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Conversations about research priorities with members of the public are rarely designed specifically to include people who identify as Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ+) and are not researchers. Generally, to address this gap, and specifically, to inform future research for CLS, we carried out a rapid review of published research priority sets covering LGBTQ+ topics, and an online workshop to prioritise identified themes. Rapid review: results. The rapid review identified 18 LGBTQ+ research priority sets. Some focussed on specific populations such as women or men, younger or older people or people living within families. Five addressed transgender and gender non- conforming populations. All of the research priority sets originated from English-speaking, high and middle-income countries (UK, US, Canada, and Australia), and date from 2016 onwards. Prioritization approaches were wide-ranging from personal commentary to expert workshops and surveys. Participants involved in setting priorities mostly included research academics, health practitioners and advocacy organisations, two studies involved LGBTQ+ public in their process. Research priorities identified in this review were then grouped into themes which were prioritised during the workshop. Workshop: results. For the workshop, participants were recruited using local (Cambridge, UK) LGBTQ+ networks and a national advert to a public involvement in research matching website to take part in an online discussion workshop. Those that took part were offered payment for their time in preparing for the workshop and taking part. Participants personal priorities and experiences contributed to a consensus development process and a final ranked list of seven research themes and participants’ experiences of healthcare, mental health advocacy, care homes, caring responsibilities, schools and family units added additional context. From the workshop the three research themes prioritised were: healthcare services delivery, prevention, and particular challenges / intersectionality of multiple challenges for people identifying as LGBTQ+. Research themes interconnected in many ways and this was demonstrated by the comments from workshop participants. This paper offers insights into why these priorities were important from participants’ perspectives and detail about how to run an inclusive and respectful public involvement research exercise. On a practical level these themes will directly inform future research direction for CLS. Conversations about research priorities with members of the public who identify as Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ+) and are not researchers are not common. We reviewed published research priorities covering LGBTQ+ topics and held an online workshop. The review identified 18 LGBTQ+ research published priority sets. Some focussed on specific populations such as women or men, younger or older people or people living within families. Five were on transgender and gender non- conforming populations. Priorities were achieved by different methods such as workshops and surveys. People involved in setting priorities mostly included researchers, health practitioners and advocacy organisations, two studies involved LGBTQ+ public in their process. Research priorities identified in the review were grouped into themes which were prioritised during the workshop. For the online workshop, participants were recruited using local (Cambridge, UK) LGBTQ+ networks and a national advert and offered payment for their time. Participants personal priorities and experiences contributed to agreeing a final list of seven research themes in priority order. Participants’ experiences of healthcare, mental health advocacy, care homes, caring responsibilities, schools and family units were helpful. From the workshop the three top research themes were: healthcare services delivery, prevention, and particular and multiple challenges of people identifying as lesbian, gay, bisexual, transgender or queer. Research themes interconnected in many ways as shown by the comments from workshop participants. This paper describes why these priorities were important from participants’ perspective and offers information about how to run an inclusive and respectful public involvement research exercise.

Pulmonary physiology is a core element of pediatric pulmonology care and research. This article reviews some of the notable publications in physiology that were published in Pediatric Pulmonology in 2020.

Background: Few lifestyle programs for young children have targeted fathers. This study examined the feasibility of a lifestyle intervention for fathers and their preschool-aged children. Method: A total of 24 father/preschool child dyads were recruited from Newcastle, Australia, into a single-arm, feasibility trial (baseline and 3-mo postbaseline assessments). The 9-session program aimed to improve physical activity and dietary habits of fathers and children. A priori feasibility benchmarks targeted recruitment (15 dyads), eligibility rate (>60%), attendance (80%), retention (≥85%), and program acceptability (≥4 out of 5). Acceptability of data collection procedures, research team program/resource management, home-program compliance, and preliminary intervention outcomes were also assessed. Results: Feasibility benchmarks were surpassed for recruitment (24 dyads), eligibility rate (61.5%), attendance (89%), retention (100%), and program acceptability (4.6 out of 5). Data collection procedures were acceptable. Challenges included mothers reporting their own dietary intake rather than their child’s, children moving during body composition measurement, and resetting pedometers. Resource and program management were excellent. Most families met home-program requirements (83%). Preliminary intervention outcomes were encouraging for fathers and children. Conclusion: Program feasibility was demonstrated by excellent recruitment, attendance, acceptability, retention, program administration, and promising preliminary intervention outcomes. A few data collection difficulties were identified. A larger scale efficacy trial is warranted.

Summary The PALM trial in the Democratic Republic of the Congo identified a statistically significant survival benefit for two monoclonal antibody-based therapeutics in the treatment of acute Ebola virus disease; however, substantial gaps remain in improving the outcomes of acute Ebola virus disease and for the survivors. Ongoing efforts are needed to develop more effective strategies, particularly for individuals with severe disease, for prevention and treatment of viral persistence in immune-privileged sites, for optimisation of post-exposure prophylaxis, and to increase therapeutic breadth. As antibody-based approaches are identified and advanced, promising small-molecule antivirals currently in clinical stage development should continue to be evaluated for filovirus diseases, with consideration of their added value in combination approaches with bundled supportive care, their penetration in tissues of interest, the absence of interaction with glycoprotein-based vaccines, and filoviral breadth.

This review aims to describe the current state of regenerative rehabilitation of severe military extremity injuries, and promising new therapies on the horizon.The nature of warfare is rapidly shifting with information operations, autonomous weapons, and the threat of full-scale peer adversary conflicts threatening to create contested environments with delayed medical evacuation to definitive care. More destructive weapons will lead to more devastating injuries, creating new challenges for limb repair and restoration. Current paradigms of delayed rehabilitation following initial stabilization, damage control surgery, and prolonged antibiotic therapy will need to shift. Advances in regenerative medicine technologies offer the possibility of treatment along the continuum of care. Regenerative rehabilitation will begin at the point of injury and require a holistic, organ-systems approach.Both technological improvements and a rapidly advancing understanding of injury pathophysiology will contribute to improved limb-salvage outcomes, and shift the calculus away from early limb amputation.

Supplemental Digital Content is available in the text., Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10−8). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Infectious disease outbreaks on the scale of the current coronavirus disease 2019 (COVID-19) pandemic are a new phenomenon in many parts of the world. Many isolation unit designs with corresponding workflow dynamics and personal protective equipment postures have been proposed for each emerging disease at the health facility level, depending on the mode of transmission. However, personnel and resource management at the isolation units for a resilient response will vary by human resource capacity, reporting requirements, and practice setting. This study describes an approach to isolation unit management at a rural Uganda Hospital and shares lessons from the Uganda experience for isolation unit managers in low- and middle-income settings.

