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Background Atrial fibrillation/flutter (AF) after transient ischemic attack (TIA) has not been well studied. We compared the likelihood of new AF diagnosis after ischemic stroke versus TIA. Methods and Results The POINT (Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled adults within 12 hours of minor ischemic stroke or high‐risk TIA. Our exposure was index event type (ischemic stroke versus TIA). The primary analysis used the original trial definition of TIA (resolution of symptoms/signs). In secondary analyses, TIA cases with infarction on neuroimaging were reclassified as strokes. Our primary outcome was a new AF diagnosis, ascertained from adverse event and treatment interruption/discontinuation reports. We calculated C‐statistics for variables associated with newly diagnosed AF. We used Kaplan‐Meier survival statistics and Cox models adjusted for demographics and vascular risk factors. Excluding 49 subjects with baseline AF, 2746 patients had index stroke and 2086 patients had index TIA. During the 90‐day follow‐up, 106 patients had newly diagnosed AF. Cumulative risks of AF were 2.7% (95% CI, 2.1%–3.4%) after stroke and 2.0% (95% CI, 1.5%–2.7%) after TIA (P=0.15). After reclassifying index events by neuroimaging, cumulative AF risk was higher after stroke (2.7%; 95% CI, 2.2%–3.4%) than TIA (1.8%; 95% CI, 1.3%–2.5%) (P=0.04). Index event type had negligible predictive utility (C‐statistic, 0.54). Conclusions Among patients with cerebral ischemia, the distinction between TIA versus minor stroke did not stratify the risk of subsequent AF diagnosis, implying that patients with TIA should undergo similar heart‐rhythm monitoring strategies as patients with ischemic stroke.

IntroductionDelayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation.MethodsThe 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers.ResultsGSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs.ConclusionOverall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population.Trial registrationNCT02723786.

Introduction Person-centred care has become internationally recognised as a critical attribute of high-quality healthcare. However, the concept has been criticised for being poorly theorised and operationalised. Serious illness is especially aligned with the need for person-centredness, usually necessitating involvement of significant others, management of clinical uncertainty, high-quality communication and joint decision-making to deliver care concordant with patient preferences. This review aimed to identify and appraise the empirical evidence underpinning conceptualisations of ‘person-centredness’ for serious illness.Methods Search strategy conducted in May 2020. Databases: CINAHL, Embase, PubMed, Ovid Global Health, MEDLINE and PsycINFO. Free text search terms related to (1) person-centredness, (2) serious illness and (3) concept/practice. Tabulation, textual description and narrative synthesis were performed, and quality appraisal conducted using QualSyst tools. Santana et al’s person-centred care model (2018) was used to structure analysis.Results PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow data: n=12,446 studies screened by title/abstract, n=144 full articles assessed for eligibility, n=18 studies retained. All studies (n=18) are from high-income countries, and are largely of high quality (median score 0.82). The findings suggest that person-centred care encompasses the patient and family being respected, given complete information, involved in decision-making and supported in their physical, psychological, social and existential needs. The studies highlight the importance of involving and supporting family/friends, promoting continuation of normality and self-identity, and structuring service organisation to enable care continuity.Conclusion Person-centred healthcare must value the social network of patients, promote quality of life and reform structurally to improve patients’ experience interacting with the healthcare system. Staff must be supported to flexibly adapt skills, communication, routines or environments for individual patients. There remains a need for primary data investigating the meaning and practice of PCC in a greater diversity of diagnostic groups and settings, and a need to ground potential components of PCC within broader universal values and ethical theory.

Soil-transmitted helminths (STH) are endemic and widespread across Sub-Saharan Africa. A community wide soil-transmitted helminth (STH) prevalence survey was performed on the island of Bubaque in Guinea-Bissau using both Kato-katz microscopy and qPCR methodology. Predictors of infection and morbidity indicators were identified using multivariable logistic regression, and diagnostic methods were compared using k statistics. Among 396 participants, prevalence of STH by microscopy was 23.2%, hookworm was the only species identified by this method and the mean infection intensity was 312 eggs per gram. qPCR analysis revealed an overall prevalence of any STH infection of 47.3%, with the majority A. duodenale (32.3%), followed by N. americanus (15.01%) and S. stercoralis (13.2%). A. lumbricoides, and T. trichiura infections were negligible, with a prevalence of 0.25% each. Agreement between diagnostic tests was k = 0.22, interpreted as fair agreement, and infection intensity measured by both methods was only minimally correlated (Rs = -0.03). STH infection overall was more common in females and adults aged 31-40. STH infection was associated with open defaecation, low socio-economic status and further distance to a water-source. The prevalence of anaemia (defined as a binary outcome by the WHO standards for age and sex) was 69.1%, and 44.2% of children were malnourished according to WHO child growth standards. Hookworm infection intensity by faecal egg count showed no statistically significant association with age (Rs 0.06) but S. Stercoralis infection intensity by qPCR cycle threshold was higher in pre-school aged children (Rs = 0.30, p-value 0.03) There was no statistically significant association between STH infection and anaemia (OR 1.0 p = 0.8), stunting (OR 1.9, p-value 0.5) and wasting (OR 2.0, p-value 0.2) in children. This study reveals a persistent reservoir of STH infection across the community, with high rates of anaemia and malnutrition, despite high-coverage of mebendazole mass-drug administration in pre-school children. This reflects the need for a new strategy to soil-transmitted helminth control, to reduce infections and ultimately eliminate transmission.

Many desiccation-tolerant plants are widely distributed and exposed to substantial environmental variation across their native range. These environmental differences generate site-specific selective pressures that could drive natural variation in desiccation tolerance across populations. If identified, such natural variation can be used to target tolerance-enhancing characteristics and identify trait associations within a common genetic background. Here, we tested for natural variation in desiccation tolerance across wild populations of the South African resurrection plant Myrothamnus flabellifolia. We surveyed a suite of functional traits related to desiccation tolerance, leaf economics, and reproductive allocation in M. flabellifolia to test for trait associations and tradeoffs. Despite considerable environmental variation across the study area, M. flabellifolia plants were extremely desiccation tolerant at all sites, suggesting that tolerance is either maintained by selection or fixed in these populations. However, we detected notable associations between environmental variation, population characteristics, and fitness traits. Relative to mesic sites, plants in xeric sites were more abundant and larger, but were slower growing and less reproductive. The negative association between growth and reproduction with plant size and abundance pointed towards a potential growth–abundance tradeoff. The finding that M. flabellifolia is more common in xeric sites despite reductions in growth rate and reproduction suggests that these plants thrive in extreme aridity.

Cement production is environmentally unsustainable due to the high anthropogenic carbon emissions produced. Supplementary cementitious materials (SCMs), derived from the by-products of different industries, have been deemed an effective way to reduce carbon emissions. The reduction in carbon emissions is achieved by lowering the clinker factor of cement, through a partial replacement with an SCM. Sugarcane Bagasse Ash (SCBA) is produced as an agricultural waste from the sugarcane industry and has gained a lot of attention for being a feasible and readily available pozzolanic material, underutilised as an SCM. This study evaluates alkali-activated sugarcane bagasse ash’s mechanical and durability performance, at varied contents, in binary blended cement concrete and ternary blended cement concrete containing silica fume (SF). Potassium Hydroxide (KOH), used as the alkali activator, is intended to enhance the reactivity of the ash, with the possibility of a high-volume SCBA content. The mechanical performance was investigated by compressive and split tensile strength tests, and durability performance was investigated using the Oxygen Permeability Index (OPI) test. In addition, a micro-CT porosity test was conducted to assess how the microstructure and porosity of the concrete affect the mechanical and durability performance. The results indicated that using SCBA in a ternary blend with SF can significantly improve the overall performance and create less porous concrete. At 30% SCBA and 10% SF replacement, the performance tests revealed the highest mechanical strength and the lowest permeability, outperforming the control concrete and the binary blended cement concrete containing only SCBA.

