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Abstract To investigate if retinal thickness has predictive utility in COVID-19 outcomes by evaluating the statistical association between retinal thickness using OCT and of COVID-19-related mortality. Secondary outcomes included associations between retinal thickness and length of stay (LoS) in hospital. In this retrospective cohort study, OCT scans from 230 COVID-19 patients admitted to the Intensive Care Unit (ITU) were compared with age and gender-matched patients with pneumonia from before March 2020. Total retinal, GCL + IPL, and RNFL thicknesses were recorded, and analysed with systemic measures collected at the time of admission and mortality outcomes, using linear regression models, Pearson’s R correlation, and Principal Component Analysis. Retinal thickness was significantly associated with all-time mortality on follow up in the COVID-19 group (p = 0.015), but not 28-day mortality (p = 0.151). Retinal and GCL + IPL layer thicknesses were both significantly associated with LoS in hospital for COVID-19 patients (p = 0.006 for both), but not for patients with pneumonia (p = 0.706 and 0.989 respectively). RNFL thickness was not associated with LoS in either group (COVID-19 p = 0.097, pneumonia p = 0.692). Retinal thickness associated with LoS in hospital and long-term mortality in COVID-19 patients, suggesting that retinal structure could be a surrogate marker for frailty and predictor of disease severity in this group of patients, but not in patients with pneumonia from other causes.

Purpose – This paper aims to identify and evaluate resolutions to key learning and teaching challenges in very large courses that involve practical mathematics, such as foundational finance. Design/methodology/approach – A design-based research approach is used across three semesters to iteratively identify practical problems within the course and then develop and evaluate resolutions to these problems. Data are collected from both students and teachers and analysed using a mixed-method approach. Findings – The results indicate that key learning and teaching challenges in large foundational finance courses can be mitigated through appropriate consistency of learning materials; check-your-understanding interactive online content targeting foundational concepts in the early weeks; connection points between students and the coordinator to increase teacher presence; a sustained focus on supporting student achievement within assessments; and signposting relevance of content for the broader program and professional settings. Multiple design iterations using a co-design approach were beneficial to incrementally improve the course and consider multiple perspectives within the design process. Practical implications – This paper develops a set of design principles to provide guidance to other practitioners who seek to improve their own courses. Originality/value – The use of design-based research and mixed-method approaches that consider both student and teacher perspectives to examine the design of very large, foundational finance courses is novel.

Abstract Optical coherence tomography angiography (OCTA) is widely used for non-invasive retinal vascular imaging, but the OCTA methods used to assess retinal perfusion vary. We evaluated the different methods used to assess retinal perfusion between OCTA studies. MEDLINE and Embase were searched from 2014 to August 2021. We included prospective studies including ≥ 50 participants using OCTA to assess retinal perfusion in either global retinal or systemic disorders. Risk of bias was assessed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies. Heterogeneity of data was assessed by Q statistics, Chi-square test, and I2 index. Of the 5974 studies identified, 191 studies were included in this evaluation. The selected studies employed seven OCTA devices, six macula volume dimensions, four macula subregions, nine perfusion analyses, and five vessel layer definitions, totalling 197 distinct methods of assessing macula perfusion and over 7000 possible combinations. Meta-analysis was performed on 88 studies reporting vessel density and foveal avascular zone area, showing lower retinal perfusion in patients with diabetes mellitus than in healthy controls, but with high heterogeneity. Heterogeneity was lowest and reported vascular effects strongest in superficial capillary plexus assessments. Systematic review of OCTA studies revealed massive heterogeneity in the methods employed to assess retinal perfusion, supporting calls for standardisation of methodology.

Summary: Replanting is an important tool for ecological recovery. Management strategies, such as planting areas with monocultures or species mixtures, have implications for restoration success. We used 16S and ITS rRNA gene amplicon sequencing and shotgun metagenomics to assess how the diversity of neighboring tree species impacted soil bacterial and fungal communities, and their functional potential, within the root zone of mānuka (Leptospermum scoparium) trees. We compared data from monoculture and mixed tree species plots and confirmed that soil microbial taxonomic and functional community profiles significantly differed (p

Some antihypertensive medications are photosensitizing. The implications for skin cancer risk remain unclear because results from prior studies are inconsistent and as new evidence is published. We performed a systematic review and meta-analysis to evaluate the association between antihypertensives and common skin cancers (cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma) and to evaluate dose–response relationships. Forty-four articles met inclusion criteria, and 42 could be meta analyzed. Increased risks were seen for basal cell carcinoma with calcium channel blockers (relative risk [RR] = 1.17, 95% confidence interval [CI] = 1.11–1.22), diuretics (RR = 1.06, 95% CI = 1.03–1.10), and thiazides (RR = 1.10, 95% CI = 1.04–1.16); for squamous cell carcinoma with calcium channel blockers (RR = 1.08, 95% CI = 1.01–1.14), diuretics (RR = 1.29, 95% CI = 1.17–1.43), and thiazides (RR = 1.36, 95% CI = 1.15–1.61); and for melanoma in angiotensin-converting enzyme inhibitors (RR = 1.09, 95% CI = 1.03–1.14), calcium channel blockers (RR = 1.08, 95% CI = 1.03–1.12), and thiazides (RR = 1.09, 95% CI = 1.02–1.17). The quality of evidence was low or very low. We observed evidence for dose–response for thiazides with basal cell carcinoma; angiotensin-converting enzyme inhibitors, diuretics, and thiazides with squamous cell carcinoma; and angiotensin-converting enzyme inhibitors, diuretics, and thiazides with melanoma. Our meta-analysis supports a potential causal association between some antihypertensives, particularly diuretics, and skin cancer risk.

Few studies have examined the relationship between exposure to natural hazards and suicide and self-harm in youth. We extend prior research by investigating the association between multiple disasters and the risks of self-harm and suicide longitudinally in a nationally representative longitudinal cohort of adolescents 14 to 15 years to 18-19 years of age. Natural disasters were identified through parental self-reports for the local area. Different types of multiple disaster exposures were investigated including compound disasters (two or more disasters occurring in the last 12 months), cascading disasters (a disaster that leads to another disaster in the subsequent wave) and consecutive disasters (multiple disasters within the last two years or over an eight-year period). Using 8,714 person-waves of data from 2,908 adolescents, findings from random effect models suggest that parental reports of fire or floods increase the risk of self-harm ideation, self-harm, and suicidal ideation. Compound disasters of fire/flood and drought were also associated with increased risk of suicidal thoughts. Cascading disasters of drought followed by fire/flood increased the risks of self-harm but recurrent consecutive droughts were associated with lower risks of suicidal ideation. Australian adolescents are exposed to high rates of natural disasters that increase the risk of self-harm and thoughts of self-harm and suicide. Climate change will increase risk of natural disaster exposure for all countries. Despite these increased risks, there was resilience to disaster exposure particularly in the case of recurrent drought suggesting that youth, families and communities may well develop protective strategies to support mental health.

Introduction Respiratory syncytial virus (RSV) is a common respiratory virus, particularly affecting children, and can cause respiratory infections such as croup and bronchiolitis. The latter is a leading cause of paediatric hospitalisation within the UK. Children

This study focuses on using machine learning techniques to accurately predict the generated power in a two-stage back-pressure steam turbine used in the paper production industry. In order to accurately predict power production by a steam turbine, it is crucial to consider the time dependence of the input data. For this purpose, the long-short-term memory (LSTM) approach is employed. Correlation analysis is performed to select parameters with a correlation coefficient greater than 0.8. Initially, nine inputs are considered, and the study showcases the superior performance of the LSTM method, with an accuracy rate of 0.47. Further refinement is conducted by reducing the inputs to four based on correlation analysis, resulting in an improved accuracy rate of 0.39. The comparison between the LSTM method and the Willans line model evaluates the efficacy of the former in predicting production power. The root mean square error (RMSE) evaluation parameter is used to assess the accuracy of the prediction algorithm used for the generator’s production power. By highlighting the importance of selecting appropriate machine learning techniques, high-quality input data, and utilising correlation analysis for input refinement, this work demonstrates a valuable approach to accurately estimating and predicting power production in the energy industry.

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Coasts lie at the interface between terrestrial and marine environments, where complex interrelationships and feedbacks between environmental, social and economic factors provide a challenge for decision-making. The knowledge and data needed to link and measure these multiple domains are often highly fragmented and incoherent. Ocean Accounting provides a means to organise relevant ocean data into a common framework, grounded in existing international statistical standards for national and environmental-economic accounting. Here, we test Ocean Accounting within Lake Illawarra, New South Wales (Australia), compiling accounts for the years between 2010 and 2020, inclusive, to measure the extent of coastal vegetation (mangrove, tidal marsh and seagrass) and associated ecosystem services flows (climate change mitigation, eutrophication mitigation) in physical and monetary terms and associated production and employment within sectors of the ocean economy. The accounts show an increase in mangroves by 2 ha and a decrease in seagrass of 80 ha. A net increase was observed in the amount of carbon, nitrogen and phosphorus sequestered across coastal vegetation, due to the expansion of mangroves. Alongside changes in ecosystem extent, a 2-fold increase in full-time ocean-related employment was observed. Fisheries catch also showed significant variation over the 10-year period, where dependencies were observed between commercial species with seagrass and tidal marsh. The relationships and measures derived from accounts provide a cohesive and integrated understanding to provide information for the management and standardised ecosystem service assessments.

Summary: Background: Tailored smoking cessation interventions, which combine behavioural and pharmaceutical support, are effective in populations with severe mental illness (SMI). We establish the cost-effectiveness of two tailored interventions in the UK: (i) a bespoke smoking cessation intervention (BSCI) versus usual care, and (ii) integrated tobacco cessation and mental health care (IC) versus standard smoking cessation clinic (SCC) referral. Methods: This economic evaluation was conducted between January 15th 2019 and August 4th 2022. We adapted a Markov model estimating smoking status, healthcare costs and quality-adjusted life years (QALYs) across the lifetime. Intervention effectiveness and costs were obtained from a systematic review and a meta-analysis. We obtained specific parameter values for populations with SMI for mortality, risk of smoking related comorbidities, and health utility. Uncertainty was analysed in deterministic and probabilistic sensitivity analysis (PSA). Findings: The BSCI was cost-effective versus usual care with an incremental cost-effectiveness ratio (ICER) of £3145 per QALY (incremental costs: £165; incremental QALYs: 0.05). Integrated care was cost-effective versus SCC with an ICER of £6875 per QALY (incremental costs: £292; incremental QALYs: 0.04). The BSCI and IC were cost-effective in 89% and 83% of PSA iterations respectively. The main area of uncertainty related to relapse rates. Interpretation: Our findings suggested that the tailored interventions were cost-effective and could increase QALYs and decrease expenditure on treating smoking related morbidities if offered to people with SMI. Funding: York Health Economics Consortium was funded by the National Institute for Health and Care Excellence to produce economic evaluations to inform public health guidelines.

Ongoing failure to resolve how wildlife and people can co-exist on private land contributes to the global decline of wildlife populations. Experience in Tasmania, Australia suggests a disconnect between wildlife researchers, environmental agencies, and private landholders that prevents new scientific insights from translating into improved wildlife management practices. This case study based on a participatory action research model, describes a wildlife conservation initiative called WildTracker. WildTracker created hands-on collaborations among private landholders, university researchers, and the Tasmanian Land Conservancy (TLC). Landholders from 3 regions (total area 9977 km2) participated in an iterative 2-year research process involving problem-framing workshops, data collection (mammals, birds, and habitat) using wildlife cameras and sound recorders, data analysis, and discussion of results. Participants contributed more than 2,000 hours to the project, resulting in more than 500,000 wildlife observations, with many landholders now implementing research findings, guided by locality-specific data on wildlife populations, feral animals, and habitat condition. WildTracker has evolved from a short-term participatory research project into an ongoing collaborative citizen science program that is documenting and contributing to on-the-ground and evolving wildlife conservation outcomes.

Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader–Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the SNURF-SNRPN promoter, including the SNORD116 snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of SNURF-SNRPN with apparently preserved expression of SNORD116.

Daedalus MASE (Mission Assessment through Simulation Exercise) is an open-source package of scientific analysis tools aimed at research in the Lower Thermosphere-Ionosphere (LTI). It was created with the purpose to assess the performance and demonstrate closure of the mission objectives of Daedalus, a mission concept targeting to perform in-situ measurements in the LTI. However, through its successful usage as a mission-simulator toolset, Daedalus MASE has evolved to encompass numerous capabilities related to LTI science and modeling. Inputs are geophysical observables in the LTI, which can be obtained either through in-situ measurements from spacecraft and rockets, or through Global Circulation Models (GCM). These include ion, neutral and electron densities, ion and neutral composition, ion, electron and neutral temperatures, ion drifts, neutral winds, electric field, and magnetic field. In the examples presented, these geophysical observables are obtained through NCAR’s Thermosphere-Ionosphere-Electrodynamics General Circulation Model. Capabilities of Daedalus MASE include: 1) Calculations of products that are derived from the above geophysical observables, such as Joule heating, energy transfer rates between species, electrical currents, electrical conductivity, ion-neutral collision frequencies between all combinations of species, as well as height-integrations of derived products. 2) Calculation and cross-comparison of collision frequencies and estimates of the effect of using different models of collision frequencies into derived products. 3) Calculation of the uncertainties of derived products based on the uncertainties of the geophysical observables, due to instrument errors or to uncertainties in measurement techniques. 4) Routines for the along-orbit interpolation within gridded datasets of GCMs. 5) Routines for the calculation of the global coverage of an in situ mission in regions of interest and for various conditions of solar and geomagnetic activity. 6) Calculations of the statistical significance of obtaining the primary and derived products throughout an in situ mission’s lifetime. 7) Routines for the visualization of 3D datasets of GCMs and of measurements along orbit. Daedalus MASE code is accompanied by a set of Jupyter Notebooks, incorporating all required theory, references, codes and plotting in a user-friendly environment. Daedalus MASE is developed and maintained at the Department for Electrical and Computer Engineering of the Democritus University of Thrace, with key contributions from several partner institutions.

