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Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Obesity is increasingly prevalent among candidates for kidney transplantation. Existing studies have shown conflicting post-transplant outcomes for obese patients which may relate to confounding bias from donor-related characteristics that were unaccounted for. We used ANZDATA Registry data to compare graft and patient survival between obese (BMI >27.5 kg/m 2 Asians; >30 kg/m 2 non-Asians) and non-obese kidney transplant recipients, while controlling for donor characteristics by comparing recipients of paired kidneys. We selected transplant pairs (2000–2020) where a deceased donor supplied one kidney to an obese candidate and the other to a non-obese candidate. We compared the incidence of delayed graft function (DGF), graft failure and death by multivariable models. We identified 1,522 pairs. Obesity was associated with an increased risk of DGF (aRR = 1.26, 95% CI 1.11–1.44, p < 0.001). Obese recipients were more likely to experience death-censored graft failure (aHR = 1.25, 95% CI 1.05–1.49, p = 0.012), and more likely to die with function (aHR = 1.32, 95% CI 1.15–1.56, p = 0.001), versus non-obese recipients. Long-term patient survival was significantly worse in obese patients with 10- and 15-year survival of 71% and 56% compared to 77% and 63% in non-obese patients. Addressing obesity is an unmet clinical need in kidney transplantation.

Blastomycosis is a rare, potentially fatal fungal infection caused by inhalation of Blastomyces spores, typically acquired outdoors in the midwestern and eastern United States. In 2023, the largest recorded U.S. blastomycosis outbreak occurred among workers at a paper mill in Michigan's Upper Peninsula. Few data exist on occupational risk factors or indoor exposure to Blastomyces, limiting prevention efforts. We assessed workplace environments and conditions associated with blastomycosis risk through a cross-sectional medical survey and environmental sampling. During April 22-28, 2023, we conducted a voluntary medical survey, including a work and health questionnaire and urine antigen testing, for 603 workers out of approximately 1,000 at the mill. We compared worker characteristics, work locations, and environmental exposures by blastomycosis case status and modeled disease risk using Poisson regression. We tested 533 environmental samples of outdoor soil, indoor surface dust, and raw materials for Blastomyces using polymerase chain reaction and culture-based methods. Twenty percent of workers were classified as blastomycosis cases based on positive urine antigen testing during the survey, self-reported provider diagnoses, or confirmed or probable case status reported by state or local health departments. Prevalence was highest among workers in paper machine line #1 (27%) and maintenance areas (25%). Adjusted analyses indicated a 40% [Prevalence Ratio (PR): 1.40; 95% confidence interval (CI): 1.00, 1.95] and 53% (PR: 1.53; 95% CI: 1.04, 2.25) higher risk for workers in these locations, respectively, compared to workers working elsewhere. Working in both locations doubled blastomycosis risk. Daily exposure to indoor pooling water was associated with a nearly two-fold higher prevalence of blastomycosis (PR: 1.79; 95% CI: 1.25, 2.57). All indoor and outdoor environmental samples were negative for Blastomyces. Blastomycosis was associated with specific indoor work locations and environmental conditions, suggesting the potential for occupational exposure to Blastomyces in indoor industrial settings. These findings may guide future outbreak investigations and occupational prevention strategies.

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the MD Anderson Symptom Inventory (the MDASI-PeriOp-BLC). The feasibility of collecting an objective measure for physical functioning, using “Timed Up & Go test” (TUGT) and PRO scores at baseline, discharge and end of study, was tested. Patients (n = 52) received care under an ERAS pathway. The more severe scores of fatigue, sleep disturbance, distress, drowsiness, frequent urination and urinary urgency at baseline predicted poor functional recovery postoperatively (OR = 1.661, 1.039–2.655, p = 0.034); other more severe symptoms at discharge (pain, fatigue, sleep disturbance, lack of appetite, drowsiness, bloating/abdominal tightness) predicted poor functional recovery (OR = 1.697, 1.114–2.584, p = 0.014) postoperatively. Compliance rates at preoperative, discharge and end of study were 100%, 79% and 77%, while TUGT completion rates were 88%, 54% and 13%, respectively. This prospective study found that more severe symptom burden at baseline and discharge is associated with poor functional recovery post-radical cystectomy for BLC. The collection of PROs is more feasible than using performance measures (TUGT) of function following radical cystectomy.

