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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

ABSTRACT Influenza A viruses present a major challenge for animal and human health. They circulate widely in wild waterfowl and frequently spillover into poultry, emphasizing the need for risk-based surveillance in wild birds and an understanding of the relative importance of different transmission mechanisms. We addressed this objective with a replicated (N = 6) experimental infection study in which we serially exposed eight cohorts of four naïve contact mallards to an experimentally infected mallard and a shared water pool. Viral concentration in the water was a better predictor of transmission than several direct measures of viral shedding in the focal duck. Our data provide quantification of transmission probability and its variation throughout the infectious period of an infected duck. Our findings highlight the need to consider environmental surveillance in risk-based surveillance planning and provide realistic parameters for identifying optimal control strategies using epidemiological inference. IMPORTANCE Wild birds are the natural reservoir hosts of influenza A viruses. Highly pathogenic strains of influenza A viruses pose risks to wild birds, poultry, and human health. Thus, understanding how these viruses are transmitted between birds is critical. We conducted an experiment where we experimentally infected mallards which are ducks that are commonly exposed to influenza viruses. We exposed several contact ducks to the experimentally infected duck to estimate the probability that a contact duck would become infected from either exposure to the virus shed directly from the infected duck or shared water contaminated with the virus from the infected duck. We found that environmental transmission from contaminated water best predicted the probability of transmission to naïve contact ducks, relatively low levels of virus in the water were sufficient to cause infection, and the probability of a naïve duck becoming infected varied over time.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Summary: Background: The initiation and cessation of opioid agonist treatment (OAT) have both been associated with elevated risk of fatal overdose. We examined risk of non-fatal overdose during OAT initiation and cessation and specifically between methadone versus buprenorphine recipients. Methods: We utilised primary care electronic health records from the Clinical Practice Research Datalink to delineate a study cohort of adults aged 18-64 who were prescribed OAT between Jan 1, 1998 and Dec 31, 2017. These records were linked to hospitalisation, mortality records and patient neighbourhood and practice-level Index of Multiple Deprivation quintiles. With inverse probability treatment weights applied and negative binomial regression models we estimated incidence rate ratios for hospital admissions among patients who experienced multiple overdoses. Findings: A total of 20898 patients were prescribed methadone or buprenorphine over 83856 person-years of follow-up. Compared with periods in treatment, patients not in treatment were 51% more likely to experience a non-fatal overdose that required hospitalisation (weighted rate ratio, wRR 1·51; 95% CI 1·42, 1·60), especially during the four weeks of OAT initiation (5·59; 5·31, 5·89) and following cessation (13·39; 12·78, 14·03). The wRR of overdose during (0·37; 0·34, 0·39) and after treatment (0·36; 0·34, 0·38) favoured buprenorphine compared to methadone. Interpretation: OAT is associated with decreased non-fatal overdose risk. Buprenorphine may act more protectively than methadone, especially during the first four weeks of treatment. Funding: National Institute for Health and Care Research (NIHR) Greater Manchester Patient Safety Translational Research Centre (PSTRC-2016-003).

Plasmodium falciparum, the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the host’s main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of PfA-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target.

Process monitoring seeks to identify anomalous plant operating states so that operators can take the appropriate actions for recovery. Instrumental to process monitoring is the labeling of known operating states in historical data, so that departures from these states can be identified. This task can be challenging and time consuming as plant data is typically high dimensional and extensive. Moreover, automation of this procedure is not trivial since ground truth labels are often unavailable. In this contribution, this problem is approached as a multi-mode classification one, and an automatic framework for labeling using unsupervised Machine Learning (ML) methods is presented. The implementation was tested using data from the Tennessee Eastman Process and an industrial pyrolysis process. A total of 9 ML ensembles were included. Hyperparameters were optimized using a multi-objective evolutionary optimization algorithm. Unsupervised clustering metrics (silhouette score, Davies-Bouldin index, and Calinski-Harabasz Index) were investigated as candidates for objective functions in the optimization implementation. Results show that ensembles and hyperparameter selection can be aided by multi-objective optimization. It was found that Silhouette score and Davies-Bouldin index are strong predictions of the ensemble’s performance and can then be used to obtain good initial results for subsequent fault detection and fault diagnosis procedures.

Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of aggregate genetic variation influencing BMI from midlife and beyond is unknown. By analysing 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 72 years. We then applied genomic structural equation modeling to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that molecular genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin genome-wide variation in BMI from middle to early old age in men and women alike.

BackgroundLittle is known about people who are admitted to medium secure services (MSSs) from prison, including characteristics and factors that influence clinical pathways and subsequent discharge. We recently published the first study to establish the circumstances by which MSS “prison-transfer” patients are returned to prison. Of particular concern was the finding that a quarter of prison-transfer patients were returned to prison by Responsible Medical Officers (RMOs) because they were not engaging with treatment or were deemed too “high risk” to remain detained within the services, circumstances that would be unacceptable when considering discharge via a community care pathway. It is important to further explore the characteristics of people admitted to MSSs from prison, and to investigate how these may differ for individuals who are returned to prison, as compared to those discharged into the community.Aim(a) To describe the characteristics of prison-transfers who receive an RMO directed discharge from MSSs; and (b) to compare these characteristics by discharge destination; prison return and community discharge.MethodsProspective cohort comparative study: all prison-transfer patients discharged under the instruction of their RMO over a 6-month period, from 33 NHS medium secure units across England and Wales. Data on patient demographic, clinical and legal characteristics were extracted via full patient health record review and collateral information from clinicians was also obtained. This information was used to complete The Historical, Clinical and Risk-−20 items (HCR-20v3) and The Structured Assessment of Protective Factors (SAPROF). Individuals who were returned to prison were compared with those who were discharged to the community.ResultsPersons returned to prison represented a vulnerable group at time of discharge as compared to those discharged into the community and had a significantly shorter length of stay in MSSs. Over half of those returned to prison had a length of stay of

Abstract Background Links between parental socioeconomic position during childhood and subsequent risks of developing mental disorders have rarely been examined across the diagnostic spectrum. We conducted a comprehensive analysis of parental income level, including income mobility, during childhood and risks for developing mental disorders diagnosed in secondary care in young adulthood. Methods National cohort study of persons born in Denmark 1980–2000 (N = 1,051,265). Parental income was measured during birth year and at ages 5, 10 and 15. Follow-up began from 15th birthday until mental disorder diagnosis or 31 December 2016, whichever occurred first. Hazard ratios and cumulative incidence were estimated. Results A quarter (25.2%; 95% CI 24.8–25.6%) of children born in the lowest income quintile families will have a secondary care-diagnosed mental disorder by age 37, versus 13.5% (13.2–13.9%) of those born in the highest income quintile. Longer time spent living in low-income families was associated with higher risks of developing mental disorders. Associations were strongest for substance misuse and personality disorders and weaker for mood disorders and anxiety/somatoform disorders. An exception was eating disorders, with low parental income being associated with attenuated risk. For all diagnostic categories examined except for eating disorders, downward socioeconomic mobility was linked with higher subsequent risk and upward socioeconomic mobility with lower subsequent risk of developing mental disorders. Conclusions Except for eating disorders, low parental income during childhood is associated with subsequent increased risk of mental disorders diagnosed in secondary care across the diagnostic spectrum. Early interventions to mitigate the disadvantages linked with low income, and better opportunities for upward socioeconomic mobility could reduce social and mental health inequalities.

The cell envelope of Gram-negative bacteria consists of two membranes surrounding a periplasm and peptidoglycan layer. Molecular machines spanning the cell envelope depend on spatial constraints and load-bearing forces across the cell envelope and surface. The mechanisms dictating spatial constraints across the cell envelope remain incompletely defined. In Escherichia coli, the coiled-coil lipoprotein Lpp contributes the only covalent linkage between the outer membrane and the underlying peptidoglycan layer. Using proteomics, molecular dynamics, and a synthetic lethal screen, we show that lengthening Lpp to the upper limit does not change the spatial constraint but is accommodated by other factors which thereby become essential for viability. Our findings demonstrate E. coli expressing elongated Lpp does not simply enlarge the periplasm in response, but the bacteria accommodate by a combination of tilting Lpp and reducing the amount of the covalent bridge. By genetic screening, we identified all of the genes in E. coli that become essential in order to enact this adaptation, and by quantitative proteomics discovered that very few proteins need to be up- or down-regulated in steady-state levels in order to accommodate the longer Lpp. We observed increased levels of factors determining cell stiffness, a decrease in membrane integrity, an increased membrane vesiculation and a dependance on otherwise non-essential tethers to maintain lipid transport and peptidoglycan biosynthesis. Further this has implications for understanding how spatial constraint across the envelope controls processes such as flagellum-driven motility, cellular signaling, and protein translocation

Abstract Background Suicide and non-fatal self-harm represent key patient safety events in mental healthcare services. However, additional important learning can also be derived by highlighting examples of optimal practice that help to keep patients safe. In this study, we aimed to explore clinicians’ views of what constitutes good practice in mental healthcare services in the context of suicide prevention. Methods Data were extracted from the National Confidential Inquiry into Suicide and Safety in Mental Health (NCISH) database, a consecutive case series study of suicide by people in contact with mental healthcare services. A large national sample of clinicians’ responses was analysed with a hybrid thematic analysis. Results Responses (n = 2331) were submitted by clinicians across 62 mental healthcare providers. The following five themes illustrated good practice that helps to: 1) promote safer environments, 2) develop stronger relationships with patients and families, 3) provide timely access to tailored and appropriate care, 4) facilitate seamless transitions, and 5) establish a sufficiently skilled, resourced and supported staff team. Conclusion This study highlighted clinicians’ views on key elements of good practice in mental health services. Respondents included practice specific to mental health services that focus on enhancing patient safety via prevention of self-harm and suicide. Clinicians possess important understanding of optimal practice but there are few opportunities to share such insight on a broader scale. A further challenge is to implement optimal practice into routine, daily care to improve patient safety and reduce suicide risk.

Background: The COVID-19 pandemic has caused considerable morbidity, mortality and disruption to people’s lives around the world. There are concerns that rates of suicide and suicidal behaviour may rise during and in its aftermath. Our living systematic review synthesises findings from emerging literature on incidence and prevalence of suicidal behaviour as well as suicide prevention efforts in relation to COVID-19, with this iteration synthesising relevant evidence up to 19 th October 2020. Method: Automated daily searches feed into a web-based database with screening and data extraction functionalities. Eligibility criteria include incidence/prevalence of suicidal behaviour, exposure-outcome relationships and effects of interventions in relation to the COVID-19 pandemic. Outcomes of interest are suicide, self-harm or attempted suicide and suicidal thoughts. No restrictions are placed on language or study type, except for single-person case reports. We exclude one-off cross-sectional studies without either pre-pandemic measures or comparisons of COVID-19 positive vs. unaffected individuals. Results: Searches identified 6,226 articles. Seventy-eight articles met our inclusion criteria. We identified a further 64 relevant cross-sectional studies that did not meet our revised inclusion criteria. Thirty-four articles were not peer-reviewed (e.g. research letters, pre-prints). All articles were based on observational studies. There was no consistent evidence of a rise in suicide but many studies noted adverse economic effects were evolving. There was evidence of a rise in community distress, fall in hospital presentation for suicidal behaviour and early evidence of an increased frequency of suicidal thoughts in those who had become infected with COVID-19. Conclusions: Research evidence of the impact of COVID-19 on suicidal behaviour is accumulating rapidly. This living review provides a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide risk as the longer term impacts of the pandemic on suicide risk are researched.