Abstract Aims This study aimed to estimate the annual mortality risk and its determinants in chronic Chagas cardiomyopathy. Methods and results We conducted a systematic search in MEDLINE, Web of Science Core Collection, Embase, Cochrane Library, and LILACS. Longitudinal studies published between 1 January 1946 and 24 October 2018 were included. A random‐effects meta‐analysis using the death rate over the mean follow‐up period in years was used to obtain pooled estimated annual mortality rates. Main outcomes were defined as all‐cause mortality, including cardiovascular, non‐cardiovascular, heart failure, stroke, and sudden cardiac deaths. A total of 5005 studies were screened for eligibility. A total of 52 longitudinal studies for chronic Chagas cardiomyopathy including 9569 patients and 2250 deaths were selected. The meta‐analysis revealed an annual all‐cause mortality rate of 7.9% [95% confidence interval (CI): 6.3–10.1; I2 = 97.74%; T2 = 0.70] among patients with chronic Chagas cardiomyopathy. The pooled estimated annual cardiovascular death rate was 6.3% (95% CI: 4.9–8.0; I2 = 96.32%; T2 = 0.52). The annual mortality rates for heart failure, sudden death, and stroke were 3.5%, 2.6%, and 0.4%, respectively. Meta‐regression showed that low left ventricular ejection fraction (coefficient = −0.04; 95% CI: −0.07, −0.02; P = 0.001) was associated with an increased mortality risk. Subgroup analysis based on American Heart Association (AHA) classification revealed pooled estimate rates of 4.8%, 8.7%, 13.9%, and 22.4% (P

Objective To investigate the associations of symptoms of mania and depression with clinical outcomes in people with unipolar depression.Design A natural language processing electronic health record study. We used network analysis to determine symptom network structure and multivariable Cox regression to investigate associations with clinical outcomes.Setting The South London and Maudsley Clinical Record Interactive Search database.Participants All patients presenting with unipolar depression between 1 April 2006 and 31 March 2018.Exposure (1) Symptoms of mania: Elation; Grandiosity; Flight of ideas; Irritability; Pressured speech. (2) Symptoms of depression: Disturbed mood; Anhedonia; Guilt; Hopelessness; Helplessness; Worthlessness; Tearfulness; Low energy; Reduced appetite; Weight loss. (3) Symptoms of mania or depression (overlapping symptoms): Poor concentration; Insomnia; Disturbed sleep; Agitation; Mood instability.Main outcomes (1) Bipolar or psychotic disorder diagnosis. (2) Psychiatric hospital admission.Results Out of 19 707 patients, at least 1 depression, overlapping or mania symptom was present in 18 998 (96.4%), 15 954 (81.0%) and 4671 (23.7%) patients, respectively. 2772 (14.1%) patients subsequently developed bipolar or psychotic disorder during the follow-up period. The presence of at least one mania (HR 2.00, 95% CI 1.85 to 2.16), overlapping symptom (HR 1.71, 95% CI 1.52 to 1.92) or symptom of depression (HR 1.31, 95% CI 1.07 to 1.61) were associated with significantly increased risk of onset of a bipolar or psychotic disorder. Mania (HR 1.95, 95% CI 1.77 to 2.15) and overlapping symptoms (HR 1.76, 95% CI 1.52 to 2.04) were associated with greater risk for psychiatric hospital admission than symptoms of depression (HR 1.41, 95% CI 1.06 to 1.88).Conclusions The presence of mania or overlapping symptoms in people with unipolar depression is associated with worse clinical outcomes. Symptom-based approaches to defining clinical phenotype may facilitate a more personalised treatment approach and better predict subsequent clinical outcomes than psychiatric diagnosis alone.

Fountain grass (Pennisetum alopecuroides) is a common ornamental grass because of its glossy foliage and showy inflorescence. However, there have been reports of populations growing outside of cultivation and demonstrating invasive tendencies. There is limited research of the chemical control of fountain grass in natural areas. The objective of this experiment was to evaluate the impact of glyphosate, sethoxydim, and fluazifop on fountain grass. Treatments consisted of 2250 and 4500 g⋅ha–1 glyphosate, 262.5 and 525 g⋅ha–1 sethoxydim, and 200 and 400 g⋅ha–1 fluazifop; a nontreated control group was also included. The percent herbicide injury was determined visually 1, 3, 4, 6, and 10 weeks after treatment (WAT). Both rates of glyphosate resulted in 100% of the foliage injured by 3 WAT. The application of flauzifop and sethoxydim led to intermediate results ranging from 15% to 23% injury by 6 WAT, with no significant difference between active ingredients or rates. Nontreated control plants exhibited little to no injury throughout the study. Flauzifop, sethoxydim, and glyphosate all caused visible injury to fountain grass. For complete, fast-acting control, glyphosate is recommended. Herbicide control coupled with restorative plantings of native plants can help reduce invasive plant pressure and improve biodiversity of natural areas.