Description, The COPII component SEC23A overlaps functionally with its paralogous protein and rescues the SEC23B-deficient CDAII defect., Congenital dyserythropoietic anemia type II (CDAII) results from loss-of-function mutations in SEC23B. In contrast to humans, SEC23B-deficient mice deletion do not exhibit CDAII but die perinatally with pancreatic degeneration. Here, we demonstrate that expression of the full SEC23A protein (the SEC23B paralog) from the endogenous regulatory elements of Sec23b completely rescues the SEC23B-deficient mouse phenotype. Consistent with these data, while mice with erythroid-specific deletion of either Sec23a or Sec23b do not exhibit CDAII, we now show that mice with erythroid-specific deletion of all four Sec23 alleles die in mid-embryogenesis with features of CDAII and that mice with deletion of three Sec23 alleles exhibit a milder erythroid defect. To test whether the functional overlap between the SEC23 paralogs is conserved in human erythroid cells, we generated SEC23B-deficient HUDEP-2 cells. Upon differentiation, these cells exhibited features of CDAII, which were rescued by increased expression of SEC23A, suggesting a novel therapeutic strategy for CDAII.

BackgroundEpidemiological evidence for specific long-term conditions is required to inform best practices regarding the substantial health inequalities experienced by sexual minority individuals compared with heterosexual peers.AimTo describe inequalities in long-term conditions among sexual minority (lesbian, gay, and bisexual [LGB]) adults.Design & settingCross-sectional analysis of 1 341 339 nationally representative survey responses from the English GP Patient Survey (GPPS).MethodStratifying by sex, the weighted prevalence and covariate-adjusted association of 15 long-term conditions were calculated, comparing sexual minority and heterosexual adults, considering variation by sexual orientation and variation in sexual orientation inequalities by deprivation, ethnic group, region, and age.ResultsAfter adjusting for deprivation, ethnic group, region, and age, 13 long-term conditions (all except cancer and hypertension) were more prevalent among sexual minority women than their heterosexual peers, with the largest inequalities for mental health problems (odds ratio [OR] 2.8, 95% confidence interval [CI] = 2.7 to 3.0), neurological conditions (OR 1.7, 95% CI = 1.5 to 1.8), dementia (OR 1.6, 95% CI = 1.3 to 1.9), and back problems (OR 1.4, 95% CI = 1.3 to 1.5). It was found that nine long-term conditions were also more prevalent among sexual minority men including mental health problems (OR 2.3, 95% CI = 2.2 to 2.4), 'all other conditions' (OR 1.8, 95% CI = 1.7 to 1.8), neurological conditions (OR 1.5, 95% CI = 1.4 to 1.6), and kidney or liver disease (OR 1.4, 95% CI = 1.3 to 1.5); inequalities were often largest for bisexual adults. Inequalities did not vary significantly by deprivation, ethnic group, or region except for mental health problems. Inequalities in multimorbidity were highest at younger ages; for example, LGB women aged 18–24 years had multimorbidity at the same level (approximately 20%) as heterosexual women aged 45–54 years.ConclusionSexual minority adults, especially bisexual adults, are at elevated risk for many long-term conditions and multimorbidity; this risk spans socioeconomic status and ethnic group, representing a significant healthcare challenge.

(1) Background: The effect of fathers on dietary intake in preschool-aged children is under-explored. The aims were to: (i) evaluate the efficacy of a family-based lifestyle intervention, Healthy Youngsters, Healthy Dads, on change in dietary intake in fathers and their preschool-aged children post-intervention (10 weeks) and at 9 months follow-up compared to a waitlist control group and (ii) investigate associations in father–child dietary intakes. (2) Methods: Linear mixed models estimated group-by-time effects for all dietary outcomes, measured by food frequency questionnaires. Cohen’s d determined effect sizes, while correlation tests determined associations in father–child dietary intakes. (3) Results: For children, medium group-by-time effects sizes were identified at 10 weeks for sodium intake (d = 0.38) and percentage energy from core foods (d = 0.43), energy-dense, nutrient-poor (EDNP) foods (d = 0.43) and prepacked snacks (d = 0.45). These findings were sustained at 9 months follow-up. For fathers, medium to large, group-by-time effect sizes were identified at 10 weeks for energy intake (d = 0.55), sodium intake (d = 0.64) and percentage energy from core foods (d = 0.49), EDNP foods (d = 0.49), and confectionary (d = 0.36). For all of these dietary variables, except sodium, effects were sustained at 9 months. Moderate to strong associations existed in father–child dietary intakes for some of the dietary variables. (4) Conclusions: Although further research is required, this study provides preliminary support for targeting fathers as agents of change to improve dietary intakes in their preschool-aged children.

Background: Men have a greater risk of colorectal cancer (CRC) than women, but population screening currently starts at the same age for both sexes. Aim: This analysis investigates whether, in a resource‐constrained setting, it would be more effective and cost‐effective for men and women to start screening for CRC at different ages. Methods and results: An economic modeling analysis was carried out using the Microsimulation Model in Cancer of the Bowel to compare sex‐stratification against screening everyone from the same age, taking an English National Health Service perspective. Screening men from age 56 and women from age 60, rather than screening everyone from age 58 using a Fecal Immunochemical Test (FIT) threshold of 120 μg/g is expected to produce an additional 0.0004 QALYs for a cost of £0.55 per person at model start (Incremental Cost‐effectiveness Ratio = £1392), and to reduce CRC cases and mortality by 25 and 19 per 100 000 people respectively, while using a similar amount of screening resources. Probabilistic sensitivity analysis indicates a 61% probability that sex‐stratification is more cost‐effective than screening everyone at age 58. Similar benefits of sex‐stratification are found at other FIT thresholds, but become negligible if mean screening start age is reduced to 50. Conclusion: Where resources are constrained and it is not feasible to screen everyone from the age of 50, starting screening earlier in men than women is likely to be more cost‐effective and gain more health benefits overall than strategies where men and women start screening at the same age.

