A Population-Based Surveillance Study of Shared Genotypes of Escherichia coli Isolates from Retail Meat and Suspected Cases of Urinary Tract Infections.

There is increasing evidence that retail food may serve as a source of Escherichia coli that causes community-acquired urinary tract infections, but the impact of this source in a community is not known. We conducted a prospective, population-based study in one community to examine the frequency of recovery of uropathogenic E. coli genotypes from retail meat samples. We analyzed E. coli isolates from consecutively collected urine samples of patients suspected to have urinary tract infections (UTIs) at a university-affiliated health service and retail meat samples from the same geographic region. We genotyped all E. coli isolates by multilocus sequence typing (MLST) and tested them for antimicrobial susceptibility. From 2016 to 2017, we cultured 233 E. coli isolates from 230 (21%) of 1,087 urine samples and 177 E. coli isolates from 120 (28%) of 427 retail meat samples. Urine samples contained 61 sequence types (STs), and meat samples had 95 STs; 12 STs (ST10, ST38, ST69, ST80, ST88, ST101, ST117, ST131, ST569, ST906, ST1844, and ST2562) were common to both. Thirty-five (81%) of 43 meat isolates among the 12 STs were from poultry. Among 94 isolates in the 12 STs, 26 (60%) of 43 retail meat isolates and 15 (29%) of 51 human isolates were pan-susceptible (P < 0.005). We found that 21% of E. coli isolates from suspected cases of UTIs belonged to STs found in poultry. Poultry may serve as a possible reservoir of uropathogenic E. coli (UPEC). Additional studies are needed to demonstrate transmission pathways of these UPEC genotypes and their food sources.IMPORTANCE Community-acquired urinary tract infection caused by Escherichia coli is one of the most common infectious diseases in the United States, affecting approximately seven million women and costing approximately 11.6 billion dollars annually. In addition, antibiotic resistance among E. coli bacteria causing urinary tract infection continues to increase, which greatly complicates treatment. Identifying sources of uropathogenic E. coli and implementing prevention measures are essential. However, the reservoirs of uropathogenic E. coli have not been well defined. This study demonstrated that poultry sold in retail stores may serve as one possible source of uropathogenic E. coli This finding adds to a growing body of evidence that suggests that urinary tract infection may be a food-borne disease. More research in this area can lead to the development of preventive strategies to control this common and costly infectious disease

A Population-Based Surveillance Study of Shared Genotypes of Escherichia coli Isolates from Retail Meat and Suspected Cases of Urinary Tract Infections.

There is increasing evidence that retail food may serve as a source of Escherichia coli that causes community-acquired urinary tract infections, but the impact of this source in a community is not known. We conducted a prospective, population-based study in one community to examine the frequency of recovery of uropathogenic E. coli genotypes from retail meat samples. We analyzed E. coli isolates from consecutively collected urine samples of patients suspected to have urinary tract infections (UTIs) at a university-affiliated health service and retail meat samples from the same geographic region. We genotyped all E. coli isolates by multilocus sequence typing (MLST) and tested them for antimicrobial susceptibility. From 2016 to 2017, we cultured 233 E. coli isolates from 230 (21%) of 1,087 urine samples and 177 E. coli isolates from 120 (28%) of 427 retail meat samples. Urine samples contained 61 sequence types (STs), and meat samples had 95 STs; 12 STs (ST10, ST38, ST69, ST80, ST88, ST101, ST117, ST131, ST569, ST906, ST1844, and ST2562) were common to both. Thirty-five (81%) of 43 meat isolates among the 12 STs were from poultry. Among 94 isolates in the 12 STs, 26 (60%) of 43 retail meat isolates and 15 (29%) of 51 human isolates were pan-susceptible (P < 0.005). We found that 21% of E. coli isolates from suspected cases of UTIs belonged to STs found in poultry. Poultry may serve as a possible reservoir of uropathogenic E. coli (UPEC). Additional studies are needed to demonstrate transmission pathways of these UPEC genotypes and their food sources.IMPORTANCE Community-acquired urinary tract infection caused by Escherichia coli is one of the most common infectious diseases in the United States, affecting approximately seven million women and costing approximately 11.6 billion dollars annually. In addition, antibiotic resistance among E. coli bacteria causing urinary tract infection continues to increase, which greatly complicates treatment. Identifying sources of uropathogenic E. coli and implementing prevention measures are essential. However, the reservoirs of uropathogenic E. coli have not been well defined. This study demonstrated that poultry sold in retail stores may serve as one possible source of uropathogenic E. coli This finding adds to a growing body of evidence that suggests that urinary tract infection may be a food-borne disease. More research in this area can lead to the development of preventive strategies to control this common and costly infectious disease

Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome

BACKGROUND: Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome. OBJECTIVE: We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder. METHODS: We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages. RESULTS: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor-dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively. CONCLUSION: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome.status: publishe

Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome.

BACKGROUND: Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome. OBJECTIVE: We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder. METHODS: We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages. RESULTS: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor-dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively. CONCLUSION: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease