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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.

INTRODUCTION The Agricultural Employees Protection Act, 2002 (AEPA) (1) is an Ontario statute that regulates labour relations for farm workers, who are excluded from unionizing under the Labour Relations Act, [...]

Groundwater flow and contaminant migration tracing is a vital method of identifying and characterising pollutant source-pathway-receptor linkages in karst aquifers. Bacteriophages are an attractive alternative tracer to non-reactive fluorescent dye tracers, as high titres (>1012 pfu mL−1) can be safely released into the aquifer, offering improved tracer detectability. However, the interpretation of bacteriophage tracer breakthrough curves is complicated as their fate and transport are impacted by aquifer physicochemical conditions. A comparative tracer migration experiment was conducted in a peri-urban catchment in southeast England to characterise the behaviour of MS2 bacteriophage relative to sodium fluorescein dye in a karstic chalk aquifer. Tracers were released into a stream sink and detected at two abstraction boreholes located 3 km and 10 km away. At both sites, the loss of MS2 phage greatly exceeded that of the solute tracer. In contrast, the qualitative shape of the dye and phage breakthrough curves were visually very similar, suggesting that the bacteriophage arriving at each site was governed by comparable transport parameters to the non-reactive dye tracer. The colloid filtration theory was applied to explain the apparent contradiction of comparable tracer breakthrough patterns despite massive phage losses in the subsurface. One-dimensional transport models were also fitted to each breakthrough curve to facilitate a quantitative comparison of the transport parameter values. The model results suggest that the bacteriophage migrates through the conduit system slightly faster than the fluorescent dye, but that the former is significantly less dispersed. These results suggest that whilst the bacteriophage tracer cannot be used to predict receptor concentrations from transport via karstic flow paths, it can provide estimates for groundwater flow and solute contaminant transit times. This study also provides insight into the attenuation and transport of pathogenic viruses in karstic chalk aquifers.

This article explores the influence of Samuel Beckett on Don DeLillo’s postmillennial, twenty-first century fiction. Although Beckett is often self-remarked as a direct influence by DeLillo, the late works – I analyse The Body Artist (2001), Cosmopolis (2003), Falling Man(2007), and the most recent, The Silence (2020) – go further than DeLillo’s earlier writings in pursuing something approximate to what Beckett terms a ‘literature of the unword’. Much like his Irish predecessor, DeLillo is also a writer caught between modernism and postmodernism (intellectually and stylistically, if not historically). In the prophetic novel Mao II (1991), protagonist Bill Gray notes: ‘Beckett is the last writer to shape the way wethink and see. After him, the major work involves midair explosions and crumbled buildings’. This vision of Beckett as an heroic author opposed to the mass mind is displaced in DeLillo’s minimalist later writings as they turn away from deploying and exploring highly textualized forms of postmodern subjectivity towards an engagement with material and bodily finitude. Drawing on Beckett’s NoHow On trilogy as a comparative case study, I claim that rethinking Beckett’s writing in terms of late modernism helps to explore his ongoing influence on DeLillo and the particular inhuman forms that populate DeLillo late career depiction of a highly mediatized, globalized and terrorized contemporary. These late works, in their ruined state of literary exhaustion, aim to – following Beckett – allow the ‘void [to] protrude like a hernia’.

Objective The longitudinal Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS) aims to assess SLE disease course overall and according to type I interferon 4 gene signature (IFNGS). Here, we describe SPOCS patient characteristics by IFNGS and baseline disease activity.Methods SPOCS (NCT03189875) is an international study of patients with SLE according to Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) criteria. Enrolled patients from 135 centres in 8 countries were followed biannually for ≤3 years from June 2017 to November 2022. Baseline demographics, disease characteristics, organ system involvement/damage and flares were analysed descriptively according to SLE Disease Activity Index-2000 score (SLEDAI-2K

