Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.

Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics such as neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 hour of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 hours for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.

Molecular analysis of persistent and recurrent Barrett's esophagus in the setting of endoscopic therapy.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. While effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre- and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (p=0.01), amplifications of oncogenes (p=0.01), and deletions of tumor suppressor genes (p=0.02). These associations were no longer significant after adjusting for patient age and BE length. Over half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre- and post-treatment samples that shared at least 50% of their driver mutations. CONCLUSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. While it was expected to find shared driver mutations in pre- and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Racial, Ethnic, and Sex Differences in Incidence-Based Mortality of Aggregate Upper Gastrointestinal Cancers.

INTRODUCTION: Current strategies for upper gastrointestinal (UGI) cancer screening primarily target cancer-specific risk, with the strongest focus on esophageal adenocarcinoma (EAC). However, all UGI cancers are amendable to screening and early detection with an upper endoscopic exam. This study assesses and explores incidence-based mortality (IBM) for cumulative UGI cancers, aiming to identify race or sex-based disparities. METHODS: We used Surveillance, Epidemiology, and End Results Research data to analyze patients diagnosed with EAC, esophageal squamous cell carcinoma (ESCC), cardia gastric cancer (CGC), non-cardia gastric cancer (NCGC), or colorectal adenocarcinoma from 2000 to 2019. Age-adjusted IBM was calculated as a rate per 100,000 population and stratified by sex and race/ethnicity. We also compared UGI cancer IBM with that of colorectal cancer, a cancer with established population-wide endoscopic screening guidelines. RESULTS: Cumulative IBM for UGI cancers was 8.40 (95% CI 8.34-8.46). The highest cancer-specific IBM rates were for EAC (2.26, 95% CI 2.23-2.29), followed by NCGC (2.07, 95% CI 2.04-2.10), CGC (1.60, 95% CI 1.57-1.62), ESCC (1.21, 95% CI 1.19-1.23), and miscellaneous UGI cancer (1.27, 95% CI 1.13-1.40). UGI cancer IBM was highest among Black males (16.43, 95% CI 15.97-16.89), American Indian/Alaska Native males (15.23, 95% CI 13.75-16.82), and Hispanic males (13.76, 95% CI 13.42-14.11). These rates are significantly greater than among White males (12.81, 95% CI 12.68-12.95). CONCLUSION: UGI cancers impose a significantly higher mortality burden on non-White population subgroups that are not currently targeted by any systematic screening approach.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response.

BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation. METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders. RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response. CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.

Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.

The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.

Biliary Complications Post Transjugular Intrahepatic Portosystemic Shunt in a Child With Portal Vein Cavernous Transformation.

The transjugular intrahepatic portosystemic shunt is a rising interventional procedure with multiple indications and high technical success but with risks of biliary injuries, an underreported scenario. We present an 11-year-old patient with biliary injury with a leak, biloma formation, and biliary obstruction caused by the percutaneous procedure. Interventional radiology drainages addressed these complications by resolving the leak and biloma. These biliary complications in percutaneous procedures and their management are rarely reported in the medical literature, making their management not standard. We highlight drainage management and the importance of sharing it to add experience to this clinical scenario and encourage sharing cases with similar diagnoses.

Combined Charlson comorbidity/C-Reactive Protein Index Is a Novel Predictor in Renal Cell Carcinoma: Analysis of the International Marker Consortium for Renal Cancer (INMARC) Registry.

OBJECTIVE: To evaluate predictive ability of a novel combined index, Charlson comorbidity index and C-reactive protein (CCI-CRP), for outcomes in renal cell carcinoma (RCC), and compare predictive outcomes with of CCI-CRP to its separate components and to the UCLA integrated staging system (UISS). PATIENTS AND METHODS: We retrospectively analyzed INMARC registry of RCC patients. Receiver Operator Characteristics (ROC) analysis was fitted to identify threshold defining low-CRP (LCRP) and high-CRP (HCRP). Patients were stratified according to CCI [low-CCI ≤ 3 (LCCI); intermediate-CCI 4-6 (ICCI); high-CCI > 6 (HCCI)] and CRP level. Kaplan-Meier analysis (KMA) was conducted for overall (OS) and cancer-specific survival (CSS). Based on survival analysis distribution we proposed a new stratification: CCI-CRP. Model performance was assessed with ROC/area under the curve (AUC) analysis and compared to CCI and CRP alone, and UISS. RESULTS: We analyzed 2,890 patients (median follow-up 30 months). ROC identified maximum product sensitivity and specificity for CRP at 3.5 mg/L. KMA revealed 5-year OS of 95.6% for LCRP/LCCI, 83% LCRP/ICCI, 73.3% LCRP/HCCI, 62.6% HCRP/LCCI, 51.6% HCRP/ICCI and 40.5% HCRP/HCCI (P < .001). From this distribution, new CCI-CRP is proposed: low CCI-CRP (LCRP/LCCI and LCRP/ICCI), intermediate CCI-CRP (LCRP/HCCI and HCRP/LCCI), and high CCI-CRP (HCRP/ICCI and HCRP/HCCI). AUC for CCI-CRP showed improved performance for predicting OS/CSS vs. CCI alone (0.73 vs. 0.63/0.77 vs. 0.60), CRP alone (0.73 vs. 0.71/0.77 vs. 0.74) and UISS (0.73 vs 0.67/0.77 vs 0.73). CONCLUSIONS: CCI-CRP, exhibits increased prognostic performance for survival outcomes in RCC compared to CCI and CRP alone, and UISS. Further investigation is requisite.