Objectives To assess the scale of ethnic inequalities in severe maternal morbidity (SMM) rates and quantify the contribution of maternal characteristics to these disparities.Design Retrospective cohort study.Setting Whole-of-population linked administrative data from 2002 to 2015 in Western Australia.Participants Women with 410 043 birth events (includes all births from the same pregnancy) of 20 weeks’ or more gestation, including terminations for congenital anomalies.Primary and secondary outcome measures Women with SMM were identified based on a composite indicator of SMM using diagnosis and procedure codes developed for use in routinely collected data. Mothers were classified into seven ethnic groups, based on their reported ethnic origin. The associations between maternal ethnic origin and SMM were examined using a log-binomial model, which estimates risk ratios (RRs) and 95% CIs. The Blinder-Oaxaca decomposition technique was employed to partition the disparity in SMM between Aboriginal and Caucasian populations into ‘explained’ and ‘unexplained’ components.Results During the study period, 9378 SMM cases were documented. In the adjusted model, Aboriginal (RR 1.73, 95% CI 1.59 to 1.87), African (RR 1.64, 95% CI 1.43 to 1.89) and ‘other’ ethnicity (RR 1.49, 95% CI 1.37 to 1.63) women were at significantly higher risk of SMM compared with Caucasian women. Teenage and older mothers and socioeconomically disadvantaged women were also at greater risk of SMM. Differences in sociodemographic characteristics explained 33.2% of the disparity in SMM between Aboriginal and Caucasian women.Conclusions There are distinct disparities in SMM by ethnicity in Western Australia, with a greater risk among Aboriginal and African women. While improvements in SES and a reduction in teenage pregnancy can potentially support a sizeable reduction in SMM rate inequalities, future research should investigate other potential pathways and targeted interventions to close the ethnicity disparity.

Marine picocyanobacteria of the genera Prochlorococcus and Synechococcus are the most abundant photosynthetic organisms on Earth, an ecological success thought to be linked to the differential partitioning of distinct ecotypes into specific ecological niches. However, the underlying processes that governed the diversification of these microorganisms and the appearance of niche-related phenotypic traits are just starting to be elucidated. Here, by comparing 81 genomes, including 34 new Synechococcus, we explored the evolutionary processes that shaped the genomic diversity of picocyanobacteria. Time-calibration of a core-protein tree showed that gene gain/loss occurred at an unexpectedly low rate between the different lineages, with for instance 5.6 genes gained per million years (My) for the major Synechococcus lineage (sub-cluster 5.1), among which only 0.71/My have been fixed in the long term. Gene content comparisons revealed a number of candidates involved in nutrient adaptation, a large proportion of which are located in genomic islands shared between either closely or more distantly related strains, as identified using an original network construction approach. Interestingly, strains representative of the different ecotypes co-occurring in phosphorus-depleted waters (Synechococcus clades III, WPC1, and sub-cluster 5.3) were shown to display different adaptation strategies to this limitation. In contrast, we found few genes potentially involved in adaptation to temperature when comparing cold and warm thermotypes. Indeed, comparison of core protein sequences highlighted variants specific to cold thermotypes, notably involved in carotenoid biosynthesis and the oxidative stress response, revealing that long-term adaptation to thermal niches relies on amino acid substitutions rather than on gene content variation. Altogether, this study not only deciphers the respective roles of gene gains/losses and sequence variation but also uncovers numerous gene candidates likely involved in niche partitioning of two key members of the marine phytoplankton.

