Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease

An appraisal of respiratory system compliance in mechanically ventilated covid-19 patients

BackgroundHeterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.MethodsWe designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe CRS—calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]—and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.ResultsWe studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Median (IQR) age was 62 (52–71), patients were predominantly males (68%) and from Europe/North and South America (88%). CRS, within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV (p = 0.417) nor with PaO2/FiO2 (p = 0.100). Females presented lower CRS than males (95% CI of CRS difference between females-males: − 11.8 to − 7.4 mL/cmH2O p RS was marginal (p = 0.139). Ventilatory management varied across CRS range, resulting in a significant association between CRS and driving pressure (estimated decrease − 0.31 cmH2O/L per mL/cmH20 of CRS, 95% CI − 0.48 to − 0.14, p RS (+ 10 mL/cm H2O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02–1.28, p = 0.018).ConclusionsThis multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV. CRS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at https://www.covid-critical.com/study.Trial registration: ACTRN12620000421932

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS : a propensity score analysis

Background: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. Methods: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Results: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). Conclusions: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.</p

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p

Global Incidence and Risk Factors Associated With Postoperative Urinary Retention Following Elective Inguinal Hernia Repair

Importance Postoperative urinary retention (POUR) is a well-recognized complication of inguinal hernia repair (IHR). A variable incidence of POUR has previously been reported in this context, and contradictory evidence surrounds potential risk factors.Objective To ascertain the incidence of, explore risk factors for, and determine the health service outcomes of POUR following elective IHR.Design, Setting, and Participants The Retention of Urine After Inguinal Hernia Elective Repair (RETAINER I) study, an international, prospective cohort study, recruited participants between March 1 and October 31, 2021. This study was conducted across 209 centers in 32 countries in a consecutive sample of adult patients undergoing elective IHR.Exposure Open or minimally invasive IHR by any surgical technique, under local, neuraxial regional, or general anesthesia.Main Outcomes and Measures The primary outcome was the incidence of POUR following elective IHR. Secondary outcomes were perioperative risk factors, management, clinical consequences, and health service outcomes of POUR. A preoperative International Prostate Symptom Score was measured in male patients.Results In total, 4151 patients (3882 male and 269 female; median [IQR] age, 56 [43-68] years) were studied. Inguinal hernia repair was commenced via an open surgical approach in 82.2% of patients (n = 3414) and minimally invasive surgery in 17.8% (n = 737). The primary form of anesthesia was general in 40.9% of patients (n = 1696), neuraxial regional in 45.8% (n = 1902), and local in 10.7% (n = 446). Postoperative urinary retention occurred in 5.8% of male patients (n = 224), 2.97% of female patients (n = 8), and 9.5% (119 of 1252) of male patients aged 65 years or older. Risk factors for POUR after adjusted analyses included increasing age, anticholinergic medication, history of urinary retention, constipation, out-of-hours surgery, involvement of urinary bladder within the hernia, temporary intraoperative urethral catheterization, and increasing operative duration. Postoperative urinary retention was the primary reason for 27.8% of unplanned day-case surgery admissions (n = 74) and 51.8% of 30-day readmissions (n = 72).Conclusions The findings of this cohort study suggest that 1 in 17 male patients, 1 in 11 male patients aged 65 years or older, and 1 in 34 female patients may develop POUR following IHR. These findings could inform preoperative patient counseling. In addition, awareness of modifiable risk factors may help to identify patients at increased risk of POUR who may benefit from perioperative risk mitigation strategies

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo