To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.
Prospective observational ...cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.
76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, -0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.
Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.
ISRCTN66726260.
Objective
Autoantibodies recognizing 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult ...myositis patients. The aim of this study was to characterize the features of juvenile anti‐HMGCR‐positive myositis patients.
Methods
The sera of 440 juvenile myositis patients were screened for anti‐HMGCR autoantibodies. Demographic and clinical features, responses to therapy, and HLA alleles were assessed. The features of anti‐HMGCR‐positive patients were compared to those of previously described adult patients with this autoantibody and to children with other myositis‐specific autoantibodies (MSAs).
Results
Five of 440 patients (1.1%) were anti‐HMGCR‐positive; none had taken statin medications. Three patients had rashes characteristic of juvenile dermatomyositis and 2 patients had immune‐mediated necrotizing myopathies. The median highest creatine kinase (CK) level of anti‐HMGCR‐positive subjects was 17,000 IU/liter. All patients had severe proximal muscle weakness, distal weakness, muscle atrophy, joint contractures, and arthralgias, which were all more prevalent in HMGCR‐positive subjects compared to MSA‐negative patients or those with other MSAs. Anti‐HMGCR‐positive patients had only partial responses to multiple immunosuppressive medications, and their disease often took a chronic course. The DRB1*07:01 allele was present in all 5 patients, compared to 26.25% of healthy controls (corrected P = 0.01); none of the 5 juvenile patients had DRB1*11:01.
Conclusion
Compared to children with other MSAs, muscle disease appears to be more severe in those with anti‐HMGCR autoantibodies. Like adults, children with anti‐HMGCR autoantibodies have severe weakness and high CK levels. In contrast to adults, in anti‐HMGCR‐positive children, there is a strong association with HLA–DRB1*07:01.
In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of ...suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine.
In the past two decades, the Argo Program has collected, processed and distributed over two million vertical profiles of temperature and salinity from the upper two kilometers of the global ocean. A ...similar number of subsurface velocity observations near 1000 dbar have also been collected. This paper recounts the history of the global Argo Program, from its aspiration arising out of the World Ocean Circulation Experiment, to the development and implementation of its instrumentation and telecommunication systems, and the various technical problems encountered. We describe the Argo data system and its quality control procedures, and the gradual changes in the vertical resolution and spatial coverage of Argo data from 1999 to 2019. The accuracies of the float data have been assessed by comparison with high-quality shipboard measurements, and are concluded to be 0.002°C for temperature, 2.4 dbar for pressure, and 0.01 PSS-78 for salinity, after delayed-mode adjustments. Finally, the challenges faced by the vision of an expanding Argo Program beyond 2020 are discussed.
BackgroundCoronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not ...participate in a randomised trial of invasive versus non-invasive management (CABG-ACS).MethodsACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated.ResultsOf 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)).Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty.At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558–841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year.ConclusionsCompared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar.Trial registration number NCT01895751.
Background:
Jones fractures result in subsequent dysfunction and remain an issue for athletes.
Purpose:
To (1) describe the epidemiology, treatment, and impact of Jones fractures identified at the ...National Football League (NFL) Scouting Combine on players’ early careers and (2) establish the value of computed tomography (CT) to determine bony healing after a fracture in prospective players.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
All players who attended the combine between 2009 and 2015 were retrospectively reviewed to identify their history of Jones fractures. The playing position, treatment method, and number of missed collegiate games were recorded. The mean overall draft pick number, number of games started and played, snap percentage, and position-specific performance scores (fantasy score) over the first 2 years in the NFL were compared between players with fractures and controls. An imaging classification system was applied based on grading of each quadrant of the fifth metatarsal (plantar, dorsal, medial, lateral), with a score of 0 for not healed or 1 for healed.
Results:
Overall, the number of Jones fractures identified was 72 in 2285 athletes (3.2%), with all treated via intramedullary screw fixation. The mean overall draft pick number for players with fractures was 111.2 ± 67.9 compared with 99.0 ± 65.9 for controls (P = .12). Performance scores for players with fractures were lower than those for controls across all positions, with a significant difference in running backs (2.6 vs 4.0, respectively; P < .001) and defensive linemen (1.4 vs 2.3, respectively; P = .02). The mean CT score was 2.5 ± 1.3. Of the 32 athletes who underwent imaging, 16 Jones fractures (50.0%) were healed or nearly healed, 12 (37.5%) were partially healed, and 4 (12.5%) showed little or no healing. The plantar cortex demonstrated the least healing (18/32; 56.3%), followed by the lateral cortex (15/32; 46.9%). Players with a mean score <1 were found to have fewer games started (2.7 ± 2.5) than those with 1 to 3 cortices healed (17.4 ± 10.4) or all cortices healed (8.7 ± 11.2).
Conclusion:
Based on CT, 50% of all players with a previous Jones fracture demonstrated incomplete healing. Moreover, position-specific performance scores over the first 2 years of a player’s career were lower across all positions for those with fractures compared with controls. Players with CT scores <1 were found to start fewer games and were drafted later than controls.
BackgroundHypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well ...understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility.HypothesisIn this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes.Methods and ResultsUsing standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of Vmax. Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes.ConclusionTogether, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.
IntroductionThe strongest genetic risk factor for atrial fibrillation (AF) is variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene Pitx2. Mice deficient in Pitx2 ...(Pitx2) have increased AF susceptibility, although the mechanism(s) remains controversial. Recent evidence indicates that with cardiac injury, Pitx2 encodes an antioxidant gene program that promotes repair. Isolevuglandins (IsoLGs) are highly reactive lipid peroxidation products that mediate a major component of oxidative stress-related injury. We used a small molecule scavenger of IsoLGs to test the hypothesis that oxidative stress is enhanced in the setting of Pitx2 deficiency to cause AF susceptibility.MethodsPitx2 and Pitx2 (wild type littermate control) mice were treated orally with either vehicle or the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) starting at weaning. At age 16-18 weeks, animals underwent transesophageal atrial pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation.ResultsPitx2 mice demonstrated a significant increase in inducible AF burden compared to control mice (242.9±105.3 vs 23.6±11 sec; n=7, 14; P<0.05). There was also a trend for an increased incidence of sustained AF (71.4% vs 21.4; P=0.055). Flow cytometry revealed that there was no increase in the number of total leukocytes in the atria of Pitx2 mice compared to control atria, nor were differences present in selected populations of immune cells (including CD3, CD19, NK1.1, F4/80, Ly6G, or CD11b/MHCII positive cells). For Pitx2 mice treated with 2-HOBA, there was trend for a reduction in AF burden (39.6±14.4 sec; n=11; P=0.075) as well as sustained AF (27.2%), while the drug had no effect in control mice. Based on cardiac histology (n=5, 5) and echocardiography (n=11, 14), no major histologic, structural, or functional abnormalities were identified in Pitx2 mice.ConclusionsThe reduction in AF burden by the IsoLG scavenger 2-HOBA supports the hypothesis that enhanced oxidative stress is responsible for AF susceptibility in the setting of Pitx2 deficiency. These results suggest a potential role for genotype-specific AF therapy (in 4q25 variant carriers) using IsoLG scavengers.
Following activation by cognate antigen, B cells undergo fine-tuning of their antigen receptors and may ultimately differentiate into antibody-secreting cells (ASCs). While antigen-specific B cells ...that express surface receptors (B cell receptors BCRs) can be readily cloned and sequenced following flow sorting, antigen-specific ASCs that lack surface BCRs cannot be easily profiled. Here, we report an approach, TRAPnSeq (antigen specificity mapping through immunoglobulin Ig secretion TRAP and Sequencing), that allows capture of secreted antibodies on the surface of ASCs, which in turn enables high-throughput screening of single ASCs against large antigen panels. This approach incorporates flow cytometry, standard microfluidic platforms, and DNA-barcoding technologies to characterize antigen-specific ASCs through single-cell V(D)J, RNA, and antigen barcode sequencing. We show the utility of TRAPnSeq by profiling antigen-specific IgG and IgE ASCs from both mice and humans and highlight its capacity to accelerate therapeutic antibody discovery from ASCs.
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•TRAPnSeq allows antigen specificity mapping through Ig secretion TRAP and Sequencing•High-throughput profiling of ASCs based on local antibody capture•TRAPnSeq enables rapid antibody discovery from ASCs and elucidates Ag+ ASC biology
Emerging techniques have enabled high-throughput profiling of antigen-specific (Ag+) B cells, which has expanded our understanding of the B cell repertoire. A key limitation of existing platforms is profiling of Ag+ antibody-secreting cells (ASCs) that downregulate their surface BCRs. TRAPnSeq improves on this limitation by incorporating an antibody secretion trap that captures secreted antibodies on the surface of ASCs, which in turn enables rapid and high-throughput profiling of Ag+ ASCs.
Asrat et al. develop a method, TRAPnSeq, that enables specific isolation and profiling of antigen-specific (Ag+) antibody-secreting cells. They show the utility of TRAPnSeq in mice and humans by performing high-throughput analysis of Ag+ IgG and IgE plasma cells.
Retention in HIV pre-exposure prophylaxis (PrEP) care is critical for effective PrEP implementation. Few studies have reported long-term lost to follow-up (LTFU) and re-engagement in PrEP care in the ...United States. Medical record data for all cisgender patients presenting to the major Rhode Island PrEP clinic from 2013 to 2019 were included. LTFU was defined as no PrEP follow-up appointment within 98 days. Re-engagement in care was defined as individuals who were ever LTFU and later attended a follow-up appointment. Recurrent event survival analysis was performed to explore factors associated with PrEP retention over time. Of 654 PrEP patients, the median age was 31 years old interquartile range (IQR): 25, 43. The majority were male (96%), White (64%), non-Hispanic (82%), and insured (97%). Overall, 72% patients were ever LTFU and 27% of those ever LTFU re-engaged in care. Female patients were 1.37 times crude hazard ratio (cHR): 1.37; 95% confidence interval (CI): 0.86-2.18 more likely to be LTFU than male patients, and a 1-year increase in age was associated with a 1% lower hazard of being LTFU (cHR: 0.99; CI: 0.98-0.99). Being either heterosexual (aHR: 2.25, 95% (CI): 1.70-2.99 or bisexual (aHR: 2.35, 95% CI: 1.15-4.82) was associated with a higher hazard of loss to follow-up compared with having same-sex partners only. The majority of PrEP users were LTFU, especially at the first 6 months of PrEP initiation. Although a significant number were re-engaged in care, targeted interventions are needed to improve retention in PrEP care. This study characterized the natural projection of loss to follow-up and re-engagement in HIV PrEP care using a longitudinal clinic cohort data and explored associated factors for guiding future interventions to improve retention in PrEP care.
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