Web-Based Cognitive Behavioral Treatment for Bulimia Nervosa: A Randomized Clinical Trial.

Importance: Despite the existence of effective treatments, many individuals with bulimia nervosa (BN) do not receive evidence-based therapies. Integrating digital interventions into routine care might reach more patients and reduce the clinical burden of BN. Objective: To evaluate the effectiveness of a web-based cognitive behavioral self-help intervention for individuals with BN. Design, Setting, and Participants: A 2-group randomized clinical trial without follow-up was conducted between February 2, 2021, and July 9, 2022, in Germany. Participants aged between 18 and 65 years who met the diagnostic criteria for BN were enrolled online via self-referral. Data analyses were conducted from October 24, 2022, to December 23, 2023. Interventions: A web-based cognitive behavioral self-help intervention including 12 weekly modules was compared with a waiting-list control group only having access to routine care. Main Outcomes and Measures: The primary outcome was the change in the number of bulimic episodes between baseline and posttreatment. Secondary outcomes included changes in global eating disorder symptoms, clinical impairment, well-being, work capacity, comorbid symptoms, self-esteem, and emotion regulation complemented by weekly measures and ecological momentary assessment. Intention-to-treat analyses were performed. Results: Participants (N = 154; mean [SD] age, 29.6 [8.6] years; 149 [96.8%] female) receiving the web-based intervention demonstrated a significantly greater decrease in bulimic episodes compared with the control group (Cohen d = -0.48; 95% CI, -0.75 to -0.20; P < .001), representing a significant change in binge-eating episodes (Cohen d = -0.61; 95% CI, -0.89 to -0.33; P < .001), but not in compensatory behaviors (Cohen d = -0.25; 95% CI, -0.51 to 0.02; P = .21). The intervention was superior in improving global eating disorder symptoms (Cohen d = -0.61; 95% CI, -0.89 to -0.32; P < .001) and clinical impairment (Cohen d = -0.62; 95% CI, -0.92 to -0.33; P < .001). No significant effects were found for well-being (Cohen d = -0.08; 95% CI, -0.37 to 0.22; P > .99) and work capacity (Cohen d = -0.01; 95% CI, -0.68 to 0.66; P = .99). Exploratory analyses indicated significant changes in self-esteem and emotion regulation difficulties, but not in comorbid symptoms. Conclusions and Relevance: In this randomized clinical trial, a web-based cognitive behavioral self-help intervention effectively decreased eating disorder symptoms and illness-related burden in individuals with BN, underlining the potential of digital interventions to complement established treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT04876196.

Dexamethasone for Cardiac Surgery: A Practice Preference-Randomized Consent Comparative Effectiveness Trial.

BACKGROUND: High-dose corticosteroids have been used to attenuate the inflammatory response to cardiac surgery and cardiopulmonary bypass, but patient outcome benefits remain unclear. Our primary aim was to determine whether using dexamethasone was superior to not using dexamethasone to increase the number of home days in the first 30 days after cardiac surgery. Our secondary aim was to evaluate efficiency, value and impact of the novel trial design. METHODS: This pragmatic, international trial incorporating a prerandomized consent design favoring local practice enrolled patients undergoing cardiac surgery across 7 hospitals in Australia and The Netherlands. Patients were randomly assigned to dexamethasone, 1 mg/kg, or not (control). The primary outcome was the number of days alive and at home up to 30 days after surgery ("home days"). Secondary outcomes included prolonged mechanical ventilation (>48 h), sepsis, renal failure, myocardial infarction, stroke and death. RESULTS: Of 2093 patients assessed for eligibility, 1951 were randomized (median age 63 years, 80% male). The median number of home days was 23.0 (IQR, 20.1 to 24.1) in the dexamethasone group and 23.1 (IQR, 20.1 to 24.6) in the no dexamethasone group; median difference 0.1 (95% CI, -0.3 to 0.5), P=0.66. The rates of prolonged mechanical ventilation, RR 0.72 (95% CI, 0.48 to 1.08), sepsis, RR 1.02 (95% CI, 0.57 to 1.82), renal failure, RR 0.94 (95% CI, 0.80 to 1.12), myocardial infarction, RR 1.20 (95% CI, 0.30 to 4.82), stroke, RR 1.06 (95% CI, 0.54 to 2.08), and death, RR 0.72 (95% CI, 0.22 to 2.35), were comparable between groups (all P>0.10). Dexamethasone reduced intensive care unit stay, median 29 (IQR, 22 to 50) h vs. 43 (24 to 72) h, P=0.004. Our novel trial design was highly efficient (89.3% enrolment). CONCLUSIONS: Among patients undergoing cardiac surgery, high-dose dexamethasone decreased intensive care unit stay but did not increase the number of home days after surgery.

A Broad-specificity Neutralizing Nanobody against Hepatitis E Virus Capsid Protein.

Hepatitis E virus (HEV) is a worldwide zoonotic and public health concern. The study of HEV biology is helpful for designing viral vaccines and drugs. Nanobodies have recently been considered appealing materials for viral biological research. In this study, a Bactrian camel was immunized with capsid proteins from different genotypes (1, 3, 4, and avian) of HEV. Then, a phage library (6.3 × 108 individual clones) was constructed using peripheral blood lymphocytes from the immunized camel, and 12 nanobodies against the truncated capsid protein of genotype 3 HEV (g3-p239) were screened. g3-p239-Nb55 can cross-react with different genotypes of HEV and block Kernow-C1/P6 HEV from infecting HepG2/C3A cells. To our knowledge, the epitope recognized by g3-p239-Nb55 was determined to be a novel conformational epitope located on the surface of viral particles and highly conserved among different mammalian HEV isolates. Next, to increase the affinity and half-life of the nanobody, it was displayed on the surface of ferritin, which can self-assemble into a 24-subunit nanocage, namely, fenobody-55. The affinities of fenobody-55 to g3-p239 were ∼20 times greater than those of g3-p239-Nb55. In addition, the half-life of fenobody-55 was nine times greater than that of g3-p239-Nb55. G3-p239-Nb55 and fenobody-55 can block p239 attachment and Kernow-C1/P6 infection of HepG2/C3A cells. Fenobody-55 can completely neutralize HEV infection in rabbits when it is preincubated with nonenveloped HEV particles. Our study reported a case in which a nanobody neutralized HEV infection by preincubation, identified a (to our knowledge) novel and conserved conformational epitope of HEV, and provided new material for researching HEV biology.

Quality and Readability of Online Health Information on Common Urologic Cancers: Assessing Barriers to Health Literacy in Urologic Oncology.

INTRODUCTION: A growing number of Americans search online for health information related to urologic oncologic care each year. The American Medical Association recommends that medical information be written at a maximum sixth-grade level in order to be comprehensible by the majority of patients. As such, it is important to assess the quality and readability of online patient education material that patients are being exposed to. METHODS: A Google search was performed using the terms "testicular cancer," "prostate cancer," "kidney cancer," and "bladder cancer," and the top 30 results for each were reviewed. Websites were categorized based on their source. Readability was assessed using the Flesch-Kincaid Grade Level, the Gunning Frequency of Gobbledygook, and the Simple Measure of Gobbledygook indices. Quality was assessed using the DISCERN Quality Index (1-5 scale). RESULTS: A total of 91 websites were included in our analysis. On average, online health information pertaining to urologic cancers is written at a 10th- to 11th-grade reading level, which is significantly higher than that of an average American adult and that recommended by the American Medical Association (P < .01). The overall quality of websites was 3.4 ± 0.7, representing moderate to high quality. There was no significant difference in readability based on cancer type or information source. CONCLUSIONS: Despite being of moderate to high quality, online patient education materials related to common urologic cancers are often written at a grade level that exceeds the reading level of an average American adult. This presents as a barrier to online health literacy and calls into question the utility of these resources.

Chemogenomics for NR1 nuclear hormone receptors.

Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity. Based on broad profiling of candidates for specificity, toxicity, and off-target liabilities, sixty-nine comprehensively annotated NR1 agonists, antagonists and inverse agonists covering all members of the NR1 family and meeting potency and selectivity standards are included in the final NR1 CG set. Proof-of-concept application of this set reveals effects of NR1 members in autophagy, neuroinflammation and cancer cell death, and confirms the suitability of the set for target identification and validation.

SALUS-A Study on Self-Tonometry for Glaucoma Patients: Design and Implementation of the Electronic Case File.

BACKGROUND: In times of omnipresent digitization and big data, telemedicine and electronic case files (ECFs) are gaining ground for networking between players in the health care sector. In the context of the SALUS study, this approach is applied in practice in the form of electronic platforms to display and process disease-relevant data of glaucoma patients. OBJECTIVES: The SALUS ECF is designed and implemented to support data acquisition and presentation, monitoring, and outcome control for patients suffering from glaucoma in a clinical setting. Its main aim is to provide a means for out- and inpatient exchange of information between various stakeholders with an intuitive user interface in ophthalmologic care. Instrument data, anamnestic data, and diagnostic assessments need to be accessible and historic data stored for patient monitoring. Quality control of the data is ensured by a reading center. METHODS: Based on an intensive requirement analysis, we implemented the ECF as a web-based application in React with a Datomic back-end exposing REST and GraphQL APIs for data access and import. A flexible role management was developed, which addresses the various tasks of multiple stakeholders in the SALUS study. Data security is ensured by a comprehensive encryption concept. We evaluated the usability and efficiency of the ECF by measuring the durations medical doctors need to enter and work with the data. RESULTS: The evaluation showed that the ECF is time-saving in comparison to paper-based assessments and offers supportive monitoring and outcome control for numerical and imaging-related data. By allowing patients and physicians to access the digital ECF, data connectivity as well as patient autonomy were enhanced. CONCLUSION: ECFs have a great potential to efficiently support all patients and stakeholders involved in the care of glaucoma patients. They benefit from the efficient management and view of the data tailored to their specific role.

Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition.

Background: The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. Results: Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. Conclusion: We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.

Oxygen-Mediated (0D) Cs4PbX6 Formation during Open-Air Thermal Processing Improves Inorganic Perovskite Solar Cell Performance.

The desire to commercialize perovskite solar cells continues to mount, motivating the development of scalable production. Evaluations of the impact of open-air processing have revealed a variety of physical changes in the fabricated devices─with few changes having the capacity to be functionalized. Here, we highlight the beneficial role of ambient oxygen during the open-air thermal processing of metastable γ-CsPbI3-based perovskite thin films and devices. Physiochemical-sensitive probes elucidate oxygen intercalation and the formation of Pb-O bonds in the CsPbI3 crystal, entering via iodine vacancies at the surface, creating superoxide (O2-) through electron transfer reactions with molecular oxygen, which drives the formation of a zero-dimensional Cs4PbI6 capping layer during annealing (>330 °C). The chemical conversion permanently alters the film structure, helping to shield the subsurface perovskite from moisture and introduces lattice anchoring sites, stabilizing otherwise unstable γ-CsPbI3 films. This functional modification is demonstrated in γ-CsPbI2Br perovskite solar cells, boosting the operational stability and photoconversion efficiency of champion devices from 12.7 to 15.4% when annealed in dry air. Such findings prompt a reconsideration of glovebox-based perovskite solar cell research and establish a scenario where device fabrication can in fact greatly benefit from ambient oxygen.

Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

Single Session Intermittent Heat Exposure With More Frequent and Shorter Cooling Breaks Facilitates Greater Training Intensity and Elicits Physiological Responses Comparable to Continuous Heat Exposure.

PURPOSE: To investigate the influence of shorter, more frequent rest breaks with per-cooling as an alternative heat-acclimation session on physiological, perceptual, and self-paced maximal cycling performance, compared with continuous heat exposure. METHODS: Thirteen participants completed 1 continuous and 3 intermittent-heat-exposure (IHE) maximal self-paced cycling protocols in a random order in heat (36 °C, 80% relative humidity): 1 × 60-minute exercise (CON), 3 × 20-minute exercise with 7.5-minute rest between sets (IHE-20), 4 × 15-minute exercise with 5-minute rest between sets (IHE-15), and 6 × 10-minute exercise with 3-minute rest between sets (IHE-10). Mixed-method per-cooling (crushed-ice ingestion and cooling vest) was applied during rest periods of all IHE protocols. RESULTS: Total distance completed was greater in IHE-10, IHE-15, and IHE-20 than in CON (+11%, +9%, and +8%, respectively), with no difference observed between IHE protocols. Total time spent above 38.5 °C core temperature was longer in CON compared with IHE-15 and IHE-20 (+62% and +78%, respectively) but similar to IHE-10 (+5%). Furthermore, a longer time above 38.5 °C core temperature occurred in IHE-10 versus IHE-15 and IHE-20 (+54% and +69%, respectively). Sweat loss did not differ between conditions. CONCLUSION: IHE with per-cooling may be a viable alternative heat-acclimation protocol in situations where training quality takes precedence over thermal stimulus or when both factors hold equal priority.