Abstract Background Soil ecosystems consist of complex interactions between biological communities and physico-chemical variables, all of which contribute to the overall quality of soils. Despite this, changes in bacterial communities are ignored by most soil monitoring programs, which are crucial to ensure the sustainability of land management practices. We applied 16S rRNA gene sequencing to determine the bacterial community composition of over 3000 soil samples from 606 sites in New Zealand. Sites were classified as indigenous forests, exotic forest plantations, horticulture, or pastoral grasslands; soil physico-chemical variables related to soil quality were also collected. The composition of soil bacterial communities was then used to predict the land use and soil physico-chemical variables of each site. Results Soil bacterial community composition was strongly linked to land use, to the extent where it could correctly determine the type of land use with 85% accuracy. Despite the inherent variation introduced by sampling across ~ 1300 km distance gradient, the bacterial communities could also be used to differentiate sites grouped by key physico-chemical properties with up to 83% accuracy. Further, individual soil variables such as soil pH, nutrient concentrations and bulk density could be predicted; the correlations between predicted and true values ranged from weak (R 2 value = 0.35) to strong (R 2 value = 0.79). These predictions were accurate enough to allow bacterial communities to assign the correct soil quality scores with 50–95% accuracy. Conclusions The inclusion of biological information when monitoring soil quality is crucial if we wish to gain a better, more accurate understanding of how land management impacts the soil ecosystem. We have shown that soil bacterial communities can provide biologically relevant insights on the impacts of land use on soil ecosystems. Furthermore, their ability to indicate changes in individual soil parameters shows that analysing bacterial DNA data can be used to screen soil quality. Video Abstract

OBJECTIVES:. To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN:. Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING:. The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS:. We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS:. We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS:. Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

Small metabolites and venom metabolites produced by insects are known to exhibit biological activity. These metabolites could be used to develop natural product-based therapeutics. To screen for these metabolites, insects must be collected and accurately identified. Natural history collections consist of identified insects and provide a source of raw material for metabolomic screening. The objective of this research was to understand whether preservation significantly altered the insect metabolomic profiles. Insects from the family Sphecidae: Podalonia tydei (Le Guillou), which were preserved in ethanol, flash frozen, and homogenized with methanol. The resulting metabolomic extracts and storage ethanol were analysed using untargeted liquid chromatography-mass spectrometry. Mass spectral data were processed with MZmine2. The data were analysed using multivariate statistical analysis. In the Principal Component Analysis, ethanol stored samples and their storage solvents clustered close together. This was verified by Analysis of Similarity (ANOSIM). Based on ANOSIM (p = 0.003, R2 = 0.48), there was significant overlap between chemical profiles of treatments (ethanol only, ethanol stored tissue, flash frozen tissue). A group of acyl-carnitines were putatively identified from the extracts. The flash frozen samples have a high relative abundance for acyl-carnitines, however the Kruskal–Wallis (p > 0.05) showed no significant difference between the median of abundance. Therefore, preserved insects from natural history collections and their ethanol storage solvents could be used for metabolomic screening. However, it would be best to use specimens from the same species preserved under various conditions to capture metabolites that may degrade or leach during preservation.

Abstract Background NHS community pharmacies provide effective smoking cessation services; however, there is scope for increasing throughput and improving quit rates. This trial examines whether the Smoking Treatment Optimisation in Pharmacies (STOP) intervention can improve smoker engagement to increase service throughput, retention and quitting. Methods This study is a pragmatic, cluster randomised controlled trial in 60 pharmacies in England and Wales. All workers in intervention pharmacies are offered STOP training while control pharmacies provide usual care. The STOP intervention, based on behavioural and organisational theories, comprises educational sessions for staff and environmental prompts in the pharmacy. Intervention fidelity is assessed by actors visiting pharmacies posing as smokers. The primary outcome is throughput, defined as the number of smokers who join the programme, set a firm quit date and undergo at least one stop smoking treatment session, and is measured using routinely collected data. Secondary outcomes include retention and quit rates at 4 weeks and continuous abstinence at 6 months verified by salivary cotinine. Cost-effectiveness is estimated using quality-adjusted life years and the probability that the intervention is effective at different levels of willingness to pay is calculated. Discussion The trial will generate evidence to inform the public health smoking cessation strategy in England and Wales, and may help to shape service commissioning decisions. The STOP intervention model may help inform the undertaking of a range of health behaviour change tasks in community pharmacies. Trial registration ClinicalTrials.gov, ISRCTN16351033. Retrospectively registered on 21 March 2017.

A circular economy relies on demonstrating the quality and environmental safety of wastes that are recovered and reused as products. Policy-level risk assessments, using generalised exposure scenarios, and informed by stakeholder communities have been used to appraise the acceptability of necessary changes to legislation, allowing wastes to be valued, reused and marketed. Through an extensive risk assessment exercise, summarised in this paper, we explore the burden of proof required to offer safety assurance to consumer and brand-sensitive food sectors in light of attempts to declassify, as wastes, quality-assured, source-segregated compost and anaerobic digestate products in the United Kingdom. We report the residual microbiological and chemical risks estimated for both products in land application scenarios and discuss these in the context of an emerging UK bioeconomy worth £52bn per annum. Using plausible worst case assumptions, as demanded by the quality food sector, risk estimates and hazard quotients were estimated to be low or negligible. For example, the human health risk of E. coli 0157 illness from exposure to microbial residuals in quality-assured composts, through a ready-to-eat vegetable consumption exposure route, was estimated at ~10−8 per person per annum. For anaerobic digestion residues, 7 × 10−3 cases of E. coli 0157 were estimated per annum, a potential contribution of 0.0007% of total UK cases. Hazard quotients for potential chemical contaminants in both products were insufficient in magnitude to merit detailed quantitative risk assessments. Stakeholder engagement and expert review was also a substantive feature of this study. We conclude that quality-assured, source-segregated products applied to land, under UK quality protocols and waste processing standards, pose negligible risks to human, animal, environmental and crop receptors, providing that risk management controls set within the standards and protocols are adhered to. Keywords: Compost, Digestate, Regulation, Risk, Bioeconomy, Quality

After publication of this supplement [1, 2], it was brought to our attention that due to an error authors were missing in the following abstracts. This has now been included in this correction.

Purpose Understanding what constitutes normal walking mechanics across the adult lifespan is crucial to the identification and intervention of early decline in walking function. Existing research has assumed a simple linear alteration in peak joint powers between young and older adults. The aim of the present study was to quantify the potential (non)linear relationship between age and the joint power waveforms of the lower limb during walking. Methods This was a pooled secondary analysis of the authors’ (MT, KD, JJ) and three publicly available datasets, resulting in a dataset of 278 adults between the ages of 19 to 86 years old. Three-dimensional motion capture with synchronised force plate assessment was performed during self-paced walking. Inverse dynamics were used to quantity joint power of the ankle, knee, and hip, which were time-normalized to 100 stride cycle points. Generalized Additive Models for location, scale and shape (GAMLSS) was used to model the effect of cycle points, age, walking speed, stride length, height, and their interaction on the outcome of each joint’s power. Results At both 1m/s and 1.5 m/s, A2 peaked at the age of 60 years old with a value of 3.09 (95% confidence interval [CI] 2.95 to 3.23) W/kg and 3.05 (95%CI 2.94 to 3.16), respectively. For H1, joint power peaked with a value of 0.40 (95%CI 0.31 to 0.49) W/kg at 1m/s, and with a value of 0.78 (95%CI 0.72 to 0.84) W/kg at 1.5m/s, at the age of 20 years old. For H3, joint power peaked with a value of 0.69 (95%CI 0.62 to 0.76) W/kg at 1m/s, and with a value of 1.38 (95%CI 1.32 to 1.44) W/kg at 1.5m/s, at the age of 70 years old. Conclusions Findings from this study do not support a simple linear relationship between joint power and ageing. A more in-depth understanding of walking mechanics across the lifespan may provide more opportunities to develop early clinical diagnostic and therapeutic strategies for impaired walking function. We anticipate that the present methodology of pooling data across multiple studies, is a novel and useful research method to understand motor development across the lifespan.