Abstract Background Antimicrobial resistance (AMR) of bacterial pathogens is an emerging public health threat. This threat extends to pets as it also compromises our ability to treat their infections. Surveillance programs in the United States have traditionally focused on collecting data from food animals, foods, and people. The Veterinary Laboratory Investigation and Response Network (Vet-LIRN), a national network of 45 veterinary diagnostic laboratories, tested the antimicrobial susceptibility of clinically relevant bacterial isolates from animals, with companion animal species represented for the first time in a monitoring program. During 2017, we systematically collected and tested 1968 isolates. To identify genetic determinants associated with AMR and the potential genetic relatedness of animal and human strains, whole genome sequencing (WGS) was performed on 192 isolates: 69 Salmonella enterica (all animal sources), 63 Escherichia coli (dogs), and 60 Staphylococcus pseudintermedius (dogs). Results We found that most Salmonella isolates (46/69, 67%) had no known resistance genes. Several isolates from both food and companion animals, however, showed genetic relatedness to isolates from humans. For pathogenic E. coli, no resistance genes were identified in 60% (38/63) of the isolates. Diverse resistance patterns were observed, and one of the isolates had predicted resistance to fluoroquinolones and cephalosporins, important antibiotics in human and veterinary medicine. For S. pseudintermedius, we observed a bimodal distribution of resistance genes, with some isolates having a diverse array of resistance mechanisms, including the mecA gene (19/60, 32%). Conclusion The findings from this study highlight the critical importance of veterinary diagnostic laboratory data as part of any national antimicrobial resistance surveillance program. The finding of some highly resistant bacteria from companion animals, and the observation of isolates related to those isolated from humans demonstrates the public health significance of incorporating companion animal data into surveillance systems. Vet-LIRN will continue to build the infrastructure to collect the data necessary to perform surveillance of resistant bacteria as part of fulfilling its mission to advance human and animal health. A One Health approach to AMR surveillance programs is crucial and must include data from humans, animals, and environmental sources to be effective.

Background: The COVID-19 pandemic has caused morbidity and mortality, as well as, widespread disruption to people’s lives and livelihoods around the world. Given the health and economic threats posed by the pandemic to the global community, there are concerns that rates of suicide and suicidal behaviour may rise during and in its aftermath. Our living systematic review (LSR) focuses on suicide prevention in relation to COVID-19, with this iteration synthesising relevant evidence up to June 7 th 2020. Method: Automated daily searches feed into a web-based database with screening and data extraction functionalities. Eligibility criteria include incidence/prevalence of suicidal behaviour, exposure-outcome relationships and effects of interventions in relation to the COVID-19 pandemic. Outcomes of interest are suicide, self-harm or attempted suicide and suicidal thoughts. No restrictions are placed on language or study type, except for single-person case reports. Results: Searches identified 2070 articles, 29 (28 studies) met our inclusion criteria, of which 14 articles were research letters or pre-prints awaiting peer review. All articles reported observational data: 12 cross-sectional; eight case series; five modelling; and three service utilisation studies. No studies reported on changes in rates of suicidal behaviour. Case series were largely drawn from news reporting in low/middle income countries and factors associated with suicide included fear of infection, social isolation and economic concerns. Conclusions: A marked improvement in the quality of design, methods, and reporting in future studies is needed. There is thus far no clear evidence of an increase in suicide, self-harm, suicidal behaviour, or suicidal thoughts associated with the pandemic. However, suicide data are challenging to collect in real time and economic effects are evolving. Our LSR will provide a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide. PROSPERO registration: CRD42020183326 01/05/2020

Background: The COVID-19 pandemic has caused widespread morbidity and mortality as well as disruption to people’s lives and livelihoods around the world; this has occurred as a result of both infection with the virus itself and the health protection measures taken to curb its spread. There are concerns that rates of suicide, suicidal behaviours and self-harm may rise during and in the aftermath of the pandemic. Given the likely rapidly expanding research evidence base on the pandemic’s impact on rates of suicide, suicidal behaviours and self-harm and emerging evidence about how best to mitigate such effects, it is important that the best available knowledge is made readily available to policymakers, public health specialists and clinicians as soon as is possible. To facilitate this, we plan to undertake a living systematic review focusing on suicide prevention in relation to COVID-19. Method: Regular automated searches will feed into a web-based screening system which will also host the data extraction form for included articles. Our eligibility criteria are wide and include aspects of incidence and prevalence of suicidal behaviour, effects of exposures and effects of interventions in relation to the COVID-19 pandemic, with minimal restrictions on the types of study design to be included. The outcomes assessed will be death by suicide; self-harm or attempted suicide (including hospital attendance and/or admission for these reasons); and suicidal thoughts/ideation. There will be no restriction on study type, except for single case reports. There will be no restriction on language of publication. The review will be updated at three-monthly intervals if a sufficient volume of new evidence justifies doing so. Conclusions: Our living review will provide a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide. Protocol registration: PROSPERO CRD42020183326 01/05/2020

Summary: Background: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NOX) as a whole and nitrogen dioxide (NO2) specifically, as well as PM10, and PM2·5, during childhood and subsequent schizophrenia risk. Methods: People born in Denmark from 1980 to 1984 (N=230 844), who were residing in the country on their tenth birthday, and who had two Danish-born parents were followed-up from their tenth birthday until schizophrenia diagnosis or Dec 31, 2016. Mean daily exposure to each pollutant (NO2, NOX, PM10, and PM2·5) at all of an individual's residential addresses from birth to their tenth birthday was modelled. Incidence rate ratios, cumulative incidence, and population attributable risks were calculated using survival analysis techniques. Findings: We analysed data between Aug 1, 2018, and Nov 15, 2019. Of 230 844 individuals included, 2189 cohort members were diagnosed with schizophrenia during follow-up. Higher concentrations of residential NO2 and NOX exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 μg/m3 NO2 had a 1·62 (95% CI 1·41–1·87) times increased risk compared with people exposed to a mean daily concentration of less than 14·5 μg/m3. The absolute risks of developing schizophrenia by the age of 37 years when exposed to daily mean concentrations of more than 26·5 μg/m3 NO2 between birth and 10 years were 1·45% (95% CI 1·30–1·62%) for men and 1·03% (0·90–1·17) for women, whereas when exposed to a mean daily concentration of less than 14·5 μg/m3, the risk was 0·80% (95% CI 0·69–0·92%) for men and 0·67% (0·57–0·79) for women. Associations between exposure to PM2·5 or PM10 and schizophrenia risk were less consistent. Interpretation: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO2 and NOX could have a potentially considerable effect on lowering schizophrenia incidence at the population level. Further investigations are necessary to establish a causal relationship. Funding: Lundbeck Foundation, Stanley Medical Research Institute, European Research Council, NordForsk, Novo Nordisk Foundation, National Health and Medical Research Council, Danish National Research Foundation.

Descriptions of soil hydraulic properties, such as the soil moisture retention curve, θ(h), and saturated hydraulic conductivities, Ks, are a prerequisite for hydrological models. Since the measurement of Ks is expensive, it is frequently derived from statistical pedotransfer functions (PTFs). Because it is usually more difficult to describe Ks than θ(h) from pedotransfer functions, Pollacco et al. (2013) developed a physical unimodal model to compute Ks solely from hydraulic parameters derived from the Kosugi θ(h). This unimodal Ks model, which is based on a unimodal Kosugi soil pore-size distribution, was developed by combining the approach of Hagen–Poiseuille with Darcy's law and by introducing three tortuosity parameters. We report here on (1) the suitability of the Pollacco unimodal Ks model to predict Ks for a range of New Zealand soils from the New Zealand soil database (S-map) and (2) further adaptations to this model to adapt it to dual-porosity structured soils by computing the soil water flux through a continuous function of an improved bimodal pore-size distribution. The improved bimodal Ks model was tested with a New Zealand data set derived from historical measurements of Ks and θ(h) for a range of soils derived from sandstone and siltstone. The Ks data were collected using a small core size of 10 cm diameter, causing large uncertainty in replicate measurements. Predictions of Ks were further improved by distinguishing topsoils from subsoil. Nevertheless, as expected, stratifying the data with soil texture only slightly improved the predictions of the physical Ks models because the Ks model is based on pore-size distribution and the calibrated parameters were obtained within the physically feasible range. The improvements made to the unimodal Ks model by using the new bimodal Ks model are modest when compared to the unimodal model, which is explained by the poor accuracy of measured total porosity. Nevertheless, the new bimodal model provides an acceptable fit to the observed data. The study highlights the importance of improving Ks measurements with larger cores.

Abstract Background Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant. Methods Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis. Results On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans. Conclusions This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.

How multitrophic relationships between wildlife communities and their ectoparasitic vectors interact to shape the diversity of vector-borne microorganisms is poorly understood. Nested levels of dependence among microbes, vectors, and vertebrate hosts may have complicated effects on both microbial community assembly and evolution. We examined Bartonella sequences from European bats and their ectoparasites with a combination of network analysis, Bayesian phylogenetics, tip-association and cophylogeny tests, and linear regression to understand the ecological and evolutionary processes that shape parasite communities. We detected seven bat–ectoparasite–Bartonella communities that can be differentiated based on bat families and roosting patterns. Tips of the Bartonella tree were significantly clustered by host taxonomy and geography. We also found significant evidence of evolutionary congruence between bat host and Bartonella phylogenies, indicating that bacterial species have evolved to infect related bat species. Exploring these ecological and evolutionary associations further, we found that sharing of Bartonella species among bat hosts was strongly associated with host phylogenetic distance and roost sharing and less strongly with geographic range overlap. Ectoparasite sharing between hosts was strongly predicted by host phylogenetic distance, roost sharing, and geographic overlap but had no additive effect on Bartonella sharing. Finally, historical Bartonella host-switching was more frequent for closely related bats after accounting for sampling bias among bat species. This study helps to disentangle the complex ecology and evolution of Bartonella bacteria in bat species and their arthropod vectors. Our work provides insight into the important mechanisms that partition parasite communities among hosts, particularly the effect of host phylogeny and roost sharing, and could help to elucidate the evolutionary patterns of other diverse vector-borne microorganisms.

Summary: Background: Since the mid-1990s, excess mortality has increased markedly for adults aged 25–44 years in the north compared with the south of England. We examined the underlying causes of this excess mortality and the contribution of socioeconomic deprivation. Methods: Mortality data from the Office of National Statistics for adults aged 25–44 years were aggregated and compared between England's five most northern versus five most southern government office regions between Jan 1, 1981, and Dec 31, 2016. Poisson regression models, adjusted for age and sex, were used to quantify excess mortality in the north compared with the south by underlying cause of death (accidents, alcohol related, cardiovascular disease and diabetes, drug related, suicide, cancer, and other causes). The role of socioeconomic deprivation, as measured by the 2015 Index of Multiple Deprivation, in explaining the excess and regional variability was also explored. Findings: A mortality divide between the north and south appeared in the mid-1990s and rapidly expanded thereafter for deaths attributed to accidents, alcohol misuse, and drug misuse. In the 2014–16 period, the northern excess was incidence rate ratio (IRR) 1·47 (95% CI 1·39–1·54) for cardiovascular reasons, 2·09 (1·94–2·25) for alcohol misuse, and 1·60 (1·51–1·70) for drug misuse, across both men and women aged 25–44 years. National mortality rates for cardiovascular deaths declined over the study period but a longstanding gap between north and south persisted (from 33·3 [95% CI 31·8–34·8] in 1981 to 15·0 [14·0–15·9] in 2016 in the north vs from 23·5 [22·3–24·8] to 9·9 [9·2–10·5] in the south). Between 2014 and 2016, estimated excess numbers of death in the north versus the south for those aged 25–44 years were 1881 (95% CI 726–2627) for women and 3530 (2216–4511) for men. Socioeconomic deprivation explained up to two-thirds of the excess mortality in the north (IRR for northern effect reduced from 1·15 [95% CI 1·14–1·15; unadjusted] to 1·05 [1·04–1·05; adjusted for Index of Multiple Deprivation]). By 2016, in addition to the persistent north–south gap, mortality rates in London were lower than in all other regions, with IRRs ranging from IRR 1·13 (95% CI 1·12–1·15) for the East England to 1·22 (1·20–1·24) for the North East, even after adjusting for deprivation. Interpretation: Sharp relative rises in deaths from cardiovascular reasons, alcohol misuse and drug misuse in the north compared with the south seem to have created new health divisions between England's regions. This gap might be due to exacerbation of existing social and health inequalities that have been experienced for many years. These divisions might suggest increasing psychological distress, despair, and risk taking among young and middle-aged adults, particularly outside of London. Funding: Medical Research Council and Wellcome Trust.

Background: People diagnosed with schizophrenia have a much reduced life expectancy compared to the general population, and a more than doubled risk of dying from cardiovascular disease (CVD). Existing CVD risk calculators can be used to detect people with an elevated predicted risk of CVD to inform interventions to reduce risk.Aims: This study aimed to compare four different risk calculators for 10-year predicted CVD risk in a sample of people with schizophrenia.Methods: Thirty participants with a diagnosis of schizophrenia spectrum disorders living within Greater Manchester, United Kingdom took part. Ten-year predicted cardiovascular risk scores were calculated using four different models: QRISK3, Framingham, PRIMROSE BMI, and PRIMROSE lipid. Risk estimates and classified risk categories were compared.Results: QRISK3 identified 11 (39%) as having >10% risk of a CV event within 10 years, 4 (14%) of whom exceeded 20%. The Framingham model identified 4 (14%) as exceeding 10%, none of whom exceeded 20%. PRIMROSE risk calculators identified no participants as having >10% risk of a CV event within 10 years. Pairwise concordance correlation coefficients between types of model ranged 0.22–0.77. Mean (± SD) age was 40 (± 10) years but QRISK3's mean “Heart age” was 58 (± 14) years.Conclusion: Risk calculators generate differing predicted CVD risk scores for patients with schizophrenia. Using one risk calculator might yield different recommended monitoring and treatment plans compared to another. Clinicians should therefore take into account other patient-related factors, such as patients' preferences and other underlying physical conditions when making treatment decisions.

Summary: Background: Childhood poverty is associated with elevated later risks for self-directed and externalised violence, but how risks are modified by parental socioeconomic mobility remains unclear. We investigated parental income trajectories during childhood and subsequent risks of self-harm and violent criminality in young adulthood. Methods: Using Danish national registers, we delineated a nested case-control study of Danish citizens born from Jan 1, 1982, to Dec 31, 2000, with first hospital-treated self-harm episodes and first violent crime convictions at ages 15–33 years. Each case was matched on age and gender to 25 randomly selected controls. Parental income was assessed in birth-year and at ages 5 years, 10 years, and 15 years. We considered parental age, the child's number of siblings, parental mental health, and parental education to be covariates. We estimated incidence rate ratios (IRRs) by conditional logistic regression inherently adjusted for age, gender, and calendar year; we then made additional adjustments for the covariates considered. Findings: We identified 21 267 first episodes of hospital-treated self-harm, to which we matched 531 675 controls, and 23 724 first violent crime convictions, to which we matched 593 100 controls. We observed inverse relationships between parental income and risks for the two outcomes for each of the ages parental income was measured. The longer a child lived in poorer circumstances, the higher their subsequent risks for self-harm and violent criminality, and vice versa for time spent living in affluent conditions. Associations were stronger for violent criminality than for self-harm. Compared with individuals who were born and remained in the most affluent families, all other income trajectories were associated with elevated risks for both outcomes. Those who remained in the least affluent quintile showed the highest risks for self-harm (IRR 7·2, 95% CI 6·6–7·9; 1174 [6%] cases) and for violent criminality (IRR 13·0; 95% CI 11·9–14·1; 1640 [7%] cases). The risk patterns were attenuated, but essentially persisted, after covariate adjustment. For any parental income level at birth, being upwardly mobile was associated with lower risk compared with downward mobility. Interpretation: Parental income represents a multitude of unmeasured familial sociodemographic indices. Tackling the causes of inequality and associated psychosocial and sociocultural challenges to enable upwards socioeconomic mobility could potentially reduce risks for self-directed and externalised violence. Funding: European Research Council.

Formal decision-analytic methods can be used to frame disease control problems, the first step of which is to define a clear and specific objective. We demonstrate the imperative of framing clearly-defined management objectives in finding optimal control actions for control of disease outbreaks. We illustrate an analysis that can be applied rapidly at the start of an outbreak when there are multiple stakeholders involved with potentially multiple objectives, and when there are also multiple disease models upon which to compare control actions. The output of our analysis frames subsequent discourse between policy-makers, modellers and other stakeholders, by highlighting areas of discord among different management objectives and also among different models used in the analysis. We illustrate this approach in the context of a hypothetical foot-and-mouth disease (FMD) outbreak in Cumbria, UK using outputs from five rigorously-studied simulation models of FMD spread. We present both relative rankings and relative performance of controls within each model and across a range of objectives. Results illustrate how control actions change across both the base metric used to measure management success and across the statistic used to rank control actions according to said metric. This work represents a first step towards reconciling the extensive modelling work on disease control problems with frameworks for structured decision making.