Coat Color Roan Shows Association with KIT Variants and No Evidence of Lethality in Icelandic Horses

Roan (Rn) horses show a typical seasonal change of color. Their body is covered with colored and white hair. We performed a descriptive statistical analysis of breeding records of Icelandic horses to challenge the hypothesis of roan being lethal in utero under homozygous condition. The roan to non-roan ratio of foals from roan × roan matings revealed homozygous roan Icelandic horses to be viable. Even though roan is known to be inherited in a dominant mode and epistatic to other coat colors, the causative mutation is still unknown. Nevertheless, an association between roan phenotype and the KIT gene was shown for different horse breeds. In the present study, we identified KIT variants by Sanger sequencing, and show that KIT is also associated with roan in the Icelandic horse breed

Use of existing hydrographic infrastructure to forecast the environmental spawning conditions for Eastern Baltic cod

The semi-enclosed nature and estuarine characteristics, together with its strongly alternating bathymetry, make the Baltic Sea prone to much stronger interannual variations in the abiotic environment, than other spawning habitats of Atlantic cod (Gadus morhua). Processes determining salinity and oxygen conditions in the basins are influenced both by long term gradual climate change, e.g. global warming, but also by short-term meteorological variations and events. Specifically one main factor influencing cod spawning conditions, the advection of highly saline and well-oxygenated water masses from the North Sea, is observed in irregular frequencies and causes strong interannual variations in stock productivity. This study investigates the possibility to use the available hydrographic process knowledge to predict the annual spawning conditions for Eastern Baltic cod in its most important spawning ground, the Bornholm Basin, only by salinity measurements from a specific location in the western Baltic. Such a prediction could serve as an environmental early warning indicator to inform stock assessment and management. Here we used a hydrodynamic model to hindcast hydrographic property fields for the last 40+ years. High and significant correlations were found for months early in the year between the 33m salinity level in the Arkona Basin and the oxygen-dependent cod spawning environment in the Bornholm Basin. Direct prediction of the Eastern Baltic cod egg survival in the Bornholm Basin based on salinity values in the Arkona Basin at the 33 m depth level is shown to be possible for eggs spawned by mid-age and young females, which currently predominate the stock structure. We recommend to routinely perform short-term predictions of the Eastern Baltic cod spawning environment, in order to generate environmental information highly relevant for stock dynamics. Our statistical approach offers the opportunity to make best use of permanently existing infrastructure in the western Baltic to timely provide scientific knowledge on the spawning conditions of Eastern Baltic cod. Furthermore it could be a tool to assist ecosystem-based fisheries management with a cost-effective implementation by including the short term predictions as a simple indicator in the annual assessments

Interventions to Ameliorate the Psychosocial Effects of the COVID-19 Pandemic on Children-A Systematic Review

The aim of this study was to identify interventions targeting children and their caregivers to reduce psychosocial problems in the course of the COVID-19 pandemic and comparable outbreaks. The review was performed using systematic literature searches in MEDLINE, Embase, PsycINFO and COVID-19-specific databases, including the CDC COVID-19 Research Database, the World Health Organisation (WHO) Global Database on COVID-19 Research and the Cochrane COVID-19 Study Register, ClinicalTrials.gov, the EU Clinical Trials Register and the German Clinical Trials Register (DRKS) up to 25th September 2020. The search yielded 6657 unique citations. After title/abstract and full text screening, 11 study protocols reporting on trials planned in China, the US, Canada, the UK, and Hungary during the COVID-19 pandemic were included. Four interventions targeted children \geq10 years directly, seven system-based interventions targeted the parents and caregivers of younger children and adolescents. Outcome measures encompassed mainly anxiety and depressive symptoms, different dimensions of stress or psychosocial well-being, and quality of supportive relationships. In conclusion, this systematic review revealed a paucity of studies on psychosocial interventions for children during the COVID-19 pandemic. Further research should be encouraged in light of the expected demand for child mental health management

In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study

AIMS: Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). METHODS AND RESULTS: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. CONCLUSION: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy

A cytosolic disulfide bridge‐supported dimerization is crucial for stability and cellular distribution of Coxsackievirus B3 protein 3A