Wrong-site surgery (WSS) is a well-known type of medical error that may cause a high degree of patient harm. In Pennsylvania, healthcare facilities are mandated to report WSS events, among other patient safety concerns, to the Pennsylvania Patient Safety Reporting System (PA-PSRS) database. In the study we identified instances of WSS events (not including near misses) that occurred during 2015–2019 and were reported to PA-PSRS. During the five-year period, we found that 178 healthcare facilities reported a total of 368 WSS events, which was an average of 1.42 WSS events per week in Pennsylvania. Also, we revealed that 76% (278 of 368) of the WSS events contributed to or resulted in temporary harm or permanent harm to the patient. Overall, the study shows that the frequency of WSS varied according to a range of variables, including error type (e.g., wrong side, wrong site, wrong procedure, wrong patient); year; facility type; hospital bed size; hospital procedure location; procedure; body region; body part; and clinician specialty. Our findings are aligned with some of the previous research on WSS; however, the current study also addresses many gaps in the literature. We encourage readers to use the visuals in the manuscript and appendices to gain new insight into the relation among the variables associated with WSS. Ultimately, the findings reported in the current study help to convey a more complete account of the variables associated with WSS, which can be used to assist staff in making informed decisions about allocating resources to mitigate risk.

This case report highlights an unusual presentation of herpes zoster mandibularis in an immunocompromised patient with previous head and neck surgery, with relative sparing of the cheek. It demonstrates the importance of critically considering past medical and surgical history in clinical diagnosis and management of the disease.

Patients’ substance use and possession at acute care hospitals is an understudied topic. To learn more about this topic, we queried the Pennsylvania Patient Safety Reporting System (PA-PSRS) for events that occurred during calendar year 2018. We identified 106 reports from 38 acute care hospitals (excluding psychiatric, detox, and behavioral health units and facilities) where a patient possessed and/or misused a substance (e.g., heroin, oxycodone, liquor). We analyzed these reports to better understand how hospital personnel attempt to prevent in-hospital substance use and manage patients who are at risk for using a substance. We explored a range of variables, including antecedent conditions and hospital personnel’s actions post-detection of a patient’s substance use or possession. We found that a relatively low percentage of patients (26%) were identified as having a prior history of substance use, despite later using or being in possession of a substance in hospital. In our sample, patients frequently acquired the substances from visitors, more than half of the substances were consumed intravenously, and opioids were the most common substance. The most prevalent actions taken by hospital personnel were conducting searches for substances and paraphernalia, use of a patient sitter or video monitor, moving patients to a different room, and implementing visitor restrictions. Based on our findings and previous research, hospitals should consider increasing their use of substance use disorder (SUD) screening tools, pharmacotherapy, and referring patients to treatment. Overall, our results can help personnel better understand the nature of and strategies that may reduce the likelihood of in-hospital substance use.

COVID-19 (i.e., coronavirus disease 2019) was declared a pandemic and has had a profound impact on healthcare systems, which may increase the risk of patient harm. We conducted a query of the Pennsylvania Patient Safety Reporting System (PA-PSRS) database to identify COVID-19–related events submitted by acute care hospitals between January 1 and April 15, 2020. We identified 343 relevant event reports from 71 hospitals and conducted a descriptive study to identify the prevalence of and relationships between 13 categories of associated factors and six categories of event outcomes. We found that 36% (124 of 343) of events had more than one associated factor and 24% (83 of 343) had more than one outcome. The most frequently identified factors were Laboratory Testing (47%; 161 of 343), Process/Protocol (25%; 87 of 343), and Isolation Integrity (22%; 74 of 343). The two most frequent outcomes were Exposure to COVID-19 Positive or Suspected Positive Patient (50%; 173 of 343) and Missed/Delayed Test or Result (31%; 108 of 343). Finally, the findings showed that seven of the associated factors had a notable impact on the frequency of Exposure to COVID-19 Positive or Suspected Positive Patient outcome. Overall, we anticipate that the results can be used to identify areas of greatest need and risk, which could help to guide allocation of resources to mitigate risk of patient harm.

Saturated mid-chain branched fatty acids (SMCBFAs) are widely used in the petrochemical industry for their high oxidative stability and low melting temperature. Dihydrosterculic acid (DHSA) is a cyclopropane fatty acid (CPA) that can be converted to SMCBFA via hydrogenation, and therefore oils rich in DHSA are a potential feedstock for SMCBFA. Recent attempts to produce DHSA in seed oil by recombinant expression of cyclopropane fatty acid synthases (CPFASes) resulted in decreased oil content and poor germination or low DHSA accumulation. Here we explored the potential for plant vegetative tissue to produce DHSA by transiently expressing CPFAS enzymes in leaf. When CPFASes from plant and bacterial origin were transiently expressed in Nicotiana benthamiana leaf, it accumulated up to 1 and 3.7% DHSA in total fatty acid methyl ester (FAME), respectively, which increased up to 4.8 and 11.8%, respectively, when the N. benthamiana endogenous oleoyl desaturase was silenced using RNA interference (RNAi). Bacterial CPFAS expression produced a novel fatty acid with a cyclopropane ring and two carbon-carbon double bonds, which was not seen with plant CPFAS expression. We also observed a small but significant additive effect on DHSA accumulation when both plant and bacterial CPFASes were co-expressed, possibly due to activity upon different oleoyl substrates within the plant cell. Lipidomics analyses found that CPFAS expression increased triacylglycerol (TAG) accumulation relative to controls and that DHSA was distributed across a range of lipid species, including diacylglycerol and galactolipids. DHSA and the novel CPA were present in phosphatidylethanolamine when bacterial CPFAS was expressed in leaf. Finally, when plant diacylglycerol acyltransferase was coexpressed with the CPFASes DHSA accumulated up to 15% in TAG. This study shows that leaves can readily produce and accumulate DHSA in leaf oil. Our findings are discussed in line with current knowledge in leaf oil production for a possible route to DHSA production in vegetative tissue.

