Racial-Ethnic Disparities in Acute Stroke Care in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study

Background-Racial-ethnic disparities in acute stroke care can contribute to inequality in stroke outcomes. We examined raceethnic disparities in acute stroke performance metrics in a voluntary stroke registry among Florida and Puerto Rico Get With the Guidelines-Stroke hospitals. Methods and Results-Seventy-five sites in the Florida Puerto Rico Stroke Registry (66 Florida and 9 Puerto Rico) recorded 58 864 ischemic stroke cases (2010-2014). Logistic regression models examined racial-ethnic differences in acute stroke performance measures and defect-free care (intravenous tissue plasminogen activator treatment, in-hospital antithrombotic therapy, deep vein thrombosis prophylaxis, discharge antithrombotic therapy, appropriate anticoagulation therapy, statin use, smoking cessation counseling) and temporal trends. Among ischemic stroke cases, 63% were non-Hispanic white (NHW), 18% were non-Hispanic black (NHB), 14% were Hispanic living in Florida, and 6% were Hispanic living in Puerto Rico. NHW patients were the oldest, followed by Hispanics, and NHBs. Defect-free care was greatest among NHBs (81%), followed by NHWs (79%) and Florida Hispanics (79%), then Puerto Rico Hispanics (57%) (P \u3c 0.0001). Puerto Rico Hispanics were less likely than Florida whites to meet any stroke care performance metric other than anticoagulation. Defect-free care improved for all groups during 2010-2014, but the disparity in Puerto Rico persisted (2010: NHWs=63%, NHBs=65%, Florida Hispanics=59%, Puerto Rico Hispanics=31%; 2014: NHWs=93%, NHBs=94%, Florida Hispanics=94%, Puerto Rico Hispanics=63%). Conclusions-Racial-ethnic/geographic disparities were observed for acute stroke care performance metrics. Adoption of a quality improvement program improved stroke care from 2010 to 2014 in Puerto Rico and all Florida racial-ethnic groups. However, stroke care quality delivered in Puerto Rico is lower than in Florida. Sustained support of evidence-based acute stroke quality improvement programs is required to improve stroke care and minimize racial-ethnic disparities, particularly in resource-strained Puerto Rico

Single-cell genome-wide association reveals a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 (ERAP1; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics

Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model

Background Respiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and accumulation of comorbidities. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological, and immunological outcomes. Methods In this human infection challenge pilot study, adults aged 18–55 years and 60–75 years were assessed for enrolment using protocol-defined inclusion and exclusion criteria. Symptoms were documented by self-completed diaries and viral load determined by quantitative PCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-fusion and post-fusion, NP, and G proteins in the blood and upper respiratory tract were measured. The study was registered with ClinicalTrials.gov, NCT03728413. Findings 381 adults aged 60–75 years (older cohort) and 19 adults aged 18–55 years (young cohort) were assessed for enrolment using protocol-defined inclusion and exclusion criteria between Nov 12, 2018, and Feb 26, 2020. 12 healthy volunteers aged 60–75 years and 21 aged 18–55 years were inoculated intranasally with RSV Memphis-37. Nine (67%) of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without serious adverse events or sequelae. Viral load peaked on day 6 post-inoculation and symptoms peaked between days 6 and 8. Increases in circulating IgG-positive and IgA-positive antigen-specific plasmablasts, serum neutralising antibodies, and pre-F specific IgG were similar younger and older adults. However, in contrast to young participants, secretory IgA titres in older volunteers failed to increase during infection and, unlike serum IgG, did not correlate with protection. Interpretation Better understanding of age-related differences in clinical outcomes and immune correlates of protection can overcome reduction in vaccine efficacy with advancing age. We identify correlates of protection in older adults, revealing previously unrecognised factors which might have implications for targeted vaccine discovery and drug development in this vulnerable group. Funding Medical Research Council and GlaxoSmithKline EMINENT Consortium

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): An international consortium of randomised placebo-controlled trials

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.  Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.  Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis

Lack of Evidence for Neonatal Misoprostol Neurodevelopmental Toxicity in C57BL6/J Mice

Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth

Making stillbirths visible: a systematic review of globally reported causes of stillbirth

BACKGROUND: Stillbirth is a global health problem. The World Health Organization (WHO) application of the International Classification of Diseases for perinatal mortality (ICD‐PM) aims to improve data on stillbirth to enable prevention. OBJECTIVES: To identify globally reported causes of stillbirth, classification systems, and alignment with the ICD‐PM. SEARCH STRATEGY: We searched CINAHL, EMBASE, Medline, Global Health, and Pubmed from 2009 to 2016. SELECTION CRITERIA: Reports of stillbirth causes in unselective cohorts. DATA COLLECTION AND ANALYSIS: Pooled estimates of causes were derived for country representative reports. Systems and causes were assessed for alignment with the ICD‐PM. Data are presented by income setting (low, middle, and high income countries; LIC, MIC, HIC). MAIN RESULTS: Eighty‐five reports from 50 countries (489 089 stillbirths) were included. The most frequent categories were Unexplained, Antepartum haemorrhage, and Other (all settings); Infection and Hypoxic peripartum (LIC), and Placental (MIC, HIC). Overall report quality was low. Only one classification system fully aligned with ICD‐PM. All stillbirth causes mapped to ICD‐PM. In a subset from HIC, mapping obscured major causes. CONCLUSIONS: There is a paucity of quality information on causes of stillbirth globally. Improving investigation of stillbirths and standardisation of audit and classification is urgently needed and should be achievable in all well‐resourced settings. Implementation of the WHO Perinatal Mortality Audit and Review guide is needed, particularly across high burden settings. FUNDING: HR, SH, SHL, and AW were supported by an NHMRC‐CRE grant (APP1116640). VF was funded by an NHMRC‐CDF (APP1123611)

Transverse Emittance Reduction in Muon Beams by Ionization Cooling

Accelerated muon beams have been considered for next-generation studies of high-energy lepton-antilepton collisions and neutrino oscillations. However, high-brightness muon beams have not yet been produced. The main challenge for muon acceleration and storage stems from the large phase-space volume occupied by the beam, derived from the muon production mechanism through the decay of pions from proton collisions. Ionization cooling is the technique proposed to decrease the muon beam phase-space volume. Here we demonstrate a clear signal of ionization cooling through the observation of transverse emittance reduction in beams that traverse lithium hydride or liquid hydrogen absorbers in the Muon Ionization Cooling Experiment (MICE). The measurement is well reproduced by the simulation of the experiment and the theoretical model. The results shown here represent a substantial advance towards the realization of muon-based facilities that could operate at the energy and intensity frontiers.Comment: 23 pages and 5 figure