Fish consumption and omega-3 polyunsaturated fatty acids from diet are positively associated with cognitive function in older adults even in the presence of exposure to lead, cadmium, selenium, and methylmercury: a cross-sectional study using NHANES 2011-2014 data.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are reported to be beneficial for cognition, but limited consumption of some fish is recommended due to high concentrations of heavy metals and persistent organics. OBJECTIVE: We aimed to determine whether dietary ω-3 PUFAs from fish consumption are associated with higher cognitive scores in older adults and explored the associations of mixtures of ω-3 PUFAs and blood concentrations of lead, cadmium, selenium, and methylmercury on cognitive performance. METHODS: We conducted a cross-sectional study with data from the NHANES 2011-2014, assessing cognitive scores of immediate recall, delayed recall, and executive function in adults ≥60 y (n = 3123). We performed multivariate linear regressions and mixture models utilizing the quantile-based g-computation method to identify associations between monthly fish consumption or dietary ω-3 PUFAs with blood concentrations of lead, cadmium, methyl mercury, and selenium on cognitive scores. RESULTS: Fish consumption had significant positive associations with all 3 cognitive scores, whereas dietary ω-3 PUFAs were only significantly associated with the Digit Symbol Substitution Test (DSST) scores. Mixture analysis showed significant positive associations with DSST scores for fish consumption (ß: 0.88; 95% CI: 0.48, 1.29) and dietary ω-3 PUFAs (ß: 0.41; 95% CI: 0.03, 0.78) with positive component weights for fish consumption, dietary ω-3 PUFAs, and blood selenium and negative component weight for blood cadmium concentrations. CONCLUSIONS: Our findings support dietary recommendations for older adults to consume fish to maintain cognitive function, likely due to biomolecular actions of ω-3 PUFAs that increase neuronal membrane fluidity, have antioxidation activity, and restore cell damage. The combination of selenium and fish consumption or ω-3 PUFAs was associated with reduced decline in cognitive scores and less negative associations from exposures to lead, cadmium, and mercury compounds.

Delayed Diagnosis of Human Immunodeficiency Virus in the Latino Population at a Federally Qualified Community Health Center in New Jersey.

Late diagnosis of human immunodeficiency virus (HIV) is associated with early progression to acquired immunodeficiency syndrome (AIDS). We examined racial/ethnic differences in presentation with advanced HIV/AIDS at a community health center in New Jersey. Records of patients diagnosed with HIV between 1990 and 2018 were reviewed. Odds ratios (OR) of presenting with AIDS at HIV diagnosis were computed in unadjusted and adjusted models. There were 182 (48.3%) Latino, 48 (12.7%) non-Latino White (NLW), 130 (34.5%) non-Latino Black, and 17 (4.5%) non-Latino of other race/ethnicity included in the analysis. Over 75% of the Latinos were foreign-born. Latino patients had higher odds of presentation with AIDS at time of HIV diagnosis than NLW in unadjusted (OR = 4.85, 95% confidence interval (95% CI): 2.28-10.31) and adjusted models (OR = 3.71, 95%CI: 1.60-8.59). Latino patients, particularly foreign-born and bisexual, had higher odds of being diagnosed with AIDS at presentation with HIV in this cohort.

Different volatile organic compounds in local point source air pollution pose distinctive elevated risks for respiratory disease-associated emergency room visits.

Air pollution increases risk of respiratory disease but prior research has focused on particulate matter and criteria air pollutants, and there are few studies on respiratory effects of volatile organic compounds (VOC). We examined zip code level relationships between emergency room (ER) visits for respiratory illness and VOC pollution in New York State from 2010 to 2018. Detailed information on VOC pollution was derived from the National Emissions Inventory, which provides point source information on VOC emissions at the zip code level. We considered four respiratory diseases: asthma, acute upper respiratory infections, chronic obstructive pulmonary disease (COPD), and lower respiratory disease, using mixed effects regression with a random intercept to account for county level variability in single pollutant models, and Random Forest Regression (RFR) to assess relative importance of VOC exposures when considered together in multipollutant models. Single pollutant models show associations between respiratory-related ER visits with all pollutants of interest across all study years, even after adjusting for poverty and smoking by zip code. The largest relative single pollutant effect sizes considered included benzene, ethylbenzene, and total (summed) VOCs. Results from RFR including all VOC exposures indicate that ethylbenzene has the greatest variable importance for asthma, acute upper respiratory infections, and COPD, with toluene and benzene most important for lower respiratory ailments. RFR results also demonstrate presence of pairwise interactive effects between VOC pollutants. Our findings show that local VOC pollution may offer a significant contribution to the risk of respiratory disease-related ER visits, and that effects vary by illness and by VOC compound. ER visit rates for respiratory illness were elevated in high poverty zip codes, although this may be attributable to the fact that the poor lack basic access to health care and use ERs more frequently for routine care.