BackgroundThe release of small non-coding RNAs (sRNAs) has been reported in parasitic nematodes, trematodes and cestodes of medical and veterinary importance. However, little is known regarding the diversity and composition of sRNAs released by different lifecycle stages and the portion of sRNAs that persist in host tissues during filarial infection. This information is relevant to understanding potential roles of sRNAs in parasite-to-host communication, as well as to inform on the location within the host and time point at which they can be detected.Methodology and principal findingsWe have used small RNA (sRNA) sequencing analysis to identify sRNAs in replicate samples of the excretory-secretory (ES) products of developmental stages of the filarial nematode Litomosoides sigmodontis in vitro and compare this to the parasite-derived sRNA detected in host tissues. We show that all L. sigmodontis developmental stages release RNAs in vitro, including ribosomal RNA fragments, 5'-derived tRNA fragments (5'-tRFs) and, to a lesser extent, microRNAs (miRNAs). The gravid adult females (gAF) produce the largest diversity and abundance of miRNAs in the ES compared to the adult males or microfilariae. Analysis of sRNAs detected in serum and macrophages from infected animals reveals that parasite miRNAs are preferentially detected in vivo, compared to their low levels in the ES products, and identifies miR-92-3p and miR-71-5p as L. sigmodontis miRNAs that are stably detected in host cells in vivo.ConclusionsOur results suggest that gravid adult female worms secrete the largest diversity of extracellular sRNAs compared to adult males or microfilariae. We further show differences in the parasite sRNA biotype distribution detected in vitro versus in vivo. We identify macrophages as one reservoir for parasite sRNA during infection, and confirm the presence of parasite miRNAs and tRNAs in host serum during patent infection.

Background: Although there has been an exponential growth in hookah use on a global scale, research within the context of South Africa is very limited. While hookah use is known internationally to be a health and addiction risk, the focus is on university students and not on families. Aim: This study aims to compare the family functioning and family satisfaction among hookah users and non-users. Setting: This study was conducted in low or middle-high class socio-economic status areas of Cape Town, South Africa. Methods: A quantitative method was employed to test for significant differences with a sample of 1193 participants, in which each participant represented a family. An independent t-test was used to test for significant differences between hookah users and non-users. Results: One-third (34%) of the participants indicated that they smoked hookah pipe, with the general age of onset being 16.5 years. In trying to understand the family context, it was found that 28% of hookah users indicated that the hookah pipe was used as a means of socialising with others in the family, and 24% of parents indicated that they were more accepting of family members smoking the hookah pipe. Findings also suggest that families of hookah users have less cohesion, expressiveness and family satisfaction, and more conflict and permissiveness than families of non-users. Conclusion: This study provides and extends knowledge regarding the family in hookah pipe use. This information could assist in reducing hookah pipe use, and building healthier and more resilient communities by formulating prevention and intervention strategies to reduce hookah use.

Abstract Background The literature suggests that although adult hospitals are establishing population health programs around the country, there is considerable definitional ambiguity regarding whether interventions are aimed at the social determinants of health or the management of existing patient populations. U.S. children’s hospitals also undertake population health programs, but less is known about how they define population health. The purpose of this study is to understand how U.S. children’s hospitals define population health, and how institutions are adjusting to new preventive health care models. Methods We conducted semi-structured interviews with key stakeholders at ten hospitals with the highest amount of staff time dedicated to population health activities as reported in the 2016 Children’s Hospital Association’s population health survey. Using a semi-structured interview guide, we interviewed representatives from each hospital. Verbatim interview notes were coded and analyzed using the data analysis software Dedoose. Data analysis followed a modified constructivist grounded theory approach. Results Our results suggest that even population health innovators employ a variety of approaches that span both population health management and public health. We present further evidence that U.S. children’s hospitals are actively debating the definition and focus of population health. Conclusions Definitional debates are ongoing even within children’s hospitals that are dedicating significant resources to population health. Increased clarity on the conceptual boundaries between population health and population health management could help preserve the theoretical differences between the two concepts, especially insofar as they mark two quite different long-term visions for health care. Without agreement about the meaning of population health within and among institutions, hospitals will not be able to know whether projects aimed at addressing the social determinants of health are likely to improve the health of populations.

Abstract Background Cognitive problems in people with schizophrenia predict poor functional recovery even with the best possible rehabilitation opportunities and optimal medication. A psychological treatment known as cognitive remediation therapy (CRT) aims to improve cognition in neuropsychiatric disorders, with the ultimate goal of improving functional recovery. Studies suggest that intervening early in the course of the disorder will have the most benefit, so this study will be based in early intervention services, which treat individuals in the first few years following the onset of the disorder. The overall aim is to investigate different methods of CRT. Methods This is a multicentre, randomised, single-blinded, controlled trial based in early intervention services in National Health Service Mental Health Trusts in six English research sites. Three different methods of providing CRT (intensive, group, and independent) will be compared with treatment as usual. We will recruit 720 service users aged between 16 and 45 over 3 years who have a research diagnosis of non-affective psychosis and will be at least 3 months from the onset of the first episode of psychosis. The primary outcome measure will be the degree to which participants have achieved their stated goals using the Goal Attainment Scale. Secondary outcome measures will include improvements in cognitive function, social function, self-esteem, and clinical symptoms. Discussion It has already been established that cognitive remediation improves cognitive function in people with schizophrenia. Successful implementation in mental health services has the potential to change the recovery trajectory of individuals with schizophrenia-spectrum disorders. However, the best mode of implementation, in terms of efficacy, service user and team preference, and cost-effectiveness is still unclear. The CIRCuiTS trial will provide guidance for a large-scale roll-out of CRT to mental health services where cognitive difficulties impact recovery and resilience. Trial registration ISRCTN, ISRCTN14678860, Registered on 6 June 2016.

Chagas disease (CD) is the third most common parasitic infection globally and can cause cardiac and gastrointestinal complications. Around 300,000 carriers of CD live in the U.S., with about 3000 of those in Colorado. We described our experience in diagnosing CD at a Colorado teaching hospital to revise screening eligibility criteria. From 2006 to 2020, we reviewed Trypanosoma cruzi (TC) IgG serology results for 1156 patients in our institution. We identified 23 patients (1.99%) who had a positive test. A total of 14/23 (60%) of positive serologies never had confirmatory testing, and 7 of them were lost to follow up. Confirmatory testing, performed in 9 patients, resulted in being positive in 3. One additional case of CD was identified by positive tissue pathology. All four confirmed cases were among patients born in Latin America. While most of the testing for CD at our institution is part of the pretransplant screening, no confirmed cases of CD derived from this strategy. Exposure risk in this population is not always documented, and initial positive results from screening are not always confirmed. The lack of standardized screening protocols for CD in our institution contributes to underdiagnosis locally and in health systems nationwide. Given a large number of individuals in the U.S. with chronic CD, improved screening is warranted.

