Background Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. Methods In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d -dimer level. Results The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d -dimer cohort, 92.9% in the low d -dimer cohort, and 97.3% in the unknown d -dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589 , NCT04505774 , NCT04359277 , and NCT02735707 .)

Hereditary xerocytosis (HX, MIM 194380)is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis. IntroductionHereditary xerocytosis (also known as HX or dehydrated stomatocytosis, DHSt; OMIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. 1 HX erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. HX patients typically exhibit mild to moderate, compensated hemolytic anemia. Erythrocyte mean corpuscular hemoglobin concentration is increased and erythrocyte osmotic fragility is decreased, both reflecting cellular dehydration.A locus for HX on chromosome 16 (16q23-q24) was first identified in a large, 3-generation Irish family. 2 This locus was refined to D16S511-16qter via study of 10 kindreds with variants of HX, pseudohyperkalemia, or nonimmune hydrops fetalis. 3,4 Recent studies of one of the original HX families from Rochester, NY, 5 and of a large HX family from Manitoba, Canada 6 confirmed the linkage of the disease phenotype to chromosome 16q, and refined the candidate region to 16q24.2-16qter, a 2.4 million-bp interval containing 51 known or predicted genes. 6 To identify the HXassociated genetic locus, we performed high-resolution single nucleotide polymorphism (SNP) typing and whole-exome sequencing on selected persons from both the New York and Canadian HX kindreds.In the refined candidate region, no regions of copy number variation were detected at 16q24.2-16qter. A large region of homozygosity was detected in this region in DNA from a presumed homozygote from the New York kindred. Exome sequencing identified novel mutations affecting PIEZO1 (encoded by the FAM38A gene) in both HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all...

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The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

IntroductionSepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis.MethodsWe searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model.ResultsOf 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n = 128) and the mean age of children ranged from 0.9 to 18 years (n = 66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I2 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I2 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I2 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma.ConclusionsInsufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient-centered outcomes are required to evaluate the impact of plasma exchange in this condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0699-2) contains supplementary material, which is available to authorized users.

positive airway pressure. The mean airway pressure during HFOV has to be kept high to prevent loss of lung volume. The high pressure may induce overinflation of the lungs and thus augment lung injury. This constant high airway pressure may interfere with cardiovascular function to a greater extent than does conventional ventilation. Finally, HFOV uses active expiration owing to the movement of the diaphragm of the ventilator, and whether this aspect of ventilation has any effect on the adult lung remains unclear.Before we commit HFOV to history, however, we must remember that there are alternative modes of high-frequency ventilation that should be studied. The 2 other modes of highfrequency ventilation are intrapulmonary percussive ventilation and high-frequency jet ventilation. These modes have been used by limited groups of practitioners for several decades now, with good results that were limited, however, by poorly designed studies. Both of these methods use a very brief, high-pressure inspiration and rely on the Venturi effect to augment the tidal volume. Inspiration is followed by a passive expiratory phase. They can be superimposed upon other ventilators with low-rate, low-volume ventilation and therefore involve lower mean airway pressure. Both of these methods do not interfere with spontaneous ventilation, so paralysis is not obligatory.Even if these methods are beneficial, I am afraid such alternative methods of ventilation will not be shown to reduce mortality in ARDS. This is because ARDS is not a disease only of the lung, but is actually a component of a general condition. Therefore, the hope to find a Bcure[ for ARDS by changing the ventilator settings alone appears unrealistic. Future studies into the efficacy of different modes of ventilation in ARDS will play an important role after we understand, and learn to modulate, the systemic response that is manifested as ARDS.

ObjectiveIron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults.DesignSystematic review and meta-analysis of randomised controlled trials (RCTs).SettingPrimary care.ParticipantsAdults (≥18 years) who were iron deficient but non-anaemic.InterventionsOral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included.ComparatorsPlacebo or active therapy.ResultsWe identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI −0.15 to 0.37; I2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I2 58%; 14 trials; 616 participants).ConclusionIn IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia.PROSPERO registration number CRD42014007085.