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Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Objectives Assess the effect of a modified muscle sparing posterior approach; SPAIRE (Save Piriformis and Internus, Repairing Externus), in hip hemiarthroplasty for displaced intracapsular fractures on postoperative mobility and function compared with a standard lateral approach.Design Pragmatic, superiority, multicenter, parallel-group, randomized controlled trial (with internal pilot). Participants, ward staff, and research staff conducting postoperative assessments were blinded to allocation. A CTU allocated treatments centrally using computer-generated lists.Setting Six hospitals in Southwest England, recruiting November 25, 2019–April 25, 2022.Participants 244 adults (≥60 years) requiring hip hemiarthroplasty (122 allocated to each approach). 90 and 85 participants allocated to SPAIRE and lateral, respectively, had primary outcome data within the prespecified data collection window.Interventions Surgery using SPAIRE or standard lateral approach. Follow-up 3 days and 120 days postoperation.Main outcome measure Oxford Hip Score (OHS), via telephone at 120 days. Secondary outcomes: function and mobility (3 days), pain (3 days, 120 days), discharge destination, length of hospital stay, complications and mortality (within 120 days), quality of life and place of residence (120 days).Results Participants’ mean age was 84.6 years (SD 7.2); 168 (69%) were women. Primary outcome: little evidence of a difference in OHS at 120 days; adjusted mean difference (SPAIRE—lateral) −1.23 (95% CI −3.96 to 1.49, p=0.37). Secondary outcomes: indication of lower participant-reported pain at 3 days in SPAIRE arm; no differences between arms for remaining outcomes.Conclusions Participants’ mobility and function are similar in the short term (3 days) and longer term (120 days), whether receiving the SPAIRE or lateral approach. Neither approach confers benefit over the other in terms of length of hospital stay, return to prefracture residence, survival within 120 days, or quality of life at 120 days. Participants receiving SPAIRE approach may experience less pain in the early postoperative period. Modifying the posterior approach in hip hemiarthroplasty to the SPAIRE approach gives equivalent patient outcomes to the lateral approach within 120 days.Trial registration number NCT04095611.

Abstract In response to the SARS-CoV-2 pandemic, we developed a multiplexed, paired-pool droplet digital PCR (MP4) screening assay. Key features of our assay are the use of minimally processed saliva, 8-sample paired pools, and reverse-transcription droplet digital PCR (RT-ddPCR) targeting the SARS-CoV-2 nucleocapsid gene. The limit of detection was determined to be 2 and 12 copies per µl for individual and pooled samples, respectively. Using the MP4 assay, we routinely processed over 1,000 samples a day with a 24-h turnaround time and over the course of 17 months, screened over 250,000 saliva samples. Modeling studies showed that the efficiency of 8-sample pools was reduced with increased viral prevalence and that this could be mitigated by using 4-sample pools. We also present a strategy for, and modeling data supporting, the creation of a third paired pool as an additional strategy to employ under high viral prevalence.

Abstract Background The HemiSPAIRE trial is being conducted to determine whether a modified muscle sparing technique (SPAIRE-“Save Piriformis and Internus, Repairing Externus”) in hip hemiarthroplasty brings clinical benefits compared to the standard lateral technique in adults aged 60 years or older, with a displaced intracapsular hip fracture. This article describes the detailed statistical analysis plan for the trial. Methods and design HemiSPAIRE is a definitive, pragmatic, superiority, multicentre, randomised controlled trial (with internal pilot) with two parallel groups. Participants, ward staff and all research staff involved in post-operative assessments are blinded to allocation. This article describes in detail (1) the primary and secondary outcomes; (2) the statistical analysis principles, including a survivor average causal effect (SACE) method chosen specifically to address the issue of potential bias from differential survival between trial arms, which was seen from data review by the Trial Steering Committee, the participants that will be included in each analysis, the covariates that will be included in each analysis, and how the results will be presented; (3) planned main analysis of the primary outcome; (4) planned analyses of the secondary outcomes; and (5) planned additional analyses of the primary and secondary outcomes. Trial registration ClinicalTrials.gov NCT04095611. Registered on 19 September 2019.

Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this ability by stimulating MSCs with inflammatory molecules, improving their migratory and secretory properties. We investigated the use of intranasally delivered adipose-derived MSCs (AdMSCs) in combating prion disease in a mouse model. Prion disease is a rare, lethal neurodegenerative disease that results from the misfolding and aggregation of the prion protein. Early signs of this disease include neuroinflammation, activation of microglia, and development of reactive astrocytes. Later stages of disease include development of vacuoles, neuronal loss, abundant aggregated prions, and astrogliosis. We demonstrate the ability of AdMSCs to upregulate anti-inflammatory genes and growth factors when stimulated with tumor necrosis factor alpha (TNFα) or prion-infected brain homogenates. We stimulated AdMSCs with TNFα and performed biweekly intranasal deliveries of AdMSCs on mice that had been intracranially inoculated with mouse-adapted prions. At early stages in disease, animals treated with AdMSCs showed decreased vacuolization throughout the brain. Expression of genes associated with Nuclear Factor-kappa B (NF-κB) and Nod-Like Receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling were decreased in the hippocampus. AdMSC treatment promoted a quiescent state in hippocampal microglia by inducing changes in both number and morphology. Animals that received AdMSCs showed a decrease in both overall and reactive astrocyte number, and morphological changes indicative of homeostatic astrocytes. Although this treatment did not prolong survival or rescue neurons, it demonstrates the benefits of MSCs in combatting neuroinflammation and astrogliosis.

Abstract Background In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years. Methods Four hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status. Results At no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status. Conclusions Using WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.

Abstract The fetus develops in a privileged environment, as the placenta serves as both a gateway for nutrients and a barrier for pathogen transfer to the fetus. Regardless, recent evidence suggests the presence of bacterial DNA in both placenta and fetus, and we have reported that DNA and protein from small numbers of bacteria gain access to the fetus from the maternal bloodstream. Other routes of environmental bacterial transfer from the mother to fetus remain unknown, as well as the physiological relevance of their presence. In these experiments, we examine multiple routes by which bacterial cellular components can enter the fetus and the fetal response to influx of bacterial DNA and protein. We inoculated maternal sheep with genetically-labeled S. aureus (Staphylococcus aureus) using three routes: intravenously, orally, and intra-vaginally. The inoculum did not produce sepsis or fever in the ewes, therefore mimicking incidental exposure to bacteria during pregnancy. 3–5 days post inoculation, we assessed the presence of bacterial components in the fetal tissues and analyzed fetal brain tissue to identify any alterations in gene expression. Our results demonstrate that components of bacteria that were introduced into the maternal mouth were detected in the fetal brain and that they stimulated changes in gene expression. We conclude that an oral route of transmission is relevant for transfer of bacterial cellular components to the fetus.

ABSTRACT Flaviviruses are important human pathogens worldwide. Diagnostic testing for these viruses is difficult because many of the pathogens require specialized biocontainment. To address this issue, we generated 39 virus-like particle (VLP)- and nonstructural protein 1 (NS1)-secreting stable cell lines in HEK-293 cells of 13 different flaviviruses, including dengue, yellow fever, Japanese encephalitis, West Nile, St. Louis encephalitis, Zika, Rocio, Ilheus, Usutu, and Powassan viruses. Antigen secretion was stable for at least 10 cell passages, as measured by enzyme-linked immunosorbent assays and immunofluorescence assays. Thirty-five cell lines (90%) had stable antigen expression over 10 passages, with three of these cell lines (7%) increasing in antigen expression and one cell line (3%) decreasing in antigen expression. Antigen secretion in the HEK-293 cell lines was higher than in previously developed COS-1 cell line counterparts. These antigens can replace current antigens derived from live or inactivated virus for safer use in diagnostic testing. IMPORTANCE Serological diagnostic testing for flaviviral infections is hindered by the need for specialized biocontainment for preparation of reagents and assay implementation. The use of previously developed COS-1 cell lines secreting noninfectious recombinant viral antigen is limited due to diminished antigen secretion over time. Here, we describe the generation of 39 flaviviral virus-like particle (VLP)- and nonstructural protein 1 (NS1)-secreting stable cell lines in HEK-293 cells representing 13 medically important flaviviruses. Antigen production was more stable and statistically higher in these newly developed cell lines than in their COS-1 cell line counterparts. The use of these cell lines for production of flaviviral antigens will expand serological diagnostic testing of flaviviruses worldwide.

Introduction Currently National Institute for Health and Care Excellence clinical guidelines in the UK suggest that surgeons performing partial hip replacements (hemiarthroplasty) should consider using the lateral approach. Alternatively, a newer, modified posterior approach using a muscle sparing technique named ‘Save Piriformis and Internus, Repairing Externus’ (SPAIRE) can be used leaving the major muscles intact. This randomised controlled trial (RCT) aims to compare the SPAIRE approach to the standard lateral approach, to determine if it allows patients to mobilise better and experience improved function after surgery.Methods and analysis HemiSPAIRE is a two-arm, assessor-blinded, definitive pragmatic RCT with nested pilot and qualitative studies. Two hundred and twenty-eight participants with displaced intracapsular fractures requiring hip hemiarthroplasty will be individually randomised 1:1 to either the SPAIRE, or control (standard lateral approach) surgical procedure. Outcomes will be assessed at postoperative day 3 (POD3) and 120 (POD120). The primary outcome measure will be level of function and mobility using the Oxford Hip Score at POD120. Secondary outcomes include: De Morton Mobility Index (DEMMI), Cumulated Ambulatory Score and Numeric Pain Rating Scale (NPRS) at POD3; DEMMI, NPRS and EQ-5D-5L at POD120, complications, acute and total length of hospital stay, and mortality. Primary analysis will be on an intention-to-treat basis. Participant experiences of the impact of surgery and recovery period will be examined via up to 20 semi-structured telephone interviews.Ethics and dissemination The protocol has been approved by Yorkshire and the Humber—Bradford Leeds Research Ethics Committee. Recruitment commenced in November 2019. Findings will be disseminated via research articles in peer-reviewed journals, presentations at conferences, public involvement events, patient groups and media releases. A summary of the trial findings will be shared with participants at the end of the study.Trial registration number NCT04095611.

Background: Frontotemporal dementia (FTD) is a common cause of young onset dementia, and whilst there are currently no treatments, there are several promising candidates in development and early phase trials. Comprehensive investigations of neuroimaging markers of disease progression across the full spectrum of FTD disorders are lacking and urgently needed to facilitate these trials. Objective: To investigate the comparative performance of multiple automated segmentation and registration pipelines used to quantify longitudinal whole-brain atrophy across the clinical, genetic and pathological subgroups of FTD, in order to inform upcoming trials about suitable neuroimaging-based endpoints. Methods: Seventeen fully automated techniques for extracting whole-brain atrophy measures were applied and directly compared in a cohort of 226 participants who had undergone longitudinal structural 3D T1-weighted imaging. Clinical diagnoses were behavioural variant FTD (n = 56) and primary progressive aphasia (PPA, n = 104), comprising semantic variant PPA (n = 38), non-fluent variant PPA (n = 42), logopenic variant PPA (n = 18), and PPA-not otherwise specified (n = 6). 49 of these patients had either a known pathogenic mutation or postmortem confirmation of their underlying pathology. 66 healthy controls were included for comparison. Sample size estimates to detect a 30% reduction in atrophy (80% power; 0.05 significance) were computed to explore the relative feasibility of these brain measures as surrogate markers of disease progression and their ability to detect putative disease-modifying treatment effects. Results: Multiple automated techniques showed great promise, detecting significantly increased rates of whole-brain atrophy (p

Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder associated with frontal and temporal atrophy. Subcortical involvement has been described as well, with early thalamic atrophy most commonly associated with the C9orf72 expansion. However thalamic involvement has not been comprehensively investigated across the FTD spectrum. Methods: We investigated thalamic volumes in a sample of 341 FTD patients (age: mean(standard deviation) 64.2(8.5) years; disease duration: 4.6(2.7) years) compared with 99 age-matched controls (age: 61.9(11.4) years). We performed a parcellation of T1 MRIs using an atlas propagation and label fusion approach to extract left and right thalamus volumes, which were corrected for total intracranial volumes. We assessed subgroups stratified by clinical diagnosis (141 behavioural variant FTD (bvFTD), 76 semantic dementia (SD), 103 progressive nonfluent aphasia (PNFA), 7 with associated motor neurone disease (FTD-MND) and 14 primary progressive aphasia not otherwise specified (PPA-NOS), genetic diagnosis (24 with MAPT, 24 with C9orf72, and 15 with GRN mutations), and pathological diagnosis (40 tauopathy, 61 TDP-43opathy, 3 FUSopathy). We assessed the diagnostic accuracy based on thalamic volume. Results: Overall, FTD patients had smaller thalami than controls (8% difference in volume, p

A youth mental health crisis has been exacerbated significantly by the COVID-19 pandemic. Teachers are often front-line support for students in need. Yet teachers themselves are struggling, making it difficult to help their students. Cognitive behavioral interventions (CBIs) have been shown to reduce mental health symptoms in school settings. Learning and implementing a psychological intervention, however, places undue burden on teachers who are already struggling. This project aimed to develop and assess the acceptability and feasibility of a brief, web-based training for educators on cognitive behavioral tools that can be implemented in classrooms without additional psychological or practical burden. Attendees (n = 193) attended one of two 1-h trainings on applying cognitive behavioural therapy (CBT) in classrooms. Attendees completed pre- and posttraining surveys on their knowledge and comfort using CBT. Following the course, attendees reported increases in knowledge and comfort using CBT skills, with large effect sizes. Attendees reported being highly satisfied with the course and likely to recommend the course to colleagues. Limitations of this work include a relatively small, homogenous sample and a low rate of completing both pre- and posttraining measures. Suggestions for future research include measuring change in practice as a result of the training. Implications of our findings are discussed.

Fetal development is thought to proceed in a sterile environment. Recent reports of the presence of bacterial DNA in human placenta, the transfer of live bacteria from mother to fetus after hypoxia in the pregnant sheep, and the presence of bacteria in the meconium of newborn infants have suggested that the fetus might be exposed to bacteria in utero. The present experiments were designed to test the hypothesis that small numbers of bacteria introduced into the maternal bloodstream (too few to induce fever or changes in maternal food consumption), can be found in the fetus days later. We injected 100 colony forming units of green-, red- and far red- fluorescent protein (GFP, RFP, FRFP) expressing S. aureus into late-gestation pregnant sheep intravenously. Five to 7 days later, the animals were euthanized and tissues collected for analysis of GFP. The inoculations did not cause any fever or other measurable behavioral response in the ewes, but did result in the appearance of GFP DNA, and protein in various tissues within the fetuses. Immunohistochemical analysis reveals GFP protein-containing bacteria that appear to be mostly contained within other cells. We were unable to recover any live GFP-expressing bacteria from the fetal tissues. We conclude that S. aureus, and perhaps other bacteria, gain access to the fetus, although it is not clear from these experiments that they survive in the fetus. It is possible that these low inocula and their progeny were effectively cleared by the fetal immune system.

Los humedales herbáceos se encuentran entre los ecosistemas más productivos del planeta debido a procesos biogeoquímicos particulares originados por plantas emergentes, lo que se traduce en magnificación de la producción de biomasa viva y deposición continua de materia orgánica muerta. Se hizo un experimento de campo en un humedal herbáceo de la región de Barlovento para cuantificar el coeficiente de descomposición foliar de Heliconia marginata (Heliconiaceae) en condiciones naturales.Heliconia marginataconforma una zona de vegetación monoespecífica a lo largo del borde suroeste del humedal. Se recolectaron hojas deH. marginata, las que una vez secas se colocaron en bolsas de descomposición y se incubaron in situ durante 68 días. A diferentes intervalos de tiempo se retiraron las bolsas para determinar el peso seco libre de cenizas. Simultáneamente se midieron algunas variables fisicoquímicas (pH, conductividad, temperatura y oxígeno disuelto) y la profundidad del agua, las mismas no mostraron diferencias significativas entre los días transcurridos del experimento. La descomposición foliar deH. marginatamostró dos etapas: descomposición moderadamente rápida durante los primeros cuatro días, con un porcentaje de pérdida de 13% del peso seco libre de cenizas, y otra donde la descomposición ocurrió lentamente. El coeficiente de descomposición deH. marginatafue 0.0068 días-1, valor comparable con los de otras especies emergentes con coeficientes altos. La vida media (t50) o tiempo para la descomposición de 50% del material vegetal fue de 147 días, pero el periodo de incubación sólo comprendió lavado de material. Una fauna folívora y detritívora casi ausente hace suponer que las características estructurales deH. marginatadeterminan una descomposición y reciclado de materia orgánica lentos dentro del ecosistema.

Anopheles aquasalis es considerado como el principal vector de malaria humana en el norte de Venezuela. El estudio longitudinal se llevó a cabo en áreas costeras de la Península de Paria, estado Sucre. El hábitat de las larvas de A. aquasalis fue clasificado como: manglar salobre y pantano herbáceo. Muestreos para recolectar larvas de mosquitos e insectos asociados se realizaron mensualmente en ambos criaderos desde enero hasta diciembre de 1999 (30 muestras). Simultáneamente se midieron cinco variables seleccionadas del agua: conductividad, salinidad, oxígeno disuelto, temperatura y pH. En ambos criaderos de determinaron las variaciones estacionales y temporales de las larvas de A. aquasalis e insectos acuáticos. Para el período de estudio, la abundancia de larvas fue mayor en el manglar. El análisis de correspondencia mostró una fuerte relación entre algunos factores químicos del agua y la abundancia de las larvas. La abundancia de las larvas de A. aquasalis en ambas épocas, se correlacionó positivamente con la salinidad del agua, pH y conductividad, y negativamente con el oxígeno disuelto, en la estación seca. La presencia de larvas se correlacionó positivamente con la presencia de Avicennia germinans. En el manglar existió una asociación positiva entre la abundancia de larvas y la abundancia de la familia Scirtidae y una correlación negativa entre la abundancia de larvas y la precipitación mensual (Spearman), así como una correlación negativa significativa entre la abundancia de Gerridae y la precipitación mensual. En el pantano herbáceo, no había asociaciones significativas entre la abundancia de las larvas de A. aquasalis y la abundancia de otros insectos acuáticos asociados al hábitat.