ObjectiveTo determine men's satisfaction with and acceptability of a once-daily, oral regimen of dimethandrolone undecanoate (DMAU) versus placebo when used for 28 days.Study designAfter a Phase I double-blind, randomized, placebo-controlled, dose-escalating trial of oral DMAU for 28-days, 57 healthy male volunteers completed a survey assessing their experience and satisfaction with the regimen. In the trial, participants were randomized to receive up to 4 DMAU capsules daily versus placebo and instructed to ingest them within 30 min of consuming a high fat meal. Pharmacokinetic and pharmacodynamic profiles were performed, followed by a 6-week recovery phase. Participants were counseled that they could not rely on the drug for contraception.ResultsFifty-seven participants were offered acceptability surveys (39 DMAU, 18 placebo). Most respondents, 80% (45/56), reported satisfaction with the method; 77% (44/57) would recommend it. 54% (31/57), reported that, if available, they would use the method as their primary contraceptive. More respondents reported satisfaction with active DMAU than placebo (87% vs. 67%; p = 0.05). Most respondents, 91% (52/57), reported no difficulty with having to take up to 4 pills within 30 min of ingesting a high-fat meal.ConclusionMost participants reported that the study method, daily oral DMAU or placebo, was satisfactory and acceptable. Having to take the drug after a high-fat meal did not detract from acceptability.ImplicationsMost participants in a 4-week trial of daily DMAU capsules would recommend and use the method. High satisfaction among DMAU and placebo groups affirms acceptability of a daily male contraceptive pill, warranting further study of oral DMAU.

Background and purposeClopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT.MethodsOf the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death.ResultsNine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33).ConclusionsThis substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent channel block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits – including transmembrane AMPAR regulatory proteins, cornichons, and GSG1L – which are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here, we show that the inclusion of the spider toxin analog 1-naphthylacetyl spermine (NASPM) in the intracellular solution results in a complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, our results identify a functional measure of CP-AMPARs, that is unaffected by their auxiliary subunit content.

Heide A Stirnadel-Farrant,1 George Mu,2 Selin Cooper-Blenkinsopp,1 Rosemary O Schroyer,3 Kevin S Thorneloe,4 Ewen M Harrison,5 Susan MS Andrews6 1Department of WorldWide Epidemiology, GlaxoSmithKline, London, UK; 2Department of Data, Methods, and Analytics, GlaxoSmithKline, Collegeville, PA, USA; 3Department of Biostatistics, GlaxoSmithKline, Collegeville, PA, USA; 4Department of Translational Medicine, GlaxoSmithKline, Collegeville, PA, USA; 5Department of Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK; 6Department of Global Clinical Operations Development R&D, GlaxoSmithKline, Research Triangle Park, NC, USACorrespondence: Susan MS Andrews, Global Clinical Operations Development R&D GlaxoSmithKline Five Moore Drive, Research Triangle Park, NC, 27709-3398, USA, Tel +1-(919) 649-3944, Email susan.m.andrews@gsk.comPurpose: A variety of definitions for delayed graft function (DGF) have been proposed, but none has consistently been shown to be superior for predicting long-term graft outcomes for kidney donation after circulatory death (DCD) transplantation. In this study, real-world clinical outcome data following DCD transplantation were explored to determine the value of various DGF definitions for predicting graft survival.Patients and Methods: Data from 4 centers registered in the UK-based National Health Service Blood and Transplant registry (2010 to mid-2015) were used to assess 4 definitions of DGF in this retrospective chart review study.Results: Depending on the definition used, the frequency of DGF ranged from 119/362 (32.9%) when DGF was determined with available registry data and based on a requirement for dialysis within 7 days post-transplantation, to 224/315 (71.1%) when based on failure to achieve a 10% fall in serum creatinine (SCr) versus baseline per 24 hours averaged over the first 72 hours. Patients without clinical DGF as determined by a physician upon chart review, or when defined as < 30% reduction in baseline SCr within 7 days post-transplantation with or without dialysis, had significantly better graft survival probability 1 year (hazard ratio 2.08 and 4.48, respectively) and 5 years post-transplant, whereas serum creatinine level over the first 72 hours post-transplant was not predictive of graft survival at 1 year. Patients with clinical DGF upon physician chart review also had higher SCr, lower estimated glomerular filtration rate levels, and were dialyzed more (2.3 days) versus patients without (0.2 days).Conclusion: Delayed graft function, determined clinically or using a functional definition, is associated with poorer renal function and remains a useful predictor of graft survival at 1 year after DCD kidney transplantation.Keywords: delayed graft function, DGF, donation after circulatory death, DCD, serum creatinine, SCr