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Effects of mixtures of polychlorinated biphenyls (PCBs) and three organochlorine pesticides on cognitive function differ between older Mohawks at Akwesasne and older adults in NHANES.

BACKGROUND: Akwesasne Mohawks has been exposed to high concentrations of polychlorinated biphenyls (PCBs) and background levels of organochlorine pesticides, hexachlorobenzene (HCB), dichlorodiphenyl dichloroethylene (DDE), and mirex. We have previously reported relative contributions to the mixture of low- and high-chlorinated PCBs, HCB, and DDE on cognitive decrements in Mohawks of various ages. OBJECTIVE: This study examines differences in the mixture effects of PCB congener groups, HCB, DDE, and mirex on cognitive function in older Mohawks and less PCB-exposed older adults from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 cycles. METHODS: We used Bayesian kernel machine regression (BKMR) to evaluate the mixture effects of different PCB congener groups, HCB, DDE, and mirex on cognitive function in both populations. Models were adjusted for age, sex, education levels, and race/ethnicity focusing on individuals 60 years and older. RESULTS: Older Mohawks had 3-fold higher mean total PCB concentrations and 1.8-fold higher mirex, but slightly lower mean DDE and HCB levels than NHANES older adults. Higher mixture concentrations were significantly associated with greater cognitive decline. In older Mohawks, low- and high-chlorinated PCBs, HCB, and DDE contributed to the cognitive score decline. In contrast, score decline in older NHANES adults were primarily from high-chlorinated PCBs and DDE with a threshold dose of approximately 2.08-2.27 ng/g and 2.02-2.40 ng/g, respectively. CONCLUSION: Mixtures of PCBs and organochlorine pesticides increase the risk of cognitive decline in both older Mohawks and NHANES older adults. However, contributions to these mixture effects show significant differences. In older Mohawks, high- and low-chlorinated PCBs, DDE, and HCB are the primary contributors, while high-chlorinated PCBs and DDE are important contributors in NHANES older adults. Due to chronic heavy exposures to PCBs, older Mohawks had a significantly increased risk of cognitive decline compared to general older adults from NHANES.

Listening to What Matters Most: Consumer Endorsed Patient Reported Outcome Measures (PROMs) for Use in Multiple Myeloma Clinical Trials: A Descriptive Exploratory Study.

BACKGROUND: Patients with multiple myeloma (MM) experience some of the highest levels of symptom burden of all hematological malignancies. Therefore, assessment of quality of life (QoL) is critical for the delivery of patient-centered cancer care. Patient reported outcome measures (PROMs) are commonly used to measure QoL in people with MM. However, it is unknown whether measures used, are appropriate and informative to address issues that matter most to patients. AIM: This exploratory study was designed to establish consumer endorsed PROMs to measure QoL in people with MM. METHOD: This was a descriptive, exploratory study. Participants were invited to provide feedback on the acceptability, appropriateness, and practicability of ten commonly used PROMs via telephone-based, semi-structured interviews and surveys. Data were analyzed using a manifest content analysis approach and descriptive statistics. RESULTS: 26 individuals participated in the study. Participants emphasized the importance of selecting a suite of PROMs that captures the diversity of quality-of-life experiences and priorities reported over the course of treatment, while minimizing the burden of completing PROMs. Based on these criteria, a suite of three PROMs - the MyPOS, the Brief Fatigue Inventory, and COST-FACIT were endorsed by study participants. CONCLUSION: To our knowledge, this is the first study of its kind to establish a suite of consumer-endorsed PROMs for use in clinical trials in patients with MM. Ensuring that the patient voice is at the center of advances in cancer treatment is a hallmark of quality cancer care.

Views of female genital mutilation survivors, men and health-care professionals on timing of deinfibulation surgery and NHS service provision: qualitative FGM Sister Study.

Background: Female genital mutilation is an important UK health-care challenge. There are no health benefits of female genital mutilation, and it is associated with lifelong physical, psychological and sexual impacts. The annual cost to the NHS to care for survivors is £100M. Deinfibulation may improve the health and well-being of some women, but there is no consensus on the optimal timing of surgery for type 3 survivors. UK care provision is reportedly suboptimal. Objectives: We aimed to explore the views of survivors, men and health-care professionals on the timing of deinfibulation surgery and NHS service provision. Methods: This was a qualitative study informed by the Sound of Silence framework. This framework is useful for researching sensitive issues and the health-care needs of marginalised populations. A total of 101 interviews with 44 survivors, 13 men and 44 health-care professionals were conducted, supplemented by two workshops with affected communities (participants, n = 10) and one workshop with stakeholders (participants, n = 30). Data were analysed using a hybrid framework method. Results: There was no clear consensus between groups on the optimal timing of deinfibulation. However, within groups, survivors expressed a preference for deinfibulation pre pregnancy; health-care professionals preferred antenatal deinfibulation, with the caveat that it should be the survivor's choice. There was no consensus among men. There was agreement that deinfibulation should take place in a hospital setting and be undertaken by a suitable health-care professional. Decision-making around deinfibulation was complex. Deficiencies in professionals' awareness, knowledge and understanding resulted in impacts on the provision of appropriate care. Although there were examples of good practice and positive care interactions, in general, service provision was opaque and remains suboptimal, with deficiencies most notable in mental health. Deinfibulation reportedly helps to mitigate some of the impacts of female genital mutilation. Interactions between survivors and health-care professionals were disproportionately framed around the law. The way in which services are planned and provided often silences the perspectives and preferences of survivors and their families. Limitations: Only a minority of the interviews were conducted in a language other than English, and the recruitment of survivors was predominantly through maternity settings, which meant that some voices may not have been heard. The sample of men was relatively small, limiting interpretation. Conclusions: In general, service provision remains suboptimal and can silence the perspectives and preferences of survivors. Deinfibulation services need to be widely advertised and information should highlight that the procedure will be carried out in hospital by suitable health-care professionals and that a range of time points will be offered to facilitate choice. Future services should be developed with survivors to ensure that they are clinically and culturally appropriate. Guidelines should be updated to better reflect the needs of survivors and to ensure consistency in service provision. Future work: Research is needed to (1) map female genital mutilation service provision; (2) develop and test effective education to address deficits in awareness and knowledge for affected communities and health-care professionals; and (3) develop, monitor and evaluate clinically and culturally competent female genital mutilation services. Trial registration: Current Controlled Trials ISRCTN14710507. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme and will be published in full in Health Technology Assessment; Vol. 27, No. 3. See the NIHR Journals Library website for further project information.

Female genital mutilation (or cutting) involves changing or removing parts of a girl's or woman's genitalia when there is no medical reason to do so. Many women and girls who have been cut live in the UK, where female genital mutilation is illegal. Some girls and women who have been cut experience problems in getting pregnant and having their baby. There are four types of cutting. Type 3 involves cutting and sewing together the genitalia, leaving only a small hole. Women and girls with type 3 mutilation can have a small operation to open their vagina. We do not know when the best time is to have this operation. We would also like to know more about how NHS female genital mutilation services can best help women. To answer these questions, we talked to 141 people, who were women who have been cut, men and health-care professionals. They told us that there is no ideal time to have the operation. Women who have been cut would like the operation before they get pregnant, but health-care professionals would like women to have it during their pregnancy. Men were not sure when it should happen. They all agreed that the operation should take place in a hospital and be carried out by a skilled professional. The way that we support women and men could be better and we need to improve the help that is offered. Sometimes women and men did not know where to go for help or how to ask for help. Women, men and health-care professionals sometimes found it hard to talk about cutting. Some health professionals did not have the right skills to undertake the operation. They told us that they need more training and clearer guidance to ensure that women feel cared for and safe.

Effects on neonatal immunoglobulin concentrations by infant mode of delivery in the upstate KIDS study (2008-2010).

PROBLEM: Previous studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS). METHOD OF STUDY: The Upstate KIDS Study (2008-2010) is a prospective cohort of mother-child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1 , IgG2 , IgG3 , IgG4 , and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status. RESULTS: IgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively. CONCLUSIONS: MOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD. Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted.

Mixture Effects of Polychlorinated Biphenyls (PCBs) and Three Organochlorine Pesticides on Cognitive Function in Mohawk Adults at Akwesasne.

The Mohawks at Akwesasne have been highly exposed to polychlorinated biphenyls (PCBs), via releases from three aluminum foundries located near the reserve. They are also exposed to organochlorine pesticides, namely hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (DDE), and mirex. Previous studies have demonstrated reduced cognition in relation to total PCBs, but the effects of the mixtures of different PCB congener groups, HCB, DDE, and mirex on cognitive function have not been studied. Therefore, cognitive performance for executive function, scored via the digit symbol substitution test (DSST), in Mohawk adults aged 17-79 years (n = 301), was assessed in relation to serum concentrations of low-chlorinated PCBs, high-chlorinated PCBs, total PCBs, HCB, DDE, and mirex. We used mixture models employing the quantile-based g-computation method. The mixture effects of low-chlorinated PCBs, high-chlorinated PCBs, HCB, DDE, and mirex were significantly associated with 4.01 DSST scores decrements in the oldest age group, 47-79 years old. There were important contributions to mixture effects from low-chlorinated PCBs, high-chlorinated PCBs, and total PCBs, with smaller contributions of HCB and DDE. Our findings indicate that exposures to both low- and high-chlorinated PCBs increase the risk of cognitive decline in older adults, while DDE and HCB have less effect.

Preferences for deinfibulation (opening) surgery and female genital mutilation service provision: A qualitative study.

OBJECTIVE: To explore the views of female genital mutilation (FGM) survivors, men and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. DESIGN: Qualitative study informed by the sound of silence framework. SETTING: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. SAMPLE: Forty-four survivors, 13 men and 44 HCPs. Ten participants at two community workshops and 30 stakeholders at a national workshop. METHODS: Hybrid framework analysis of 101 interviews and three workshops. RESULTS: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Although there were examples of good practice, in general, FGM service provision was suboptimal. CONCLUSION: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision.

Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT.

TRIAL DESIGN: A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne®, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. METHODS: Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 µg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. RESULTS: A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. LIMITATIONS: The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. FUTURE WORK: Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. CONCLUSIONS: Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17405024. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

Miscarriage is a common complication of pregnancy, affecting approximately one in four women. Sometimes, medical treatment (i.e. tablets) may be offered to start or speed up the miscarriage process in order for the womb to empty itself. A drug called misoprostol (a tablet that makes the womb contract) is currently recommended for this treatment. However, the addition of another drug called mifepristone [a tablet that reduces pregnancy hormones (Mifegyne^®, Exelgyn, Paris, France)] might help the miscarriage to resolve more quickly. Therefore, we carried out the MifeMiso trial to test if mifepristone plus misoprostol is more effective than misoprostol alone in resolving miscarriage within 7 days. Women were randomly allocated by a computer to receive either mifepristone or placebo, followed by misoprostol 2 days later. Neither the women nor their health-care professionals knew which treatment they received. Some women also talked to the researchers about their experiences of taking part in the study. In total, 711 women were randomised to receive either mifepristone plus misoprostol or placebo plus misoprostol. Overall, 83% of women who received mifepristone plus misoprostol had miscarriage resolution within 7 days, compared with 76% of the women who received a placebo plus misoprostol. Surgery was required less often in women who received mifepristone plus misoprostol: 17% of women who received it required surgery, compared with 25% of women who received the placebo. Treatment with mifepristone did not appear to have any negative effects. Treatment with mifepristone plus misoprostol was more cost-effective than misoprostol alone, with an average saving of £182 per woman. Having taken part in the study, most women would choose medical management again and would recommend it to someone they knew who was experiencing a miscarriage.

Persistent sodium currents in SCN1A developmental and degenerative epileptic dyskinetic encephalopathy.