A bstract An inclusive search for long-lived exotic particles decaying to a pair of muons is presented. The search uses data collected by the CMS experiment at the CERN LHC in proton-proton collisions at s = 13 TeV in 2016 and 2018 and corresponding to an integrated luminosity of 97.6 fb − 1 . The experimental signature is a pair of oppositely charged muons originating from a common secondary vertex spatially separated from the pp interaction point by distances ranging from several hundred μ m to several meters. The results are interpreted in the frameworks of the hidden Abelian Higgs model, in which the Higgs boson decays to a pair of long-lived dark photons Z D , and of a simplified model, in which long-lived particles are produced in decays of an exotic heavy neutral scalar boson. For the hidden Abelian Higgs model with m (Z D ) greater than 20 GeV and less than half the mass of the Higgs boson, they provide the best limits to date on the branching fraction of the Higgs boson to dark photons for cτ (Z D ) (varying with m (Z D )) between 0.03 and ≈0 . 5 mm, and above ≈0 . 5 m. Our results also yield the best constraints on long-lived particles with masses larger than 10 GeV produced in decays of an exotic scalar boson heavier than the Higgs boson and decaying to a pair of muons.

This study evaluates the accuracy and transferability of Bayesian case detection systems (BCD) that use clinical notes from emergency department (ED) to detect influenza cases. A BCD uses natural language processing (NLP) to infer the presence or absence of clinical findings from ED notes, which are fed into a Bayesain network classifier (BN) to infer patients' diagnoses. We developed BCDs at the University of Pittsburgh Medical Center (BCDUPMC) and Intermountain Healthcare in Utah (BCDIH). At each site, we manually built a rule-based NLP and trained a Bayesain network classifier from over 40,000 ED encounters between Jan. 2008 and May. 2010 using feature selection, machine learning, and expert debiasing approach. Transferability of a BCD in this study may be impacted by seven factors: development (source) institution, development parser, application (target) institution, application parser, NLP transfer, BN transfer, and classification task. We employed an ANOVA analysis to study their impacts on BCD performance. Both BCDs discriminated well between influenza and non-influenza on local test cases (AUCs > 0.92). When tested for transferability using the other institution's cases, BCDUPMC discriminations declined minimally (AUC decreased from 0.95 to 0.94, p<0.01), and BCDIH discriminations declined more (from 0.93 to 0.87, p<0.0001). We attributed the BCDIH decline to the lower recall of the IH parser on UPMC notes. The ANOVA analysis showed five significant factors: development parser, application institution, application parser, BN transfer, and classification task. We demonstrated high influenza case detection performance in two large healthcare systems in two geographically separated regions, providing evidentiary support for the use of automated case detection from routinely collected electronic clinical notes in national influenza surveillance. The transferability could be improved by training Bayesian network classifier locally and increasing the accuracy of the NLP parser.

Background: Congenital heart disease (CHD) affecting the conotruncal region of the heart, occur in half of patients with 22q11.2 deletion syndrome. This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, mapped to the 22q11.2 region, encoding a T-box transcription factor, is one of the main genes for the etiology of the syndrome. We suggest that genetic modifiers of CHD in patients with 22q11.2 deletion syndrome may be in the TBX1 gene network. Methods: To identify genetic modifiers of 22q11.2 deletion syndrome, we analyzed whole genome sequence of subjects with 22q11.2DS, of which 456 were cases with conotruncal heart defects and 537 were controls with normal cardiac structures. We retained the most damaging rare coding variants and examined 19 functional gene sets for association that were weighted upon expression of genes in cardiac progenitor cells in mouse embryos identified by RNA-sequencing. Results: We identified rare damaging coding variants in chromatin regulatory genes as modifiers of conotruncal heart defects in 22q11.2DS. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2 deletion syndrome cases. Many of these genes were identified as risk factors for sporadic CHD in the general population increasing the likelihood that these genes are medically important contributors for CHD. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. Some of the genes identified, such as KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models, providing mechanistic validation of these genes found. Conclusions: Our findings indicate that disturbance of chromatin regulatory genes impact a TBX1 gene network serving as genetic modifiers of 22q11.2 deletion syndrome. Since some of these chromatin regulatory genes were found in individuals with sporadic CHD, we suggest that there are shared mechanisms involving the TBX1 gene network in the etiology of CHD. Competing Interest Statement Jacob A.S. Vorstman has served as a consultant for NoBias Therapeutics, Inc for the design of a medication trial for individuals with 22q11DS (unrelated to the content of this work). Michael J. Owen reports a research grant from Takeda Pharmaceuticals outside the scope of the current work.