Skaftárkatlar are two subglacial lakes located beneath the Vatnajökull ice cap in Iceland associated with geothermal and volcanic activity. Previous studies of these lakes with ribosomal gene (16S rDNA) tag sequencing revealed a limited diversity of bacteria adapted to cold, dark, and nutrient-poor waters. In this study, we present analyses of metagenomes from the lake which give new insights into its microbial ecology. Analyses of the 16S rDNA genes in the metagenomes confirmed the existence of a low-diversity core microbial assemblage in the lake and insights into the potential metabolisms of the dominant members. Seven taxonomic genera, Sulfuricurvum, Sulfurospirillum, Acetobacterium, Pelobacter/Geobacter, Saccharibacteria, Caldisericum, and an unclassified member of Prolixibacteraceae, comprised more than 98% of the rDNA reads in the library. Functional characterisation of the lake metagenomes revealed complete metabolic pathways for sulphur cycling, nitrogen metabolism, carbon fixation via the reverse Krebs cycle, and acetogenesis. These results show that chemolithoautotrophy constitutes the main metabolism in this subglacial ecosystem. This assemblage and its metabolisms are not reflected in enrichment cultures, demonstrating the importance of in situ investigations of this environment.

Objectives To study the mortality of patients with COVID-19 in Sierra Leone, to explore the factors associated with mortality during the COVID-19 pandemic and to highlight the complexities of treating patients with a novel epidemic disease in a fragile health system.Study design A prospective single-centre cohort study. Data were extracted from paper medical records and transferred onto an electronic database. Specific indicators were compared between survivors and non-survivors, using descriptive statistics in Stata V.17.Study setting The infectious diseases unit (IDU) at Connaught Hospital in Freetown, Sierra LeoneParticipants Participants were all patients admitted to the IDU between March and July 2020.Aims of study The primary outcome of the study was to examine the all-cause mortality of hospitalised patients with suspected COVID-19 in Sierra Leone and the secondary outcome measures were to examine factors associated with mortality in patients positive for COVID-19.Results 261 participants were included in the study. Overall, 41.3% of those admitted to the IDU died, compared with prepandemic in-hospital mortality of 23.8%. Factors contributing to the higher mortality were COVID-19 infection (aOR 5.61, 95% CI 1.19 to 26.30, p=0.02) and hypertension (aOR 9.30, 95% CI 1.18 to 73.27, p=0.03)Conclusions This study explores the multiple factors underpinning a doubling in facility mortality rate during the COVID-19 pandemic in Sierra Leone . It provides an insight into the realities of providing front-line healthcare during a pandemic in a fragile health system.

Globally, Indigenous children have historical and contemporary connections with government child protection services that have caused significant harm to their long-term health and wellbeing. Innovative, culturally secure and recovery focussed service provision is required. This paper describes a research protocol that has been designed by Indigenous researchers led by Indigenous Elders, to explore culturally secure care planning and service delivery in out-of-home care agencies in Australia. Using participatory action research methods, we will collect data using a variety of forums, including focus groups and semi-structured interviews. These data will explore the challenges for out-of-home care agencies in providing culturally secure care-planning, cultural activity and resources, and explore solutions to address factors that influence health and can assist to redress social inequities for Indigenous children. We aim to recruit approximately 100 participants for the qualitative study and 40 participants for the quantitative survey. Study participants will initially be recruited using purposive sampling, and as the study progresses will be recruited using a mixture of purposive and convenience sampling techniques. The rich data that this study is expected to yield, will inform ways to collect cultural information about Indigenous children and ways to provide cultural connections and activities that will have benefit to Indigenous children and families, and a broad range of social services. [ABSTRACT FROM AUTHOR]

Disability policy in many countries encourages people to self-manage their disability support funds, yet few people do. This is also the case with Australia's National Disability Insurance Scheme (NDIS). Little is known about who chooses self-management and how they sustain it. This project explored the conditions and resources conducive to self-management in the interests of the person with disability. It used Katzman and Kinsella's typology of self-management work to analyse the current conditions that facilitate or hinder self-management. The research demonstrated unequal take-up of self-management, particularly by location and disability type. Often, a family member self-manages on behalf of the person with disability. Conditions and resources people needed to sustain self-management included prior experience and socio-economic advantage, or resources to fill these gaps. Implications are that resources such as advocates, peers, organisations or support coordination can help fill the gap between people with and without personal and social advantages. In many countries, people with disability have the option to self-manage their disability support funds. But many people do not choose to do so. We asked people who self-manage their funds or who self-manage on behalf of their family member with disability about how they do it and what helps them to make it successful. Their experiences show that self-managing is easier if they have money, education and prior knowledge about managing. People without these advantages can also self-manage. They may need support from peers, organisations, advocates or support coordinators. [ABSTRACT FROM AUTHOR]

BackgroundCombination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population.MethodsIn a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.ResultsA total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02).ConclusionsIn patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