Pathogenic variants in the voltage-gated sodium channel gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies. There is considerable heterogeneity in both the types of causative variants and associated phenotypes; a recent expansion of the phenotypic spectrum of SCN1A associated epilepsies now includes an early onset severe developmental and epileptic encephalopathy with regression and a hyperkinetic movement disorder. Herein, we report a female with a developmental and degenerative epileptic-dyskinetic encephalopathy, distinct and more severe than classic Dravet syndrome. Clinical diagnostics indicated a paternally inherited c.5053G>T; p. A1685S variant of uncertain significance in SCN1A. Whole-exome sequencing detected a second de novo mosaic (18%) c.2345G>A; p. T782I likely pathogenic variant in SCN1A (maternal allele). Biophysical characterization of both mutant channels in a heterologous expression system identified gain-of-function effects in both, with a milder shift in fast inactivation of the p. A1685S channels; and a more severe persistent sodium current in the p. T782I. Using computational models, we show that large persistent sodium currents induce hyper-excitability in individual cortical neurons, thus relating the severe phenotype to the empirically quantified sodium channel dysfunction. These findings further broaden the phenotypic spectrum of SCN1A associated epilepsies and highlight the importance of testing for mosaicism in epileptic encephalopathies. Detailed biophysical evaluation and computational modelling further highlight the role of gain-of-function variants in the pathophysiology of the most severe phenotypes associated with SCN1A.

Interventions for preventing weight gain after smoking cessation.

BACKGROUND: Most people who stop smoking gain weight. This can discourage some people from making a quit attempt and risks offsetting some, but not all, of the health advantages of quitting. Interventions to prevent weight gain could improve health outcomes, but there is a concern that they may undermine quitting. OBJECTIVES: To systematically review the effects of: (1) interventions targeting post-cessation weight gain on weight change and smoking cessation (referred to as 'Part 1') and (2) interventions designed to aid smoking cessation that plausibly affect post-cessation weight gain (referred to as 'Part 2'). SEARCH METHODS: Part 1 - We searched the Cochrane Tobacco Addiction Group's Specialized Register and CENTRAL; latest search 16 October 2020. Part 2 - We searched included studies in the following 'parent' Cochrane reviews: nicotine replacement therapy (NRT), antidepressants, nicotine receptor partial agonists, e-cigarettes, and exercise interventions for smoking cessation published in Issue 10, 2020 of the Cochrane Library. We updated register searches for the review of nicotine receptor partial agonists. SELECTION CRITERIA: Part 1 - trials of interventions that targeted post-cessation weight gain and had measured weight at any follow-up point or smoking cessation, or both, six or more months after quit day. Part 2 - trials included in the selected parent Cochrane reviews reporting weight change at any time point. DATA COLLECTION AND ANALYSIS: Screening and data extraction followed standard Cochrane methods. Change in weight was expressed as difference in weight change from baseline to follow-up between trial arms and was reported only in people abstinent from smoking. Abstinence from smoking was expressed as a risk ratio (RR). Where appropriate, we performed meta-analysis using the inverse variance method for weight, and Mantel-Haenszel method for smoking. MAIN RESULTS: Part 1: We include 37 completed studies; 21 are new to this update. We judged five studies to be at low risk of bias, 17 to be at unclear risk and the remainder at high risk.  An intermittent very low calorie diet (VLCD) comprising full meal replacement provided free of charge and accompanied by intensive dietitian support significantly reduced weight gain at end of treatment compared with education on how to avoid weight gain (mean difference (MD) -3.70 kg, 95% confidence interval (CI) -4.82 to -2.58; 1 study, 121 participants), but there was no evidence of benefit at 12 months (MD -1.30 kg, 95% CI -3.49 to 0.89; 1 study, 62 participants). The VLCD increased the chances of abstinence at 12 months (RR 1.73, 95% CI 1.10 to 2.73; 1 study, 287 participants). However, a second study  found that no-one completed the VLCD intervention or achieved abstinence. Interventions aimed at increasing acceptance of weight gain reported mixed effects at end of treatment, 6 months and 12 months with confidence intervals including both increases and decreases in weight gain compared with no advice or health education. Due to high heterogeneity, we did not combine the data. These interventions increased quit rates at 6 months (RR 1.42, 95% CI 1.03 to 1.96; 4 studies, 619 participants; I2 = 21%), but there was no evidence at 12 months (RR 1.25, 95% CI 0.76 to 2.06; 2 studies, 496 participants; I2 = 26%). Some pharmacological interventions tested for limiting post-cessation weight gain (PCWG) reduced weight gain at the end of treatment (dexfenfluramine, phenylpropanolamine, naltrexone). The effects of ephedrine and caffeine combined, lorcaserin, and chromium were too imprecise to give useful estimates of treatment effects. There was very low-certainty evidence that personalized weight management support reduced weight gain at end of treatment (MD -1.11 kg, 95% CI -1.93 to -0.29; 3 studies, 121 participants; I2 = 0%), but no evidence in the longer-term 12 months (MD -0.44 kg, 95% CI -2.34 to 1.46; 4 studies, 530 participants; I2 = 41%). There was low to very low-certainty evidence that detailed weight management education without personalized assessment, planning and feedback did not reduce weight gain and may have reduced smoking cessation rates (12 months: MD -0.21 kg, 95% CI -2.28 to 1.86; 2 studies, 61 participants; I2 = 0%; RR for smoking cessation 0.66, 95% CI 0.48 to 0.90; 2 studies, 522 participants; I2 = 0%). Part 2: We include 83 completed studies, 27 of which are new to this update. There was low certainty that exercise interventions led to minimal or no weight reduction compared with standard care at end of treatment (MD -0.25 kg, 95% CI -0.78 to 0.29; 4 studies, 404 participants; I2 = 0%). However, weight was reduced at 12 months (MD -2.07 kg, 95% CI -3.78 to -0.36; 3 studies, 182 participants; I2 = 0%). Both bupropion and fluoxetine limited weight gain at end of treatment (bupropion MD -1.01 kg, 95% CI -1.35 to -0.67; 10 studies, 1098 participants; I2 = 3%); (fluoxetine MD -1.01 kg, 95% CI -1.49 to -0.53; 2 studies, 144 participants; I2 = 38%; low- and very low-certainty evidence, respectively). There was no evidence of benefit at 12 months for bupropion, but estimates were imprecise (bupropion MD -0.26 kg, 95% CI -1.31 to 0.78; 7 studies, 471 participants; I2 = 0%). No studies of fluoxetine provided data at 12 months. There was moderate-certainty that NRT reduced weight at end of treatment (MD -0.52 kg, 95% CI -0.99 to -0.05; 21 studies, 2784 participants; I2 = 81%) and moderate-certainty that the effect may be similar at 12 months (MD -0.37 kg, 95% CI -0.86 to 0.11; 17 studies, 1463 participants; I2 = 0%), although the estimates are too imprecise to assess long-term benefit. There was mixed evidence of the effect of varenicline on weight, with high-certainty evidence that weight change was very modestly lower at the end of treatment (MD -0.23 kg, 95% CI -0.53 to 0.06; 14 studies, 2566 participants; I2 = 32%); a low-certainty estimate gave an imprecise estimate of higher weight at 12 months (MD 1.05 kg, 95% CI -0.58 to 2.69; 3 studies, 237 participants; I2 = 0%). AUTHORS' CONCLUSIONS: Overall, there is no intervention for which there is moderate certainty of a clinically useful effect on long-term weight gain. There is also no moderate- or high-certainty evidence that interventions designed to limit weight gain reduce the chances of people achieving abstinence from smoking.

Exploring stakeholder views on intervening in hospital around childhood secondhand smoke exposure (Precedent): a protocol for a qualitative study.

INTRODUCTION: Secondhand smoke exposure (SHSe) in childhood is linked with increased morbidity and mortality. Hospital or secondary care contact may present a 'teachable moment' to provide parents with support to change their home smoking behaviours to reduce children's SHSe. There is a lack of robust qualitative evidence around parents and healthcare professionals (HCPs) views on using this teachable moment to successfully initiate behavioural change. We aim to identify and understand what is important to stakeholders with a view to informing the development of a support package to help parents change their home smoking behaviours. METHODS AND ANALYSIS: This qualitative study will be theoretically underpinned by the Capability, Opportunity and Motivation Behaviour (COM-B) model of behavioural change. It will involve semistructured interviews and/or discussion groups with up to 20 parents who smoke and up to 25 HCPs. Stakeholders will be recruited from a single National Health Service children's hospital in England. Interviews and/or discussion groups will be audio recorded, transcribed and anonymised. The transcripts and any field notes will be analysed using the framework method. Initially, we will apply COM-B to the data deductively and will then code inductively within each domain. ETHICS AND DISSEMINATION: The protocol for this study received a favourable outcome from the East Midlands Leicester Central Research Ethics Committee (19/EM/0171). Results will be written up as part of a PhD thesis, submitted for publication in peer-reviewed journals and presentation at conferences. TRIAL REGISTRATION NUMBER: ISRCTN40084089.