Funder: Wellcome Trust, ObjectiveTo describe patterns of anticoagulation prescription and persistence for those aged ≥65 years with atrial fibrillation (AF).MethodsDescriptive cohort study using electronic general practice records of patients in England, who attended an influenza vaccination aged ≥65 years and were diagnosed with AF between 2008 and 2018. Patients were stratified by 10-year age group and year of diagnosis. Proportion anticoagulated, type of anticoagulation (direct oral anticoagulant (DOAC) or warfarin) initiated at diagnosis and persistence with anticoagulation over time are reported.Results42 290 patients (49% female), aged 65-74 (n=11 722), 75-84 (n=19 055) and 85+ (n=11 513) years at AF diagnosis are included. Prescription of anticoagulation at diagnosis increased over the time period from 55% to 86% in people aged 65-74 years, from 54% to 86% in people aged 75-84 years and from 27% to 75% in people aged 85 years and over. By 2018, 92% of patients with newly diagnosed AF were started on a DOAC. Survivor function for 5-year persistence in patients prescribed DOAC was 0.80 (95% CI 0.77 to 0.82) and for warfarin 0.71 (95% CI 0.70 to 0.72). Survivor function for any anticoagulation at 5 years was 0.79 (95% CI 0.78 to 0.81), 0.73 (95% CI 0.72 to 0.75) and 0.58 (95% CI 0.59 to 0.64) for people aged 65-74, 75-84 and 85+ years, respectively.ConclusionsRates of anticoagulation in AF in those aged ≥65 years have increased from 2008 to 2018, over which time period there has been a shift from initiating anticoagulation with warfarin to DOAC. Persistence with anticoagulation is higher in people on DOACs than on warfarin and in people aged

Sex and gender bias in health care is complex, and research into how to reduce it is lacking. A recent scoping review on interventions to reduce gender disparities in clinical care1 found just 22 studies, with only two based in primary care, of which neither were centred around health services that would be classified as primary care in the UK. In her book, Invisible Women: Exposing Data Bias in a World Designed for Men , 2 Caroline Criado Perez makes the argument that women live in a world built on data from men. In contrast with the arguments of Criado Perez, primary care consultation data used in both clinical care and in research is probably an example where the data do not inherently have a bias against women. In primary care, many of the health impacts of gender bias will be encountered and supported. GPs provide support for domestic violence, sexual exploitation, and other social concerns that disproportionately affect women.3 Primary care is where a significant proportion of contraception, preconception, and termination of pregnancy healthcare services are accessed. Women are more likely to be informal caregivers than men; caring roles are associated with poorer health-related quality of life.4 GP records identifying carers within their practice populations allowed unpaid carers to be identified in early cohorts for eligibility for COVID-19 vaccination.5 In addition, women also access health care more frequently than men, with the data for each healthcare contact recorded,6 …

Background General population surveys are increasingly offering broader response options for questions on sexual orientation-for example, not only gay or lesbian, but also "something else" (SE) and "don't know" (DK). However, these additional response options are potentially confusing for those who may not know what the terms mean. Researchers studying sexual orientation-based disparities face difficult methodological trade-offs regarding how best to classify respondents identifying with the SE and DK categories. Objectives Develop respondent-level probabilities of sexual minority orientation without excluding or misclassifying the potentially ambiguous SE and DK responses. Compare 3 increasingly inclusive analytic approaches for estimating health disparities using a single item: (a) omitting SE and DK respondents; (b) classifying SE as sexual minority and omitting DK; and (c) a new approach classifying only SE and DK respondents with >50% predicted probabilities of being sexual minorities as sexual minority. Materials and methods We used the sociodemographic information and follow-up questions for SE and DK respondents in the 2013-2014 National Health Interview Survey to generate predicted probabilities of identifying as a sexual minority adult. Results About 94% of the 144 SE respondents and 20% of the 310 DK respondents were predicted to identify as a sexual minority adult, with higher probabilities for younger, wealthier, non-Hispanic white, and urban-dwelling respondents. Using a more specific definition of sexual minority orientation improved the precision of health and health care disparity estimates. Conclusions Predicted probabilities of sexual minority orientation may be used in this and other surveys to improve representation and categorization of those who identify as a sexual minority adult.

Background: Trial evidence supports statin use after ischemic stroke and recent American, European and British guidelines recommend high-intensity statins for this indication. Limited data are available describing current statin use among these patients in unselected settings. We conducted a cohort study to examine secular trends and factors associated with statin use and dose following ischemic stroke. Methods: A retrospective cohort study of patients with first ischemic stroke between 2000 and 2014 was conducted using the Clinical Practice Research Datalink (CPRD). Proportions of statin users and high-intensity statin users within 2 years after stroke were estimated for each calendar year. We used Cox regression models to explore potential factors associated with statin use and Poisson regression models to calculate risk ratios for the use of a high-intensity statin. Results: A total of 80,442 patients with first stroke were analyzed. The proportion using statins within 2 years after stroke increased from 25% in 2000 to 70% in 2006 and remained at about 75% through 2014. Among post-stroke statin users, high-intensity use accounted for approximately 15% between 2004 and 2011 and then increased to almost 35% in 2014. Older patients (aged ≥75 years), younger patients (

Background Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed “radical cure”). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. Methods This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to Results In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P Conclusions Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167. opens in new tab.)

Introduction: Viral respiratory infection causes significant mortality and morbidity, particularly in patients with chronic airways diseases such as cystic fibrosis. In order to enter host cells and replicate, most respiratory viruses require an acidic intracellular and endosomal environment. We study the beneficial effects of airway alkalinization by an inhaled drug, Optate, that we currently have demonstrated is safe to inhale by healthy subjects and those with stable airways disease. We have recently shown that Optate safely inhibits SARS-CoV-2 infection in primary human airway epithelial cells (HAECs). We hypothesized that Optate would also inhibit other viral infections. Methods: Viral isolates of influenza A (FluA), influenza B (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) were obtained clinically from patients symptomatic of viral respiratory infection. RhMK cells were infected with isolates and treated with 120 mM Optate or placebo. Cells in each group were stained with FITC-conjugated antibodies for the corresponding virus;viral particles were imaged with fluorescent microscopy and images were quantified in ImageJ. Cytopathic effect (CPE) was also evaluated in each group by visual microscopy. Results: FluA, FluB, and RSV infection were significantly inhibited in cells treated with Optate compared to placebo, demonstrated by a significant decrease in fluorescent intensity (n = 4, p 0.05). No visual signs of CPE were noted in the Optate treated FluA, FluB, and RSV groups (< 5% of cells showed signed of injury) compared to the placebo FluA, FluB, and RSV groups (∼ 50% of cells showed signs of injury. CPE was similar between Optate and placebo HRV groups (∼50% of cells showed signs of injury). Conclusions: Optate inhibits FluA, FluB, and RSV infection without causing CPE, similar to its inhibition of SARS-CoV-2 infection. HRV infection was not affected by Optate treatment, suggesting HRV may not require acidic endosomal pH to enter cells and replicate. These findings suggest that Optate may be an inhaled therapeutic for patients with respiratory viral infections.

BACKGROUND: A prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self-administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ-8 (TARP γ-8). This study evaluated the preclinical efficacy of JNJ-55511118, a novel, selective, high-affinity inhibitor of TARP γ-8-bound AMPARs, in reducing chronic operant alcohol self-administration. METHODS: Separate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR-4 schedule of reinforcement. After a 40-day baseline, JNJ-55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self-administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded. RESULTS: During baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ-55511118 decreased multiple parameters of alcohol self-administration but did not reduce behavior-matched sucrose-only self-administration. JNJ-55511118 had no effect on sweetened alcohol or sucrose self-administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ-55511118 (1 mg/kg) had no effect on open-field activity in male mice. CONCLUSIONS: This study shows for the first time that TARP γ-8-bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ-55511118 in reducing alcohol self-administration in male mice suggests that inhibition of TARP γ-8-bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 infection, has led to a pandemic of acute respiratory illness. Pharmacologic treatments for COVID-19 have included treatments that target infection prevention, prevention of viral replication, reduce inflammation, and manage symptoms of respiratory failure caused by the disease. This is a review of key pharmacologic treatments for COVID-19 based on peer-reviewed articles from 2020.

ObjectiveTo describe patterns of anticogulation prescribing and persistence for those aged ≥65 years with atrial fibrillation (AF).MethodsDescriptive cohort study using electronic general practice records of patients in England who attended a flu vaccination aged ≥65, and were diagnosed with AF between 2008-2018. Patients were stratified by 10 year age group and year of diagnosis. Proportion anticoagulated, type of anticoagulation (direct oral anticoagulant (DOAC) or Warfarin) initiated at diagnosis, and persistence with anticoagulation over time are reported.Results42,290 patients (49% female), aged 65-74 (n=11,722), 75-84 (n=19,055) and 85+ (n=11,513) at AF diagnosis are included. Prescription of anticoagulation at diagnosis increased over the time period from 55% to 86% in people aged 65-74, from 54% to 86% in people aged 75-84 and from 27% to 75% in people aged 85 and over. No patients were prescribed DOACs as a first anticoagulation agent in 2008, by 201892% of new AF patients were started on DOACs. Survivor function for 5 year persistence for patients taking only a single type of anticoagulant was 0.80 (0.77:0.82) for DOACs and0.71(0.70:0.72) for warfarin, Survivor function for any anticoagulation at 5 years was0.79(0.78:0.81), 0.73(0.72:0.75), 0.58(0.59:0.64) for people aged 65-74, 75-84 and 85+ respectively.ConclusionsRates of anticoagulation for new AF in those aged ≥65 have increased from 2008 to 2018, over which time there has been a shift from initiating anticoaguation with warfarin to DOACs. Persistence with anticoagulation is higher in people on DOACs than on warfarin, and in people under the aged of 85.Key MessagesWhat is already known?Anticoagulation is a highly effective way of reducing the risk of stroke associated with AF, but is underused, particularly in older people. The introduction of DOACs has been associated with increasing use of anticoagulation in AF.What does this study add?Our study provides up to date information on anticoagulation for AF in older people who are most at risk of AF related stroke and highlights particular increases in use of anticoagulation in people aged 85 and over.DOACs are now the major class of anticoagulant prescribed to patients with new AF in UK general practice.Long term persistence with anticoagulation is higher with DOACs than warfarin, but drops in all age groups over 5 years.How might this impact on clinical practice?Improved uptake of anticoagulation at all ages removes one of the potential barriers to screening for atrial fibrillation, but new strategies may be needed to enhance longer term persistence with treatment.

Funder: Research Trainees Coordinating Centre; funder-id: http://dx.doi.org/10.13039/501100000659, Background: There is considerable heterogeneity in individuals’ risk of disease and thus the absolute benefits and harms of population-wide screening programmes. Using colorectal cancer (CRC) screening as an exemplar, we explored how people make decisions about screening when presented with information about absolute benefits and harms, and how those preferences vary with baseline risk, between screening tests and between individuals. Method: We conducted two linked studies with members of the public: a think-aloud study exploring decision making in-depth and an online randomised experiment quantifying preferences. In both, participants completed a web-based survey including information about three screening tests (colonoscopy, sigmoidoscopy, and faecal immunochemical testing) and then up to nine scenarios comparing screening to no screening for three levels of baseline risk (1%, 3% and 5% over 15 years) and the three screening tests. Participants reported, after each scenario, whether they would opt for screening (yes/no). Results: Of the 20 participants in the think-aloud study 13 did not consider absolute benefits or harms when making decisions concerning CRC screening. In the online experiment (n = 978), 60% expressed intention to attend at 1% risk of CRC, 70% at 3% and 77% at 5%, with no differences between screening tests. At an individual level, 535 (54.7%) would attend at all three risk levels and 178 (18.2%) at none. The 27% whose intention varied by baseline risk were more likely to be younger, without a family history of CRC, and without a prior history of screening. Conclusions: Most people in our population were not influenced by the range of absolute benefits and harms associated with CRC screening presented. For an appreciable minority, however, magnitude of benefit was important.

We present an overview of solids reflectance spectra that report quantitative reflectance spectra between 1.3 and 16 µm of both natural and anthropogenic materials. The spectra can be used for myriad applications.

Objectives To describe cervical cancer screening participation among women who have sex exclusively with women (WSEW) and women who have sex with women and men (WSWM) compared with women who have sex exclusively with men (WSEM), and women who have never had sex and compare this with bowel (colorectal) and breast screening participation. To explore whether there is evidence of differential stage 3 cervical intraepithelial neoplasia (CIN3) or cervical cancer risk. Methods We describe cervical, bowel and breast cancer screening uptake in age groups eligible for the national screening programmes, prevalent CIN3 and cervical cancer at baseline, and incident CIN3 and cervical cancer at five years follow-up, among 218,674 women in UK Biobank, a cohort of healthy volunteers from the UK. Results Compared with WSEM, in adjusted analysis [odds ratio (95% confidence interval)], WSEW 0.10 (0.08–0.13), WSWM 0.73 (0.58–0.91), and women who have never had sex 0.02 (0.01–0.02) were less likely to report ever having attended cervical screening. There were no differences when considering bowel cancer screening uptake ( p = 0.61). For breast cancer screening, attendance was lower among WSWM 0.79 (0.68 to 0.91) and women who have never had sex 0.47 (0.29–0.58), compared with WSEM. There were incident and prevalent cases of both CIN3 and cervical cancer among WSEW and WSWM. Compared with WSEM with a single male partner, among WSEW there was a twofold increase in CIN3 1.91 (1.01 to 3.59); among WSWM with only one male partner, this was 2.25 (1.19 to 4.24). Conclusions These findings highlight the importance of improving uptake of cervical screening among all women who have sex with women and breast screening among WSWM and women who have never had sex.

