Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

CD4 and CD8 T cell proliferation and differentiation in response to Listeria monocytogenes infection

Mounting evidence suggests that the mechanisms that regulate T cell proliferation, acquisition of effector function, and memory cell formation and maintenance are different for CD4 and CD8 T cells. We compared the proliferation of adoptively transferred TCR transgenic CD4 and CD8 T cells in response to Listeria monocytogenes (LM) infection and found that CD4 T cells undergo limited division, differentiation, and clonal expansion in comparison to CD8 T cells. To further investigate these differences, we developed an adoptive transfer system that enables the visualization of primary polyclonal T cell responses. Surprisingly, we observed a difference in the extent of division between transferred monoclonal CD4 T cells and polyclonal CD4 T cells in response to LM infection. Adoptively transferred TCR transgenic CD4 T cells divided a limited number of times in response to LM infection while transferred CD4 T cells from C57BL/6 mice divided extensively under the same infection conditions. Titration of transferred TCR transgenic CD4 T cells revealed that reducing the precursor frequency increased the mean number of divisions underwent by these cells and increased the percent of responding CD4 T cells that differentiated into effector CD4 T cells as determined by IFN-γ secretion. Moreover, the transfer of a low number of naive TCR transgenic CD4 T cells provided better protection against LM infection in the liver than the transfer of a large number of the same cells. In contrast, adoptively transferred TCR transgenic CD8 T cells and polyclonal CD8 T cells from C57BL/6 mice both divided and differentiated extensively following infection. Thus, clonal competition induced by abnormally high precursor frequencies limits the extent of division and differentiation of CD4 T cells more than CD8 T cells. These results also show that CD4 T cell division and differentiation is quite extensive in response to LM infection and that the adoptive transfer of TCR transgenic CD4 T cells may underestimate the extent of a natural CD4 T cell response. However, despite this robust response, our data indicates that CD4 T cells provide only limited protection against LM infection in comparison to CD8 T cells

CD4 and CD8 T cell proliferation and differentiation in response to Listeria monocytogenes infection

Mounting evidence suggests that the mechanisms that regulate T cell proliferation, acquisition of effector function, and memory cell formation and maintenance are different for CD4 and CD8 T cells. We compared the proliferation of adoptively transferred TCR transgenic CD4 and CD8 T cells in response to Listeria monocytogenes (LM) infection and found that CD4 T cells undergo limited division, differentiation, and clonal expansion in comparison to CD8 T cells. To further investigate these differences, we developed an adoptive transfer system that enables the visualization of primary polyclonal T cell responses. Surprisingly, we observed a difference in the extent of division between transferred monoclonal CD4 T cells and polyclonal CD4 T cells in response to LM infection. Adoptively transferred TCR transgenic CD4 T cells divided a limited number of times in response to LM infection while transferred CD4 T cells from C57BL/6 mice divided extensively under the same infection conditions. Titration of transferred TCR transgenic CD4 T cells revealed that reducing the precursor frequency increased the mean number of divisions underwent by these cells and increased the percent of responding CD4 T cells that differentiated into effector CD4 T cells as determined by IFN-γ secretion. Moreover, the transfer of a low number of naive TCR transgenic CD4 T cells provided better protection against LM infection in the liver than the transfer of a large number of the same cells. In contrast, adoptively transferred TCR transgenic CD8 T cells and polyclonal CD8 T cells from C57BL/6 mice both divided and differentiated extensively following infection. Thus, clonal competition induced by abnormally high precursor frequencies limits the extent of division and differentiation of CD4 T cells more than CD8 T cells. These results also show that CD4 T cell division and differentiation is quite extensive in response to LM infection and that the adoptive transfer of TCR transgenic CD4 T cells may underestimate the extent of a natural CD4 T cell response. However, despite this robust response, our data indicates that CD4 T cells provide only limited protection against LM infection in comparison to CD8 T cells

De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with “DA2A with severe neurological abnormalities” and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with “atypical” forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s

De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s)

Congenital titinopathy: Comprehensive characterisation and pathogenic insights

Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105–1124.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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