Irritable Bowel Syndrome in Veterans with Gulf War Illness Evaluated at VA's War-Related Illness and Injury Study Center.

INTRODUCTION: Excess rates of Gulf War illness (GWI) and irritable bowel syndrome (IBS), two chronic multisymptom illnesses, have long been documented among nearly 700,000 veterans who served in the 1990-1991 Persian Gulf War. We sought to report the prevalence, characteristics, and association of GWI and IBS decades after the war in a clinical cohort of deployed Gulf War veterans (GWVs) who were evaluated at the Department of Veterans Affairs' War Related Illness and Injury Study Center (WRIISC) for unexplained chronic symptoms. MATERIALS AND METHODS: We analyzed data gathered from clinical intake questionnaires of deployed GWVs who were evaluated at WRIISC clinics between 2008 and 2020. We applied Centers for Disease Control (CDC) criteria to determine the prevalence of severe GWI. IBS was identified using Rome IV diagnostic criteria (current IBS) and veterans' self-reported "history of physician-diagnosed IBS." We examined associations between IBS and GWI using bivariate analyses and multivariable logistic regression. RESULTS: Among the N = 578 GWVs evaluated by the WRIISC, severe GWI (71.8%), history of physician-diagnosed IBS (50.3%) and current IBS (42.2%) were all highly prevalent. Nearly half of GWVs with severe GWI met Rome criteria for IBS (45.8%), and over half reported a history of physician-diagnosed IBS (56.1%). In multivariable models, severe GWI was significantly associated both with current IBS (adjusted odds ratio (aOR): 1.68, 95% CI: 1.11, 2.54) and with veteran-reported history of physician-diagnosed IBS (aOR: 2.15, 95% CI: 1.43, 2.23). IBS with diarrhea (IBS-D) was the most common subtype among GWVs with current IBS (61.1%). However, IBS-mixed affected a significantly greater proportion of veterans with severe GWI, compared to veterans who did not have severe GWI (P = .03). CONCLUSIONS: More than 20 years after the Persian Gulf War, our findings indicate a high degree of comorbidity between severe GWI and IBS among deployed GWVs seeking care for unexplained illnesses. Our results suggest GWVs with GWI should be screened for IBS for which evidence-based treatments are available and could potentially reduce symptom burden. Conversely, symptoms of IBS should trigger additional evaluation for non-gastrointestinal symptoms in deployed Gulf War veterans to identify possible GWI and ensure a comprehensive approach to care.

Identifying long-term survivors and those at higher or lower risk of relapse among patients with cytogenetically normal acute myeloid leukemia using a high-dimensional mixture cure model.

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups.Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

BACKGROUND: Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. METHODS: This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. RESULTS: A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p = .370). The median (interquartile range) white blood cell (WBC) count was 3.1 (2.1-5.6) at LET initiation which increased to 5.1 (3.9-7.2) at the end of follow-up (p <.001). For VGCV controls, WBC was 4.8 (3.4-7.2) at baseline and 5.4 (3.6-7.2) at the end of follow-up; this difference was not statistically significant (p = .395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). CONCLUSION: LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

The Effect of a Collaborative Pediatric Emergency Readiness Improvement Intervention on Patients' Hospital Outcomes.

OBJECTIVE: We hypothesized that collaborative intervention to improve weighted pediatric readiness score (WPRS) will be associated with decreased pediatric intensive care (PICU) mortality, PICU and hospital length of stay. METHODS: This study analyzes the transfer of acutely ill and injured patients from general emergency departments (GEDs) to our institution. The intervention involved customized assessment reports focusing on team performance and systems improvement for pediatric readiness, sharing best practices and clinical resources, designation of a nurse PECC at each GED and ongoing interactions at 2 and 4 months. Data was collected from charts before and after the intervention, focusing on patients transferred to our pediatric emergency department (ED) or directly admitted to our PICU from the GEDs. Clinical outcomes such as PICU length of stay (LOS), hospital LOS, and PICU mortality were assessed. Descriptive statistics were used for demographics, and various statistical tests were employed to analyze the data. Bivariate analyses and multivariable models were utilized to examine patient outcomes and the association between the intervention and outcomes. RESULTS: There were 278 patients in the pre-intervention period and 314 patients in the post-intervention period. Multivariable analyses revealed a significant association between the change in WPRS and decreased PICU LOS (ß=-0.05 [95% CI: -0.09, -0.01), p=0.023), and hospital LOS (ß=-0.12 [95% CI: -0.21, -0.04], p=0.004), but showed no association between the intervention and other patient outcomes. CONCLUSIONS: In this cohort, improving pediatric readiness scores in GEDs was associated with significant improvements in PICU and hospital length of stay. Future initiatives should focus on disseminating pediatric readiness efforts to improve outcomes of critically ill children nationally. WHATS NEW: Improving pediatric readiness scores in general emergency departments is associated with improved downstream clinical outcomes demonstrated by reduced PICU and hospital length of stay.

Effect of letermovir initiation on tacrolimus concentrations among lung transplant recipients receiving concomitant azole antifungal prophylaxis.

BACKGROUND: The antiviral letermovir has been increasingly used as off-label cytomegalovirus prophylaxis in solid organ transplant recipients. Observational studies have reported notable increases in tacrolimus (FK) exposure following letermovir; however, whether a significant interaction occurs in the setting of existing moderate-to-strong CYP3A4 inhibition is unknown. Therefore, the purpose of this study was to evaluate FK trough changes before and after letermovir among lung transplant recipients receiving azole antifungal prophylaxis. METHODS: This retrospective cohort study included lung transplant recipients newly initiated on letermovir between 2019-2022 following valganciclovir intolerance. Tacrolimus doses and concentrations were collected up to 30 days before and after the letermovir start date. No pre-emptive FK dose adjustments occurred prior to letermovir initiation. Patients admitted to the hospital or lacking an appropriately timed trough in the pre- or post-period were excluded. RESULTS: A total of 78 lung transplant recipients receiving FK (1.5 mg median total daily dose) and itraconazole (56.4%), isavuconazole (25.6%) or posaconazole (17.9%) prophylaxis were included. Letermovir was started at a median of 8.4 months post-transplant. The pre-/post-letermovir median FK trough was 9.6/9.0 ng/mL (p = .151), median dose-corrected trough was 4.2/4.7 ng/mL/mg (+11.9%, p = .032), and median weight-based dose-corrected trough was 362/326 [ng/mL]/[mg/kg/day] (-9.9%, p = .036). There was no significant difference in the proportion of patients within their goal trough range before and after letermovir initiation (62% vs. 72%, p = .229). CONCLUSION: Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate-to-strong CYP3A4 inhibitors.

Penalized Bayesian forward continuation ratio model with application to high-dimensional data with discrete survival outcomes.

While time-to-event data are often continuous, there are several instances where discrete survival data, which are inherently ordinal, may be available or are more appropriate or useful. Several discrete survival models exist, but the forward continuation ratio model with a complementary log-log link has a survival interpretation and is closely related to the Cox proportional hazards model, despite being an ordinal model. This model has previously been implemented in the high-dimensional setting using the ordinal generalized monotone incremental forward stagewise algorithm. Here, we propose a Bayesian penalized forward continuation ratio model with a complementary log-log link and explore different priors to perform variable selection and regularization. Through simulations, we show that our Bayesian model outperformed the existing frequentist method in terms of variable selection performance, and that a 10% prior inclusion probability performed better than 1% or 50%. We also illustrate our model on a publicly available acute myeloid leukemia dataset to identify genomic features associated with discrete survival. We identified nine features that map to ten unique genes, five of which have been previously associated with leukemia in the literature. In conclusion, our proposed Bayesian model is flexible, allows simultaneous variable selection and uncertainty quantification, and performed well in simulation studies and application to real data.

Prioritizing Patient Experiences in the Management of Diabetes and Its Complications: An Endocrine Society Position Statement.

Diabetes can be an arduous journey both for people with diabetes (PWD) and their caregivers. While the journey of every person with diabetes is unique, common themes emerge in managing this disease. To date, the experiences of PWD have not been fully considered to successfully implement the recommended standards of diabetes care in practice. It is critical for health-care providers (HCPs) to recognize perspectives of PWD to achieve optimal health outcomes. Further, existing tools are available to facilitate patient-centered care but are often underused. This statement summarizes findings from multistakeholder expert roundtable discussions hosted by the Endocrine Society that aimed to identify existing gaps in the management of diabetes and its complications and to identify tools needed to empower HCPs and PWD to address their many challenges. The roundtables included delegates from professional societies, governmental organizations, patient advocacy organizations, and social enterprises committed to making life better for PWD. Each section begins with a clinical scenario that serves as a framework to achieve desired health outcomes and includes a discussion of resources for HCPs to deliver patient-centered care in clinical practice. As diabetes management evolves, achieving this goal will also require the development of new tools to help guide HCPs in supporting PWD, as well as concrete strategies for the efficient uptake of these tools in clinical practice to minimize provider burden. Importantly, coordination among various stakeholders including PWD, HCPs, caregivers, policymakers, and payers is critical at all stages of the patient journey.

Doxycycline versus cephalexin treatment of presumed streptococcal skin and soft tissue infection among adults presenting to the emergency department.

Among 100 propensity score-matched emergency department patients receiving ≤14 days doxycycline versus cephalexin monotherapy for outpatient treatment of nonpurulent (presumed streptococcal) skin and soft tissue infection, a low rate of 14-day clinical failure was observed [6% each group; odds ratio (OR), 1.34 (0.21-8.69); P = 0.745], defined as hospital admission, i.v. antibiotic therapy, or change in oral antibiotic. Doxycycline may represent a reasonable therapeutic alternative for this indication in regions with low tetracycline resistance.

Early Experiences with Intrathecal Administration of Amphotericin B Liposomal Formulation at a Neurosurgical Center.

BACKGROUND: Intrathecal administration of amphotericin B represents an important adjunctive therapy for management of severe fungal meningitis. Intrathecal preparations have traditionally used amphotericin B deoxycholate. Liposomal amphotericin B is an alternative formulation with good clinical outcomes as systemic therapy, but scant data exist investigating intrathecal use. OBJECTIVE: The aim of this exploratory study was to evaluate outcomes following intrathecal administration of liposomal amphotericin B for treatment of severe fungal meningitis. METHODS: A national shortage of amphotericin B deoxycholate necessitated revision of institutional protocols at a southwestern neurosurgical center in Spring 2023. A starting intrathecal daily dose of 0.125-0.5 mg liposomal amphotericin B was recommended (dependent on insertion device), with 0.125-0.25 mg slow titration every 48 h and up to a 2 mg maximum daily dose. RESULTS: Four cases of fungal meningitis treated with adjunctive intrathecal amphotericin B liposomal formulation were reviewed. This included three cases of coccidioidal meningitis and one case of presumed Fusarium solani meningitis following an outbreak. All patients had initial disease improvement following initiation of intrathecal amphotericin B and were able to tolerate long-term therapy. One coccidioidal meningitis patient expired of neurologic complications shortly after being moved from the intensive care unit (ICU) to a floor unit. All other patients were successfully discharged from the hospital. New headache was the only reported adverse effect, which was managed with dose reduction and did not require therapy discontinuation. CONCLUSIONS: Liposomal amphotericin B may be feasibly administered intrathecally for the adjunctive treatment of severe fungal meningitis.

Evaluation of lung volumes and gas exchange in surfactant-deficient rabbits between variable and fixed servo pressures during high-frequency jet ventilation.

OBJECTIVE: To investigate a novel servo pressure (SP) setting during high-frequency jet ventilation (HFJV) for a lung protective strategy in a neonatal model of acute respiratory distress. STUDY DESIGN: Comparison of efficacy between variable (standard) and fixed SP settings in a randomized animal study using rabbits (n = 10, mean weight = 1.80 kg) with surfactant deficiency by repeated lung lavages. RESULTS: Rabbits in the fixed SP group had greater peak inspiratory pressure, SP, minute volume, pH, and PaO2, and lower PaCO2 after lung lavage than the variable SP group. Lung volume monitoring with electrical impedance tomography showed that fixed SP reduced the decline of the global lung tidal variation at 30 min after lung lavage (-17.4% from baseline before lavage) compared to variable SP (-44.9%). CONCLUSION: HFJV with fixed SP significantly improved gas exchange and lung volumes compared to variable SP. Applying a fixed SP may have important clinical implications for patients receiving HFJV.

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder.