The ability to control a behavioral task or stimulate neural activity based on animal behavior in real-time is an important tool for experimental neuroscientists. Ideally, such tools are (1) noninvasive, (2) low-latency, and (3) provide interfaces to trigger external hardware based on posture (i.e., not just objectbased-tracking). Recent advances in pose estimation with deep learning allows researchers to train deep neural networks to accurately quantify a wide variety of animal behaviors. In extending our efforts towards the animal pose estimation toolbox DeepLabCut, here, we provide a new DeepLabCut-Live! package that achieves low-latency real-time pose estimation (within 15 ms, at >100 FPS), with an additional forwardprediction module that achieves zero-latency feedback. We also provide three options for using this tool with ease: a stand-alone GUI (called DLC-Live!GUI), integration into Bonsai and into AutoPilot. Lastly, we benchmarked performance on a wide range of systems so that experimentalists can easily decide what hardware is required for their needs. Highlights The DeepLabCut-Live! package is available via pip install deeplabcut-live The Bonsai-DLC plugin is available The AutoPilot-DLC plugin is available The DeepLabCut-Live! GUI package is available via pip install deeplabcut-live-gui

Population-based screening for colorectal cancer is an effective and cost-effective way of reducing colorectal cancer incidence and mortality. Many genetic and phenotypic risk factors for colorectal cancer have been identified, leading to development of colorectal cancer risk scores with varying discrimination. However, these are not currently used by population screening programs. We performed an economic analysis to assess the cost-effectiveness, clinical outcomes, and resource impact of using risk-stratification based on phenotypic and genetic risk, taking a UK National Health Service perspective. Biennial fecal immunochemical test (FIT), starting at an age determined through risk-assessment at age 40, was compared with FIT screening starting at a fixed age for all individuals. Compared with inviting everyone from age 60, using a risk score with area under the receiver operating characteristic curve of 0.721 to determine FIT screening start age, produces 418 QALYs, costs £247,000, and results in 218 fewer colorectal cancer cases and 156 fewer colorectal cancer deaths per 100,000 people, with similar FIT screening invites. There is 96% probability that risk-stratification is cost-effective, with net monetary benefit (based on £20,000 per QALY threshold) estimated at £8.1 million per 100,000 people. The maximum that could be spent on risk-assessment and still be cost-effective is £114 per person. Lower benefits are produced with lower discrimination risk scores, lower mean screening start age, or higher FIT thresholds. Risk-stratified screening benefits men more than women. Using risk to determine FIT screening start age could improve the clinical outcomes and cost effectiveness of colorectal cancer screening without using significant additional screening resources. Prevention Relevance: Colorectal cancer screening is essential for early detection and prevention of colorectal cancer, but implementation is often limited by resource constraints. This work shows that risk-stratification using genetic and phenotypic risk could improve the effectiveness and cost-effectiveness of screening programs, without using substantially more screening resources than are currently available.

ObjectivesAtrial fibrillation (AF) is a heart condition associated with a fivefold increased risk of stroke. The condition can be detected in primary care and treatment can greatly reduce the risk of stroke. In recent years, a number of policy initiatives have tried to improve diagnosis and treatment of AF, including local National Health Service schemes and the Quality and Outcomes Framework. We aimed to examine trends in the incidence of recorded AF in primary care records from English practices between 2004 and 2018.DesignLongitudinal cohort study.SettingEnglish primary care electronic health records linked to Index of Multiple Deprivation data.ParticipantsCohort of 3.5 million patients over 40 years old registered in general practices in England, contributing 22 million person-years of observation between 2004 and 2018.Primary and secondary outcome measuresIncident AF was identified through newly recorded AF codes in the patients’ records. Yearly incidence rates were stratified by gender, age group and a measure of deprivation.ResultsIncidence rates were stable before 2010 and then rose and peaked in 2015 at 5.07 (95% CI 4.94 to 5.20) cases per 1000 person-years. Incidence was higher in males (4.95 (95% CI 4.91 to 4.99) cases per 1000 person-years vs 4.12 (95% CI 4.08 to 4.16) in females) and rises markedly with age (0.58 (95% CI 0.56 to 0.59) cases per 1000 person-years in 40–54 years old vs 21.7 (95% CI 21.4 to 22.0) cases in over 85s). The increase in incidence over time was observed mainly in people over the age of 75, particularly men. There was no evidence that temporal trends in incidence were associated with deprivation.ConclusionsChanges in clinical practice and policy initiatives since 2004 have been associated with increased rates of diagnosis of AF up until 2015, but rates declined from 2015 to 2018.

Background Western Equine Encephalitis (WEE) is a naturally acquired infection and potentially devastating bioweapon, with no specific human countermeasures. An experimental inactivated Western Equine Encephalitis Vaccine (WEEV; WEE TSI-GSD 210) has been used under an IND (investigational New Drug) protocol at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. Methods Over 24 years from 1987 to 2011, 876 subjects received 3 primary vaccine doses under 3 studies with 1,537 booster doses administered (FY87-8, phase 2, laboratory workers, vaccine lots 1-81-1, 1-81-2, and 2-1-91; FY99-12, phase 2 laboratory workers, lot 2-1-91; and FY09-02, phase 1 healthy volunteer, lot 3-1-92). Post-vaccination safety and immunogenicity [plaque reduction neutralization test 80% (PRNT80) > 1:40] were analyzed. Results Overall PRNT80 response to the primary series in FY87-8 was 42% (326/770) but dropped to 16% (14/87) in FY99-12, prompting study FY09-02, which achieved 89% (17/19). The first booster response rate was 68% (814/1194) in FY87-8, 53% (171/324) in FY99-12, and 100% (10/10) in FY09-02. The majority of definitely related adverse reactions (AEs) were mild and local with no definitely related serious AEs. No laboratory acquired WEE infection was documented during this period despite 4 reported exposures in vaccinated subjects. Conclusion The TSI-GSD 210 WEE vaccine was immunogenic, safe and well tolerated. Use of this vaccine could be considered in an emergency setting. Despite decades of safe and effective use under IND, full licensure is not planned due to manufacturing constraints, and a strategic decision to develop alternatives. Clinical trial registration https://clinicaltrials.gov/, identifier NCT01159561.

BACKGROUND Eastern equine encephalitis virus (EEEV) is a mosquito borne alphavirus spread primarily in Atlantic and Gulf Coast regions of the United States. EEEV is the causative agent of a devastating meningoencephalitis syndrome, with approximately 30% mortality and significant morbidity. There is no licensed human vaccine against EEEV. An inactivated EEEV vaccine has been offered under investigational new drug (IND) protocols at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. METHODS Healthy at-risk laboratory personnel received inactivated PE-6 strain EEEV (TSI-GSD 104) vaccine under two separate IND protocols. Protocol FY 99-11 (2002-2008) had a primary series consisting of doses on day 0, 7, and 28. Protocol FY 06-31 (2008-2016) utilized a primary series with doses on day 0 and 28, and month 6. Participants with an inadequate immune response, plaque reduction neutralization test with 80% cut-off (PRNT80) titer

We report a case of retinal atrophy and progressive preretinal fibrosis in an eye previously treated with intravenous and intra-arterial chemotherapy (IAC), which evolved immediately after treatment with intravitreal injection of melphalan. The atrophy and fibrosis progressed later to proliferative retinopathy with dystrophic ossification. The patient was originally diagnosed with bilateral retinoblastoma at 4 months of age and was treated with systemic chemotherapy followed by IAC. New vitreous seeds developed and required treatment with intravitreal chemotherapy. There was resolution of vitreous seeding after 2 doses of intravitreal melphalan, but clinically the eye developed new, widespread retinal atrophy and fibrosis within 1 month of the second injection. This was followed by phthisis and late proliferative retinopathy nearly 1 year later. Retinoblastoma specialists should be aware of this potential complication of combined chemotherapy treatments.

The Rabbit Welfare Association and Fund (RWAF) has recently completed a survey of 1200 owners, 80 veterinary professionals and those working for 25 rescue centres on rabbit bonding practices, success factors and breakdowns. The results are now available.1 We would like to highlight three findings. The bonds between male and female rabbits are the easiest to form, least likely to require temporary separation and by far the least likely …

Lassa virus (LASV), an arenavirus causing Lassa fever, is endemic to West Africa with up to 300,000 cases and between 5000 and 10,000 deaths per year. Rarely seen in the United States, Lassa virus is a CDC category A biological agent inasmuch deliberate aerosol exposure can have high mortality rates compared to naturally acquired infection. With the need for an animal model, specific countermeasures remain elusive as there is no FDA-approved vaccine. This natural history of aerosolized Lassa virus exposure in Macaca fascicularis was studied under continuous telemetric surveillance. The macaque response to challenge was largely analogous to severe human disease with fever, tachycardia, hypotension, and tachypnea. During initial observations, an increase trend of activated monocytes positive for viral glycoprotein was accompanied by lymphocytopenia. Disease uniformly progressed to high viremia followed by low anion gap, alkalosis, anemia, and thrombocytopenia. Hypoproteinemia occurred late in infection followed by increased levels of white blood cells, cytokines, chemokines, and biochemical markers of liver injury. Viral nucleic acids were detected in tissues of three non-survivors at endpoint, but not in the lone survivor. This study provides useful details to benchmark a pivotal model of Lassa fever in support of medical countermeasure development for both endemic disease and traditional biodefense purposes.

Background The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. Methods and findings Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (, Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments., Author summary Why was this study done? Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite (‘radical cure’); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find? We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean? These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (

The aim of this study was to compare and externally validate risk scores developed to predict incident colorectal cancer that include common genetic variants (SNPs), with or without established lifestyle/environmental (questionnaire-based/classical/phenotypic) risk factors. We externally validated 23 risk models from a previous systematic review in 443,888 participants ages 37 to 73 from the UK Biobank cohort who had 6-year prospective follow-up, no prior history of colorectal cancer, and data for incidence of colorectal cancer through linkage to national cancer registries. There were 2,679 (0.6%) cases of incident colorectal cancer. We assessed model discrimination using the area under the operating characteristic curve (AUC) and relative risk calibration. The AUC of models including only SNPs increased with the number of included SNPs and was similar in men and women: the model by Huyghe with 120 SNPs had the highest AUC of 0.62 [95% confidence interval (CI), 0.59–0.64] in women and 0.64 (95% CI, 0.61–0.66) in men. Adding phenotypic risk factors without age improved discrimination in men but not in women. Adding phenotypic risk factors and age increased discrimination in all cases (P < 0.05), with the best performing models including SNPs, phenotypic risk factors, and age having AUCs between 0.64 and 0.67 in women and 0.67 and 0.71 in men. Relative risk calibration varied substantially across the models. Among middle-aged people in the UK, existing polygenic risk scores discriminate moderately well between those who do and do not develop colorectal cancer over 6 years. Consideration should be given to exploring the feasibility of incorporating genetic and lifestyle/environmental information in any future stratified colorectal cancer screening program.

BACKGROUND: Health services have failed to respond to the pressures of multimorbidity. Improved measures of multimorbidity are needed for conducting research, planning services and allocating resources.METHODS: We modelled the association between 37 morbidities and 3 key outcomes (primary care consultations, unplanned hospital admission, death) at 1 and 5 years. We extracted development (n = 300 000) and validation (n = 150 000) samples from the UK Clinical Practice Research Datalink. We constructed a general-outcome multimorbidity score by averaging the standardized weights of the separate outcome scores. We compared performance with the Charlson Comorbidity Index.RESULTS: Models that included all 37 conditions were acceptable predictors of general practitioner consultations (C-index 0.732, 95% confidence interval [CI] 0.731–0.734), unplanned hospital admission (C-index 0.742, 95% CI 0.737–0.747) and death at 1 year (C-index 0.912, 95% CI 0.905–0.918). Models reduced to the 20 conditions with the greatest combined prevalence/weight showed similar predictive ability (C-indices 0.727, 95% CI 0.725–0.728; 0.738, 95% CI 0.732–0.743; and 0.910, 95% CI 0.904–0.917, respectively). They also predicted 5-year outcomes similarly for consultations and death (C-indices 0.735, 95% CI 0.734–0.736, and 0.889, 95% CI 0.885–0.892, respectively) but performed less well for admissions (C-index 0.708, 95% CI 0.705–0.712). The performance of the generaloutcome score was similar to that of the outcome-specific models. These models performed significantly better than those based on the Charlson Comorbidity Index for consultations (C-index 0.691, 95% CI 0.690–0.693) and admissions (C-index 0.703, 95% CI 0.697–0.709) and similarly for mortality (C-index 0.907, 95% CI 0.900–0.914).INTERPRETATION: The Cambridge Multimorbidity Score is robust and can be either tailored or not tailored to specific health outcomes. It will be valuable tothose planning clinical services, policymakers allocating resources and researchers seeking to account for the effect of multimorbidity.

In vivo magnetic resonance spectroscopy (MRS) can provide clinically valuable metabolic information from brain tumors that can be used for prognosis and monitoring response to treatment. Unfortunately, this technique has not been widely adopted in clinical practice or even clinical trials due to the difficulty in acquiring and analyzing the data. In this work we propose a computational approach to solve one of the most critical technical challenges: the problem of quickly and accurately positioning an MRS volume of interest (a cuboid voxel) inside a tumor using MR images for guidance. The proposed automated method comprises a convolutional neural network to segment the lesion, followed by a discrete optimization to position an MRS voxel optimally within the lesion. In a retrospective comparison, the novel automated method is shown to provide improved lesion coverage compared to manual voxel placement.

Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Mohammad S. Hossain and colleagues explore P. vivax infection following P. falciparum treatment in this analysis of 42 published studies., Author summary Why was this study done? Plasmodium vivax is the most geographically widespread human malaria species; outside of sub-Saharan Africa, it almost invariably coexists with P. falciparum. A recent systematic review of 153 studies across 21 countries revealed that within 63 days of being treated for P. falciparum monoinfection, more than 15% of patients treated with an artemisinin-based combination therapy (ACT) had an episode of P. vivax malaria, far greater than expected for patients in similar locations who do not have acute malaria. We hypothesised that patients presenting with P. falciparum in coendemic locations are at high risk of carrying P. vivax dormant liver stages (hypnozoites) and would therefore potentially benefit from presumptive radical cure. What did the researchers do and find? We undertook an individual patient data meta-analysis to define the risk of vivax parasitaemia (blood stream infection) after treatment of P. falciparum malaria in different coendemic environments and to explore the factors underlying these risks. In total, 42 studies enrolling 15,341 patients were included in the analysis. By day 63, the risk of P. vivax ranged from 12.8% following dihydroartemisinin-piperaquine (DP) to 42.4% following artesunate-amodiaquine (AA). The highest rate of P. vivax malaria was in patients residing in areas with high risk of relapses and those who were slow to clear their initial parasitaemia. What do these findings mean? There is a high risk of vivax malaria after treatment of falciparum infection after all ACTs, although the risk varies substantially between locations. The correlation between the risk of P. vivax and the initial clearance of P. falciparum raises the possibility that the host response to acute malaria may be triggering the reactivation of P. vivax dormant liver stages. Universal radical cure with treatment to kill the liver stages may be warranted for reducing P. vivax, but the benefits will vary considerably between geographical locations, and further prospective clinical efficacy studies will be needed to determine the risks and benefits of such a strategy.

Funder: The Health Foundation, Objective: To contribute objective evidence on health care utilization among migrants to the UK to inform policy and service planning. Methods: We analysed data from Understanding Society, a household survey with fieldwork from 2015 to 2017, and the European Health Interview Survey with data collected between 2013 and 2014. We explored health service utilization among migrants to the UK across primary care, inpatient admissions and maternity care, outpatient care, mental health, dental care and physiotherapy. We adjusted for age, sex, long-term health conditions and time since moving to the UK. Results: Health care utilization among migrants to the UK was lower than utilization among the UK-born population for all health care dimensions except inpatient admissions for childbirth; odds ratio (95%CI) range 0.58 (0.50–0.68) for dental care to 0.88 (0.78–0.98) for primary care). After adjusting for differences in age and self-reported health, these differences were no longer observed, except for dental care (odds ratio 0.57, 95%CI 0.49–0.66, P < 0.001). Across primary care, outpatient and inpatient care, utilization was lower among those who had recently migrated, increasing to the levels of the nonmigrant population after 10 years or more since migrating to the UK. Conclusions: This study finds that newly arrived migrants tend to utilize less health care than the UK population and that this pattern was at least partly explained by better health, and younger age. Our findings contribute nationally representative evidence to inform public debate and decision-making on migration and health.

Measures of the adipokine chemerin are elevated in multiple cardiovascular diseases, including hypertension, but little mechanistic work has been done to implicate chemerin as being causative in such diseases. The chemerin knockout (KO) rat was created to test the hypothesis that removal of chemerin would reduce pressure in the normal and hypertensive state. Western analyses confirmed loss of chemerin in the plasma and tissues of the KO vs. wild-type (WT) rats. Chemerin concentration in plasma and tissues was lower in WT females than in WT males, as determined by Western analysis. Conscious male and female KO rats had modest differences in baseline measures vs. the WT that included systolic, diastolic, mean arterial and pulse pressures, and heart rate, all measured telemetrically. The mineralocorticoid deoxycorticosterone acetate (DOCA) and salt water, combined with uninephrectomy as a hypertensive stimulus, elevated mean and systolic blood pressures of the male KO higher than the male WT. By contrast, all pressures in the female KO were lower than their WT throughout DOCA-salt treatment. These results revealed an unexpected sex difference in chemerin expression and the ability of chemerin to modify blood pressure in response to a hypertensive challenge.—Watts, S. W., Darios, E. S., Mullick, A. E., Garver, H., Saunders, T. L., Hughes, E. D., Filipiak, W. E., Zeidler, M. G., McMullen, N., Sinal, C. J., Kumar, R. K., Ferland, D. J., Fink, G. D. The chemerin knockout rat reveals chemerin dependence in female, but not male, experimental hypertension.

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.

Efficacy of EMDR and TF-CBT for posttraumatic stress symptoms (PTSS) was explored through meta-analysis. A comprehensive search yielded 494 studies of children and adolescents with PTSS who received treatment with these evidence-based therapeutic modalities. Thirty total studies were included in the meta-analysis. The overall Cohen’s d was small (−0.359) and statistically significant (p

RATIONALE: There is a clear need for discovery of effective medications to treat behavioral pathologies associated with alcohol addiction, such as chronic drinking. OBJECTIVE: The goal of this preclinical study was to assess effects of chronic alcohol drinking on the nucleus accumbens (NAcb) proteome to identify and validate novel targets for medications development. MATERIALS AND METHODS: Two-dimensional difference in-gel electrophoresis (2D-DIGE) with matrix assisted laser desorption ionization tandem time-of-flight (MALDI-TOF/TOF) was used to assess effects of chronic voluntary home-cage (24-h access) alcohol drinking on the NAcb proteome of C57BL/6J mice. To extend these findings to a model of alcohol self-administration and reinforcement, we investigated potential regulation of the positive reinforcing effects of alcohol by the target protein glutathione S-transferase Pi 1 (GSTP1) using a pharmacological inhibition strategy in mice trained to self-administer alcohol or sucrose. RESULTS: Expression of 52 unique proteins in the NAcb was changed by chronic alcohol drinking relative to water control (23 upregulated, 29 downregulated). Ingenuity Pathway Analysis showed that alcohol drinking altered an array of protein networks associated with neurological and psychological disorders, molecular and cellular functions, and physiological systems and development. DAVID functional annotation analysis identified 9 proteins (SNCA, GSTP1, PRDX3, PPP3R1, EIF5A, PHB, PEBP1/RKIP, GAPDH, AND SOD1) that were significantly overrepresented in a functional cluster that included the Gene Ontology categories “response to alcohol” and “aging.” Immunoblots confirmed changes in Pebp1 (RKIP) and GSTP1 in NAcb with no change in amygdala or frontal cortex, suggesting anatomical specificity. Systemic inhibition of GSTP1 with Ezatiostat (0–30 mg/kg, i.p.) dose-dependently reduced the reinforcing effects of alcohol as measured by operant self-administration, in the absence of motor effects. Sucrose self-administration was also reduced but in a manner associated with nonspecific motor inhibition. CONCLUSIONS: Protein expression profiling identified an array of proteins and networks in the NAcb, including GSTP1, that are novel molecular targets of chronic alcohol drinking. Pharmacological inhibition of GSTP1 significantly reduced the positive reinforcing effects of alcohol, which regulate repetitive use and abuse liability. The observation that this protein was both up-regulated after chronic drinking and that its inhibition could modulate the reinforcing properties of alcohol suggests that it is a key target for alcohol-related pathologies. Proteomic strategies combined with specific preclinical models has potential to identify and validate novel targets of alcohol that may be useful in the medical management of alcohol addiction.

