Summary 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 ...

This retrospective study describes the clinical course of 38 patients with idiopathic pulmonary fibrosis (IPF) admitted to the intensive care unit (ICU). There were 25 males and 13 females who were the mean age of 68.3 +/- 11.5 years. Twenty patients were on corticosteroids at the time of admission to the hospital, and 24 had been on home oxygen therapy. The most common reason for ICU admission was respiratory failure. The Acute Physiology and Chronic Health Evaluation III-predicted ICU and hospital mortality rates were 12% and 26%, whereas the actual ICU and hospital mortality rates were 45% and 61%, respectively. We did not find significant differences in pulmonary function or echocardiogram findings between survivors and nonsurvivors. Mechanical ventilation was used in 19 patients (50%). Sepsis developed in nine patients. Multiple organ failure developed in 14% of the survivors and in 43% of the nonsurvivors (p = 0.14). Ninety-two percent of the hospital survivors died at a median of 2 months after discharge. These findings suggest that patients with IPF admitted to the ICU have poor short- and long-term prognosis. Patients with IPF and their families should be informed about the overall outlook when they make decisions about life support and ICU care.

Pulmonary hypertension (PH) is associated with poor outcomes in the dialysis and general populations, but its effect in CKD is unclear. We evaluated the prevalence and predictors of PH measures and their associations with long-term clinical outcomes in patients with nondialysis-dependent CKD. Chronic Renal Insufficiency Cohort (CRIC) Study participants who had Doppler echocardiography performed were considered for inclusion. PH was defined as the presence of estimated pulmonary artery systolic pressure (PASP) .35 mmHg and/or tricuspid regurgitant velocity (TRV) .2.5 m/s. Associations between PH, PASP, and TRV and cardiovascular events, renal events, and all-cause mortality were examined using Cox proportional hazards models. Of 2959 eligible participants, 21% (n=625) had PH, with higher rates among those with lower levels of kidney function. In the multivariate model, older age, anemia, lower left ventricular ejection fraction, and presence of left ventricular hypertrophy were associated with greater odds of having PH. After adjusting for relevant confounding variables, PH was independently associated with higher risk for death (hazard ratio, 1.38; 95% confidence interval, 1.10 to 1.72) and cardiovascular events (hazard ratio, 1.23; 95% confidence interval, 1.00 to 1.52) but not renal events. Similarly, TRV and PASP were associated with death and cardiovascular events but not renal events. In this study of patients with CKD and preserved left ventricular systolic function, we report a high prevalence of PH. PH and higher TRV and PASP (echocardiographic measures of PH) are associated with adverse outcomes in CKD. Future studies may explain the mechanisms that underlie these findings.

No abstract

No abstract

ImportanceUse of non-invasive respiratory modalities in COVID-19 has the potential to reduce rates of intubation and mortality in severe disease however data regarding the use of high-flow nasal cannula (HFNC) in this population is limited.ObjectiveTo interrogate clinical and laboratory features of SARS-CoV-2 infection associated with high-flow failure.DesignWe conducted a retrospective cohort study to evaluate characteristics of high-flow therapy use early in the pandemic and interrogate factors associated with respiratory therapy failure.SettingMultisite single centre hospital system within the metropolitan Detroit region.ParticipantsPatients from within the Detroit Medical Center (n=104, 89% African American) who received HFNC therapy during a COVID-19 admission between March and May of 2020.Primary outcomeHFNC failure is defined as death or intubation while on therapy.ResultsTherapy failure occurred in 57% of the patient population, factors significantly associated with failure centred around markers of multiorgan failure including hepatic dysfunction/transaminitis (OR=6.1, 95% CI 1.9 to 19.4, p<0.01), kidney injury (OR=7.0, 95% CI 2.7 to 17.8, p<0.01) and coagulation dysfunction (OR=4.5, 95% CI 1.2 to 17.1, p=0.03). Conversely, comorbidities, admission characteristics, early oxygen requirements and evaluation just prior to HFNC therapy initiation were not significantly associated with success or failure of therapy.ConclusionsIn a population disproportionately affected by COVID-19, we present key indicators of likely HFNC failure and highlight a patient population in which aggressive monitoring and intervention are warranted.

OBJECTIVECritically ill patients with pulmonary hypertension (PH) pose additional challenges due to the existence of right ventricular (RV) dysfunction. The purpose of this study was to assess the impact of hemodynamic factors on the outcome.METHODSWe reviewed the records of patients with a diagnosis of PH admitted to the intensive care unit. In addition to evaluating traditional hemodynamic parameters, we defined severe PH as right atrial pressure >20 mmHg, mean pulmonary artery pressure >55 mmHg, or cardiac index (CI) <2 L/min/m2. We also defined the RV functional index (RFI) as pulmonary artery systolic pressure (PASP) adjusted for CI as PASP/CI; increasing values reflect RV dysfunction.RESULTSFifty-three patients (mean age 60 years, 72% women, 79% Blacks), were included in the study. Severe PH was present in 68% of patients who had higher Sequential Organ Failure Assessment (SOFA) score (6.8 ± 3.3 vs 3.8 ± 1.6; P = 0.001) and overall in-hospital mortality (36% vs 6%; P = 0.02) compared to nonsevere patients, although Acute Physiology and Chronic Health Evaluation (APACHE) II scores (19.9 ± 7.5 vs 18.5 ± 6.04; P = 0.52) were similar and sepsis was more frequent among nonsevere PH patients (31 vs 64%; P = 0.02). Severe PH (P = 0.04), lower mean arterial pressure (P = 0.04), and CI (P = 0.01); need for invasive ventilation (P = 0.02) and vasopressors (P = 0.03); and higher SOFA (P = 0.001), APACHE II (P = 0.03), pulmonary vascular resistance index (PVRI) (P = 0.01), and RFI (P = 0.004) were associated with increased mortality. In a multivariate model, SOFA [OR = 1.45, 95% confidence interval (C.I.) = 1.09–1.93; P = 0.01], PVRI (OR = 1.12, 95% C.I. = 1.02–1.24; P = 0.02), and increasing RFI (OR = 1.06, 95% C.I. = 1.01–1.11; P = 0.01) were independently associated with mortality.CONCLUSIONPH is an independent risk factor for mortality in critically ill patients. Composite factors rather than individual hemodynamic parameters are better predictors of outcome. Monitoring of RV function using composite hemodynamic factors resulting in specific interventions is likely to improve survival and needs to be studied further.

A practical IV insulin protocol that has been extensively tested is presented. The protocol has been implemented at multiple institutions indicating its ease of use and excellent results.