Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Long-term outcomes of SARS-CoV-2 variants and other respiratory infections: evidence from the Virus Watch prospective cohort in England.

This study compared the likelihood of long-term sequelae following infection with SARS-CoV-2 variants, other acute respiratory infections (ARIs) and non-infected individuals. Participants (n=5,630) were drawn from Virus Watch, a prospective community cohort investigating SARS-CoV-2 epidemiology in England. Using logistic regression, we compared predicted probabilities of developing long-term symptoms (>2 months) during different variant dominance periods according to infection status (SARS-CoV-2, other ARI, or no infection), adjusting for confounding by demographic and clinical factors and vaccination status. SARS-CoV-2 infection during early variant periods up to Omicron BA.1 was associated with greater probability of long-term sequalae (adjusted predicted probability (PP) range 0.27, 95% CI = 0.22-0.33 to 0.34, 95% CI = 0.25-0.43) compared with later Omicron sub-variants (PP range 0.11, 95% CI 0.08-0.15 to 0.14, 95% CI 0.10-0.18). While differences between SARS-CoV-2 and other ARIs (PP range 0.08, 95% CI 0.04-0.11 to 0.23, 95% CI 0.18-0.28) varied by period, all post-infection estimates substantially exceeded those for non-infected participants (PP range 0.01, 95% CI 0.00, 0.02 to 0.03, 95% CI 0.01-0.06). Variant was an important predictor of SARS-CoV-2 post-infection sequalae, with recent Omicron sub-variants demonstrating similar probabilities to other contemporaneous ARIs. Further aetiological investigation including between-pathogen comparison is recommended.

Cost and economic evidence for asset-based approaches to health improvement and their evaluation methods: a systematic review.

BACKGROUND: Asset-based approaches (ABAs) tackle health inequalities by empowering people in more disadvantaged communities, or targeted populations, to better utilise pre-existing local community-based resources. Using existing resources supports individuals to better manage their own health and its determinants, potentially at low cost. Targeting individuals disengaged with traditional service delivery methods offers further potential for meaningful cost-savings, since these people often require costly care. Thus, improving prevention, and management, of ill-health in these groups may have considerable cost implications. AIM: To systematically review the extent of current cost and economic evidence on ABAs, and methods used to develop it. METHODS: Search strategy terms encompassed: i) costing; ii) intervention detail; and iii) locality. Databases searched: Medline, CENTRAL and Wed of Science. Researchers screened 9,116 articles. Risk of bias was assessed using the Critical Appraisal Skills Programme (CASP) tool. Narrative synthesis summarised findings. RESULTS: Twelve papers met inclusion criteria, representing eleven different ABAs. Within studies, methods varied widely, not only in design and comparators, but also in terms of included costs and outcome measures. Studies suggested economic efficiency, but lack of suitable comparators made more definitive conclusions difficult. CONCLUSION: Economic evidence around ABAs is limited. ABAs may be a promising way to engage underserved or minority groups, that may have lower net costs compared to alternative health and wellbeing improvement approaches. ABAs, an example of embedded services, suffer in the context of economic evaluation, which typically consider services as mutually exclusive alternatives. Economics of the surrounding services, mechanisms of information sharing, and collaboration underpin the success of assets and ABAs. The economic evidence, and evaluations in general, would benefit from increased context and detail to help ensure more nuanced and sophisticated understanding of the economics of ABAs. Further evidence is needed to reach conclusions about cost-effectiveness of ABAs.

Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019.

BACKGROUND: Rehabilitation has often been seen as a disability-specific service needed by only few of the population. Despite its individual and societal benefits, rehabilitation has not been prioritised in countries and is under-resourced. We present global, regional, and country data for the number of people who would benefit from rehabilitation at least once during the course of their disabling illness or injury. METHODS: To estimate the need for rehabilitation, data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to calculate the prevalence and years of life lived with disability (YLDs) of 25 diseases, impairments, or bespoke aggregations of sequelae that were selected as amenable to rehabilitation. All analyses were done at the country level and then aggregated to seven regions: World Bank high-income countries and the six WHO regions (ie, Africa, the Americas, Southeast Asia, Europe, Eastern Mediterranean, and Western Pacific). FINDINGS: Globally, in 2019, 2·41 billion (95% uncertainty interval 2·34-2·50) individuals had conditions that would benefit from rehabilitation, contributing to 310 million [235-392] YLDs. This number had increased by 63% from 1990 to 2019. Regionally, the Western Pacific had the highest need of rehabilitation services (610 million people [588-636] and 83 million YLDs [62-106]). The disease area that contributed most to prevalence was musculoskeletal disorders (1·71 billion people [1·68-1·80]), with low back pain being the most prevalent condition in 134 of the 204 countries analysed. INTERPRETATION: To our knowledge, this is the first study to produce a global estimate of the need for rehabilitation services and to show that at least one in every three people in the world needs rehabilitation at some point in the course of their illness or injury. This number counters the common view of rehabilitation as a service required by only few people. We argue that rehabilitation needs to be brought close to communities as an integral part of primary health care to reach more people in need. FUNDING: Bill & Melinda Gates Foundation.

Risk factors for post-COVID-19 condition in previously hospitalised children using the ISARIC Global follow-up protocol: a prospective cohort study.

BACKGROUND: The long-term sequelae of coronavirus disease 2019 (COVID-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with COVID-19 and associated risk factors. METHODS: This is a prospective cohort study of children (≤18 years old) admitted to hospital with confirmed COVID-19. Children admitted between 2 April 2020 and 26 August 2020 were included. Telephone interviews used the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 Health and Wellbeing Follow-up Survey for Children. Persistent symptoms (>5 months) were further categorised by system(s) involved. RESULTS: 518 out of 853 (61%) eligible children were available for the follow-up assessment and included in the study. Median (interquartile range (IQR)) age was 10.4 (3-15.2) years and 270 (52.1%) were girls. Median (IQR) follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms, among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: older age "6-11 years" (OR 2.74, 95% CI 1.37-5.75) and "12-18 years" (OR 2.68, 95% CI 1.41-5.4), and a history of allergic diseases (OR 1.67, 95% CI 1.04-2.67). CONCLUSIONS: A quarter of children experienced persistent symptoms months after hospitalisation with acute COVID-19 infection, with almost one in 10 experiencing multisystem involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up.

Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021.

Importance: Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID). Objective: To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration. Design, Setting, and Participants: Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022. Exposures: Symptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age. Results: A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months. Conclusions and Relevance: This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

Incidence and risk factors for persistent symptoms in adults previously hospitalized for COVID-19.

BACKGROUND: The long-term sequalae of COVID-19 remain poorly characterized. We assessed persistent symptoms in previously hospitalized patients with COVID-19 and assessed potential risk factors. METHODS: Data were collected from patients discharged from 4 hospitals in Moscow, Russia between 8 April and 10 July 2020. Participants were interviewed via telephone using an ISARIC Long-term Follow-up Study questionnaire. RESULTS: 2,649 of 4755 (56%) discharged patients were successfully evaluated, at median 218 (IQR 200, 236) days post-discharge. COVID-19 diagnosis was clinical in 1291 and molecular in 1358. Most cases were mild, but 902 (34%) required supplemental oxygen and 68 (2.6%) needed ventilatory support. Median age was 56 years (IQR 46, 66) and 1,353 (51.1%) were women. Persistent symptoms were reported by 1247 (47.1%) participants, with fatigue (21.2%), shortness of breath (14.5%) and forgetfulness (9.1%) the most common symptoms and chronic fatigue (25%) and respiratory (17.2%) the most common symptom categories. Female sex was associated with any persistent symptom category OR 1.83 (95% CI 1.55 to 2.17) with association being strongest for dermatological (3.26, 2.36 to 4.57) symptoms. Asthma and chronic pulmonary disease were not associated with persistent symptoms overall, but asthma was associated with neurological (1.95, 1.25 to 2.98) and mood and behavioural changes (2.02, 1.24 to 3.18), and chronic pulmonary disease was associated with chronic fatigue (1.68, 1.21 to 2.32). CONCLUSIONS: Almost half of adults admitted to hospital due to COVID-19 reported persistent symptoms 6 to 8 months after discharge. Fatigue and respiratory symptoms were most common, and female sex was associated with persistent symptoms.

Omega-3 and polyunsaturated fat for prevention of depression and anxiety symptoms: systematic review and meta-analysis of randomised trials.

BACKGROUND: There is strong public belief that polyunsaturated fats protect against and ameliorate depression and anxiety. AIMS: To assess effects of increasing omega-3, omega-6 or total polyunsaturated fat on prevention and treatment of depression and anxiety symptoms. METHOD: We searched widely (Central, Medline and EMBASE to April 2017, trial registers to September 2016, ongoing trials updated to August 2019), including trials of adults with or without depression or anxiety, randomised to increased omega-3, omega-6 or total polyunsaturated fat for ≥24 weeks, excluding multifactorial interventions. Inclusion, data extraction and risk of bias were assessed independently in duplicate, and authors contacted for further data. We used random-effects meta-analysis, sensitivity analyses, subgrouping and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment. RESULTS: We included 31 trials assessing effects of long-chain omega-3 (n = 41 470), one of alpha-linolenic acid (n = 4837), one of total polyunsaturated fat (n = 4997) and none of omega-6. Meta-analysis suggested that increasing long-chain omega-3 probably has little or no effect on risk of depression symptoms (risk ratio 1.01, 95% CI 0.92-1.10, I2 = 0%, median dose 0.95 g/d, duration 12 months) or anxiety symptoms (standardised mean difference 0.15, 95% CI 0.05-0.26, I2 = 0%, median dose 1.1 g/d, duration 6 months; both moderate-quality evidence). Evidence of effects on depression severity and remission in existing depression were unclear (very-low-quality evidence). Results did not differ by risk of bias, omega-3 dose, duration or nutrients replaced. Increasing alpha-linolenic acid by 2 g/d may increase risk of depression symptoms very slightly over 40 months (number needed to harm, 1000). CONCLUSIONS: Long-chain omega-3 supplementation probably has little or no effect in preventing depression or anxiety symptoms. DECLARATION OF INTEREST: L.H. and A.A. were funded to attend the World Health Organization Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health meetings and present review results. The authors report no other conflicts of interest.

Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials.

BACKGROUND: The relationship between long-chain omega-3 (LCn3), alpha-linolenic acid (ALA), omega-6 and total polyunsaturated fatty acid (PUFA) intakes and cancer risk is unclear. METHODS: We searched Medline, Embase, CENTRAL and trials registries for RCTs comparing higher with lower LCn3, ALA, omega-6 and/or total PUFA, that assessed cancers over ≥12 months. Random-effects meta-analyses, sensitivity analyses, subgrouping, risk of bias and GRADE were used. RESULTS: We included 47 RCTs (108,194 participants). Increasing LCn3 has little or no effect on cancer diagnosis (RR1.02, 95% CI 0.98-1.07), cancer death (RR0.97, 95% CI 0.90-1.06) or breast cancer diagnosis (RR1.03, 95% CI 0.89-1.20); increasing ALA has little or no effect on cancer death (all high/moderate-quality evidence). Increasing LCn3 (NNTH 334, RR1.10, 95% CI 0.97-1.24) and ALA (NNTH 334, RR1.30, 95% CI 0.72-2.32) may slightly increase prostate cancer risk; increasing total PUFA may slightly increase risk of cancer diagnosis (NNTH 125, RR1.19, 95% CI 0.99-1.42) and cancer death (NNTH 500, RR1.10, 95% CI 0.48-2.49) but total PUFA doses were very high in some trials. CONCLUSIONS: The most extensive systematic review to assess the effects of increasing PUFAs on cancer risk found increasing total PUFA may very slightly increase cancer risk, offset by small protective effects on cardiovascular diseases.

Embedding Physical Activity into the Healthcare Curriculum - A Case Study.

Physical inactivity is a key risk factor for a wide range of non-communicable diseases, yet a large proportion of the population fail to meet recommended physical activity levels. Healthcare has been identified as a key setting in which to intervene to encourage physical activity behaviour change. However, those working in the healthcare sector must be provided with training opportunities to increase knowledge, competence and motivation. We reviewed the structure and content of the current health-related courses at the University of East Anglia to identify opportunities to deliver more content on physical activity. We identified five areas for action: the development of new learning outcomes; the creation and delivery of taught sessions on physical activity; providing resources to faculty members to support the integration of the topic across all relevant modules and courses; the development of electronic resources for students; and modifications to the Problem-Based Learning (PBL) scenarios. Taking a multi-faceted and integrated approach was important to avoid physical activity being viewed as a 'bolt-on' topic. It also helped to maximise exposure to the topic while minimising disruption to the course structure and timetable. The actions taken have proved feasible and have been well received by students and staff.

Humanising medicine: teaching on tri-morbidity using expert patient narratives in medical education.

Expert patients have recognised benefits for both students and patients in medical education. However, marginalised patients such as homeless patients are less likely to participate. Learning from such individuals is crucial for future doctors, who can, in turn, aid their inclusion in society and improve access to health care. A 'humanising medicine' lecture was delivered to Year Four medical students at Norwich Medical School. The lecture utilised narratives from patients with experience of homelessness and tri-morbidity (physical and mental health problems and substance abuse). We used a qualitative approach to evaluate this teaching and understand the experience of both students and patients. Students were asked to complete questionnaires, whereas expert patients were interviewed. We thematically analysed data using an inductive approach. Students reported an increased understanding, empathy and preparedness to consult with marginalised patients. Expert patients described positive feelings about their involvement, giving something back, and the therapeutic benefits of telling their story. We found that including marginalised patients in medical education had positive benefits for both students and patients. Our findings suggest that expert patient narratives are valuable in medical education particularly in teaching and learning about medical complexity and tri-morbidity.

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake probably slightly decreases triglycerides (by 15%, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants), high-density lipoprotein (HDL) (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably has little or no effect on adiposity (body weight MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via TG reduction.

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake slightly reduces total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants) and probably slightly decreases triglycerides (MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on high-density lipoprotein (HDL) (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight.

Global Cardiovascular and Renal Outcomes of Reduced GFR.

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.

Community treatment orders: towards a new research agenda.

OBJECTIVES: The aim of this study was to report on a half-day multi-stakeholder symposium on community treatment orders (CTOs) hosted by the Melbourne Social Equity Institute (MSEI), which identified research gaps and opportunities, and produced an agreed agenda for future CTO research. METHODS: The MSEI convened a symposium for 22 experts in CTO research to discuss research priorities in this field in Australasia. An independent moderator elicited views and recommendations and produced a report detailing possible research projects. RESULTS: Research on CTOs is contentious and there is a need to gather and examine information regarding both their use and utility. Due to the complexities involved, it was agreed that research should be undertaken in partnership with persons with had lived experience of mental health problems, clinicians, policymakers and other interdisciplinary stakeholders. Five key areas for future investigation were identified. CONCLUSIONS: The issues and recommendations arising from the symposium should shape the scope, nature and conduct of future research directions in the field.

Missed opportunities in the evaluation of public health interventions: a case study of physical activity programmes.

BACKGROUND: Evidence-based approaches are requisite in evaluating public health programmes. Nowhere are they more necessary than physical activity interventions where evidence of effectiveness is often poor, especially within hard to reach groups. Our study reports on the quality of the evaluation of a government funded walking programme in five 'Walking Cities' in England. Cities were required to undertake a simple but robust evaluation using the Standard Evaluation Framework (SEF) for physical activity interventions to enable high quality, consistent evaluation. Our aim was not to evaluate the outcomes of this programme but to evaluate whether the evaluation process had been effective in generating new and reliable evidence on intervention design and what had worked in 'real world' circumstances. METHODS: Funding applications and final reports produced by the funder and the five walking cities were obtained. These totalled 16 documents which were systematically analysed against the 52 criteria in the SEF. Data were cross checked between the documents at the bid and reporting stage with reference to the SEF guidance notes. RESULTS: Generally, the SEF reporting requirements were not followed well. The rationale for the interventions was badly described, the target population was not precisely specified, and neither was the method of recruitment. Demographics of individual participants, including socio-economic status were reported poorly, despite being a key criterion for funding. CONCLUSIONS: Our study of the evaluations demonstrated a missed opportunity to confidently establish what worked and what did not work in walking programmes with particular populations. This limited the potential for evidence synthesis and to highlight innovative practice warranting further investigation. Our findings suggest a mandate for evaluability assessment. Used at the planning stage this may have ensured the development of realistic objectives and crucially may have identified innovative practice to implement and evaluate. Logic models may also have helped in the development of the intervention and its means of capturing evidence prior to implementation. It may be that research-practice partnerships between universities and practitioners could enhance this process. A lack of conceptual clarity means that replicability and scaling-up of effective interventions is difficult and the opportunity to learn from failure lost.

Extreme rituals in a BDSM context: the physiological and psychological effects of the 'Dance of Souls'.

Participation in extreme rituals (e.g., fire-walking, body-piercing) has been documented throughout history. Motivations for such physically intense activities include religious devotion, sensation-seeking and social bonding. The present study aims to explore an extreme ritual within the context of bondage/discipline, dominance/submission and sadism/masochism (BDSM): the 'Dance of Souls', a 160-person ritual involving temporary piercings with weights or hooks attached and dancing to music provided by drummers. Through hormonal assays, behavioural observations and questionnaires administered before, during and after the Dance, we examine the physiological and psychological effects of the Dance, and the themes of spirituality, connectedness, transformation, release and community reported by dancers. From before to during the Dance, participants showed increases in physiological stress (measured by the hormone cortisol), self-reported sexual arousal, self-other overlap and decreases in psychological stress and negative affect. Results suggest that this group of BDSM practitioners engage in the Dance for a variety of reasons, including experiencing spirituality, deepening interpersonal connections, reducing stress and achieving altered states of consciousness.

A spatial equity analysis of a public health intervention: a case study of an outdoor walking group provider within local authorities in England.

INTRODUCTION: If an intervention is not well spatially targeted, appropriate levels of uptake, efficacy, long-term compliance and improved health outcomes are unlikely to be attained. Effective health interventions should seek to achieve not only absolute improvements in health but also to reduce inequity. There is often a disparity whereby preventative interventions are more likely to be successful amongst the more affluent, a process which has been coined the 'inverse prevention law'. Physical inactivity is known to be socially patterned and disproportionately prevalent in disadvantaged communities yet there is a lack of clear evidence on which interventions have the potential to influence inequity. Walking groups have been found to have multiple health benefits and increase physical activity. In England the major facilitator is a not for profit organisation which has 70,000 regular walkers and is lay led with 10,000 volunteers. The aim of this study was to evaluate the extent to which walking groups operated in those places with the greatest health need and whether consequently the scheme has the potential to influence health inequity. METHOD: The work used a spatial approach whereby geographical variations in walking group provision within the 326 local authorities in England (mean population 163,410) were linked to health and socio-economic measures of population need. RESULTS: Generally, greater need was not associated with higher provision of the walking group intervention. Although the magnitude of differences was small, provision of the intervention tended to be poorest in those local authorities with the greatest health need, as measured by our indicators. CONCLUSIONS: Without targeting those areas with greater health and socio-economic need, there is a concern that walking groups may not be set up in areas that need them most. There is therefore a potential that this intervention could, albeit in a small way, widen inequity between local authorities. However small-scale and well-intentioned, interventions need to be evaluated for their potential impact on inequity.

Is there evidence that walking groups have health benefits? A systematic review and meta-analysis.

OBJECTIVE: To assess the health benefits of outdoor walking groups. DESIGN: Systematic review and meta-analysis of walking group interventions examining differences in commonly used physiological, psychological and well-being outcomes between baseline and intervention end. DATA SOURCES: Seven electronic databases, clinical trial registers, grey literature and reference lists in English language up to November 2013. ELIGIBILITY CRITERIA: Adults, group walking outdoors with outcomes directly attributable to the walking intervention. RESULTS: Forty-two studies were identified involving 1843 participants. There is evidence that walking groups have wide-ranging health benefits. Meta-analysis showed statistically significant reductions in mean difference for systolic blood pressure -3.72 mm Hg (-5.28 to -2.17) and diastolic blood pressure -3.14 mm Hg (-4.15 to -2.13); resting heart rate -2.88 bpm (-4.13 to -1.64); body fat -1.31% (-2.10 to -0.52), body mass index -0.71 kg/m(2) (-1.19 to -0.23), total cholesterol -0.11 mmol/L (-0.22 to -0.01) and statistically significant mean increases in VO(2max) of 2.66 mL/kg/min (1.67-3.65), the SF-36 (physical functioning) score 6.02 (0.51 to 11.53) and a 6 min walk time of 79.6 m (53.37-105.84). A standardised mean difference showed a reduction in depression scores with an effect size of -0.67 (-0.97 to -0.38). The evidence was less clear for other outcomes such as waist circumference fasting glucose, SF-36 (mental health) and serum lipids such as high-density lipids. There were no notable adverse side effects reported in any of the studies. CONCLUSIONS: Walking groups are effective and safe with good adherence and wide-ranging health benefits. They could be a promising intervention as an adjunct to other healthcare or as a proactive health-promoting activity.

Ectrodactyly ectodermal dysplasia clefting (EEC) syndrome: a rare cause of congenital lacrimal anomalies.

A 9-year-old girl with a medical history significant for ectrodactyly ectodermal dysplasia clefting (EEC) syndrome was referred for evaluation of congenital left-sided epiphora. The patient had undergone successful right external dacryocystorhinostomy at age 5 to treat congenital right-sided epiphora. On examination, several ocular anomalies were noted, including absence of the upper eyelid puncta, absence of the left inferior punctum, a left lacrimal fistula opening at the left caruncle, increased left tear lake, bilateral hypoplastic meibomian glands, mild conjunctival injection, and thin eyelid cilia and brow hair. Systemic findings included cleft lip and palate status-post repair, ectrodactyly of the hands and feet, adontia and microdontia, a pointed nose, and lightly pigmented, dry hair and skin. The patient underwent examination under anesthesia and left conjunctivodacryocystorhinostomy with insertion of a Jones tube with resolution of lacrimation postoperatively. To the authors' knowledge, this is the second report detailing management of congenital lacrimal anomalies in EEC syndrome, and the first describing management of punctal atresia with conjunctivodacryocystorhinostomy and Jones tube placement.