Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Search for gravitational waves associated with the August 2006 timing glitch of the Vela pulsar

The physical mechanisms responsible for pulsar timing glitches are thought to excite quasinormal mode oscillations in their parent neutron star that couple to gravitational-wave emission. In August 2006, a timing glitch was observed in the radio emission of PSR B0833-45, the Vela pulsar. At the time of the glitch, the two colocated Hanford gravitational-wave detectors of the Laser Interferometer Gravitational-wave observatory (LIGO) were operational and taking data as part of the fifth LIGO science run (S5). We present the first direct search for the gravitational-wave emission associated with oscillations of the fundamental quadrupole mode excited by a pulsar timing glitch. No gravitational-wave detection candidate was found. We place Bayesian 90% confidence upper limits of 6.3×10-21 to 1.4×10-20 on the peak intrinsic strain amplitude of gravitational-wave ring-down signals, depending on which spherical harmonic mode is excited. The corresponding range of energy upper limits is 5.0×1044 to 1.3×1045 erg

Emergency Department Pediatric Readiness and Short-term and Long-term Mortality Among Children Receiving Emergency Care

ImportanceEmergency departments (EDs) with high pediatric readiness (coordination, personnel, quality improvement, safety, policies, and equipment) are associated with lower mortality among children with critical illness and those admitted to trauma centers, but the benefit among children with more diverse clinical conditions is unknown.ObjectiveTo evaluate the association between ED pediatric readiness, in-hospital mortality, and 1-year mortality among injured and medically ill children receiving emergency care in 11 states.Design, Setting, and ParticipantsThis is a retrospective cohort study of children receiving emergency care at 983 EDs in 11 states from January 1, 2012, through December 31, 2017, with follow-up for a subset of children through December 31, 2018. Participants included children younger than 18 years admitted, transferred to another hospital, or dying in the ED, stratified by injury vs medical conditions. Data analysis was performed from November 1, 2021, through June 30, 2022.ExposureED pediatric readiness of the initial ED, measured through the weighted Pediatric Readiness Score (wPRS; range, 0-100) from the 2013 National Pediatric Readiness Project assessment.Main Outcomes and MeasuresThe primary outcome was in-hospital mortality, with a secondary outcome of time to death to 1 year among children in 6 states.ResultsThere were 796 937 children, including 90 963 (11.4%) in the injury cohort (mean [SD] age, 9.3 [5.8] years; median [IQR] age, 10 [4-15] years; 33 516 [36.8%] female; 1820 [2.0%] deaths) and 705 974 (88.6%) in the medical cohort (mean [SD] age, 5.8 [6.1] years; median [IQR] age, 3 [0-12] years; 329 829 [46.7%] female, 7688 [1.1%] deaths). Among the 983 EDs, the median (IQR) wPRS was 73 (59-87). Compared with EDs in the lowest quartile of ED readiness (quartile 1, wPRS of 0-58), initial care in a quartile 4 ED (wPRS of 88-100) was associated with 60% lower in-hospital mortality among injured children (adjusted odds ratio, 0.40; 95% CI, 0.26-0.60) and 76% lower mortality among medical children (adjusted odds ratio, 0.24; 95% CI, 0.17-0.34). Among 545 921 children followed to 1 year, the adjusted hazard ratio of death in quartile 4 EDs was 0.59 (95% CI, 0.42-0.84) for injured children and 0.34 (95% CI, 0.25-0.45) for medical children. If all EDs were in the highest quartile of pediatric readiness, an estimated 288 injury deaths (95% CI, 281-297 injury deaths) and 1154 medical deaths (95% CI, 1150-1159 medical deaths) may have been prevented.Conclusions and RelevanceThese findings suggest that children with injuries and medical conditions treated in EDs with high pediatric readiness had lower mortality during hospitalization and to 1 year.</jats:sec

A multisystem, cardio-renal investigation of post-COVID-19 illness

AbstractThe pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov IDNCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (allP &lt; 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.</jats:sec