ABSTRACT Marine Synechococcus comprise a numerically and ecologically prominent phytoplankton group, playing a major role in both carbon cycling and trophic networks in all oceanic regions except in the polar oceans. Despite their high abundance in coastal areas, our knowledge of Synechococcus communities in these environments is based on only a few local studies. Here, we use the global metagenome data set of the Ocean Sampling Day (June 21st, 2014) to get a snapshot of the taxonomic composition of coastal Synechococcus communities worldwide, by recruitment on a reference database of 141 picocyanobacterial genomes, representative of the whole Prochlorococcus, Synechococcus, and Cyanobium diversity. This allowed us to unravel drastic community shifts over small to medium scale gradients of environmental factors, in particular along European coasts. The combined analysis of the phylogeography of natural populations and the thermophysiological characterization of eight strains, representative of the four major Synechococcus lineages (clades I to IV), also brought novel insights about the differential niche partitioning of clades I and IV, which most often co-dominate the Synechococcus community in cold and temperate coastal areas. Altogether, this study reveals several important characteristics and specificities of the coastal communities of Synechococcus worldwide. IMPORTANCE Synechococcus is the second most abundant phytoplanktonic organism on Earth, and its wide genetic diversity allowed it to colonize all the oceans except for polar waters, with different clades colonizing distinct oceanic niches. In recent years, the use of global metagenomics data sets has greatly improved our knowledge of “who is where” by describing the distribution of Synechococcus clades or ecotypes in the open ocean. However, little is known about the global distribution of Synechococcus ecotypes in coastal areas, where Synechococcus is often the dominant phytoplanktonic organism. Here, we leverage the global Ocean Sampling Day metagenomics data set to describe Synechococcus community composition in coastal areas worldwide, revealing striking community shifts, in particular along the coasts of Europe. As temperature appears as an important driver of the community composition, we also characterize the thermal preferenda of 8 Synechococcus strains, bringing new insights into the adaptation to temperature of the dominant Synechococcus clades.

To achieve universal health coverage, health system strengthening (HSS) is required to support the of delivery of high-quality care. The aim of the National Institute for Health Research Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme, with three healthcare platforms involving eight work-packages. Key to effective health system strengthening (HSS) is the pre-implementation phase of research where efforts focus on applying participatory methods to embed the research programme within the existing health system. To conceptualise the approach, we provide an overview of the key methods applied across work-package to address this important phase of research conducted between 2017 and 2021. Work-packages are being undertaken in publicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe. Stakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers are the main research participants. In each work-package, initial activities engage stakeholders and build relationships to ensure co-production and ownership of HSSIs. A mixed-methods approach is then applied to understand and address determinants of high-quality care delivery. Methods such as situation analysis, cross-sectional surveys, interviews and focus group discussions are adopted to each work-package aim and context. At the end of the pre-implementation phase, findings are disseminated using focus group discussions and participatory Theory of Change workshops where stakeholders from each work package use findings to select HSSIs and develop a programme theory. ASSET places a strong emphasis of the pre-implementation phase in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and stakeholder engagement. This common approach will inform the design and evaluation of the HSSIs to increase effectiveness across work packages and contexts, to better understand what works, for whom, and how.

Introduction Women from ethnic minority groups are at more risk of adverse outcomes in pregnancy compared with those from white British groups; suboptimal care may contribute to this increased risk. This study aimed to examine serious clinical incidents at two maternity units to explore causative factors for women from ethnic minorities and determine whether these differed from white women.Methods A retrospective review was conducted of all serious incidents (n=36) occurring in a large National Health Service maternity provider (~14 000 births per annum) between 2018 and 2020. Data were collected from case records for variables which could mediate the association between ethnicity and adverse outcome. The incident reviews were blinded and reviewed by two independent investigators and data regarding root causes and contributory factors were extracted.Results Fourteen of the 36 incidents (39%) occurred in women from minority ethnic groups, which is comparable to the maternity population. Women involved in serious clinical incidents frequently had pre-existing medical or obstetric complications. Booking after 12 weeks’ gestation occurred more frequently in women from minority ethnic groups than in the background population. There were differences in root causes of serious incidents between groups, a lack of situational awareness was the most frequent cause in white women and staff workload was most frequent in women from minority ethnic groups. Communication issues and detection of deterioration were similar between the two groups.Discussion Although there was no difference in the proportion of serious incidents between the groups, there were differences in medical and pregnancy-related risk factors between groups and in the root causes identified. Efforts are needed to ensure equity of early access to antenatal care and to ensure that there is adequate staffing to ensure that women’s needs are met; this is particularly cogent when there are complex medical or social needs.