Demand for plant-based proteins and plant-based food products is increasing globally. This trend is driven mainly by global population growth and a consumer shift towards more sustainable and healthier diets. Existing plant-based protein foods and meat mimetics often possess undesirable flavor and sensory properties and there is a need to better understand the formation of desirable meat-like flavors from plant precursors to improve acceptance of novel high-protein plant foods. This study aimed to comprehensively characterize the non-volatile flavor metabolites and the volatiles generated in grilled meat (beef, chicken, and pork) and compare these to commercially available meat substitutes and traditional high-protein plant-based foods (natto, tempeh, and tofu). Solid phase microextraction with gas-chromatography mass-spectrometry was used for elucidation of the flavor volatilome. Untargeted characterization of the non-volatile metabolome was conducted using Orbitrap mass spectrometry and Compound DiscovererTM datamining software. The study revealed greater diversity and higher concentrations of flavor volatiles in plant-based foods in comparison to grilled meat, although the odor activity of specific volatiles was not considered. On average, the total amount of volatiles in plant-based products were higher than in meat. A range of concentrations of free amino acids, dipeptide, tripeptides, tetrapeptides, nucleotides, flavonoids, and other metabolites was identified in meat and plant-based foods.

Predicting and simplifying which pathogens may spill over from animals to humans is a major priority in infectious disease biology. Many efforts to determine which viruses are at risk of spillover use a subset of viral traits to find trait-based associations with spillover. We adapt a new method—phylofactorization—to identify not traits but lineages of viruses at risk of spilling over. Phylofactorization is used to partition the International Committee on Taxonomy of Viruses viral taxonomy based on non-human host range of viruses and whether there exists evidence the viruses have infected humans. We identify clades on a range of taxonomic levels with high or low propensities to spillover, thereby simplifying the classification of zoonotic potential of mammalian viruses. Phylofactorization by whether a virus is zoonotic yields many disjoint clades of viruses containing few to no representatives that have spilled over to humans. Phylofactorization by non-human host breadth yields several clades with significantly higher host breadth. We connect the phylogenetic factors above with life-histories of clades, revisit trait-based analyses, and illustrate how cladistic coarse-graining of zoonotic potential can refine trait-based analyses by illuminating clade-specific determinants of spillover risk.

Men sex workers in Vancouver have largely transitioned from street to online solicitation coinciding with losing “Boystown,” the main outdoor sex work stroll for men. This article explores strategies and barriers to increase safety among men and trans sex workers and clients of men in Vancouver, Canada. Qualitative interviews were conducted (2012-2013) with 61 self-identifed men who currently buy and/or sell sex in a community-based research project known as CHAPS (Community Health Assessment of Men Who Purchase and Sell Sex). Drawing on a socioecological framework, thematic analysis of interview transcripts was conducted utilizing ATLAS.ti 7 software among men (39 workers; 8 buyers). Narratives indicate that gentrification and urban planning led to social isolation and loss of social support networks among men in the sex industry. Concurrently, the restructuring of sex work to online increased workers’ safety and control. Narratives reveal how the Internet can provide greater opportunities to negotiate terms of sex work and enhanced screening using webcams, reducing risks of violence, stigma, and police harassment for both workers and clients compared with the street. This study highlights how losing Boystown led to a loss of community and solidarity: key protective measures for sex workers. Online solicitation increased workers’ capacity to screen prospective clients and prevent violence. Recent legal reforms in Canada to further criminalize sex work raise significant concern for human rights and health of individuals in the sex industry, and point to the critical need to include voices of men and trans sex workers and buyers in policy discussions.

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.

This article investigates how migration and remittances affect forest cover in eight rural communities in Guatemala and Chiapas, Mexico. Based on household surveys and remote sensing data, we found little evidence to support the widespread claim that migration takes pressure off forests. In the Chiapas sites, we observed no significant changes in forest cover since 1990, while in the Guatemalan sites, migration may have increased demand for agricultural land, leading to an average annual forest loss of 0.73% during the first decade of the millennium. We suggest that when attractive opportunities exist to invest in agriculture and land expansion, remittances and returnee savings provide fresh capital that is likely to increase pressure on forests. Our study also has implications for the understanding of migration flows; in particular, migration has not implied an exodus out of agriculture for the remaining household members nor for the returning migrants. On the contrary, returning migrants are more likely to be involved in farming activities after their return than they were before leaving.

BackgroundElectronic health records (EHRs) are widely used in mental health services. Case registers using EHRs from secondary mental healthcare have the potential to deliver large-scale projects evaluating mental health outcomes in real-world clinical populations.MethodsWe describe the Camden and Islington NHS Foundation Trust (C&I) Research Database which uses the Clinical Record Interactive Search (CRIS) tool to extract and de-identify routinely collected clinical information from a large UK provider of secondary mental healthcare, and demonstrate its capabilities to answer a clinical research question regarding time to diagnosis and treatment of bipolar disorder.ResultsThe C&I Research Database contains records from 108,168 mental health patients, of which 23,538 were receiving active care. The characteristics of the patient population are compared to those of the catchment area, of London, and of England as a whole. The median time to diagnosis of bipolar disorder was 76 days (interquartile range: 17-391) and median time to treatment was 37 days (interquartile range: 5-194). Compulsory admission under the UK Mental Health Act was associated with shorter intervals to diagnosis and treatment. Prior diagnoses of other psychiatric disorders were associated with longer intervals to diagnosis, though prior diagnoses of schizophrenia and related disorders were associated with decreased time to treatment.ConclusionsThe CRIS tool, developed by the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC), functioned very well at C&I. It is reassuring that data from different organizations deliver similar results, and that applications developed in one Trust can then be successfully deployed in another. The information can be retrieved in a quicker and more efficient fashion than more traditional methods of health research. The findings support the secondary use of EHRs for large-scale mental health research in naturalistic samples and settings investigated across large, diverse geographical areas.

Public gardens can benefit from the introduction of new plants to the horticulture industry. There are many ways to develop and discover new plants in the public garden setting, whether it be through plant breeding, exploration or simply discovering a sport or mutation. The characteristics of plants suitable for the commercial display industry include short time to flower, no day-length requirement, easy and fast propagation, natural branching and inherent short height. Over the last 20 years, the process of plant development and introduction has changed enormously. Now, elements such as strong brands and marketing campaigns, plant patents or plant breeders’ rights, trademarks and the ability of a new plant to thrive in mass production settings are important considerations when making a new plant release. In addition, public gardens must evaluate potential commercial partners to ensure that they get the maximum benefits from the process. This paper describes that process and gives recommendations for some of the key stages with reference to plants released by Longwood Gardens in Philadelphia.