Introduction Maternal mental health disorders such as anxiety and depression are major public health concerns. Evidence shows a link between maternal mental health disorders and preterm birth and low birth weight. However, the impacts of maternal mental health disorders on stillbirth and infant mortality have been less investigated and inconsistent findings have been reported. Thus, using the available literature, we plan to examine whether prenatal maternal mental health disorders impact the risk of stillbirth and infant mortality.Methods and analysis This systematic review and meta-analysis will adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and will be registered with the International Prospective Register of Systematic Reviews. Systematic searches will be conducted (from database inception to December 2019) in Medline, Embase, PsycINFO and Scopus for studies examining the association of prenatal mental health disorders and stillbirth and infant mortality. The search will be limited to studies published in English language and in humans only, with no restriction on the year of publication. Two independent reviewers will evaluate records and assess the quality of individual studies. The Newcastle–Ottawa scales and GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach will be used to assess the methodological quality and bias of the included studies. In addition to a narrative synthesis, a random-effects meta-analysis will be conducted when sufficient data are available. I2 statistics will be used to assess between-study heterogeneity in the estimated effect size.Ethics and dissemination As it will be a systematic review and meta-analysis based on previously published evidence, there will be no requirement for ethical approval. Findings will be published in a peer-reviewed journal and will be presented at various conferences.PROSPERO registration number 159834.

Samantha Wilkinson,1 Ian J Douglas,1 Elizabeth Williamson,1 Heide A Stirnadel-Farrant,2 Damian Fogarty,3 Ana Pokrajac,4 Liam Smeeth,1 Laurie A Tomlinson1 1Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; 2GlaxoSmithKline, Stevenage, UK; 3Belfast Health and Social Care Trust, Belfast, UK; 4West Herts Hospitals NHS Trust, Watford, UK Purpose: To understand the patient characteristics associated with treatment choice at the first treatment intensification for type 2 diabetes.Patients and methods: This is a noninterventional study, using UK electronic primary care records from the Clinical Practice Research Datalink. We included adults treated with metformin monotherapy between January 2000 and July 2017. The outcome of interest was the drug prescribed at first intensification between 2014 and 2017. We used multinomial logistic regression to calculate the ORs for associations between the drugs and patient characteristics.Results: In total, 14,146 people started treatment with an intensification drug. Younger people were substantially more likely to be prescribed sodium-glucose co-transporter-2 inhibitors (SGLT2is), than sulfonylureas (SUs): OR for SGLT2i prescription for those aged

Abstract Background A combination of safety concerns and labeling changes impacted use of erythropoiesis-stimulating agents (ESAs) in renal anemia. Data regarding contemporary utilization in pre-dialysis chronic kidney disease (CKD) are lacking. Methods Electronic healthcare records and medical claims data of pre-dialysis CKD patients were aggregated from a large US managed care provider (2011–13). ESA use patterns, characteristics, and outcomes of ESA-treated/untreated patients were quantified. Results At baseline, 109/32,308 patients (0.3%) were ESA users. Treated patients were older, had more advanced CKD (58.8% vs 5.4% with stage 4/5 vs 3) and greater prevalence of comorbid diabetes, hypertension, heart failure, and peripheral vascular disease. An additional 266 patients initiated ESA: hemoglobin at initiation was 8–10 g/dL in 193 of these and >10 g/dL in the remainder; 61.7% had stage 4/5 CKD; prevalence of cardiovascular disease was high (50.8% heart failure; 25.2% prior myocardial infarction; 24.1% prior stroke). During follow-up, rates of death and cardiovascular events were higher in baseline ESA users and ESA naives versus non-users. Conclusions ESA use in pre-dialysis CKD patients was exceedingly rare and directed disproportionately to older, sicker patients; these patients had high rates of death and cardiovascular events. These data provide context for contemporary use of ESA in pre-dialysis CKD.

Abstract Background Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis. Results An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient’s local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient’s local healthcare provider. Conclusion The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

When transferring highly infective patients to specialist hospitals, safe systems of work minimise the risk to healthcare staff. The EpiShuttle is a patient transport system that was developed to fit into an air ambulance. A validated decontamination procedure is required before the system can be adopted in the UK. Hydrogen peroxide (H2O2) vapour fumigation may offer better penetration of the inaccessible parts than the liquid disinfectant wiping that is currently suggested. To validate this, an EpiShuttle was fumigated in a sealed test chamber. Commercial bacterial spore indicators (BIs), alongside organic liquid suspensions and dried surface samples of MS2 bacteriophage (a safe virus surrogate), were placed in and around the EpiShuttle, for the purpose of evaluation. The complete kill of all of the BIs in the five test runs demonstrated the efficacy of the fumigation cycle. The log reduction of the MS2 that was dried on the coupons ranged from 2.66 to 4.50, but the log reduction of the MS2 that was in the organic liquids only ranged from 0.07 to 1.90, confirming the results of previous work. Fumigation with H2O2 alone may offer insufficient inactivation of viruses in liquid droplets, therefore a combination of fumigation and disinfectant surface wiping was proposed. Initial fumigation reducing contamination with minimal intervention allows disinfectant wipe cleaning to be completed more safely, with a second fumigation step inactivating the residual pathogens.

Resurrection plants have an extraordinary ability to survive extreme water loss but still revive full metabolic activity when rehydrated. These plants are useful models to understand the complex biology of vegetative desiccation tolerance. Despite extensive studies of resurrection plants, many details underlying the mechanisms of desiccation tolerance remain unexplored. To summarize the progress in resurrection plant research and identify unexplored questions, we conducted a systematic review of 15 model angiosperm resurrection plants. This systematic review provides an overview of publication trends on resurrection plants, the geographical distribution of species and studies, and the methodology used. Using the Preferred Reporting Items for Systematic reviews and Meta–Analyses protocol we surveyed all publications on resurrection plants from 2000 and 2020. This yielded 185 empirical articles that matched our selection criteria. The most investigated plants were Craterostigma plantagineum (17.5%), Haberlea rhodopensis (13.7%), Xerophyta viscosa (reclassified as X. schlechteri) (11.9%), Myrothamnus flabellifolia (8.5%), and Boea hygrometrica (8.1%), with all other species accounting for less than 8% of publications. The majority of studies have been conducted in South Africa, Bulgaria, Germany, and China, but there are contributions from across the globe. Most studies were led by researchers working within the native range of the focal species, but some international and collaborative studies were also identified. The number of annual publications fluctuated, with a large but temporary increase in 2008. Many studies have employed physiological and transcriptomic methodologies to investigate the leaves of resurrection plants, but there was a paucity of studies on roots and only one metagenomic study was recovered. Based on these findings we suggest that future research focuses on resurrection plant roots and microbiome interactions to explore microbial communities associated with these plants, and their role in vegetative desiccation tolerance.

Vegetative desiccation tolerance, or the ability to survive the loss of ~95% relative water content (RWC), is rare in angiosperms, with these being commonly called resurrection plants. It is a complex multigenic and multi-factorial trait, with its understanding requiring a comprehensive systems biology approach. The aim of the current study was to conduct a label-free proteomic analysis of leaves of the resurrection plant Xerophyta schlechteri in response to desiccation. A targeted metabolomics approach was validated and correlated to the proteomics, contributing the missing link in studies on this species. Three physiological stages were identified: an early response to drying, during which the leaf tissues declined from full turgor to a RWC of ~80–70%, a mid-response in which the RWC declined to 40% and a late response where the tissues declined to 10% RWC. We identified 517 distinct proteins that were differentially expressed, of which 253 proteins were upregulated and 264 were downregulated in response to the three drying stages. Metabolomics analyses, which included monitoring the levels of a selection of phytohormones, amino acids, sugars, sugar alcohols, fatty acids and organic acids in response to dehydration, correlated with some of the proteomic differences, giving insight into the biological processes apparently involved in desiccation tolerance in this species.