Strain-dependence of Te interstitial diffusion in CdTe.

While the dominant defects which control non-radiative recombination and long-range interstitial diffusion in CdTe correspond to Cd vacancies and Te anti-sites, the short-range diffusion of Te and Se interstitials between these defects is also of interest, since they both play a role in defect passivation. In addition, since CdTe thin films are typically polycrystalline and may also involve interfaces with materials with different lattice constants, the effects of strain are also of interest. Here we present the results of molecular dynamics (MD) simulations of Te interstitial diffusion in zincblende CdTe for values of the triaxial strain ranging from -2% (compressive) strain to +2.8% (tensile) strain. By carrying out MD simulations of Te interstitial diffusion over a range of temperatures, and then carrying out Arrhenius fits, we have determined the effective activation barrier E_a and prefactor D_0 for each value of the global strain. We find that both E_a and D_0 exhibit non-monotonic behavior, increasing with both compressive and tensile strain. We also present an analysis of the key diffusion pathways for 3 different values of the strain which explains the non-monotonic strain dependence obtained in our simulations. Our results also indicate that in each case, the diffusion of interstitial Te involves a variety of concerted events with a wide range of activation barriers. .

Determining value in the treatment of activated PI3Kδ syndrome in Spain: a multicriteria decision analysis from the perspective of key stakeholders.

Introduction: Activated phosphoinositide 3-kinase (PI3K)δ syndrome (APDS) is an ultra-rare inborn error of immunity (IEI) combining immunodeficiency and immune dysregulation. This study determined what represents value in APDS in Spain from a multidisciplinary perspective applying multicriteria decision analysis (MCDA) methodology. Methods: A multidisciplinary committee of nine experts scored the evidence matrix. A specific framework for orphan drug evaluation in Spain and the weights assigned by a panel of 98 evaluators and decision-makers was used. Re-evaluation of scores was performed. Results: APDS is considered a very severe disease with important unmet needs, including misdiagnosis and diagnostic delay. Current management is limited to treatment of symptoms with off-label use of therapies supported by limited evidence. Therapeutic benefit is partial, resulting in limited disease control. Haematopoietic stem cell transplantation (HSCT), the only potential curative alternative, is restricted to a reduced patient population and without evidence of long-term efficacy or safety. All options present a limited safety profile. Data on patients' quality of life are lacking. APDS is associated with high pharmacological, medical and indirect costs. Conclusions: APDS is considered a severe disease, with limited understanding by key stakeholders of how treatment success is assessed in clinical practice, the serious impact that has on patients and the associated high economic burden. This study brings to light how MCDA methodology could represent a useful tool to complement current clinical and decision-making methods used by APDS experts and evaluators.

Median Arcuate Ligament Syndrome (MALS) in Hepato-Pancreato-Biliary Surgery: A Narrative Review and Proposed Management Algorithm.

Median arcuate ligament syndrome (MALS) is an uncommon condition characterized by the compression of the celiac trunk by the median arcuate ligament. Due to the anatomical proximity to the foregut, MALS has significant implications in hepato-pancreato-biliary (HPB) surgery. It can pose complications in pancreatoduodenectomy and orthotopic liver transplantation, where the collateral arterial supply from the superior mesenteric artery is often disrupted. The estimated prevalence of MALS in HPB surgery is approximately 10%. Overall, there is consensus for a cautious approach to MALS when embarking on complex foregut surgery, with a low threshold for intraoperative median arcuate ligament release or hepatic artery reconstruction. The role of endovascular intervention in the management of MALS prior to HPB surgery continues to evolve, but more evidence is required to establish its efficacy. Recognizing the existing literature gap concerning optimal management in this population, we describe our tertiary center experience as a clinical algorithm to facilitate decision-making. Research question: What is the significance and management of median arcuate ligament syndrome in patients undergoing hepato-pancreato-biliary surgery?

Bi2Te3-Based Thermoelectric Modules for Efficient and Reliable Low-Grade Heat Recovery.

Bismuth-telluride-based alloy has long been considered as the most promising candidate for low-grade waste heat power generation. However, optimizing the thermoelectric performance of n-type Bi2Te3 is more challenging than that of p-type counterparts due to its greater sensitivity to texture, and thus limits the advancement of thermoelectric modules. Herein, the thermoelectric performance of n-type Bi2Te3 is enhanced by incorporating a small amount of CuGaTe2, resulting in a peak ZT of 1.25 and a distinguished average ZT of 1.02 (300-500 K). The decomposed Cu+ strengthens interlayer interaction, while Ga+ optimizes carrier concentration within an appropriate range. Simultaneously, the emerged numerous defects, such as small-angle grain boundaries, twin boundaries, and dislocations, significantly suppresses the lattice thermal conductivity. Based on the size optimization by finite element modelling, the constructed thermoelectric module yields a high conversion efficiency of 6.9% and output power density of 0.31 W cm-2 under a temperature gradient of 200 K. Even more crucially, the efficiency and output power little loss after subjecting the module to 40 thermal cycles lasting for 6 days. This study demonstrates the efficient and reliable Bi2Te3-based thermoelectric modules for broad applications in low-grade heat harvest.

Island density scaling in reversible submonolayer growth with attachment barriers.

Island nucleation and growth play an important role in thin-film growth. One quantity of particular interest is the exponent χ, which describes the dependence of the saturation island density N_{sat}∼(D_{h}/F)^{-χ} on the ratio D_{h}/F of the monomer hopping rate D_{h} to the deposition rate F. While standard rate equation (RE) theory predicts that χ=i/(i+2) (where i is the critical island size), more recently it has been predicted that in the presence of a strong barrier to the attachment of monomers to islands, a significantly larger value χ=2i/(i+3) may be observed. While this prediction has recently been tested using kinetic Monte Carlo simulations for the case of irreversible growth corresponding to i=1, it has not been tested for the case of reversible island growth corresponding to i>1. Here we present a mean-field self-consistent RE method which we have used to study the dependence of the effective value of χ on D_{h}/F and barrier-strength for i=1,2,3, and 6. Both the no-nucleation-barrier case in which there exists a barrier for monomers to attach to islands larger than the critical island size (but not to smaller islands) and the nucleation-barrier case in which there is a barrier for monomers to attach to islands of all sizes are studied. In all cases, we find that the existence of attachment barriers significantly increases the effective value of χ for a given barrier strength. In addition, for i=1 we find good agreement between our extrapolated asymptotic value of χ and the theoretical strong-barrier prediction both with and without a nucleation barrier. In contrast, for i>1 the value of χ is significantly larger in the presence of a nucleation barrier than in its absence. In particular, while an asymptotic analysis of our results for i>1 also leads to excellent agreement with the strong barrier prediction in the presence of a nucleation barrier, in the absence of a nucleation barrier the asymptotic values are significantly lower.

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.

Mortality and major postoperative complications within 1 year after vascular surgery: a prospective cohort study.

INTRODUCTION: Patients undergoing vascular procedures are prone to developing postoperative complications affecting their short­term mortality. Prospective reports describing the incidence of long­term complications after vascular surgery are lacking. OBJECTIVES: We aimed to describe the incidence of complications 1 year after vascular surgery and to evaluate an association between myocardial injury after noncardiac surgery (MINS) and 1­year mortality. PATIENTS AND METHODS: This is a substudy of a large prospective cohort study Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION). Recruitment took place in 28 centers across 14 countries from August 2007 to November 2013. We enrolled patients aged 45 years or older undergoing vascular surgery, receiving general or regional anesthesia, and hospitalized for at least 1 night postoperatively. Plasma cardiac troponin T concentration was measured before the surgery and on the first, second, and third postoperative day. The patients or their relatives were contacted 1 year after the procedure to assess the incidence of major postoperative complications. RESULTS: We enrolled 2641 patients who underwent vascular surgery, 2534 (95.9%) of whom completed 1­year follow­up. Their mean (SD) age was 68.2 (9.8) years, and the cohort was predominantly male (77.5%). The most frequent 1­year complications were myocardial infarction (224/2534, 8.8%), amputation (187/2534, 7.4%), and congestive heart failure (67/2534, 2.6%). The 1­year mortality rate was 8.8% (223/2534). MINS occurred in 633 patients (24%) and was associated with an increased 1­year mortality (hazard ratio, 2.82; 95% CI, 2.14-3.72; P <0.001). CONCLUSIONS: The incidence of major postoperative complications after vascular surgery is high. The occurrence of MINS is associated with a nearly 3­fold increase in 1­year mortality.

Proceedings from the inaugural Artificial Intelligence in Primary Immune Deficiencies (AIPID) conference.

Here, we summarize the proceedings of the inaugural Artificial Intelligence in Primary Immune Deficiencies conference, during which experts and advocates gathered to advance research into the applications of artificial intelligence (AI), machine learning, and other computational tools in the diagnosis and management of inborn errors of immunity (IEIs). The conference focused on the key themes of expediting IEI diagnoses, challenges in data collection, roles of natural language processing and large language models in interpreting electronic health records, and ethical considerations in implementation. Innovative AI-based tools trained on electronic health records and claims databases have discovered new patterns of warning signs for IEIs, facilitating faster diagnoses and enhancing patient outcomes. Challenges in training AIs persist on account of data limitations, especially in cases of rare diseases, overlapping phenotypes, and biases inherent in current data sets. Furthermore, experts highlighted the significance of ethical considerations, data protection, and the necessity for open science principles. The conference delved into regulatory frameworks, equity in access, and the imperative for collaborative efforts to overcome these obstacles and harness the transformative potential of AI. Concerted efforts to successfully integrate AI into daily clinical immunology practice are still needed.

High Performance Thermoelectric Power of Bi0.5Sb1.5Te3 Through Synergistic Cu2GeSe3 and Se Incorporations.

Bi2Te3-based alloys are the benchmark for commercial thermoelectric (TE) materials, the widespread demand for low-grade waste heat recovery and solid-state refrigeration makes it imperative to enhance the figure-of-merits. In this study, high-performance Bi0.5Sb1.5Te3 (BST) is realized by incorporating Cu2GeSe3 and Se. Concretely, the diffusion of Cu and Ge atoms optimizes the hole concentration and raises the density-of-states effective mass (md *), compensating for the loss of "donor-like effect" exacerbated by ball milling. The subsequent Se addition further increases md *, enabling a total 28% improvement of room-temperature power factor (S2σ), reaching 43.6 µW cm-1 K-2 compared to the matrix. Simultaneously, the lattice thermal conductivity is also significantly suppressed by multiscale scattering sources represented by Cu-rich nanoparticles and dislocation arrays. The synergistic effects yield a peak ZT of 1.41 at 350 K and an average ZT of 1.23 (300-500 K) in the Bi0.5Sb1.5Te2.94Se0.06 + 0.11 wt.% Cu2GeSe3 sample. More importantly, the integrated 17-pair TE module achieves a conversion efficiency of 6.4%, 80% higher than the commercial one at ΔT = 200 K. These results validate that the facile composition optimization of the BST/Cu2GeSe3/Se is a promising strategy to improve the application of BST-based TE modules.

Enhanced Thermoelectric Performance of P-Type (Bi,Sb)2 Te3 by Incorporating Non-Stoichiometric Ag5 Te3 and Refining Te-Se Ratio.

Power generation modules utilizing thermoelectric (TE) materials are suitable for recycling widespread low-grade waste heat (<600 K), highlighting the immediate necessity for advanced Bi2 Te3 -based alloys. Herein, the substantial enhancement in TE performance of the p-type Bi0.4 Sb1.6 Te3 (BST) sintered sample is realized by subtly incorporating the non-stoichiometric Ag5 Te3 and counteractive Se. Specifically, Ag atoms diffused into the BST lattice improve the density-of-states effective mass (md * ) and boost the hole concentration for the suppressed bipolar effect. The addition of Se further improves md * prompting the room-temperature power factor upgrade to 46 W cm-1  K-2 . Concurrently, the lattice thermal conductivity is considerably lowered by multiple scattering sources exemplified by Sb-rich nanoprecipitates and dense dislocations. These synergistic results yield a high peak ZT of 1.44 at 375 K and an average ZT of 1.28 between 300 and 500 K in the Bi0.4 Sb1.6 Te2.95 Se0.05 + 0.05 wt.% Ag5 Te3 sample. More significantly, when coupled with n-type zone-melted Bi2 Te2.7 Se0.3 , the integrated 17-pair TE module achieves a competitive conversion efficiency of 6.1% and an output power density of 0.40 W cm-2 at a temperature difference of 200 K, demonstrating great potential for practical applications.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Lipid compartments and lipid metabolism as therapeutic targets against coronavirus.

Lipids perform a series of cellular functions, establishing cell and organelles' boundaries, organizing signaling platforms, and creating compartments where specific reactions occur. Moreover, lipids store energy and act as secondary messengers whose distribution is tightly regulated. Disruption of lipid metabolism is associated with many diseases, including those caused by viruses. In this scenario, lipids can favor virus replication and are not solely used as pathogens' energy source. In contrast, cells can counteract viruses using lipids as weapons. In this review, we discuss the available data on how coronaviruses profit from cellular lipid compartments and why targeting lipid metabolism may be a powerful strategy to fight these cellular parasites. We also provide a formidable collection of data on the pharmacological approaches targeting lipid metabolism to impair and treat coronavirus infection.

Opioid Prescribing Patterns After Colorectal Resections in the United States of America.

Background The opioid epidemic is a significant source of morbidity and mortality in the United States of America. Minimizing opioid prescribing after operations has become an important component of post-operative care pathways. We hypothesized that opioid prescribing has decreased over time after colorectal resections. Methods This is a retrospective study from 2012 to 2019 using the Optum Clinformatics database (Eden Prairie, MN). We included patients aged 18 years or older who had an elective colorectal resection. Our primary outcome was the rate of opioid prescription at post-operative discharge. Secondary outcomes included the rates of gabapentinoid (GABA) prescribing post-operatively. Results Of 17,900 patients, the most common procedure was sigmoid colectomy (35%). Most procedures were open (N=10,626, 59.4%). The most common indication was benign disease (N=12,439, 69.5%). Post-operative opioid prescribing decreased from 64.4% in 2012 to 46.7% in 2019. In the adjusted model, the odds of post-operative opioid prescription were 37% lower in 2019 than in 2012 (OR, 0.63; 95% CI, 0.56-0.72; p<0.0001). At 60 days and one year post surgery, opioid prescribing decreased from 11.6% and 5.9% in 2012 to 7.2% and 5.2% in 2019 (p<0.0001). At 60 days, gabapentinoid prescribing increased from 2.3% in 2012 to 4.0% in 2019 (p=0.0016). Conclusions Our data show that opioid prescribing is common after colorectal surgery with an overall post-operative prescription rate of 55.8%. The modification of post-operative pathways to include guidance on opioid prescribing and non-opioid alternatives may curb opioid prescribing, decrease the number of new persistent opioid users, and decrease the number of opioids available for diversion.

Molecular Challenges in the Diagnosis of X-Linked Chronic Granulomatous Disease: CNVs, Intronic Variants, Skewed X-Chromosome Inactivation, and Gonosomal Mosaicism.

