Cardiogenic Shock: Protocols, Teams, Centers, and Networks

The mortality of cardiogenic shock (CS) remains unacceptably high. Delays in the recognition of CS and access to disease-modifying or hemodynamically stabilizing interventions likely contribute to poor outcomes. In parallel to successful initiatives in other disease states, such as acute ST-elevation MI and major trauma, institutions are increasingly advocating the use of a multidisciplinary ‘shock team’ approach to CS management. A volume–outcome relationship exists in CS, as with many other acute cardiovascular conditions, and the emergence of ‘shock hubs’ as experienced facilities with an interest in improving CS outcomes through a hub-and-spoke ‘shock network’ approach provides another opportunity to deliver improved CS care as widely and equitably as possible. This narrative review outlines improvements from a networked approach to care, discusses a team-based and protocolized approach to CS management, reviews the available evidence and discusses the potential benefits, challenges, and opportunities of such systems of care

Condoms and Contradictions: Assessing Sexual Health Knowledge in Lesbian, Gay, Bisexual, Trans, and Queer Youth Labelled with Intellectual Disabilities

Background: Accessible, culturally relevant data collection tools to assess the sexual health knowledge of lesbian, gay, bisexual, trans, queer and questioning (LGBTQ) young people labelled with intellectual disabilities are sparse. Materials and Methods: Using community-based participatory research (CBPR) we piloted a variety of interactive activities designed to assess the sexual health knowledge and decision making skills of LGBTQ young people with intellectual disabilities. Results: Posters created by youth participants suggested substantial sexual health knowledge and empowerment, while individual knowledge assessment scores indicated a range in understanding of risks and strategies to avoid pregnancy, HIV and herpes. Conclusions: These findings reinforce the importance of using multiple strategies to assess sexual knowledge with this population. Creative evaluation strategies catering to the cultural specificities, sexual experiences, and cognitive abilities of diverse youth help to clarify gaps in knowledge and areas for renewed attention. Keywords: HIV/AIDS; community-based participatory research; intellectual disabilities; lesbian, gay, bisexual, and trans (LGBT); sexual health Les outils de collecte des données, accessibles et culturellement appropriés, afin d’évaluer les connaissances sur la santé sexuelle des jeunes LGBT (Lesbiennes, Gais, Bisexuel-les et Trans) ayant des handicaps intellectuels sont rares. Nous avons pilotés une variété d’activités interactives ayant pour but l’évaluation des connaissances en santé sexuelle et des compétences pour la prise de décision de jeunes LGBT ayant des handicaps intellectuels. Les affiches créées par les jeunes participants indiquent une responsabilisation et une connaissance approfondie de la santé sexuelle. Les résultats des évaluations de la connaissance en santé sexuelle indiquent une bonne compréhension des risques et des stratégies pour éviter la grossesse, Le VIH et l’herpès. Les résultats obtenus renforcent l’importance d’utiliser diverses stratégies pour évaluer la connaissance en santé sexuelle de cette population. Des stratégies d’évaluation créatives qui adressent les spécificités culturelles, les expériences sexuelles et les habilités cognitives de différents jeunes aident à clarifier les lacunes en connaissance et les domaines qui nécessitent une attention accrue. Mots-clés: VIH/SIDA; recherche participative axée sur la communauté; handicaps intellectuels; (LGBT) lesbiennes, gais, bisexuel-les et trans; santé sexuell

Letter [Paracetamol (acetaminophen) poisoning - No need to change current guidelines to accident departments] [Correspondence]

Paracetamol is an effective, simple analgesic that is well tolerated by adults and children at therapeutic doses. In many countries it is available without prescription. Unfortunately, its ready availability is associated with episodes of poisoning that prompt 3.3% of inquiries to US regional poisons centres,1 10% of inquiries to the UK National Poisons Information Service,2 and up to 43% of all admissions to hospital with self poisoning in the United Kingdom.3 In the United States paracetamol alone accounted for 4.1% of deaths from poisoning reported to American poisons centres in 1997.1 Most deaths are associated with deliberate self poisoning, but therapeutic misadventures do occur rarely, in both adults and children..

A novel prostate cancer subtyping classifier based on luminal and basal phenotypes

Background: Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought. Methods: Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts. Results: Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09–0.51). Conclusions: With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features. Plain language summary: Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors—the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management

Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis

Cyclin-dependent kinase 5 drives T cell activation and disease in EAE in part by regulating the actin binding protein coronin 1a

Let’s not forget tautomers

A compound exhibits tautomerism if it can be represented by two structures that are related by an intramolecular movement of hydrogen from one atom to another. The different tautomers of a molecule usually have different molecular fingerprints, hydrophobicities and pKa’s as well as different 3D shape and electrostatic properties; additionally, proteins frequently preferentially bind a tautomer that is present in low abundance in water. As a result, the proper treatment of molecules that can tautomerize, ~25% of a database, is a challenge for every aspect of computer-aided molecular design. Library design that focuses on molecular similarity or diversity might inadvertently include similar molecules that happen to be encoded as different tautomers. Physical property measurements might not establish the properties of individual tautomers with the result that algorithms based on these measurements may be less accurate for molecules that can tautomerize—this problem influences the accuracy of filtering for library design and also traditional QSAR. Any 2D or 3D QSAR analysis must involve the decision of if or how to adjust the observed Ki or IC50 for the tautomerization equilibria. QSARs and recursive partitioning methods also involve the decision as to which tautomer(s) to use to calculate the molecular descriptors. Docking virtual screening must involve the decision as to which tautomers to include in the docking and how to account for tautomerization in the scoring. All of these decisions are more difficult because there is no extensive database of measured tautomeric ratios in both water and non-aqueous solvents and there is no consensus as to the best computational method to calculate tautomeric ratios in different environments

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice