A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ...Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.
We explored patterns of change in bacterioplankton and phytoplankton community composition in response to typhoons in a subtropical, subalpine freshwater humic lake in Taiwan. Thermal profiles with ...depth, near-surface dissolved oxygen, and meteorological conditions were measured at high temporal resolution using an instrumented buoy. We collected samples across a time series spanning two typhoon seasons and assessed bacterial community composition at each time point using a fingerprinting technique targeting the internal transcribed spacer region of the ribosomal RNA operon. Wind and rain associated with the typhoons mixed the otherwise stably stratified water column. After each of six typhoon-induced mixing events, the bacterial community composition was reset to similar conditions, revealing a surprisingly deterministic pattern of recovery that was reminiscent of secondary succession following large infrequent disturbances in terrestrial ecosystems. Distinct bacterial assemblages were associated with epilimnion and hypolimnion samples collected more than 80 d after a mixing event. These assemblages were also distinct from the communities observed in the generally unstratified water column within 7 d after a typhoon. Our results were surprising since bacterial communities are not expected to respond in such predictable ways because of their immense complexity and diversity. In contrast, phytoplankton communities did not recover in a predictable way after typhoons.
Analysis of habituation is widely used to characterize animal cognitive phenotypes and their modulation. Although zebrafish (
Danio rerio) are increasingly utilized in neurobehavioral research, their ...habituation responses have not been extensively investigated. Utilizing the novel tank test, we examine intra- and inter-session habituation and demonstrate robust habituation responses in adult zebrafish. Analyzing the intra-session habituation to novelty further, we also show that selected anxiogenic drugs (caffeine, pentylenetetrazole), as well as stress-inducing alarm pheromone, attenuated zebrafish habituation. Some acute anxiolytic agents, such as morphine and ethanol, while predictably reducing zebrafish anxiety, had no effects on habituation. Chronic ethanol and fluoxetine treatments improved intra-session habituation in zebrafish. In general, our study parallels literature on rodent habituation responses to novelty, and reconfirms zebrafish as a promising model for cognitive neurobehavioral research.
Abstract
High-throughput digital pathology offers considerable advantages over traditional semiquantitative and manual methods of counting pathology. We used brain tissue from 5 clinical-pathologic ...cohort studies of aging; the Religious Orders Study, the Rush Memory and Aging Project, the Minority Aging Research Study, the African American Clinical Core, and the Latino Core to (1) develop a workflow management system for digital pathology processes, (2) optimize digital algorithms to quantify Alzheimer disease (AD) pathology, and (3) harmonize data statistically. Data from digital algorithms for the quantification of β-amyloid (Aβ, n = 413) whole slide images and tau-tangles (n = 639) were highly correlated with manual pathology data (r = 0.83 to 0.94). Measures were robust and reproducible across different magnifications and repeated scans. Digital measures for Aβ and tau-tangles across multiple brain regions reproduced established patterns of correlations, even when samples were stratified by clinical diagnosis. Finally, we harmonized newly generated digital measures with historical measures across multiple large autopsy-based studies. We describe a multidisciplinary approach to develop a digital pathology pipeline that reproducibly identifies AD neuropathologies, Aβ load, and tau-tangles. Digital pathology is a powerful tool that can overcome critical challenges associated with traditional microscopy methods.
•Individuals most often share Lynch syndrome test results with first-degree relatives.•Details of genetic results and associated cancer risks most challenging topics.•Probands and family members find ...different resources most helpful for learning.•Providers may distribute resources to encourage family communication.
To explore patterns of communication among families with a Lynch syndrome diagnosis and understand what resources could facilitate family communication.
127 probands (i.e., first person in family with identified mutation) and family members participated in semi-structured interviews about: how they learned about the Lynch syndrome diagnosis, with whom they shared genetic test results, confidence in sharing results with other family members, and helpfulness of educational resources.
Both probands and family members were most likely to share genetic test results with parents and siblings, and least likely to share results with aunts, uncles, and cousins. Most participants felt very confident sharing their test results with family members, but reported that certain topics such as cancer risk were challenging to convey. Probands reported the most helpful resources to be access to a specialty clinic or website, while family members described general printed materials as most helpful.
Families affected by Lynch syndrome may experience barriers to communication with more distant relatives, and may benefit from receiving specific resources (e.g., websites about Lynch syndrome, print materials) to facilitate family communication.
Providers could emphasize the need to share information with more distant family members and provide appropriate supportive resources.
Effects of extra‐column volume on apparent separation parameters were studied in ultra‐high pressure liquid chromatography with columns and inlet connection tubings of various internal diameters (id) ...using 50‐mm long columns packed with 1.8‐μm particles under isocratic conditions. The results showed that apparent retention factors were on average 5, 11, 18, and 41% lower than those corrected with extra‐column volumes for 4.6‐, 3.0‐, 2.1‐, and 1.0‐mm id columns, respectively, when the extra‐column volume (11.3 μL) was kept constant. Also, apparent pressures were 31, 16, 12, and 10% higher than those corrected with pressures from extra‐column volumes for 4.6‐, 3.0‐, 2.1‐, and 1.0‐mm id columns at the respective optimum flow rate for a typical ultra‐high pressure liquid chromatography system. The loss in apparent efficiency increased dramatically from 4.6‐ to 3.0‐ to 2.1‐ to 1.0‐mm id columns, less significantly as retention factors increased. The column efficiency was significantly improved as the inlet tubing id was decreased for a given column. The results suggest that maximum ratio of extra‐column volume to column void volume should be approximately 1:10 for column porosity more than 0.6 and a retention factor more than 5, where 80% or higher of theoretically predicted efficiency could be achieved.
This scoping review provides an up-to-date overview of the evidence on adolescent and youth-friendly health services (AYFHS) in sub-Saharan African countries. We conducted a search of four databases ...and grey literature sources to identify English language publications from January 1, 2005, to December 14th, 2022. The review synthesized evidence on the models and characteristics of AYFHS, the application of World Health Organization (WHO) standards, and whether AYFHS have improved young people’s health outcomes. In total, 77 sources were included in the review, representing 47 AYFHS initiatives spanning 19 countries, and three multi-country reports. Most commonly, AYFHS were delivered in public health facilities and focused on sexual and reproductive health, with limited application of WHO standards. Some evidence suggested that AYFHS increased young people’s health service utilization and contraceptives uptake. There is a clear need to strengthen and develop innovative and multi-pronged approaches to delivering and evaluating AYFHS in this region.
Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein ...Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.
In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689.
Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9–2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136–193) following a single intravenous 10 mg/kg dose.
TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season.
PATH's Malaria Vaccine Initiative.
Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by ...intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.
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