Las plantas carnívoras acuáticas del género Utricularia (Lentibulariaceae), capturan pequeños organismos acuáticos, como rotíferos, copépodos, y cladóceros, por medio de estructuras anatómicas semejantes a vesículas. Este estudio tuvo como objetivo determinar el tamaño y tipo de presas de U. gibba y U. inflata, recolectados en un pequeño lago y en un pastizal inundado, respectivamente, en la localidad de la Península de Paria (Estado Sucre, Venezuela). La acidez, conductividad, cantidad de oxígeno disuelto y la salinidad del agua se midieron in situ para cada sitio de muestreo; también se tomaron muestras de agua para determinar niveles de N-Kjeldahl, P-total, Na+, K+, Ca++, Mg++ y Cl-. Se midieron cincuenta vesículas de cada especie y se analizaron sus contenidos. Los valores de N-Kjeldahl y P-total fueron similares en ambos sitios, y semejantes a los conocidos para ecosistemas eutróficos; sin embargo, las concentraciones de Na+, K+, Ca++, Mg++ y los valores in situ de los parámetros del agua fueron más altos en el pastizal inundado. Las vesículas contenían los siguientes grupos de zooplancton: rotíferos, cladóceros, copépodos, anélidos, rizópodos, e insectos; y las siguientes divisiones de fitoplancton: Bacillariophyta, Chlorophyta, Cyanophyta y Euglenophyta. Las vesículas presentadas por U. inflata fueron menores en tamaño y en cantidad, pero mayores en abundancia y riqueza total de morfoespecies algales y animales en comparación con U. gibba. La similitud en cuanto a composición de presas a nivel taxonómico, entre las dos especies de plantas carnívoras, fue baja.

Vegetation and seed banks association with seasonal water depth variations were studied in a herbaceous wetland of a tropical lake in Monagas, Venezuela. The sampling was done in 10x10m² quadrates located at random in two zones of the lagoon. In each sampling four quadrates per zone were analyzed for relative species density, species richness, life forms and water depth. Soil samples were taken simultaneously for ize and composition of the seed banks (seedling emergence method). Soil pH was five. The organic total fraction of the soil varied between 38% and 52%, and the conductivity between 114 and 182 µmhos/cm. 50 species were recorded: 46% perennial herbs, 22% vines, 12% suffrutescents and 10% hydrophytes. The highest species richness was recorded during periods of rain and rain-dry transition. Hymenachne amplexicaulis, Leersia hexandra, Sacciolepis striata and Polygonum acuminatum were among the most important species numerically. The total density of seed bank varied between 5689 and 13936 seedlings/m². In the seed bank there were 58 species: 43% perennial herbs, 22% suffrutescents, 12% vines 9% annual herbs and 9%, hydrophytes. The highest species richness in the seed bank was during periods of dry and dry-rain transition. Cyperus odoratus, Eleocharis interstincta, Ludwigia hyssopifolia, L. lithospermifolia and Polygonum acuminatum had the highest densities. The potential flora of these wetlands included 76 species, but only 33 (43%) were common to the seed bank and the vegetation.

This article addresses a key political question regarding the relationship between states and their citizens: how harsh are judicial systems in their punishment of those who deviate from the law? Punitiveness is a fraught concept in the existing literature and robust measurement methods maximizing conceptual complexity are lacking. Here I develop a functional approach to punitiveness through a revised conceptualization and operationalization of this key variable while cautioning against the solitary use of incarceration rates to measure state intention. Punitiveness is conceptually disaggregated into three main components: (1) a commitment to punishment over rehabilitation, (2) the degree of harshness of response to crime (i.e., a longer sentence in prison), and (3) the lack of a logical progression of punishment based on the severity of crime committed or intent of the offender. These axes are further disaggregated into measurable indicators to build a novel index of punitiveness (P‐Index) from the legal codes of 26 countries. Ultimately, this rules‐as‐data measure offers researchers purchase on the puzzling variation in punitiveness across contexts, which persists regardless of current and historical crime levels, offering particular utility for supply‐side political‐economic explanations. [ABSTRACT FROM AUTHOR]

Byline: Madeline. Adelman, Elizabeth. Gordon Spratt, Ben. Friedman Case Report A 71-year-old woman presented with a 10-month history of increasing, non-pruritic coin-shaped skin lesions on her neck, trunk, and extremities. [...]