Nurses' and teachers' perceived barriers and facilitators to the uptake of the Human Papilloma Virus (HPV) vaccination program in Iquitos, Peru: A qualitative study.

Globally, over 300,000 women die of cervical cancer annually. Given that human papillomavirus vaccines are highly effective in the primary prevention of cervical cancer, it is important to explore the barriers and facilitators to vaccination uptake in areas where the burden of disease remains high. This study, informed by the socio-ecological model, aimed to qualitatively explore vaccination uptake via in-depth interviews with eleven nurses and ten teachers involved in vaccine delivery in Iquitos, Peru. The results highlighted that vaccine uptake was influenced by multiple factors including individuals' knowledge and attitudes, community beliefs, geography, and policy level variables. Findings suggested that professionals were informed and supportive of the HPV vaccination program but perceived that parents were uninformed about the vaccine. There is a need for community education programs, for a revision of the process of obtaining parental consent, for improved communication between professionals and for involvement of grassroots staff in policy making.

'It's not magic': A qualitative analysis of geriatric physicians' explanations of cardio-pulmonary resuscitation in hospital admissions.

BACKGROUND: Discussing patient preferences for cardio-pulmonary resuscitation (CPR) is routine in hospital admission for older people. The way the conversation is conducted plays an important role for patient comprehension and the ethics of decision making. OBJECTIVE: The objective was to examine how CPR is explained in geriatric rehabilitation hospital admission interviews, focussing on circumstances in which physicians explain CPR and the content of these explanations. METHOD: We recorded forty-three physician-patient admission interviews taking place in a hospital in French-speaking Switzerland, during which CPR was discussed. Data were analysed in French with thematic and conversation analysis, and the extracts used for publication were translated into English. RESULTS: Mean patient age was 83.7 years; 53.5% were admitted for rehabilitation after surgery or traumatism. CPR was explained in 53.8% of the conversations. Most explanations were brief and concerned the technical procedures, mentioning only rarely potential outcome. With one exception, medical indication and prognosis of CPR did not feature in these explanations. Explanations occurred either before the patient's answer (as part of the question about CPR preferences) or after the patient's answer, generated by patients' indecision, misunderstanding and by the need to clarify answers. DISCUSSION AND CONCLUSIONS: The scarcity and simplicity of CPR explanations highlight a reluctance to have in-depth discussions and reflect the assumption that CPR does not need explaining. Providing patients with accurate information about the outcomes and risks of CPR is incremental for reaching informed decisions and patient-centred care. PATIENT CONTRIBUTION: Patients were involved in the data collection stage of the study.

Can wearable technology be used to approximate cardiopulmonary exercise testing metrics?