BackgroundRisk assessment is central to primary prevention of cardiovascular disease (CVD), but there remains a need to better understand the use of evidence-based interventions in practice. This study examines: (i) the policies and guidelines for risk assessment in Europe, (ii) the use of risk assessment tools in clinical practice and (iii) the barriers to, and facilitators of, risk assessment.MethodsData were collected from academics, clinicians and policymakers in an online questionnaire targeted at experts from all European Union member states, and in 8 in-depth country case studies that were developed from a targeted literature review and 36 interviews.ResultsThe European Society of Cardiology (ESC) produces European guidelines for CVD risk assessment and recommends the Systematic COronary Risk Evaluation tool, which is the most widely used risk assessment tool in Europe. The use of risk assessment tools is variable. Lack of time and resources are important barriers. Integrating risk assessment tools into clinical systems and providing financial incentives to carry out risk assessments could increase implementation. Novel biomarkers would need to be supported by evidence of their clinical effectiveness and cost-effectiveness to be introduced in clinical practice. These findings were consistent across Europe.ConclusionsEfforts to improve the assessment of CVD risk in clinical practice should be carried out by or in collaboration with, the ESC. Increasing the use of existing risk assessment tools is likely to offer greater gains in primary prevention than the development of novel biomarkers.

Background: This study aimed to compare and externally validate risk scores developed to predict incident colorectal cancer (CRC) that include variables routinely available or easily obtainable via self-completed questionnaire. Methods: External validation of fourteen risk models from a previous systematic review in 373 112 men and women within the UK Biobank cohort with 5-year follow-up, no prior history of CRC and data for incidence of CRC through linkage to national cancer registries. Results: There were 1719 (0.46%) cases of incident CRC. The performance of the risk models varied substantially. In men, the QCancer10 model and models by Tao, Driver and Ma all had an area under the receiver operating characteristic curve (AUC) between 0.67 and 0.70. Discrimination was lower in women: the QCancer10, Wells, Tao, Guesmi and Ma models were the best performing with AUCs between 0.63 and 0.66. Assessment of calibration was possible for six models in men and women. All would require country-specific recalibration if estimates of absolute risks were to be given to individuals. Conclusions: Several risk models based on easily obtainable data have relatively good discrimination in a UK population. Modelling studies are now required to estimate the potential health benefits and cost-effectiveness of implementing stratified risk-based CRC screening.

Background The NHS Health Check programme is a prevention initiative offering cardiovascular risk assessment and management advice to adults aged 40–74 years across England. Its effectiveness depends on uptake. When it was introduced in 2009, it was anticipated that all those eligible would be invited over a 5-year cycle and 75% of those invited would attend. So far in the current cycle from 2013 to 2018, 33.8% of those eligible have attended, which is equal to 48.5% of those invited to attend. Understanding the reasons why some people do not attend is important to maximise the impact of the programmes. Aim To review why people do not attend NHS Health Checks. Design and setting A systematic review and thematic synthesis of qualitative studies. Method An electronic literature search was carried out of MEDLINE, Embase, Health Management Information Consortium, Cumulative Index to Nursing and Allied Health Literature, Global Health, PsycINFO, Web of Science, OpenGrey, the Cochrane Library, NHS Evidence, Google Scholar, Google, ClinicalTrials.gov, and the ISRCTN registry from 1 January 1996 to 9 November 2016, and the reference lists of all included papers were also screened manually. Inclusion criteria were primary research studies that reported the views of people who were eligible for but had not attended an NHS Health Check. Results Nine studies met the inclusion criteria. Reasons for not attending included lack of awareness or knowledge, misunderstanding the purpose of the NHS Health Check, aversion to preventive medicine, time constraints, difficulties with access to general practices, and doubts regarding pharmacies as appropriate settings. Conclusion The findings particularly highlight the need for improved communication and publicity around the purpose of the NHS Health Check programme and the personal health benefits of risk factor detection., This work was funded by a grant from Public Health England. Juliet A Usher-Smith was funded by a National Institute for Health Research (NIHR) Clinical Lectureship and Fiona M Walter by an NIHR Clinician Scientist award (RG 68235). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. All researchers were independent of the funding body and the funder had no role in data collection, analysis and interpretation of data; in the writing of the report; or decision to submit the article for publication.

Ebola virus disease (EVD) is a serious global health concern because case fatality rates are approximately 50% due to recent widespread outbreaks in Africa. Well-defined nonhuman primate (NHP) models for different routes of Ebola virus exposure are needed to test the efficacy of candidate countermeasures. In this natural history study, four rhesus macaques were challenged via aerosol with a target titer of 1000 plaque-forming units per milliliter of Ebola virus. The course of disease was split into the following stages for descriptive purposes: subclinical, clinical, and decompensated. During the subclinical stage, high levels of venous partial pressure of carbon dioxide led to respiratory acidemia in three of four of the NHPs, and all developed lymphopenia. During the clinical stage, all animals had fever, viremia, and respiratory alkalosis. The decompensatory stage involved coagulopathy, cytokine storm, and liver and renal injury. These events were followed by hypotension, elevated lactate, metabolic acidemia, shock and mortality similar to historic intramuscular challenge studies. Viral loads in the lungs of aerosol-exposed animals were not distinctly different compared to previous intramuscularly challenged studies. Differences in the aerosol model, compared to intramuscular model, include an extended subclinical stage, shortened clinical stage, and general decompensated stage. Therefore, the shortened timeframe for clinical detection of the aerosol-induced disease can impair timely therapeutic administration. In summary, this nonhuman primate model of aerosol-induced EVD characterizes early disease markers and additional details to enable countermeasure development.