Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or ...side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.
Although most critically ill patients receive invasive mechanical ventilation (IMV), few studies have characterized how IMV is discontinued in practice.
To describe practice variation in IMV ...discontinuation internationally, associations between initial discontinuation events and outcomes, and factors associated with the use of select discontinuation strategies and failed initial spontaneous breathing trials (SBTs).
Prospective, multinational, observational study of critically ill adults who received IMV for at least 24 hours from 142 intensive care units (ICUs) in 19 countries within 6 regions (27 in Canada, 23 in India, 22 in the UK, 26 in Europe, 21 in Australia/New Zealand, and 23 in the US).
Receiving IMV.
Primary analyses characterized types of initial IMV discontinuation events (extubation, SBT, or tracheostomy) and associations with clinical outcomes (including duration of ventilation, ICU and hospital mortality, and ICU and hospital length of stay). Secondary analyses examined the associations between SBT outcome and SBT timing and clinical outcomes.
Among 1868 patients (median interquartile range age, 61.8 48.9-73.1 years; 1173 62.8% men) 424 (22.7%) underwent direct extubation, 930 (49.8%) had an initial SBT (761 81.8% successful), 150 (8.0%) underwent direct tracheostomy, and 364 (19.5%) died before a weaning attempt. Across regions, there was variation in the use of written directives to guide care, daily screening, SBT techniques, ventilator modes, and the roles played by clinicians involved in weaning. Compared with initial direct extubation, patients who had an initial SBT had higher ICU mortality (20 4.7% vs 96 10.3%; absolute difference, 5.6% 95% CI, 2.6%-8.6%), longer duration of ventilation (median of 2.9 vs 4.1 days; absolute difference, 1.2 days 95% CI, 0.7-1.6), and longer ICU stay (median of 6.7 vs 8.1 days; absolute difference, 1.4 days 95% CI, 0.8-2.4). Patients whose initial SBT failed (vs passed) had higher ICU mortality (29 17.2% vs 67 8.8%; absolute difference, 8.4% 95% CI, 2.0%-14.7%), longer duration of ventilation (median of 6.1 vs 3.5 days; absolute difference, 2.6 days 95% CI, 1.6-3.6), and longer ICU stay (median of 10.6 vs 7.7 days; absolute difference, 2.8 days 95% CI, 1.1-5.2). Compared with patients who underwent early initial SBTs, patients who underwent late initial SBTs (>2.3 days after intubation) had longer duration of ventilation (median of 2.1 vs 6.1 days; absolute difference, 4.0 days 95% CI, 3.7-4.5), longer ICU stay (median of 5.9 vs 10.8 days; absolute difference, 4.9 days 95% CI, 4.0-6.3), and longer hospital stay (median of 14.3 vs 22.8 days; absolute difference, 8.5 days 95% CI, 6.0-11.0).
In this observational study of invasive mechanical ventilation discontinuation in 142 ICUs in Canada, India, the UK, Europe, Australia/New Zealand, and the US from 2013 to 2016, weaning practices varied internationally.
ClinicalTrials.gov Identifier: NCT03955874.
Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ ...dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons.
Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013-2014.
None.
Sepsis was defined using electronic health record-derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals' claims data was low and variable: median 30% (range, 5-54%) for sepsis, 66% (range, 26-84%) for acute kidney injury, 39% (range, 16-60%) for thrombocytopenia, 36% (range, 29-44%) for hepatic injury, and 66% (range, 29-84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data.
Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals' sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.
Solid organ transplant recipients are at an increased risk of tuberculosis and transplant candidates should be screened early in their evaluation with a detailed history, tuberculin skin test or ...tuberculosis interferon-gamma release assay, and chest radiograph. For latent tuberculosis treatment, isoniazid and rifamycin-based regimens have advantages and disadvantages; treatment decisions should be customized. Tuberculosis after solid organ transplantation generally occurs after months or years; early infections should raise the possibility of donor-derived infections. Tuberculosis diagnosis and treatment in solid organ transplant recipients may be complicated by protean manifestations, drug interactions, and adverse drug reactions.
Abstract
Motivation
There is widespread interest in identifying genetic variants that exhibit parent-of-origin effects (POEs) wherein the effect of an allele on phenotype expression depends on its ...parental origin. POEs can arise from different phenomena including genomic imprinting and have been documented for many complex traits. Traditional tests for POEs require family data to determine parental origins of transmitted alleles. As most genome-wide association studies (GWAS) sample unrelated individuals (where allelic parental origin is unknown), the study of POEs in such datasets requires sophisticated statistical methods that exploit genetic patterns we anticipate observing when POEs exist. We propose a method to improve discovery of POE variants in large-scale GWAS samples that leverages potential pleiotropy among multiple correlated traits often collected in such studies. Our method compares the phenotypic covariance matrix of heterozygotes to homozygotes based on a Robust Omnibus Test. We refer to our method as the Parent of Origin Inference using Robust Omnibus Test (POIROT) of multiple quantitative traits.
Results
Through simulation studies, we compared POIROT to a competing univariate variance-based method which considers separate analysis of each phenotype. We observed POIROT to be well-calibrated with improved power to detect POEs compared to univariate methods. POIROT is robust to non-normality of phenotypes and can adjust for population stratification and other confounders. Finally, we applied POIROT to GWAS data from the UK Biobank using BMI and two cholesterol phenotypes. We identified 338 genome-wide significant loci for follow-up investigation.
Availability and implementation
The code for this method is available at https://github.com/staylorhead/POIROT-POE.
HHV‐6 and septic shock: Tenuous proof of causation Epstein, David J.; Tan, Susanna K.; Deresinski, Stan
American journal of transplantation,
January 2019, 2019-01-00, 20190101, Volume:
19, Issue:
1
Journal Article
Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; ...however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.
The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a ...new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit ).
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