in satisfactory and in a majority of patients within 20 This study also found that increasing the dose in an increase in the of patients with satisfactory and a time to onset of Other that the time for premedicated children from their parents is min with a sedative between 20 and min The of administered midazolam and in the discharge of patients is controversial. Although recent studies noted that administrated midazolam is not associated with a discharge two studies involving children undergoing that and recovery are in the children who oral midazolam study involving children who myringotomies using or anesthesia indicated that children who were given oral midazolam experienced significant in recovery time but no in discharge time from the hospital Finally, et al. have the of a combination of preoperative oral midazolam and The investigators found that requirements by and discharge was in children who had been given midazolam preoperatively. The investigators suggested that the increased postoperative may have been to of and midazolam on As indicated a significant of children experiences maladaptive behavioral changes after surgery (1). In children who were premedicated with oral midazolam had a significantly decreased incidence of negative behavioral changes during the first after surgery However, this study noted that by 2 wk postoperatively there were no significant differences between the midazolam and The mechanism by which midazolam the incidence of postoperative behavioral changes is not but it may be related to of the perioperative process Children who received a benzodiazepine for dental and were about the experience dental than children who were not about their dental This may be particularly important for children undergoing surgical in children after oral midazolam as early as min and anxiolytic effects are as early as min after administration This timing to onset of is of importance in surgery where the of is very Midazolam and can be with which The dose in children is mg/kg given IV in a of up to 1.0 mg Some children who are with will experience it is to for can also be intranasally in a dose of given by from a is a that is very which the a good for administration and Oral transmucosal fentanyl administered in the of a to a and as the was the first sedative by the and in for use in children. Oral transmucosal in and dosage is in a and given to children in the dosage of for sedative is often associated with which usually min after children begin to the children before induction of anesthesia does however, to decreased or with induction in young children In a small of can cause a leading to significant a in be present this is administered in children is associated with a incidence of postoperative and that is not easily by In fact, at least study was because of a very incidence of preoperative A significant of is that it the postoperative et al. reported that preoperative is as effective as IV fentanyl given for of postoperative in children undergoing is an that a of and from the of ketamine compared with other premedicants is that it less given in sedative doses A of ketamine as compared with other premedicants is the of increased and which can to can also cause and in children, which can parents if they are not informed about this increased incidence of postoperative is associated with preoperative administration of ketamine The effects are all dose related and can be with the use of a small dose of administered ketamine mg/kg) the time of onset of the of administered ketamine is also dose related with administered ketamine mg/kg) an onset of of min and ketamine leading to within 20 min administration may be associated with and during the postoperative recent studies have found that use of a benzodiazepine given to children undergoing ketamine did not the incidence of In addition, the incidence of postoperative and is no different in children receiving midazolam, or a combination of ketamine and midazolam together The IV preparation of ketamine can be with or to an oral of which is by most children. can be also be given intranasally rectally and IM mg/kg) care discharge time of children who received administered ketamine is reported not to be compared with administered midazolam provided that of surgery is than min administered IM in an emergency room however, was found to significantly delay discharge and increase compared with midazolam administered rectally or intranasally et al. reported that the combination of midazolam and ketamine administrated had a rate of satisfactory compared with with either oral was also found to be to IM and in children undergoing The provided and and there was less need for IV as compared with the IM is an first developed as an but found to have and sedative Orally administrated in a dose of anesthetic and for postoperative requirements by 50% in children premedicated with This in may be to the of as well as a administered is also as effective as administered fentanyl for postoperative in children undergoing The recovery of children who is to the recovery of children who oral but significantly less postoperative as compared with One major drawback for the use of as a sedative premedicant is its onset of action. has to be administered as early as min before surgery In children, is at min for administered and min for rectally administered for the research should on the development of sedatives that will be well have a very time for onset of and have of action. In addition, developed preoperative sedatives should such as and should anesthetic requirements and reduce postoperative Finally, new methods of sedative premedications should also be For of should be as well as oral transmucosal methods for other than usually at least 1 for effective serum of drugs to be is can significantly the of a and has been effective in fentanyl in adults within min at 2 Finally, the of treatment modalities such as should be research is in these The to for review of this

Anesthesia & Analgesia · review · 408 citationsread the source →

Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology

Despite over 50 yr of experience with steroid replacement therapy, the management of congenital adrenal hyperplasia (CAH) remains difficult, and clinical practice varies substantially throughout the world. To consider the evidence for best practice, to formulate management guidelines, and to consider innovative therapies, The Lawson Wilkins Pediatric Endocrine Society (LWPES) and The European Society for Pediatric Endocrinology (ESPE) convened a meeting in Gloucester, MA, March 14–17, 2002. The 40 participating physicians, psychologists, scientists, and surgeons from 12 countries on 4 continents agreed with the following consensus statement; this statement is concerned exclusively with CAH caused by 21-hydroxylase deficiency and does not address the other, rarer forms of CAH. The newborn female with CAH and ambiguous external genitalia requires urgent expert medical attention. The ambiguity is highly distressing to the family; therefore, immediate comprehensive evaluation is needed by referral to, or a visit by, a pediatric endocrinologist. An important goal is to ensure that the parents develop a positive relationship with their child. A well-organized multidisciplinary team (including specialists in pediatric endocrinology, psychosocial services, pediatric surgery/urology, and genetics) is essential for the diagnosis and management of the infant with ambiguous genitalia. It is important that the coordinator of the team has experience in the long-term care of the patient with CAH and provides a consistent message to the parents. Every newborn with ambiguous genitalia, a suspected diagnosis of CAH, or an abnormal result in a newborn screen for 17-hydroxyprogesterone (17OHP) should be evaluated by a pediatric endocrinologist. The evaluation of an infant with ambiguous genitalia includes a complete history, a physical examination, a reliable ultrasound investigation of the internal genitalia and adrenals, karyotype or fluorescence in situ hybridization for sex chromosome material, and a rapid, reliable plasma or serum measurement of 17OHP. Premature newborns may need serial measurements of 17OHP to differentiate false positive results from affected infants with CAH. Neonatal mass screening for 21-hydroxylase deficiency identifies both male and female affected infants, prevents incorrect sex assignment, and decreases mortality and morbidity (1–4). Therefore, newborn screening for CAH is beneficial and is recommended. Newborn screening is sufficiently specific and sensitive to detect almost all infants with classical CAH and some infants with nonclassical CAH (NCCAH). Sampling of blood spots should be performed, ideally between 48 and 72 h of age, and sent to the screening laboratory without delay. At present, direct binding assays for blood-spot 17OHP are the only practical method for screening. Each screening laboratory needs to establish validated cut-off levels related to gestational age and birth-weight, because 17OHP levels decline with increasing gestational age. Only laboratories with excellent internal and external quality control, demonstrated accuracy, and a rapid turn-around time on a large number of samples should be used. The laboratory should report immediately any abnormal result to the physician responsible for the patient. A reliable CAH screening program requires both clinical evaluation and laboratory investigation for diagnostic confirmation. A positive screening result needs to be confirmed either by a validated 17OHP measurement of a second serum/plasma sample, a urine sample for a steroid profile, or analysis of the CYP21 gene. Newborn screening, using 17OHP, may detect other forms of CAH. In uncertain cases, additional specific tests are required. Measurements of androstenedione, aldosterone, cortisol, and testosterone by direct immunoassays are of limited value for diagnosis in the newborn. Molecular genetic analysis is not essential for the diagnosis but may be helpful to confirm the basis of the defect, to aid in genetic counseling, and to establish the diagnosis in uncertain cases. Ten mutations account for 90–95% of the affected alleles, but molecular genetic analysis is complicated by multiple copies of the genes and the possibility of multiple mutations on one allele (5, 6). The clinical features may not correlate with the genetic mutation in a small percentage of cases. Parental DNA samples are essential to segregate alleles. Salt wasters may not be apparent in the first days, or even weeks, after birth by electrolyte measurements. Salt wasters may be differentiated from simple virilizers by serial serum/plasma and/or urine electrolytes, plasma renin activity (PRA) or direct renin, and the results of CYP21 molecular analysis. Prenatal treatment has been advocated for fetuses at risk for classic CAH but is not appropriate for nonclassic CAH. The appropriateness, ethics, and outcomes of the prenatal treatment of CAH with dexamethasone remain controversial (7, 8). However, based on more than 200 fetuses treated to term and more than 1000 partially treated fetuses, it is clear that very early institution of treatment ameliorates the genital virilization in all affected females and completely eliminates it in more than 85% (7, 9). Variations in outcome may be attributable to starting treatment late, interruption of treatment, and individual differences in dexamethasone metabolism and androgen sensitivity. No consistent untoward effects have been reported, and birth weight is not reduced. However, few treated fetuses have reached adulthood, and long-term prospective studies have not been done. Thus, all agree that the results to date are very good, but long-term safety has not yet been proven in patients treated to term or in the 7 of 8 fetuses in whom treatment is stopped because they are male or unaffected. Treated mothers experience greater weight gain, edema, and striae than untreated mothers, but present data do not show increased risk of hypertension or gestational diabetes (9). Feto/maternal glucocorticoid physiology and pharmacology are poorly understood. Available data indicate that human fetal cortisol levels are low, approximately 20 nm or 0.7 μg/dl (10); the administered dose of dexamethasone may result in fetal concentrations of glucocorticoid that greatly exceed normal levels. However, the data on serum cortisol values in the fetus are scanty, and fetal serum dexamethasone values have not been reported. Several recent reports have raised concerns about the use of short-term, very-high-dose glucocorticoids in late pregnancy or in premature infants (11). Animal studies have reported numerous complications from long-term, high-dose treatment of pregnant rodents and primates. Treatment of pregnant rats with 20 μg/kg·d dexamethasone was associated with decreased birth weight and adult hypertension, whereas similar treatment of pregnant sheep caused no apparent complications. However, the relevance of any of these studies to human physiology is not known. Components of a prenatal treatment program include prepregnancy genetic counseling and genotyping of the proband and parents, followed by diagnosis on fetal DNA obtained by chorionic villous biopsy. Fetal sex should be determined by Y chromosome PCR or karyotype. Allele-specific PCR should identify at least 90% of affected alleles. This number can be increased to nearly 100% with microsatellite analysis; Southern blotting; and, occasionally, DNA sequencing (5, 6). Competent core laboratories should study large numbers of samples. Inclusion criteria for prenatal treatment include: 1) a previously affected sibling or first-degree relative with known mutations causing classic CAH, proven by DNA analysis; 2) reasonable expectation that the father is the same as the proband’s; 3) availability of rapid, high-quality genetic analysis; 4) therapy started less than 9 wk after the last menstrual period; 5) no plans for therapeutic abortion; and 6) reasonable expectation of patient compliance. The optimal dosage and timing is 20 μg/kg maternal body weight·d, in three divided doses, starting as soon as pregnancy is confirmed, and no later than 9 wk after the last menstrual period. Treatment is continued to term in the affected female fetus and discontinued in all other fetuses. Maternal blood pressure (BP), weight, glycosuria, HbA1C plasma cortisol, dehydroepiandrosterone sulfate, and androstenedione should be measured initially and then every 2 months, adding plasma or urinary estriol after 15–20 wk of gestation. There is substantial difference of opinion concerning whether prenatal treatment of CAH is a research endeavor. However, all are agreed that this requires a team consisting of a pediatric endocrinologist, an expert in high-risk obstetrics, a genetic counselor, and a reliable molecular genetics laboratory. It is not the “standard of care” for obstetricians in the community. The treatment of 7 out of 8 fetuses who cannot be helped by prenatal treatment creates an ethical dilemma for which there is no clear answer, and parents should be aware of this. We believe that this specialized and demanding therapy should be undertaken by designated teams using nationally or multinationally approved protocols, subject to institutional review boards or ethics committees in recognized centers. Written informed consent must be obtained after the balanced review of the risks and benefits of treatment. Families and clinicians should be obliged to undertake prospective follow-up of prenatally treated children whether they have CAH or not. The data should be entered into a central database audited by an independent safety committee. Study protocols should consider all psychological/behavioral and somatic effects of excess prenatal glucocorticoids and androgens that have been observed in animal experiments or in human studies. Long-term follow-up into late adolescence is mandatory. Relevant control populations should be identified. These studies should also include the partially treated fetuses. Funding agencies, such as the National Institutes of Health or the European Commission, should be encouraged to support such long-term studies. The decision about surgery should be made by the parents, together with the clinical team, after complete disclosure of all relevant clinical information and all available options have been discussed and after informed consent has been obtained. The goals of surgery are: 1) genital appearance compatible with gender; 2) unobstructed urinary emptying without incontinence or infections; and 3) good adult sexual and reproductive function. Once a decision has been made to raise a newborn as female, surgery for those with virilized genitalia caused by CAH is recommended when the patient has a high proximal junction between the vagina and urethra (12, 13). Surgery on infants with ambiguous genitalia requires a high degree of expertise and should only be performed in centers with significant experience. Based on recent clinical experience, the recommended time for surgery is at age 2–6 months; although, at present, this is not universal practice. It is important to note that surgery at this stage is technically easier than at later stages. When the degree of virilization is less (minimal clitoromegaly and the junction between the vagina and urethra near the perineum), surgery may not be necessary. In such cases, the decision to operate should be based on appropriate contrast studies of the urinary tract and examination under anesthesia, with cystoscopy. Surgery to reduce clitoral size requires careful consideration. Total removal of the clitoris should never be performed. If clitoral reduction is elected, it is crucial to preserve the neurovascular bundle, the glans, and the preputial skin related to the glans (14, 15). The early operation should be a one-stage complete repair using the newest techniques of vaginoplasty, clitoral, and labial surgery (12–14, 16) and should be carried out at a center with experience of at least 3–4 cases/yr. Revision vaginoplasty is often required at adolescence, and the timing should be decided with the patient and family. Patients who wish to consider further procedures should be treated by a surgeon experienced in the current techniques. Surgery between the age of 12 months and adolescence is not recommended in the absence of complications causing medical problems. Vaginal dilatations are contraindicated at this stage, although this procedure is often useful in adolescence and in adulthood. Repeated genital examinations should be minimized. Genital photography should be discouraged and only be done with parental consent and, except in infancy, performed only under anesthesia. At each designated center, one surgical team should be responsible for all surgery involving ambiguous genitalia. There should be close cooperation between centers to broaden experience, to audit results, and to allow adequate evaluation of outcomes. We acknowledge that there are concerns about early surgery. However, surgical techniques have improved. We urge caution in judging outcome from outdated procedures. Systematic studies are needed to evaluate ultimate function for all girls undergoing surgery. It is recognized that 46,XX children with significant virilization may present at a later age. Consideration for sex reassignment must be undertaken only after thorough psychological evaluation of patient and family. Surgery appropriate to gender assignment should be undertaken after a period of endocrine treatment. Females with CAH show behavioral masculinization, most pronounced in gender role behavior, less so in sexual orientation, and rarely in gender identity (17–19). Even in females with psychosexual problems, general psychological adjustment seems to be similar to that of females without CAH. Currently, there is insufficient evidence to support rearing a 46,XX infant at Prader stage 5 as male. Whereas studies of women whose surgery was performed 20–30 yr ago indicate a range of psychosexual difficulties, there is reason for optimism that outcome will be better with current surgical and medical treatment. We recognize a need for greater availability of professional psychological services and support groups for patients and families. Decisions concerning sex assignment and associated genital surgery must consider the culture in which a child and her/his family are embedded. As the pace of societal change, including the flexibility of gender role, increases, more frequent review of management policies and long-term outcomes is important. Recognizing that treatment does not mimic physiologic secretion, the goal is to replace deficient steroids while minimizing adrenal sex hormone and glucocorticoid excess, preventing virilization, optimizing growth, and protecting potential fertility. Outcome is not always ideal. Consensus is based on clinical experience. During infancy, initial reduction of markedly elevated adrenal sex hormones may require up to 25 mg hydrocortisone (HC)/m2·d, but typical dosing is 10–15 mg/m2·d divided three times daily. HC oral suspension is not recommended (20); divided or of HC should be in requires to cortisol for HC is the of first doses, infancy, may and other Therefore, complete adrenal should be data to or Whereas HC is and glucocorticoids may be an at or near the of and need to be daily. may be because this is the The dose should be approximately one the dose of The dosage of dexamethasone is daily. of these more glucocorticoids should include in to weight, and other clinical and laboratory These steroids have with In children with age, such as in with CAH, of therapy may central treatment with a classic CAH patients should be treated with at diagnosis in the newborn period. in early range from whereas typical are on the therapy will reduce and levels and the dosage of glucocorticoid required. The need for should be based on and are often needed in infancy, at in The method of diagnosis a with However, a of 17OHP may also as a reliable screening Treatment is only recommended for patients those with an age with a with the family menstrual and the may be based on physical and of or steroid measurements may include serum/plasma electrolytes, serum 17OHP, androstenedione, and/or and or direct renin, every months and every months The time from the last glucocorticoid dose should be the of the adrenal should be into Patients adequate replacement therapy may have hormone levels the normal measurements include urinary or blood and laboratory data will indicate a need for dose physical growth, and indicate or Patients with CAH should medical and information concerning therapy for should have an of HC or glucocorticoid levels of cortisol patients should be increased of glucocorticoids when or when to oral after and surgery. in may also require steroid and such as does not require increased dosing should be times the glucocorticoid dose for patients to oral and patients and those to oral steroids require or concentrations should be and and replacement may be required. or patients may or When an may be followed by of for and dosage are as for children than yr of age, 25 mg followed by for children yr of age, 50 mg followed by and for and mg followed by CAH and should be by and and made available to other pediatric endocrine of useful as family include: and The practice of frequent genital examinations in females should be Therefore, there is clinical or laboratory evidence of control or one to the and size of the genital examinations should not be performed. In females or the of the use of or of sexual genital examination with to the of the may need to be performed. the patient and/or family should be of the for the examinations and support of the patient both classic and and family should be a of the comprehensive care and management of these and/or patients should be the of and counseling at the time of the initial sexual gender role, and related to with a should be the pediatric or for infants, and with CAH. In late adolescence or even early adulthood, care is to an internal in the same institution or clinical We that a team should also as a a and a with specific expertise and in the treatment of such should be that with treatment is important to normal and reduce the risk of a mass by may not be of clinical physical examinations and, as and of both to in the of such removal of a glucocorticoid may be in or The of the genital repair in and adult women needs to be and should be about and other sexual as as is useful with should be an increased risk of However, the risk is not available and may on the and degree of with The risk of women with CAH or an affected fetus is women with CAH should be and in a center and experienced to such that do not the such as HC and should be used. should be when in prenatal should be to maternal serum testosterone concentrations near the range of normal for pregnancy When surgery has been performed, to to the genital When is performed, of HC have to be increased and after A should be present to care of the newborn and to diagnostic procedures when an affected child is to the results of prenatal by is in adrenal androgens and the of It should be only in therapy is in of HC and is with institution of at the of The patient must be throughout for of adrenal The procedure should only be carried out long-term follow-up is and in the of approved clinical studies. The use of in CAH is on but of with Based on the of an in male sexual it was that the effects of elevated androgens on adult be by using an to androgen and/or an to of androgen to studies in CAH show control of and at glucocorticoid dosage Long-term safety data are not and reproductive effects are not known. function has to be Patients with CAH from of and of the adrenal as deficiency This may a role in to therapeutic are under genetic diagnosis for CAH is but further research is required to therapy is not in with this CAH patients on glucocorticoid treatment have levels. in adult patients with have beneficial effects of replacement but the relevance in CAH is have the potential for activity of glucocorticoids At present, there are no specific that are of or and clinical experience with is Therefore, the use of these cannot be at A of patients with CAH with an of Thus, an is by patients with CAH, and the adult is substantially less than However, some CAH patients to normal adult A small of CAH patients have been treated with for 2 either or in with a This and but adult data are not yet These are to all of the management of this in from diagnosis adulthood. The multidisciplinary of management is with the that such expert teams need appropriate and There remain important in about this and these have been therapeutic are as require evaluation into practice. In the should on early optimal medical and surgical treatment, and to compliance. The for support of the consensus meeting in The following convened in Gloucester, March 14–17, and to this The and The also the of and congenital adrenal European Society for Pediatric Lawson Wilkins Pediatric Endocrine nonclassical plasma renin

The Journal of Clinical Endocrinology & Metabolism · review · 331 citationsread the source →

Promoting positive change in the face of adversity: experiences of cancer and post-traumatic growth.

The increasing population of cancer survivors underscores the need to develop a complete understanding of the survivorship experience, including positive aspects. The aim of this study was to explore people's experiences of cancer to assess the relevance of the post-traumatic growth (PTG) construct and to identify potentially modifiable factors that may promote PTG. Group interviews were conducted with 15 people (eight men, seven women) aged between 36 and 85 who had been diagnosed with cancer and completed treatment. Participants identified that while a cancer diagnosis is a traumatic event and has an immense impact, there is potential for PTG. Participants described examples of positive change within their relationships, perceptions of self and life in general perception, and spirituality. Various modifiable factors were identified as enabling participants to experience growth including social support, finding information, complementary therapy use, lifestyle changes and physical activity. Modifiable factors such as physical activity and searching for information have the potential to influence the development of PTG by providing cancer survivors with an opportunity to regain control. Encouraging and developing research that examines the relationship between modifiable factors and PTG will assist in the development of interventions that address the unique needs of cancer survivors.

European journal of cancer care · 40 citationsread the source →

Assessing the psychometric properties of the Biphasic Sleep Scale (BiSS): A novel 16-item self-report measure.

Biphasic sleep, characterized by nighttime sleep plus daytime napping, has demonstrated some cognitive, health and performance impacts when compared with consolidated monophasic sleep. This motivated the development and validation of the Biphasic Sleep Scale, reported in this paper. Scale development involved a literature review, expert input and individual interviews. The 16-item Biphasic Sleep Scale was then administered to an international online sample (n = 6965) alongside well-established validated sleep scales. To ensure a robust evaluation of the Biphasic Sleep Scale, the sample was divided into two parts: with 15% (n = 1000) of the participants allocated to the exploratory analytic phase; and the remaining 85% (n = 5965) reserved for confirmatory analyses. Psychometric evaluation included both exploratory and confirmatory factor analysis, reliability analysis, correlations, network analysis, and item response theory. Exploratory factor analysis indicated a three-factor structure assessing daytime napping as to likelihood, consequences and effect on nighttime sleep. Confirmatory factor analysis largely confirmed this model with no sex invariance. The three-factor structure showed adequate fit. The Biphasic Sleep Scale demonstrated good internal consistency (α = 0.88, Ω = 0.89). Network analysis revealed varying centrality and connectivity of items. Item response theory found items covering a range of biphasic sleep levels. Significant positive correlations with sleep criteria provided evidence for convergent validity. Further testing is warranted to confirm the factor structure, refine model parsimony, and establish clinical utility. With additional validation, it is hoped that the Biphasic Sleep Scale will become a widely utilized tool.

Journal of sleep research · 1 citationsread the source →

Social Participation Among Older Adults Before and After Long-Term Care Facility Entry.

Importance: Social participation is essential throughout life and is associated with decreased mortality and increased quality of life. It is unknown whether long-term care facility (LTCF) entry disrupts or facilitates it. Objectives: To determine longitudinal trends in social participation before and after entry into nursing homes (NHs) and assisted living facilities (ALs) and to explore factors associated with participation. Design, setting, and participants: This nationally representative longitudinal cohort study using prospectively collected annual data from the US National Health and Aging Trends Study from 2011 to 2019 included community-dwelling Medicare beneficiaries entering LTCFs. Interviews conducted 4 years before and 2 years after NH or AL entry (index date) were included. Data analysis was performed from September 16, 2022, to May 25, 2025. Main outcomes and measures: Two categories of social participation comprising 5 activities were assessed: socialization (visiting with friends or family and going out for enjoyment) and community participation (attending religious services, participating in clubs or other organized activities, and volunteering). Participation over time was modeled using linear splines before, upon, and after LTCF entry. Modified Poisson regressions were used to explore associations with maintaining and starting activities, adjusted for age, sex, race and ethnicity, and proxy response were used. Results: The total sample included 606 LTCF entrants (weighted mean [SD] age 85 [7.4] years, 404 female [66% weighted]), of whom 104 individuals were Black (7%), 23 Hispanic (4%), 464 White (86%); and 15 of any other race and ethnicity (3%). Before entry, social participation decreased in all activities (-4.7 to -2.0% annually). Of the total, 275 (44%) entered a NH and 331 (56%) entered an AL facility. Upon entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance increased (15.6% and 12.6%, respectively). Before LTCF entry, social participation decreased in all activities (-4.7 to -2.0% annually). After entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance (12.6%) increased (15.6% and 12.6%, respectively). In exploratory analyses, women were more likely to maintain visits (adjust risk ratio [aRR], 1.3; 95% CI, 1.1-1.5) and start attending religious services (aRR, 1.6; 95% CI, 1.0-2.8). NH residents were less likely to go out for enjoyment (aRR, 0.6; 95% CI, 0.5-0.8 for maintaining; aRR, 0.6; 95% CI, 0.4-1.0 for starting) and keep attending religious services (aRR, 0.7; 95% CI, 0.6-0.9). Black, Hispanic, and residents of other race or ethnicity were much less likely to start going out for enjoyment (aRR, 0.3; 95% CI, 0.1-0.8). Conclusions and relevance: This cohort study found that LTCF entry generally promoted community participation and reduced socialization. Benefits may be less likely among men, NH entrants, and residents of racial and ethnic minority groups.

JAMA internal medicine · 4 citationsread the source →

The role of social risk factors and engagement with maternity services in ethnic disparities in maternal mortality: A retrospective case note review.

Background: Reasons for ethnic disparities in maternal death in the UK are unclear and may be explained by differences in social risk factors and engagement with maternity services. Methods: In this retrospective systematic case note review, we used anonymised medical records from MBRRACE-UK for all Other than White, and White European/Other women plus a random sample of White British/Irish women who died in pregnancy or up to 1 year afterwards from 01/01/2015 to 12/31/2017. We used a standardised data extraction tool developed from a scoping review to explore social risk factors and engagement with maternity services. Findings: Of 489 women identified, 219 were eligible for the study and 196 case notes were reviewed, including 103/119 from Other than White groups, 33/37 White European/Other and a random sample of 60/333 White British/Irish. The presence of three or more social risk factors was 11⋅7% (12/103) in Other than White women, 18⋅2% (6/33) for White European/Other women and 36⋅7% (22/60) in White British/Irish women. Across all groups engagement with maternity services was good with 85⋅5% (148/196) receiving the recommended number of antenatal appointments as was completion of antenatal mental health assessment (123/173, 71⋅1%). 15⋅5% (16/103) of Other than White groups had pre-existing co-morbidities and 51⋅1% (47/92) had previous pregnancy problems while women across White ethnic groups had 3⋅2% (3/93) and 33⋅3% (27/81) respectively. Three or more unscheduled healthcare attendances occurred in 60⋅0% (36/60) of White British/Irish, 39⋅4% (13/33) in White European/Other and 35⋅9% (37/103) of Other than White women. Evidence of barriers to following healthcare advice was identified for a fifth of all women. None of the 17 women who required an interpreter received appropriate provision at all key points throughout their maternity care. Interpretation: Neither increased social risk factors or barriers to engagement with maternity services appear to underlie disparities in maternal mortality. Management of complex social factors and interpreter services need improvement. Funding: National Institute for Health Research (NIHR) Applied Research Collaboration West Midlands.

EClinicalMedicine · 6 citationsread the source →

Adverse effects of COVID-19-related lockdown on pain, physical activity and psychological well-being in people with chronic pain.

Countries across the world imposed lockdown restrictions during the COVID-19 pandemic. It has been proposed that lockdown conditions, including social and physical distancing measures, may disproportionately impact those living with chronic pain and require rapid adaptation to treatment and care strategies. Using an online methodology, we investigated how lockdown restrictions in the United Kingdom impacted individuals with chronic pain (N = 431) relative to a healthy control group (N = 88). Data were collected during the most stringent period of lockdown in the United Kingdom (mid-April to early-May 2020). In accordance with the fear-avoidance model, we hypothesised lockdown-related increases in pain and psychological distress, which would be mediated by levels of pain catastrophising. Responses indicated that people with chronic pain perceived increased pain severity, compared to their estimation of typical pain levels prior to lockdown (p < .001). They were also more adversely affected by lockdown conditions compared to pain-free individuals, demonstrating greater self-perceived increases in anxiety and depressed mood, increased loneliness and reduced levels of physical exercise (p ⩽ .001). Hierarchical regression analysis revealed that pain catastrophising was an important factor relating to the extent of self-perceived increases in pain severity during lockdown (β = .27, p < .001) and also mediated the relationship between decreased mood and pain. Perceived decreases in levels of physical exercise also related to perceptions of increased pain (β = .15, p < .001). Interestingly, levels of pain intensity (measured at two time points at pre and during lockdown) in a subgroup (N = 85) did not demonstrate a significant change. However, individuals in this subgroup still reported self-perceived pain increases during lockdown, which were also predicted by baseline levels of pain catastrophising. Overall, the findings indicate that people with chronic pain suffer adverse effects of lockdown including self-perceived increases in their pain. Remote pain management provision to target reduction of pain catastrophising and increase health behaviours including physical activity could be beneficial for this vulnerable population.

British journal of pain · 83 citationsread the source →

Anxiety and Emotional Intelligence: Comparisons Between Combat Sports, Gender and Levels Using the Trait Meta-Mood Scale and the Inventory of Situations and Anxiety Response.

The present study compared emotional intelligence and anxiety between six combat sports of lower, intermediate and high-level female and male athletes. The sample was composed by 444 athletes (age: 24.7 ± 8.8 years, body mass: 72.4 ± 12.1 kg, height: 1.82 ± 0.3 m, and practice time: 13.1 ± 7.4 years) separated by sex (male n = 273, female n = 171) from different combat sports (jiu-jitsu n = 142, judo n = 137, karate n = 57, kendo n = 63, taekwondo n = 25, and freestyle wrestling n = 20) of three levels (high-level n = 57, intermediate n = 137 and low-level n = 142). Inventory of situations and anxiety response (ISRA) provided an independent evaluation for the three systems: cognitive, motor and physiological, as well as a total with four factors of analysis (anxiety before the evaluation, interpersonal, phobic and before habitual, and daily situations). Trait Meta-Mood Scale (TMMS-24) verified emotional intelligence scales. Descriptive results are demonstrated by percentage or median (first quartile Q1; third quartile Q3), Kruskal-Wallis and Mann-Whitney tests were conducted to compare groups, p ≤ 0.05. The main results demonstrated 10% more total anxiety for wrestling and judo compared to the other groups (p ≤ 0.05). Female athletes showed 15% more anxiety than men, while emotional attention demonstrated 10% better results for women. Significant differences were observed between high- versus low-level athletes in the total anxiety with 85 (44; 143) versus 122 (69; 186) of ISRA index and emotional repair with 30 (25; 34) versus 27 (22; 32) of TMMS-24 index. Emotional intelligence seems to be higher in female and in higher level, while anxiety appears to be prevalent in judo and wrestling, low-level and in female athletes. These outcomes provide support for the hypothesis that emotional abilities are an important contributor to emotional intelligence, particularly differentiating high level athletes than other levels. Results can be incorporated into strategies for reducing anxiety and improving emotional intelligence, considering particularities of gender and level groups.

Frontiers in psychology · 25 citationsread the source →

Life expectancy and active life expectancy by marital status among older U.S. adults: Results from the U.S. Medicare Health Outcome Survey (HOS).

Background: Previous investigations of the relationship between marital status and life expectancy and healthy life expectancy rely on the assumption that participants will remain in a given marital status until death. This study estimated total life expectancy (TLE) and active life expectancy (ALE) for respondents by their baseline marital status using a large longitudinal sample of the U.S. community-dwelling elderly population. Methods: Data were from the Medicare Health Outcomes Survey Cohort 15 (2012 baseline, 2014 follow-up). We included respondents aged ≥65 years (n = 164,597). Multi-state models estimated TLE and ALE by marital status to allow participants' marital status to change during the remaining lifetime. Results: Between 65 and 85 years, married men and women had a longer TLE and ALE than unmarried men and women. For example, at 65 years, TLE for married men was 18.6 years, 2.2 years longer than unmarried men, and ALE for married men was 12.3 years, 2.4 years longer than unmarried men. Similarly, at 65 years, TLE for married women was 21.1 years, 1.5 years longer than unmarried women, and ALE for married women was 13.0 years, 2.0 years longer than unmarried women. Such marriage protection effects decreased with age. In subgroups of unmarried persons, never married persons had the shortest TLE and ALE among men, and never married, divorced, and widowed persons had a similar, and shorter, TLE and ALE among women. The difference in TLE between married and unmarried persons was smaller after adjusting for baseline activity limitation status. Conclusions: This study provides additional evidence for marriage's protective effect, with the magnitude of protection being greater for younger as compared to older persons. Selection bias was a large contributor to longer life expectancy among married persons.

SSM - population health · 26 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 →

Validation of the Impact of Event Scale With Modifications for COVID-19 (IES-COVID19).

Viral outbreaks can be experienced as disruptive and can be associated with trauma-related stress symptoms. In the current study, we adjusted the Dutch version of the Impact of Event Scale (IES) to assess traumatic stress symptoms related to the impact of the COVID-19 outbreak. The psychometric properties of this Impact of Event Scale with modifications for COVID-19 (IES-COVID19) were investigated by administering the IES-COVID19 to 380 university students who participated during the early stage of the COVID-19 outbreak, upon invitation via e-mail. Using confirmatory factor analysis, the factor structure of the IES-COVID19 was found to be similar to the original IES, indicating two latent factors: intrusion and avoidance, χ2 (85) = 147.51, CFI = .92, TLI = .90, RMSEA = .044, SRMR = .049. Cronbach's alpha showed acceptable internal consistency of the total IES-COVID19, α = .75. Pearson's correlations of the IES-COVID19 over time were also sufficient, demonstrating adequate test-retest reliability, r = .62. Significant correlations (ranging between .15 and .50) between the IES-COVID19 and symptoms of depression, anxiety, stress, stress-related rumination, as well as negative social interactions, demonstrate adequate convergent validity. Overall, the IES-COVID19 shows to be a valid and reliable measure that can be utilized to investigate trauma-related stress symptoms of intrusion and avoidance related to the short- and long-term impact of the COVID-19 outbreak.

Frontiers in psychiatry · 62 citationsread the source →

Early life undernutrition and adult height: The Dutch famine of 1944-45.

Current research shows strong associations between adult height and several positive outcomes such as higher cognitive skills, better earning capacity, increased chance of marriage and better health. It is therefore relevant to investigate the determinants of adult height. There is mixed evidence on the effects of undernutrition during early life on adult height. Therefore, our study aims at assessing the impact of undernutrition during gestation and at ages younger than 15 on adult height. We used data from the Longitudinal Aging Study Amsterdam. Exposure to undernutrition was determined by place of residence during the Dutch famine during World War II. Included respondents were born between 15 May 1930 and 1 November 1945 and lived in the northern part of the Netherlands during the famine period (n=1008). Exposure data was collected using interviews and questionnaires and adult height was measured. Exposed and non-exposed respondents were classified in the age categories pregnancy- age 1 (n=85), age 1-5 (n=323), age 6-10 (n=326) or puberty (age 11-15, n=274). Linear regression analyses were used to test the associations of adult height with exposure. The robustness of the regression results was tested with sensitivity analyses. In the models adjusted for covariates (i.e., number of siblings, education level of parents, and year of birth) and stratified by gender, adult height was significantly shorter for females exposed at ages younger than 1 (-4.45cm [-7.44--1.47]) or at ages younger than 2 (-4.08cm [-7.20--0.94]). The results for males were only borderline significant for exposure under age 1 (-3.16 [-6.82-0.49]) and significant for exposure under age 2 (-4.09cm [-7.20--0.96]). Exposure to the Dutch famine at other ages was not consistently significantly associated with adult height. In terms of public health relevance, the study's results further underpin the importance of supporting pregnant women and young parents exposed to undernutrition.

Economics and human biology · 24 citationsread the source →

Excess years of life lost to COVID-19 and other causes of death by sex, neighbourhood deprivation, and region in England and Wales during 2020: A registry-based study.

Background: Deaths in the first year of the Coronavirus Disease 2019 (COVID-19) pandemic in England and Wales were unevenly distributed socioeconomically and geographically. However, the full scale of inequalities may have been underestimated to date, as most measures of excess mortality do not adequately account for varying age profiles of deaths between social groups. We measured years of life lost (YLL) attributable to the pandemic, directly or indirectly, comparing mortality across geographic and socioeconomic groups. Methods and findings: We used national mortality registers in England and Wales, from 27 December 2014 until 25 December 2020, covering 3,265,937 deaths. YLLs (main outcome) were calculated using 2019 single year sex-specific life tables for England and Wales. Interrupted time-series analyses, with panel time-series models, were used to estimate expected YLL by sex, geographical region, and deprivation quintile between 7 March 2020 and 25 December 2020 by cause: direct deaths (COVID-19 and other respiratory diseases), cardiovascular disease and diabetes, cancer, and other indirect deaths (all other causes). Excess YLL during the pandemic period were calculated by subtracting observed from expected values. Additional analyses focused on excess deaths for region and deprivation strata, by age-group. Between 7 March 2020 and 25 December 2020, there were an estimated 763,550 (95% CI: 696,826 to 830,273) excess YLL in England and Wales, equivalent to a 15% (95% CI: 14 to 16) increase in YLL compared to the equivalent time period in 2019. There was a strong deprivation gradient in all-cause excess YLL, with rates per 100,000 population ranging from 916 (95% CI: 820 to 1,012) for the least deprived quintile to 1,645 (95% CI: 1,472 to 1,819) for the most deprived. The differences in excess YLL between deprivation quintiles were greatest in younger age groups; for all-cause deaths, a mean of 9.1 years per death (95% CI: 8.2 to 10.0) were lost in the least deprived quintile, compared to 10.8 (95% CI: 10.0 to 11.6) in the most deprived; for COVID-19 and other respiratory deaths, a mean of 8.9 years per death (95% CI: 8.7 to 9.1) were lost in the least deprived quintile, compared to 11.2 (95% CI: 11.0 to 11.5) in the most deprived. For all-cause mortality, estimated deaths in the most deprived compared to the most affluent areas were much higher in younger age groups, but similar for those aged 85 or over. There was marked variability in both all-cause and direct excess YLL by region, with the highest rates in the North West. Limitations include the quasi-experimental nature of the research design and the requirement for accurate and timely recording. Conclusions: In this study, we observed strong socioeconomic and geographical health inequalities in YLL, during the first calendar year of the COVID-19 pandemic. These were in line with long-standing existing inequalities in England and Wales, with the most deprived areas reporting the largest numbers in potential YLL.

PLoS medicine · 30 citationsread the source →

End-of-life decisions in Burn Intensive Care Units - An International Survey.

Introduction: Burn victims and their families are faced with an unexpected, life changing injury, and they don't have the necessary time to adjust to the trauma. Even though there is extensive literature exploring the attitudes of intensive care physicians on forgoing life-sustaining treatment, little is known about end-of-life practices in specialised burn intensive care units (ICUs). The aim of this study was to evaluate physician beliefs, values, considerations and difficulties in end-of-life decisions in burn ICUs. Methods: Two hundred and fifty questionnaires were distributed via electronic mail to burn specialists, randomly selected from the directories of the 45(th) annual meeting of American Burn Association and the 15(th) European Burns Association Congresses. Results: A moral difference between withdrawing and withholding was stated by 73% of physicians, with withholding being viewed as more preferable (42% vs 37%). Primary reasons given by physicians for the decision to withhold/withdraw the treatment were the patient's medical condition/high probability of death (68%), unresponsiveness to therapy (68%), severity of burn (78%) and poor outcome in terms of quality of life (44%). Vasopressors (85%), blood products (68%) and renal replacement therapy (85%) were the common modalities withheld/withdrawn. Almost 50% involved the patients in the end-of-life decisions and 66% involved the family. Conclusions: In this first international study on end-of-life attitudes, burn ICU physicians clearly distinguish between withhold and withdrawal decisions, with the majority preferring the former. In contrast to general ICUs, treatment limitation accounts only for the minority of the deaths.

Burns : journal of the International Society for Burn Injuries · 20 citationsread the source →

Objective Daytime Napping is Associated with Disease Severity and Inflammation in Patients with Mild to Moderate Dementia1.

Background: Patients with dementia report excessive daytime sleep/sleepiness, which is associated with worse cognitive performance. Inflammatory markers may be elevated in patients with dementia and have been proposed as mediators of sleep/sleepiness. Objective: To examine the association of objective daytime napping with cognitive performance and peripheral markers of inflammation in patients with dementia as compared to not cognitively impaired (NCI) controls. Methods: A sub-sample of 46 patients with mild-to-moderate dementia and 85 NCI controls, were recruited from a large, population-based cohort of 3,140 elders (≥60 years) in Crete, Greece. All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and a single morning measure of IL-6 and TNFα plasma levels. Comparisons of sleep parameters and inflammation markers between diagnostic groups, and between nappers and non-nappers within each diagnostic group, were conducted using ANCOVA controlling for demographics/related clinical factors. Associations between inflammatory markers, sleep variables, and neuropsychological performance were assessed within each group using partial correlation analysis controlling for confounders. Results: Patients with dementia slept 15 minutes longer during the day than NCI. Within dementia patients, nappers had significantly worse performance on autobiographic memory (p = 0.002), working memory (p = 0.007), episodic memory (p = 0.010), and assessment of daily function (p = 0.012) than non-nappers. Finally, IL-6 levels were significantly associated with nap duration within dementia patients who napped (r = 0.500, p = 0.01). Conclusions: Daytime napping in patients with dementia is associated with worse cognitive performance and increased IL-6 levels. In dementia, objective daytime napping, may be a marker of the severity of the disease.

Journal of Alzheimer's disease : JAD · 21 citationsread the source →

Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study.

Background: In China, depressive disorders have been estimated to be the second leading cause of years lived with disability. However, nationally representative epidemiological data for depressive disorders, in particular use of mental health services by adults with these disorders, are unavailable in China. The present study, part of the China Mental Health Survey, 2012-15, aims to describe the socioeconomic characteristics and the use of mental health services in people with depressive disorders in China. Methods: The China Mental Health Survey was a cross-sectional epidemiological survey of mental disorders in a multistage clustered-area probability sample of adults of Chinese nationality (≥18 years) from 157 nationwide representative population-based disease surveillance points in 31 provinces across China. Trained investigators interviewed the participants with the Composite International Diagnostic Interview 3.0 to ascertain the presence of lifetime and 12-month depressive disorders according to DSM-IV criteria, including major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Participants with 12-month depressive disorders were asked whether they received any treatment for their emotional problems during the past 12 months and, if so, the specific types of treatment providers. The Sheehan Disability Scale (SDS) was used to assess impairments associated with 12-month depressive symptoms. Data-quality control procedures included logic check by computers, sequential recording check, and phone-call check by the quality controllers, and reinterview check by the psychiatrists. Data were weighted according to the age-sex-residence distribution data from China's 2010 census population survey to adjust for differential probabilities of selection and differential response, as well as to post-stratify the sample to match the population distribution. Findings: 28 140 respondents (12 537 [44·6%] men and 15 603 [55·4%] women) completed the survey between July 22, 2013, and March 5, 2015. Ethnicity data (Han or non-Han) were collected for only a subsample. Prevalence of any depressive disorders was higher in women than men (lifetime prevalence odds ratio [OR] 1·44 [95% CI 1·20-1·72] and 12-month prevalence OR 1·41 [1·12-1·78]), in unemployed people than employed people (lifetime OR 2·38 [95% CI 1·68-3·38] and 12-month OR 2·80 [95% CI 1·88-4·18]), and in people who were separated, widowed, or divorced compared with those who were married or cohabiting (lifetime OR 1·87 [95% CI 1·39-2·51] and 12-month OR 1·85 [95% CI 1·40-2·46]). Overall, 574 (weighted % 75·9%) of 744 people with 12-month depressive disorders had role impairment of any SDS domain: 439 (83·6%) of 534 respondents with major depressive disorder, 207 (79·8%) of 254 respondents with dysthymic disorder, and 122 (59·9%) of 189 respondents with depressive disorder not otherwise specified. Only an estimated 84 (weighted % 9·5%) of 1007 participants with 12-month depressive disorders were treated in any treatment sector: 38 (3·6%) in speciality mental health, 20 (1·5%) in general medical, two (0·3%) in human services, and 21 (2·7%) in complementary and alternative medicine. Only 12 (0·5%) of 1007 participants with depressive disorders were treated adequately. Interpretation: Depressive disorders in China were more prevalent in women than men, unemployed people than employed, and those who were separated, widowed, or divorced than people who were married or cohabiting. Most people with depressive disorders reported social impairment. Treatment rates were very low, and few people received adequate treatment. National programmes are needed to remove barriers to availability, accessibility, and acceptability of care for depression in China. Funding: National Health Commission and Ministry of Science and Technology of People's Republic of China. Translation: For the Chinese translation of the abstract see Supplementary Materials section.

The lancet. Psychiatry · 591 citationsread the source →

Dietary inflammatory index, cardiometabolic conditions and depression in the Seguimiento Universidad de Navarra cohort study.

Only one prospective study has analysed the relationship between the inflammatory properties of diet and risk of depression thus far. The aim of this study was to assess the association between the dietary inflammatory index (DII) and the incidence of depression. In a cohort study of 15 093 university graduates, participants completed a validated FFQ at baseline and after 10 years of follow-up. The DII was calculated based on the FFQ. Each of the twenty-eight nutrients or foods received a score based on findings from the peer-reviewed literature reporting on the relationships between diet and inflammatory biomarkers (IL-1β, IL-4, IL-6, IL-10, TNF-α and C-reactive protein). Participants were classified as having depression if they reported a new clinical diagnosis of depression by a physician, antidepressant drugs, or both. Multivariable Cox regression models were used to estimate hazard ratios (HR) of depression according to quintiles of the DII. After a median 8·5 years of follow-up, we observed 1051 incident cases of depression. The HR for participants in the highest quintile of DII (strongly pro-inflammatory) was 1·47 (95% CI 1·17, 1·85) compared with those in the bottom quintile, with a significant dose-response relationship (P trend=0·01). In the subgroup analyses, the association between DII and depression was stronger among participants >55 years and among those with cardiometabolic comorbidities (HR 2·70; 95% CI 1·22, 5·97 and HR 1·80; 95% CI 1·27, 2·57, respectively). A pro-inflammatory diet was associated with a significantly higher risk of depression in a Mediterranean population. This association was stronger among older subjects and subjects with cardiometabolic diseases.

The British journal of nutrition · 90 citationsread the source →

Development of a scale to measure the psychological resources of grit in adults.

Grit, a personality trait characterized by  having passion and perseverance for long-term goals, has been linked to increased performance, retention, and well-being in various fields. In the 15 years since the original grit scale was published, many studies have investigated factors that promote grit. However, a scale has not yet been developed measuring characteristics that can contribute to higher levels of grit. This study aimed to develop a novel scale to measure the psychological resources of grit. The Delphi technique was used to obtain consensus from a national and international panel of academics and practitioners who are experts in grit and related constructs. A total of 30 participants rated 100 scale items over three rounds of online surveys. Experts agreed that items selected for the final scale (n = 20) were essential, with 85% rating them as important or very important. The scale, called the Grit Psychological Resources Scale, has promise as a helpful tool for practitioners involved in staff development and building capabilities that contribute to goal achievement.

Nursing & health sciences · 4 citationsread the source →

Estimating the effect of HIV on cervical cancer elimination in South Africa: Comparative modelling of the impact of vaccination and screening.

Background: In 2020, the World Health Organization (WHO) launched its initiative to eliminate cervical cancer as a public health problem. To inform global efforts for countries with high HIV and cervical cancer burden, we assessed the impact of human papillomavirus (HPV) vaccination and cervical cancer screening and treatment in South Africa, on cervical cancer and the potential for achieving elimination before 2120, considering faster HPV disease progression and higher cervical cancer risk among women living with HIV(WLHIV) and HIV interventions. Methods: Three independent transmission-dynamic models simulating HIV and HPV infections and disease progression were used to predict the impact on cervical cancer incidence of three scenarios for all women: 1) girls' vaccination (9-14 years old), 2) girls' vaccination plus 1 lifetime cervical screen (at 35 years), and 3) girls' vaccination plus 2 lifetime cervical screens (at 35 and 45 years) and three enhanced scenarios for WLHIV: 4) vaccination of young WLHIV aged 15-24 years, 5) three-yearly cervical screening of WLHIV aged 15-49 years, or 6) both. Vaccination assumed 90% coverage and 100% lifetime protection with the nonavalent vaccine (against HPV-16/18/31/33/45/52/58). Cervical cancer screening assumed HPV testing with uptake increasing from 45% (2023), 70% (2030) to 90% (2045+). We also assumed that UNAIDS 90-90-90 HIV treatment and 70% male circumcision targets are reached by 2030. We examined three elimination thresholds: age-standardised cervical cancer incidence rates below 4 or 10 per 100,000 women-years, and >85% reduction in cervical cancer incidence rate. We conducted sensitivity analyses and presented the median age-standardised predictions of outcomes of the three models (minimum-maximum across models). Findings: Girls' vaccination could reduce age-standardised cervical cancer incidence from a median of 47.6 (40.9-79.2) in 2020 to 4.5 (3.2-6.3) per 100,000 women-years by 2120, averting on average ∼4% and ∼46% of age-standardised cumulative cervical cancer cases over 25 and 100 years, respectively, compared to the basecase. Adding 2 lifetime screens helped achieve elimination over the century among all women (2120 cervical cancer incidence: 3.6 (1.9-3.6) per 100,000 women-years), but not among WLHIV (10.8 (5.3-11.6)), and averted more cumulative cancer cases overall (∼45% over 25 years and ∼61% over 100 years compared to basecase) than girls' vaccination alone. Adding three-yearly cervical screening among WLHIV (to girls' vaccination and 2 lifetime cervical screens) further reduced age-standardised cervical cancer incidence to 3.3 (1.8-3.6) per 100,000 women-years overall and to 5.2 (3.9-8.5) among WLHIV by 2120 and averted on average 12-13% additional cumulative cancer cases among all women and 21-24% among WLHIV than girls' vaccination and 2 lifetime cervical screens over 25 years or longer. Long-term vaccine protection and using the nonavalent vaccine was required for elimination. Interpretation: High HPV vaccination coverage of girls and 2 lifetime cervical screens could eliminate cervical cancer among women overall in South Africa by the end of the century and substantially decrease cases among all women and WLHIV over the short and medium term. Cervical cancer elimination in WLHIV would likely require enhanced prevention strategies for WLHIV. Screening of WLHIV remains an important strategy to reduce incidence and alleviate disparities in cervical cancer burden between women with and without HIV, despite HIV interventions scale-up. Funding: World Health Organization. National Cancer Institute, National Institutes of Health. MRC Centre for Global Infectious Disease Analysis, UK Medical Research Council. National Institute of Child Health and Human Development research. Cancer Association of South Africa. Canadian Institutes of Health Research and the Fonds de recherche du Québec - Santé research.

EClinicalMedicine · 19 citationsread the source →

Family and Caregiver Spillover Effects in Cost-Utility Analyses of Alzheimer's Disease Interventions.

Background and objective: Alzheimer's disease or dementia can impose a significant burden on family and other informal caregivers. This study investigated how the inclusion of family/informal caregiver spillover effects in a cost-utility analysis may influence the reported value of Alzheimer's disease/dementia interventions. Methods: We used PubMed to identify Alzheimer's disease or dementia cost-utility analyses published from 1 January, 2000 to 31 March, 2018. We reviewed and abstracted information from each study using a two-reader consensus process. We investigated the frequency and methods in which family/caregiver spillover costs and health effects were incorporated into cost-utility analyses, and examined how their inclusion may influence the reported incremental cost-effectiveness ratios. Results: Of 63 Alzheimer's disease/dementia cost-utility analyses meeting inclusion criteria, 44 (70%) considered at least some family/caregiver spillover costs or health effects. Thirty-two studies incorporated spillover costs only, two incorporated spillover health effects only, and ten incorporated both. The most common approach for accounting for spillover was adding informal caregiving time costs to patient costs (n = 36) and adding informal caregiver quality-adjusted life-years to patient values (n = 7). In a subset of 33 incremental cost-effectiveness ratio pairs from 19 studies, incorporating spillover outcomes made incremental cost-effectiveness ratios more favorable (n = 15; 45%) or kept the intervention cost saving (n = 13; 39%) in most cases. In fewer cases, including spillover increased incremental cost-effectiveness ratios (n = 2; 6%), kept the intervention dominated [more costs/less quality-adjusted life-years] (n = 2; 6%), or changed incremental cost-effectiveness ratio from dominated to less cost/less quality-adjusted life-years (n = 1; 3%). In 11 cases (33%), adding spillover effects into analyses resulted in a lower incremental cost-effectiveness ratio that crossed a common cost-effectiveness threshold, which could have downstream implications for programs or policies that are adopted based on cost-effectiveness analysis results. Discussion: Most Alzheimer's disease/dementia cost-utility analyses incorporated spillover costs, often as caregiver time costs, but considered spillover health impacts less often. In about 85% of the analyses, including Alzheimer's disease/dementia spillover cost or health effects decreased incremental cost-effectiveness ratios or kept the intervention cost saving. The broader value of an Alzheimer's disease/dementia intervention to society may in some cases be underestimated without considering these spillover effects on family and informal caregivers.

PharmacoEconomics · 53 citationsread the source →

The prevalence of self-reported deliberate self harm in Irish adolescents.

Background: Deliberate self harm is major public health problem, in particular among young people. Although several studies have addressed the prevalence of deliberate self harm among young people in the community, little is known about the extent to which deliberate self harm comes to the attention of medical services, the self harm methods used and the underlying motives. The aim of this study was to determine the prevalence of deliberate self harm in adolescents and the methods, motives and help seeking behaviour associated with this behaviour. Methods: A cross-sectional survey using an anonymous self-report questionnaire was administered in 39 schools in the Southern area of the Health Service Executive, Ireland. Of the 4,583 adolescents aged 15-17 years who were invited to participate in the survey, 3,881 adolescents took part (response: 85%). Results: A lifetime history of DSH was reported by 9.1% (n = 333) of the adolescents. DSH was more common among females (13.9%) than males (4.3%). Self cutting (66.0%) and overdose (35.2%) were the most common DSH methods. A minority of participants accessed medical services after engaging in DSH (15.3%). Conclusion: DSH is a significant problem in Irish adolescents and the vast majority do not come to the attention of health services. Innovative solutions for prevention and intervention are required to tackle DSH in adolescents.

BMC public health · 47 citationsread the source →

Barriers to health care access among refugee asylum seekers.

Objective: Asylum seekers have poor access to health care. Qualitative data portraying their experience is lacking. Methods: We conducted focus groups and comprehensive interviews with 35 asylum seekers and 15 expert providers/advocacy organization representatives. Purposive sampling was used to recruit subgroups. Interviews were recorded, coded, and analyzed. Results: Participants: 85% male, mostly from African countries. Major barriers: a) Internal, including mental illness, fatalism, mistrust, and perceived discrimination; b) Structural, including affordability, limited services, inadequate interpretation, resettlement challenges such as shelter, food, and employment insecurity; health care for urgent care only; and poor cultural competency; c) Barriers in social assimilation, including difficulty navigating a complex system and inadequate community support. Conclusion: Significant inter-related barriers exist at the individual, provider, and system levels. Strategies to improve access include targeting social programs and mental health services, expanding Medicaid eligibility/enrollment, promoting community-based organizations, enforcing the use of trained medical interpreters, and improving cultural competency.

Journal of health care for the poor and underserved · 122 citationsread the source →

Suffering among carers working in critical care can be reduced by an intensive communication strategy on end-of-life practices.

Purpose: Burnout syndrome (BOS) has frequently been reported in healthcare workers, and precipitating factors include communication problems in the workplace and stress related to end-of-life situations. We evaluated the effect of an intensive communication strategy on BOS among caregivers working in intensive care (ICU). Methods: Longitudinal, monocentric, before-and-after, interventional study. BOS was evaluated using the Maslach Burnout Inventory (MBI) and depression using the Centre for Epidemiologic Studies Depression Scale (CES-D) in 2007 (period 1) and 2009 (period 2). Between periods, an intensive communication strategy on end-of-life practices was implemented, based on improved organisation, better communication, and regular staff meetings. Results: Among 62 caregivers in the ICU, 53 (85%) responded to both questionnaires in period 1 and 49 (79%) in period 2. We observed a significant difference between periods in all three components of the MBI (emotional exhaustion, p = 0.04; depersonalization p = 0.04; personal accomplishment, p = 0.01). MBI classified burnout as severe in 15 (28%) caregivers in period 1 versus 7 (14%) in period 2, p < 0.01, corresponding to a 50% risk reduction. Symptoms of depression as evaluated by the CES-D were present in 9 (17%) caregivers in period 1 versus 3 (6%) in period 2, p < 0.05, corresponding to a risk reduction of almost 60%. Conclusion: The implementation of an active, intensive communication strategy regarding end-of-life care in the ICU was associated with a significant reduction in the rate of burnout syndrome and depression in a stable population of caregiving staff.

Intensive care medicine · 72 citationsread the source →

Reliability and Validity of the Revised Experiences in Close Relationships (ECR-R) Self-Report Measure of Adult Romantic Attachment

Three studies examine the psychometric properties (i.e., the test-retest reliability, convergent, and discriminant validity) of Fraley, Waller, and Brennan's Revised Experiences in Close Relationships (ECR-R) self-report measure of romantic attachment anxiety (model of self) and avoidance (model of others). Longitudinal analyses suggest that the ECR-R provided highly stable indicators of latent attachment during a 3-week period (85% shared variance). Hierarchical linear modeling analyses further validated the ECR-R, suggesting that it explained between 30% to 40% of the between-person variation in social interaction diary ratings of attachment-related emotions experienced during interactions with a romantic partner and only 5% to 15% of that in interactions with family and friends. Guidelines are offered regarding the conditions where highly reliable and precise measures of romantic attachment, such as the ECR-R, are deemed necessary and where shorter, albeit slightly less reliable measures, such as Bartholomew and Horowitz's Relationship Questionnaire, may also be viable.

Personality and Social Psychology Bulletin · 553 citationsread the source →