Chronic granulomatous disease (CGD) is a prototypical inborn error of immunity affecting phagocytes, in which these cells are unable to produce reactive oxygen species. CGD is caused by defects in genes encoding subunits of the NADPH oxidase enzyme complex (CYBA, CYBB, CYBC1, NCF1, NCF2, NCF4); inflammatory responses are dysregulated, and patients are highly susceptible to recurrent severe bacterial and fungal infections. X-linked CGD (XL-CGD), caused by mutations in the CYBB gene, is the most common and severe form of CGD. In this study, we describe the analytical processes undertaken in 3 families affected with XL-CGD to illustrate several molecular challenges in the genetic diagnosis of this condition: in family 1, a girl with a heterozygous deletion of CYBB exon 13 and skewed X-chromosome inactivation (XCI); in family 2, a boy with a hemizygous deletion of CYBB exon 7, defining its consequences at the mRNA level; and in family 3, 2 boys with the same novel intronic variant in CYBB (c.1151 + 6 T > A). The variant affected the splicing process, although a small fraction of wild-type mRNA was produced. Their mother was a heterozygous carrier, while their maternal grandmother was a carrier in form of gonosomal mosaicism. In summary, using a variety of techniques, including an NGS-based targeted gene panel and deep amplicon sequencing, copy number variation calling strategies, microarray-based comparative genomic hybridization, and cDNA analysis to define splicing defects and skewed XCI, we show how to face and solve some uncommon genetic mechanisms in the diagnosis of XL-CGD.

Long-term Outcomes of Single and Dual En Bloc Kidney Transplants From Small Pediatric Donors: An ANZDATA Registry Study.

Kidney transplants from small pediatric donors are considered marginal and often transplanted as dual grafts. This study aimed to compare long-term outcomes between recipients of single kidney transplants (SKTs) and dual en bloc kidney transplants (EBKTs) from small pediatric donors. Methods: Data were obtained from the Australia and New Zealand Dialysis and Transplant Registry. All adult recipients of kidney transplants from donors aged ≤5 y were identified. The primary outcome of interest was death-censored graft survival by donor type. The secondary outcomes were early graft loss, delayed graft function, serum creatinine posttransplantation, acute rejection, and patient survival. Results: There were 183 adult recipients of kidney transplants from donors aged ≤5 y old. Of these, 60 patients had EBKT grafts, 79 patients had SKT grafts, and 44 patients had grafts of unknown type. Compared with SKT donors, EBKT donors had lower mean age (P < 0.001) and body weight (P < 0.001). There was no significant difference in death-censored graft survival between the groups, with median survival of 23.8 y (interquartile range 21.2-25) in the EBKT cohort and 21.8 y (11.6-26.8) in the SKT cohort (hazard ratio 1.3; 95% confidence interval, 0.59-2.64; P = 0.56). EBKT grafts had lower acute rejection rates than SKT grafts (P = 0.014). There was no significant difference observed between groups with respect to early graft loss, delayed graft function, posttransplantation serum creatinine posttransplantation, or patient survival. Conclusions: EBKT and SKTs from small pediatric donors are associated with excellent long-term graft survival rates.

Virulence of Shigatoxigenic and Enteropathogenic Escherichia coli O80:H2 in Galleria mellonella Larvae: Comparison of the Roles of the pS88 Plasmids and STX2d Phage.

The invasiveness properties of Shigatoxigenic and enteropathogenic Escherichia coli (STEC and EPEC) O80:H2 in humans and calves are encoded by genes located on a pS88-like ColV conjugative plasmid. The main objectives of this study in larvae of the Galleria mellonella moth were therefore to compare the virulence of eight bovine STEC and EPEC O80:H2, of two E. coli pS88 plasmid transconjugant and STX2d phage transductant K12 DH10B, of four E. coli O80:non-H2, and of the laboratory E. coli K12 DH10B strains. Thirty larvae per strain were inoculated in the last proleg with 10 µL of tenfold dilutions of each bacterial culture corresponding to 10 to 106 colony-forming units (CFUs). The larvae were kept at 37 °C and their mortality rate was followed daily for four days. The main results were that: (i) not only the STEC and EPEC O80:H2, but also different E. coli O80:non-H2 were lethal for the larvae at high concentrations (from 104 to 106 CFU) with some variation according to the strain; (ii) the Stx2d toxin and partially the pS88 plasmid were responsible for the lethality caused by the E. coli O80:H2; (iii) the virulence factors of E. coli O80:non-H2 were not identified. The general conclusions are that, although the Galleria mellonella larvae represent a useful first-line model to study the virulence of bacterial pathogens, they are more limited in identifying their actual virulence properties.

Pre-Diagnosis Pain in Patients With Pancreatic Cancer Signals the Need for Aggressive Symptom Management.

OBJECTIVE: This study assessed the impact of pancreatic cancer (PC) pain on associated symptoms, activities, and resource utilization from 2016 to 2020 in an online patient registry. PATIENTS AND METHODS: Responses from PC patient volunteers (N = 1978) were analyzed from online surveys in a cross-sectional study. Comparisons were performed between PC patient groups reporting, (1) the presence vs. absence of pre-diagnosis PC pain, (2) high (4-8) vs. low (0-3) pain intensity scores on an 11-point numerical rating scale (NRS), and (3) year of PC diagnosis (2010-2020). Descriptive statistics and all bivariate analyses were performed using Chi-square or Fisher's Exact tests. RESULTS: PC pain was the most frequently reported pre-diagnosis symptom (62%). Pre-diagnostic PC pain was reported more frequently by women, those with a younger age at diagnosis, and those with PC that spread to the liver and peritoneum. Those with pre-diagnostic PC pain vs. those without reported higher pain intensities (2.64 ± 2.54 vs.1.56 ± 2.01 NRS mean ± SD, respectively, P = .0039); increased frequencies of post-diagnosis symptoms of cramping after meals, feelings of indigestion, and weight loss (P = .02-.0001); and increased resource utilization in PC pain management: (ER visits N = 86 vs. N = 6, P = .018 and analgesic prescriptions, P < .03). The frequency of high pain intensity scores was not decreased over a recent 11-year span. CONCLUSIONS: PC pain continues to be a prominent PC symptom. Patients reporting pre-diagnosis PC pain experience increased GI metastasis, symptoms burden, and are often undertreated. Its mitigation may require novel treatments, more resources dedicated to ongoing pain management and surveillance to improve outcomes.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans.

Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial.

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

Escherichia coli O80 in Healthy Cattle: Absence of Shigatoxigenic and Enteropathogenic E. coli O80:H2 and (Phylo) Genomics of Non-Clonal Complex 165 E. coli O80.

The origin of human and calf infections by Shigatoxigenic (STEC) and enteropathogenic (EPEC) Escherichia coli O80:H2 is still unknown. The aim of this study was to identify E. coli O80 in healthy cattle with an emphasis on melibiose non-fermenting E. coli O80:H2. Faecal materials collected from 149 bulls at 1 slaughterhouse and 194 cows on 9 farms were tested with O80 antigen-encoding gene PCR after overnight growth in enrichment broths. The 53 O80 PCR-positive broths were streaked on different (semi-)selective agar plates. Five E. coli colonies from 3 bulls and 11 from 2 cows tested positive with the O80 PCR, but no melibiose non-fermenting E. coli was isolated. However, these 16 E. coli O80 were negative with PCR targeting the fliCH2, eae, stx1, stx2 and hlyF genes and were identified by WGS to serotypes and sequence types O80:H6/ST8619 and O80:H45/ST4175. They were phylogenetically related to E. coli O80:H6 and O80:H45 isolated from different animal species in different countries, respectively, but neither to STEC and EPEC O80:H2/ST301, nor to other serotypes of the clonal complex 165. As a conclusion, healthy adult cattle were not identified as a source of contamination of humans and calves by STEC or EPEC O80:H2.