A missense variant effect map for the human tumor-suppressor protein CHK2.

The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers.

Integrated Multi-Organ Ultrasound.

Integrated multi-organ ultrasound is increasingly used across various medical specialties. It should be performed in conjunction with history, physical examination, and other investigations in the diagnostic process to enhance the detection of conditions in the lung, heart, and abdomen. Multi-organ ultrasound has been shown to improve diagnostic accuracy in a sizeable portion of patients, potentially altering treatment plans.

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Effect of a Point-of-Care Ultrasound-Driven vs Standard Diagnostic Pathway on 24-Hour Hospital Stay in Emergency Department Patients with Dyspnea-Protocol for A Randomized Controlled Trial.

Purpose: Point-of-care ultrasound (POCUS) helps emergency department (ED) physicians make prompt and appropriate decisions, but the optimal diagnostic integration and potential clinical benefits remain unclear. We describe the protocol and statistical analysis plan for a randomized controlled trial. The objective is to determine the effect of a POCUS-driven diagnostic pathway in adult dyspneic ED patients on the proportion of patients having a hospital stay of less than 24 hours when compared to the standard diagnostic pathway.

Benchmarking computational variant effect predictors by their ability to infer human traits.

Background: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts.

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A focused point-of-care abdominal ultrasound is an examination performed at the patient's location and interpreted within the clinical context. This review gives an overview of this examination modality. The objective is to rapidly address predefined dichotomised questions about the presence of an abdominal aortic aneurysm, gallstones, cholecystitis, hydronephrosis, urinary retention, free intraperitoneal fluid, and small bowel obstruction.

Pacybara: accurate long-read sequencing for barcoded mutagenized allelic libraries.

Motivation: Long-read sequencing technologies, an attractive solution for many applications, often suffer from higher error rates. Alignment of multiple reads can improve base-calling accuracy, but some applications, e.g.

Point-of-Care Lung Ultrasound in Emergency Medicine: A Scoping Review With an Interactive Database.

Background: This scoping review was conducted to provide an overview of the evidence of point-of-care lung ultrasound (LUS) in emergency medicine. By emphasizing clinical topics, time trends, study designs, and the scope of the primary outcomes, a map is provided for physicians and researchers to guide their future initiatives.

Research Question: Which study designs and primary outcomes are reported in published studies of LUS in emergency medicine?

Study Design And Methods: We performed a systematic search in the PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Library databases for LUS studies published prior to May 13, 2023.

Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.

Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions.

Management of medical emergency patients in Danish emergency departments.

Introduction: In many emergency departments (ED), specialised teams are activated to take care of medical emergency patients (MEP). The aim of this study was to describe the organisation of the management of adult MEPs in Danish EDs. The study examined trigger team activation criteria, training and composition of trigger teams.

Genome-scale mapping of DNA damage suppressors through phenotypic CRISPR-Cas9 screens.

To maintain genome integrity, cells must accurately duplicate their genome and repair DNA lesions when they occur. To uncover genes that suppress DNA damage in human cells, we undertook flow-cytometry-based CRISPR-Cas9 screens that monitored DNA damage. We identified 160 genes whose mutation caused spontaneous DNA damage, a list enriched in essential genes, highlighting the importance of genomic integrity for cellular fitness.

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Focused cardiac ultrasound (FoCUS) is a point-of-care cardiac examination performed and interpreted by the emergency physician in the clinical context. This review summarises the current knowledge of FoCUS. The objective is to answer four predefined clinical questions: Are there any signs of pericardial effusion? Are there any signs of right ventricular dilatation? Are there any signs of reduced or hyperdynamic left ventricular function? Are there any signs of abnormal inferior vena cava? FoCUS is not a replacement for echocardiography but a useful tool in detecting cardiopulmonary pathology and haemodynamic abnormalities in the emergency setting.

A comprehensive map of human glucokinase variant activity.

Background: Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity to cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up to 10 million people worldwide. Patients with GCK-MODY are frequently misdiagnosed and treated unnecessarily.

Pacybara: Accurate long-read sequencing for barcoded mutagenized allelic libraries.

Long read sequencing technologies, an attractive solution for many applications, often suffer from higher error rates. Alignment of multiple reads can improve base-calling accuracy, but some applications, e.g.

Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.

Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as "variants of uncertain significance" (VUS). Using saturation mutagenesis, selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions.

Lack of Thoracentesis Competencies and Training in Danish Emergency Departments: A Danish Nationwide Study.

Background: Dyspnea caused by pleural effusion is a common reason for admission to the emergency department (ED). In such cases, thoracentesis performed in the ED may allow for swift symptom relief, diagnostics, and early patient discharge. However, the competence level of thoracentesis and training in the ED are currently unclear.

Focused lung ultrasound to predict respiratory failure in patients with symptoms of COVID-19: a multicentre prospective cohort study.

Background: In this study we aimed to assess if a focused lung ultrasound examination predicts the need for mechanical ventilation, admission to an intensive care unit, high-flow oxygen treatment, death from COVID-19 within 30 days and 30-day all-cause mortality in patients with clinical suspicion of COVID-19 or PCR-verified SARS-CoV-2 infection.

Methods: A multicentre prospective cohort trial was performed. Film clips from focused lung ultrasound examinations were recorded and rated by blinded observers using different scoring systems.

The Framing of machine learning risk prediction models illustrated by evaluation of sepsis in general wards.

Problem framing is critical to developing risk prediction models because all subsequent development work and evaluation takes place within the context of how a problem has been framed and explicit documentation of framing choices makes it easier to compare evaluation metrics between published studies. In this work, we introduce the basic concepts of framing, including prediction windows, observation windows, window shifts and event-triggers for a prediction that strongly affects the risk of clinician fatigue caused by false positives. Building on this, we apply four different framing structures to the same generic dataset, using a sepsis risk prediction model as an example, and evaluate how framing affects model performance and learning.

Improved pathogenicity prediction for rare human missense variants.

The success of personalized genomic medicine depends on our ability to assess the pathogenicity of rare human variants, including the important class of missense variation. There are many challenges in training accurate computational systems, e.g.

Shifting landscapes of human MTHFR missense-variant effects.

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment.

[Point-of-care ultrasound in emergency departments in Denmark].

Point-of-are ultrasound (PoCUS) has become an integrated part of initial diagnostics and procedural guidance after establishing emergency departments and a speciality in emergency medicine in Denmark. Focused PoCUS is a fast examination, which is done and interpreted bedside to answer clinical, predefined dichotomous questions. Emergency physicians have an obligate course in PoCUS as part of their training and must be certified to get speciality recognition.

MaveRegistry: a collaboration platform for multiplexed assays of variant effect.

Summary: Multiplexed assays of variant effect (MAVEs) are capable of experimentally testing all possible single nucleotide or amino acid variants in selected genomic regions, generating 'variant effect maps', which provide biochemical insight and functional evidence to enable more rapid and accurate clinical interpretation of human variation. Because the international community applying MAVE approaches is growing rapidly, we developed the online MaveRegistry platform to catalyze collaboration, reduce redundant efforts, allow stakeholders to nominate targets and enable tracking and sharing of progress on ongoing MAVE projects.

Availability And Implementation: MaveRegistry service: https://registry.