BACKGROUND: Consumer wrist-worn wearable activity monitors are widely available, low cost and are able to provide a direct measurement of several markers of physical activity. Despite this, there is limited data on their use in perioperative risk prediction. We explored whether these wearables could accurately approximate metrics (anaerobic threshold, peak oxygen uptake and peak work) derived using formalised cardiopulmonary exercise testing (CPET) in patients undergoing high-risk surgery. METHODS: Patients scheduled for major elective intra-abdominal surgery and undergoing CPET were included. Physical activity levels were estimated through direct measures (step count, floors climbed and total distance travelled) obtained through continuous wear of a wrist worn activity monitor (Garmin Vivosmart HR+) for 7 days prior to surgery and self-report through completion of the short International Physical Activity Questionnaire (IPAQ). Correlations and receiver operating characteristic (ROC) curve analysis explored the relationships between parameters provided by CPET and physical activity. DEVICE SELECTION: Our choice of consumer wearable device was made to maximise feasibility outcomes for this study. The Garmin Vivosmart HR+ had the longest battery life and best waterproof characteristics of the available low-cost devices. RESULTS: Of 55 patients invited to participate, 49 (mean age 65.3 ± 13.6 years; 32 males) were enrolled; 37 provided complete wearable data for analyses and 36 patients provided full IPAQ data. Floors climbed, total steps and total travelled as measured by the wearable device all showed moderate correlation with CPET parameters of peak oxygen uptake (peak VO2) (R = 0.57 (CI 0.29-0.76), R = 0.59 (CI 0.31-0.77) and R = 0.62 (CI 0.35-0.79) respectively), anaerobic threshold (R = 0.37 (CI 0.01-0.64), R = 0.39 (CI 0.04-0.66) and R = 0.42 (CI 0.07-0.68) respectively) and peak work (R = 0.56 (CI 0.27-0.75), R = 0.48 (CI 0.17-0.70) and R = 0.50 (CI 0.2-0.72) respectively). Receiver operator curve (ROC) analysis for direct and self-reported measures of 7-day physical activity could accurately approximate the ventilatory equivalent for carbon dioxide (VE/VCO2) and the anaerobic threshold. The area under these curves was 0.89 for VE/VCO2 and 0.91 for the anaerobic threshold. For peak VO2 and peak work, models fitted using just the wearable data were 0.93 for peak VO2 and 1.00 for peak work. CONCLUSIONS: Data recorded by the wearable device was able to consistently approximate CPET results, both with and without the addition of patient reported activity measures via IPAQ scores. This highlights the potential utility of wearable devices in formal assessment of physical functioning and suggests they could play a larger role in pre-operative risk assessment. ETHICS: This study entitled "uSing wearable TEchnology to Predict perioperative high-riSk patient outcomes (STEPS)" gained favourable ethical opinion on 24 January 2017 from the Welsh Research Ethics Committee 3 reference number 17/WA/0006. It was registered on ClinicalTrials.gov with identifier NCT03328039.

A Mixed-Methods Systematic Review and Synthesis of Secondary Care Interventions to Reduce Secondhand Smoke Exposure Among Children and Young People.

INTRODUCTION: Childhood secondhand smoke exposure (SHSe) is linked with increased morbidity and mortality. Hospital or secondary care contact presents a "teachable moment" to support parents to change their home smoking behaviors to reduce children's SHSe. AIMS AND METHODS: This mixed-methods review explores: (1) if existing interventions in this context are effective, (2) if they are reported in sufficient detail to be replicated, (3) the experiences of health care professionals delivering such interventions, and (4) the experiences of parents receiving such interventions. Five electronic databases and the gray literature were searched for relevant literature published and indexed January 1980 to February 2020. Fourteen papers reporting 12 studies (nine quantitative and five qualitative) were included. Aligned with the Joanna Briggs Institute method, a segregated approach was used involving independent syntheses of the quantitative and qualitative data followed by an overall mixed-methods synthesis. RESULTS: There was some evidence of effective interventions that resulted in a short-term (<6 months) reduction in children's SHSe when SHSe was subjectively measured. This was not seen in longer-term follow-up (>6 months) or when SHSe was measured objectively. Inconsistencies with reporting make replication challenging. Experiential evidence suggests a mismatch between stakeholder preferences and interventions being offered. CONCLUSIONS: The pediatric secondary care interventions included in this analysis failed to show statistically significant evidence of longer-term effectiveness to reduce children's SHSe in all but one low-quality study. There was also inadequate reporting of interventions limiting assessment of effectiveness. It offers further insights into areas to target to develop effective interventions. IMPLICATIONS: This review used rigorous methods to explore the current, global literature on how children's exposure to secondhand smoke is being tackled in secondary care. This review identified only one low-quality intervention study showing a statistically significant reduction in children's SHSe beyond 6 months. Synthesis with qualitative research identifies a mismatch between what parents want in an intervention and what has been delivered to date. Reporting quality needs to be improved to ensure that interventions can be replicated and studies conducted within the National Health Service to ensure suitability to this setting.

Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. METHODS: MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 µg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. FINDINGS: Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. INTERPRETATION: Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.