Contrary to critics and advocates of contractarianism alike, I argue that mutual advantage contractarianism entails rights and protections for animals. In section one I outline the criteria that must be met in order for an individual to qualify for moral rights on the contractarian view. I then introduce an alternative form of ‘rights,’ which I call ‘protectorate status,’ from which an individual can receive protections indirectly. In section two I suggest guidelines for assigning animal rights based on two ways of categorizing animals. On the basis of the categorization according to benefit derived, I argue that animals used for companionship, security, hunting assistance, transportation, entertainment, medical service, nourishment, or clothing will tend to qualify for basic rights against starvation, predation, and disease. On the basis of the categorization according to species, I argue that, on top of the basic rights above, dogs tend to qualify for rights against abuse, and against frivolous medical experimentation, as well as further negotiated rights. Cows have the basic rights against starvation, predation, and disease, but squirrels and bears have no rights. In section three I argue that some animals qualify for protectorate status, which would establish various protections for different animals, but would also generally prohibit cruelty towards animals.

Anecdotal evidence suggests that the timing and intensity of the Central American Midsummer Drought (MSD) may be changing, while observations from limited meteorological station data and paleoclimate reconstructions show neither significant nor consistent trends in seasonal rainfall. Climate model simulations project robust future drying across the region, but internal variability is expected to dominate until the end of the century. Here we use a high-resolution gridded precipitation dataset to investigate these apparent discrepancies and to quantify the spatiotemporal complexities of the MSD. We detect spatially variable trends in MSD timing, the amount of rainy season precipitation, the number of consecutive and total dry days, and extreme wet events at the local scale. At the regional scale, we find a positive trend in the duration, but not the magnitude of the MSD, which is dominated by spatially heterogeneous trends and interannual variability linked to large-scale modes of ocean-atmosphere circulation. Although the current climate still reflects predominantly internal variability, some Central American communities are already experiencing significant changes in local characteristics of the MSD. A detailed spatiotemporal understanding of MSD trends and variability can contribute to evidence-based adaptation planning and help reduce the vulnerability of Central American communities to both natural rainfall variability and anthropogenic change.

Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the HCM phenotype. Furthermore TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare missense variant in TTN cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN, however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.

This systematic review aimed to assess the efficacy of cognitive‐behavioural approaches (CBT) in addressing the immediate and longer‐term sequelae of sexual abuse on children and young people up to 18 years of age. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week 3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). We included 10 trials, involving 847 participants. The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials. Abstract BACKGROUND Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents (‘child sexual abuse‘) is a substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post‐traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive‐behavioural approaches are used to help children and their non‐offending or ‘safe’ parent to manage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive‐behavioural approaches interventions for children who have been sexually abused, which was first published in 2006. OBJECTIVES To assess the efficacy of cognitive‐behavioural approaches (CBT) in addressing the immediate and longer‐term sequelae of sexual abuse on children and young people up to 18 years of age. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week 3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA We included randomised or quasi‐randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control. DATA COLLECTION AND ANALYSIS At least two review authors independently assessed the eligibility of titles and abstracts identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots). RESULTS We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a non‐offending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged ‘low risk of bias’ with regards to sequence generation and only one study was judged ‘low risk of bias’ in relation to allocation concealment. All studies were judged ‘high risk of bias’ in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited. Depression, post‐traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be ‘moderate’ at best. Meta‐analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post‐traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2 = 0%; P value for heterogeneity = 0.84). No study reported adverse effects. AUTHORS' CONCLUSIONS The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials. Plain language summary The sexual abuse of children is a substantial social problem that affects large numbers of children and young people worldwide. For many children, though not all, it can result in a range of psychological and behavioural problems, some of which can continue into adulthood. Knowing what is most likely to benefit children already traumatised by these events is important. This review aimed to find out if cognitive‐behavioural approaches (CBT) help reduce the negative impact of sexual abuse on children. Ten studies, in which a total of 847 children participated, met the inclusion criteria for the review. The reporting of studies was poor, and there appear to be significant weaknesses in study quality. The evidence suggests that CBT may have a positive impact on the effects of child sexual abuse, including depression, post‐traumatic stress and anxiety, but the results were generally modest. Implications for practice and further research are noted.

BackgroundCardiopulmonary arrest in children is an uncommon event, and often fatal. Resuscitation is often attempted, but at what point, and under what circumstances do continued attempts to re-establish circulation become futile? The uncertainty around these questions can lead to unintended distress to the family and to the resuscitation team.ObjectivesTo define the likely outcomes of cardiopulmonary resuscitation in children, within different patient groups, related to clinical features.Data sourcesMEDLINE, MEDLINE in-Process & Other non-Indexed Citations, EMBASE, Cochrane database of systematic reviews and Cochrane central register of trials, Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment database, along with reference lists of relevant systematic reviews and included articles.Study eligibility criteriaProspective cohort studies which derive or validate a clinical prediction model of outcome following cardiopulmonary arrest.Participants and interventionsChildren or young people (aged 0 - 18 years) who had cardiopulmonary arrest and received an attempt at resuscitation, excluding resuscitation at birth.Study appraisal and synthesis methodsRisk of bias assessment developed the Hayden system for non-randomised studies and QUADAS2 for decision rules. Synthesis undertaken by narrative, and random effects meta-analysis with the DerSimonian-Laird estimator.ResultsMore than 18,000 episodes in 16 data sets were reported. Meta-analysis was possible for survival and one neurological outcome; others were reported too inconsistently. In-hospital patients (average survival 37.2% (95% CI 23.7 to 53.0%)) have a better chance of survival following cardiopulmonary arrest than out-of-hospital arrests (5.8% (95% CI 3.9% to 8.6%)). Better neurological outcome was also seen, but data were too scarce for meta-analysis (17% to 71% 'good' outcomes, compared with 2.8% to 3.2%).LimitationLack of consistent outcome reporting and short-term neurological outcome measures limited the strength of conclusions that can be drawn from this review.Conclusions and implications of key findingsThere is a need to collaboratively, prospectively, collect potentially predictive data on these rare events to understand more clearly the predictors of survival and long-term neurological outcome.Systematic review registration numberPROSPERO 2013:CRD42013005102.

Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare.Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay).The median diagnostic delay was 62 days (interquartile range: 17-243) and median treatment delay was 31 days (4-122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18-3.06) and treatment delay (4.40, 3.63-5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33-0.41) and substance misuse disorders (0.44, 0.31-0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay.Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner in order to facilitate improved clinical outcomes, such as developing specialist early intervention services to identify and treat people with bipolar disorder.