The first 20 months of the COVID-19 pandemic: Mortality, intubation and ICU rates among 104,590 patients hospitalized at 21 United States health systems

Main objective: There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. Study design and methods: University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. Results and significance: The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. Conclusions: Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. Trial registration: ClinicalTrials.gov Identifier:&nbsp;NCT04506528&nbsp;(https://clinicaltrials.gov/ct2/show/NCT04506528).</p

65 YEARS OF THE DOUBLE HELIX Genetics informs precision practice in the diagnosis and management of pheochromocytoma

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.Peer reviewe

Statistical learning of peptide retention behavior in chromatographic separations: a new kernel-based approach for computational proteomics

<p>Abstract</p> <p>Background</p> <p>High-throughput peptide and protein identification technologies have benefited tremendously from strategies based on tandem mass spectrometry (MS/MS) in combination with database searching algorithms. A major problem with existing methods lies within the significant number of false positive and false negative annotations. So far, standard algorithms for protein identification do not use the information gained from separation processes usually involved in peptide analysis, such as retention time information, which are readily available from chromatographic separation of the sample. Identification can thus be improved by comparing measured retention times to predicted retention times. Current prediction models are derived from a set of measured test analytes but they usually require large amounts of training data.</p> <p>Results</p> <p>We introduce a new kernel function which can be applied in combination with support vector machines to a wide range of computational proteomics problems. We show the performance of this new approach by applying it to the prediction of peptide adsorption/elution behavior in strong anion-exchange solid-phase extraction (SAX-SPE) and ion-pair reversed-phase high-performance liquid chromatography (IP-RP-HPLC). Furthermore, the predicted retention times are used to improve spectrum identifications by a <it>p</it>-value-based filtering approach. The approach was tested on a number of different datasets and shows excellent performance while requiring only very small training sets (about 40 peptides instead of thousands). Using the retention time predictor in our retention time filter improves the fraction of correctly identified peptide mass spectra significantly.</p> <p>Conclusion</p> <p>The proposed kernel function is well-suited for the prediction of chromatographic separation in computational proteomics and requires only a limited amount of training data. The performance of this new method is demonstrated by applying it to peptide retention time prediction in IP-RP-HPLC and prediction of peptide sample fractionation in SAX-SPE. Finally, we incorporate the predicted chromatographic behavior in a <it>p</it>-value based filter to improve peptide identifications based on liquid chromatography-tandem mass spectrometry.</p

Community-based knowledge transfer and exchange: Helping community-based organizations link research to action

<p>Abstract</p> <p>Background</p> <p>Community-based organizations (CBOs) are important stakeholders in health systems and are increasingly called upon to use research evidence to inform their advocacy, program planning, and service delivery efforts. CBOs increasingly turn to community-based research (CBR) given its participatory focus and emphasis on linking research to action. In order to further facilitate the use of research evidence by CBOs, we have developed a strategy for community-based knowledge transfer and exchange (KTE) that helps CBOs more effectively link research evidence to action. We developed the strategy by: outlining the primary characteristics of CBOs and why they are important stakeholders in health systems; describing the concepts and methods for CBR and for KTE; comparing the efforts of CBR to link research evidence to action to those discussed in the KTE literature; and using the comparison to develop a framework for community-based KTE that builds on both the strengths of CBR and existing KTE frameworks.</p> <p>Discussion</p> <p>We find that CBR is particularly effective at fostering a climate for using research evidence and producing research evidence relevant to CBOs through community participation. However, CBOs are not always as engaged in activities to link research evidence to action on a larger scale or to evaluate these efforts. Therefore, our strategy for community-based KTE focuses on: an expanded model of 'linkage and exchange' (<it>i.e</it>., producers and users of researchers engaging in a process of asking and answering questions together); a greater emphasis on both producing and disseminating systematic reviews that address topics of interest to CBOs; developing a large-scale evidence service consisting of both 'push' efforts and efforts to facilitate 'pull' that highlight actionable messages from community relevant systematic reviews in a user-friendly way; and rigorous evaluations of efforts for linking research evidence to action.</p> <p>Summary</p> <p>Through this type of strategy, use of research evidence for CBO advocacy, program planning, and service delivery efforts can be better facilitated and continually refined through ongoing evaluations of its impact.</p

Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice

Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo.Here, we show that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in PME-1(-/-) tissues, which also displayed alterations in phosphoproteome content.These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP

Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity

MicroRNA-96 Directly Inhibits γ-Globin Expression in Human Erythropoiesis

Fetal hemoglobin, HbF (α2γ2), is the main hemoglobin synthesized up to birth, but it subsequently declines and adult hemoglobin, HbA (α2β2), becomes predominant. Several studies have indicated that expression of the HbF subunit γ-globin might be regulated post-transcriptionally. This could be confered by ∼22-nucleotide long microRNAs that associate with argonaute proteins to specifically target γ-globin mRNAs and inhibit protein expression. Indeed, applying immunopurifications, we found that γ-globin mRNA was associated with argonaute 2 isolated from reticulocytes that contain low levels of HbF (<1%), whereas association was significantly lower in reticulocytes with high levels of HbF (90%). Comparing microRNA expression in reticulocytes from cord blood and adult blood, we identified several miRNAs that were preferentially expressed in adults, among them miRNA-96. The overexpression of microRNA-96 in human ex vivo erythropoiesis decreased γ-globin expression by 50%, whereas the knock-down of endogenous microRNA-96 increased γ-globin expression by 20%. Moreover, luciferase reporter assays showed that microRNA-96 negatively regulates expression of γ-globin in HEK293 cells, which depends on a seedless but highly complementary target site located within the coding sequence of γ-globin. Based on these results we conclude that microRNA-96 directly suppresses γ-globin expression and thus contributes to HbF regulation

Search for light top squark pair production in final states with leptons and b -jets with the ATLAS detector in s=7\sqrt{s}=7 TeV proton-proton collisions

The results of a search for pair production of light top squarks are presented, using 4.7 fb^-1 of sqrt(s) = 7 TeV proton-proton collisions collected with the ATLAS detector at the Large Hadron Collider. This search targets top squarks with masses similar to, or lighter than, the top quark mass. Final states containing exclusively one or two leptons (e, mu), large missing transverse momentum, light-jets and b-jets are used to reconstruct the top squark pair system. Global mass scale variables are used to separate the signal from a large ttbar background. No excess over the Standard Model expectations is found. The results are interpreted in the framework of the Minimal Supersymmetric Standard Model, assuming the top squark decays exclusively to a chargino and a b-quark. Light top squarks with masses between 123-167 GeV are excluded for neutralino masses around 55 GeV