RNA viruses in the Picornaviridae family express a large 250 kDa viral polyprotein that is processed by virus-encoded proteinases into mature functional proteins with specific functions for virus replication. One of these proteins is the highly conserved enteroviral transmembrane protein 3A that assists in reorganizing cellular membranes associated with the Golgi apparatus. Here, we studied the molecular properties of the Coxsackievirus B3 (CVB3) protein 3A with regard to its dimerization and its functional stability. By applying mutational analysis and biochemical characterization, we demonstrate that protein 3A forms DTT-sensitive disulfide-linked dimers via a conserved cytosolic cysteine residue at position 38 (Cys38). Homodimerization of CVB3 protein 3A via Cys38 leads to profound stabilization of the protein, whereas a C38A mutation promotes a rapid proteasome-dependent elimination of its monomeric form. The lysosomotropic agent chloroquine (CQ) exerted only minor stabilizing effects on the 3A monomer but resulted in enrichment of the homodimer. Our experimental data demonstrate that disulfide linkages via a highly conserved Cys-residue in enteroviral protein 3A have an important role in the dimerization of this viral protein, thereby preserving its stability and functional integrity

Unintended health and societal consequences of international travel measures during the COVID-19 pandemic: A scoping review

RATIONALE FOR REVIEW International travel measures to contain the COVID-19 pandemic represent a relatively intrusive form of non-pharmaceutical intervention. To inform decision-making on the (re)implementation, adaptation, relaxation or suspension of such measures, it is essential to not only assess their effectiveness but also their unintended effects. This scoping review maps existing empirical studies on the unintended consequences, both predicted and unforeseen, and beneficial or harmful, of international travel measures. We searched multiple health, non-health and COVID-19-specific databases. The evidence was charted in a map in relation to the study design, intervention and outcome categories identified and discussed narratively. KEY FINDINGS Twenty-three studies met our inclusion criteria-nine quasi-experimental, two observational, two mathematical modelling, six qualitative, and four mixed-methods studies. Studies addressed different population groups across various countries worldwide. Seven studies provided information on unintended consequences of the closure of national borders, six looked at international travel restrictions, and three investigated mandatory quarantine of international travelers. No studies looked at entry and/or exit screening at national borders exclusively, however six studies considered this intervention in combination with other international travel measures. In total, eleven studies assessed various combinations of the aforementioned interventions. The outcomes were mostly referred to by the authors as harmful. Fifteen studies identified a variety of economic consequences, six reported on aspects related to quality of life, well-being, and mental health, and five on social consequences. One study each provided information on equity, equality, and the fair distribution of benefits and burdens, environmental consequences and health system consequences. CONCLUSIONS/RECOMMENDATIONS This scoping review represents the first step towards a systematic assessment of the unintended benefits and harms of international travel measures during COVID-19. The key research gaps identified might be filled with targeted primary research, as well as the additional consideration of gray literature and non-empirical studies

Identification of Mutant Genes and Introgressed Tiger Salamander DNA in the Laboratory Axolotl, \u3cem\u3eAmbystoma mexicanum\u3c/em\u3e

The molecular genetic toolkit of the Mexican axolotl, a classic model organism, has matured to the point where it is now possible to identify genes for mutant phenotypes. We used a positional cloning–candidate gene approach to identify molecular bases for two historic axolotl pigment phenotypes: white and albino. White (d/d) mutants have defects in pigment cell morphogenesis and differentiation, whereas albino (a/a) mutants lack melanin. We identified in white mutants a transcriptional defect in endothelin 3 (edn3), encoding a peptide factor that promotes pigment cell migration and differentiation in other vertebrates. Transgenic restoration of Edn3 expression rescued the homozygous white mutant phenotype. We mapped the albino locus to tyrosinase (tyr) and identified polymorphisms shared between the albino allele (tyra) and tyr alleles in a Minnesota population of tiger salamanders from which the albino trait was introgressed. tyra has a 142 bp deletion and similar engineered alleles recapitulated the albinophenotype. Finally, we show that historical introgression of tyrasignificantly altered genomic composition of the laboratory axolotl, yielding a distinct, hybrid strain of ambystomatid salamander. Our results demonstrate the feasibility of identifying genes for traits in the laboratory Mexican axolotl

Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

PURPOSE: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. METHODS: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. RESULTS: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. CONCLUSION: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-022-04049-w

Converting habits of antibiotic use for respiratory tract infections in German primary care – study protocol of the cluster-randomized controlled CHANGE-3 trial

Background: The overuse of antibiotics is a major cause for the worldwide rise of antibiotic resistance. Although it is well known that acute respiratory tract infections (ARTI) are mainly caused by viruses and are often self limiting, antibiotics are too frequently prescribed in primary care. CHANGE-3 examines whether a complex intervention focusing on improving communication and provision of prescribing feedback reduces antibiotic use in patients suffering from ARTI. Methods/design: The CHANGE-3 trial is a cluster-randomized controlled trial nested within a web-based public campaign conducted in two regions in Germany. A total of 114 medical practices will be included. Practices randomized to the intervention will receive a practice-specific antibiotic-prescription feedback and an educational outreach visit. During the visit the whole practice team will receive an introduction to e-learning modules addressing patient-centered communication on antibiotics. Furthermore, the practices will receive tablet PCs with information on antibiotics and the treatment of ARTI to be presented to patients. Practices randomized to the control will provide care as usual. The primary outcome measure is the antibiotic prescribing rate for patients with a history of ARTI. Data collected before the intervention, during the intervention and after the intervention will be compared. The use of narrow- vs. broad-spectrum antibiotics will be analyzed as a secondary outcome. A process evaluation is also part of the trial. Discussion: This study should contribute to the growing body of research on reducing antibiotic prescription. Trial registration: ISRCTN, ISRCTN15061174. Registered retrospectively on 13 July 2018

Measures implemented in the school setting to contain the COVID-19 pandemic: a scoping review.

BACKGROUND: In response to the spread of SARS-CoV-2 and the impact of COVID-19, national and subnational governments implemented a variety of measures in order to control the spread of the virus and the associated disease. While these measures were imposed with the intention of controlling the pandemic, they were also associated with severe psychosocial, societal, and economic implications on a societal level. One setting affected heavily by these measures is the school setting. By mid-April 2020, 192 countries had closed schools, affecting more than 90% of the world's student population. In consideration of the adverse consequences of school closures, many countries around the world reopened their schools in the months after the initial closures. To safely reopen schools and keep them open, governments implemented a broad range of measures. The evidence with regards to these measures, however, is heterogeneous, with a multitude of study designs, populations, settings, interventions and outcomes being assessed. To make sense of this heterogeneity, we conducted a rapid scoping review (8 October to 5 November 2020). This rapid scoping review is intended to serve as a precursor to a systematic review of effectiveness, which will inform guidelines issued by the World Health Organization (WHO). This review is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and was registered with the Open Science Framework. OBJECTIVES: To identify and comprehensively map the evidence assessing the impacts of measures implemented in the school setting to reopen schools, or keep schools open, or both, during the SARS-CoV-2/COVID-19 pandemic, with particular focus on the types of measures implemented in different school settings, the outcomes used to measure their impacts and the study types used to assess these. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the CDC COVID-19 Research Articles Downloadable Database for preprints, and the WHO COVID-19 Global literature on coronavirus disease on 8 October 2020. SELECTION CRITERIA: We included studies that assessed the impact of measures implemented in the school setting. Eligible populations were populations at risk of becoming infected with SARS-CoV-2, or developing COVID-19 disease, or both, and included people both directly and indirectly impacted by interventions, including students, teachers, other school staff, and contacts of these groups, as well as the broader community. We considered all types of empirical studies, which quantitatively assessed impact including epidemiological studies, modelling studies, mixed-methods studies, and diagnostic studies that assessed the impact of relevant interventions beyond diagnostic test accuracy. Broad outcome categories of interest included infectious disease transmission-related outcomes, other harmful or beneficial health-related outcomes, and societal, economic, and ecological implications. DATA COLLECTION AND ANALYSIS: We extracted data from included studies in a standardized manner, and mapped them to categories within our a priori logic model where possible. Where not possible, we inductively developed new categories. In line with standard expectations for scoping reviews, the review provides an overview of the existing evidence regardless of methodological quality or risk of bias, and was not designed to synthesize effectiveness data, assess risk of bias, or characterize strength of evidence (GRADE). MAIN RESULTS: We included 42 studies that assessed measures implemented in the school setting. The majority of studies used mathematical modelling designs (n = 31), while nine studies used observational designs, and two studies used experimental or quasi-experimental designs. Studies conducted in real-world contexts or using real data focused on the WHO European region (EUR; n = 20), the WHO region of the Americas (AMR; n = 13), the West Pacific region (WPR; n = 6), and the WHO Eastern Mediterranean Region (EMR; n = 1). One study conducted a global assessment and one did not report on data from, or that were applicable to, a specific country. Three broad intervention categories emerged from the included studies: organizational measures to reduce transmission of SARS-CoV-2 (n = 36), structural/environmental measures to reduce transmission of SARS-CoV-2 (n = 11), and surveillance and response measures to detect SARS-CoV-2 infections (n = 19). Most studies assessed SARS-CoV-2 transmission-related outcomes (n = 29), while others assessed healthcare utilization (n = 8), other health outcomes (n = 3), and societal, economic, and ecological outcomes (n = 5). Studies assessed both harmful and beneficial outcomes across all outcome categories. AUTHORS' CONCLUSIONS: We identified a heterogeneous and complex evidence base of measures implemented in the school setting. This review is an important first step in understanding the available evidence and will inform the development of rapid reviews on this topic