Gulf War illness (GWI) is a chronic multisymptom disorder of unknown etiology that is believed to be caused by neurotoxicant exposure experienced during deployment to the Gulf War. Posttraumatic stress disorder (PTSD) covaries with GWI and is believed to play a role in GWI symptoms. The present study examined the association between self-reported military exposures and GWI, stratified by PTSD status, in veterans from the Gulf War Era Cohort and Biorepository who were deployed to the Persian Gulf during the war. Participants self-reported current GWI and PTSD symptoms as well as military exposures (e.g., pyridostigmine [PB] pills, pesticides/insecticides, combat, chemical attacks, and oil well fires) experienced during the Gulf War. Deployed veterans' (N = 921) GWI status was ascertained using the Centers for Disease Control and Prevention definition. Individuals who met the GWI criteria were stratified by PTSD status, yielding three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression, adjusted for covariates, was used to examine associations between GWI/PTSD groups and military exposures. Apart from insect bait use, the GWI+/PTSD+ group had higher odds of reporting military exposures than the GWI+/PTSD- group, adjusted odds ratio (aOR) = 2.15, 95% CI [1.30, 3.56]-aOR = 6.91, 95% CI [3.39, 14.08]. Except for PB pills, the GWI+/PTSD- group had a higher likelihood of reporting military exposures than the GWI- group, aOR = 2.03, 95% CI [1.26, 3.26]-aOR = 4.01, 95% CI [1.57, 10.25]. These findings are consistent with roles for both PTSD and military exposures in the etiology of GWI.

Trimethoprim-sulfamethoxazole significantly reduces the risk of nocardiosis in solid organ transplant recipients: systematic review and individual patient data meta-analysis.

BACKGROUND: Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial. OBJECTIVES: To assess the effect of TMP-SMX in the prevention of nocardiosis after SOT, its dose-response relationship, its effect on preventing disseminated nocardiosis, and the risk of TMP-SMX resistance in case of breakthrough infection. METHODS: A systematic review and individual patient data meta-analysis. DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, and Scopus up to 19 September 2023. STUDY ELIGIBILITY CRITERIA: (a) Risk of nocardiosis between SOT recipients with and without TMP-SMX prophylaxis, or (b) sufficient details to determine the rate of TMP-SMX resistance in breakthrough nocardiosis. PARTICIPANTS: SOT recipients. INTERVENTION: TMP-SMX prophylaxis versus no prophylaxis. ASSESSMENT OF RISK OF BIAS: Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) for comparative studies; dedicated tool for non-comparative studies. METHODS OF DATA SYNTHESIS: For our primary outcome (i.e. to determine the effect of TMP-SMX on the risk of nocardiosis), a one-step mixed-effects regression model was used to estimate the association between the outcome and the exposure. Univariate and multivariable unconditional regression models were used to adjust for the potential confounding effects. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Individual data from three case-control studies were obtained (260 SOT recipients with nocardiosis and 519 uninfected controls). TMP-SMX prophylaxis was independently associated with a significantly decreased risk of nocardiosis (adjusted OR = 0.3, 95% CI 0.18-0.52, moderate certainty of evidence). Variables independently associated with an increased risk of nocardiosis were older age, current use of corticosteroids, high calcineurin inhibitor concentration, recent acute rejection, lower lymphocyte count, and heart transplant. Breakthrough infections (66/260, 25%) were generally susceptible to TMP-SMX (pooled proportion 98%, 95% CI 92-100). CONCLUSIONS: In SOT recipients, TMP-SMX prophylaxis likely reduces the risk of nocardiosis. Resistance appears uncommon in case of breakthrough infection.

Modeling purple basil, sage, spearmint, and sweet basil responses to daily light integral and mean daily temperature.

Mean daily temperature (MDT) and daily light integral (DLI) can interact to influence growth and development of plants. Our objectives were to determine 1) the extent DLI and MDT influence growth and development of purple basil 'Dark Opal' (Ocimum basilicum), sage 'Extrakta' (Salvia officinalis), spearmint 'Spanish' (Mentha spicata), and sweet basil 'Nufar' (Ocimum basilicum) and 2) the influence on purple basil color. Young plants were transplanted into hydroponic systems in five greenhouse compartments with MDT set points of 23, 26, 29, 32, or 35°C and DLIs from 5 to 19 mol·m‒2·d‒1, respectively. At harvest, growth, development, and leaf color was measured. Branch number of all genera increased as MDT increased from ~23 to 35°C. Sweet basil branch number increased as DLI increased from 5.5 to 13.2 mol·m‒2·d‒1, but the effect of DLI was attenuated as MDT decreased. In contrast, increasing DLI from ~5-6 to ~18-19 mol·m‒2·d‒1 increased sage and spearmint branch number more when MDT was lower (~23°C) compared to ~35°C, while branch number of purple basil was not influenced by DLI. The optimal MDT (MDTopt) for sage and spearmint fresh mass decreased from 27.5 to 23.5°C and from 30.4 to 27.8°C, respectively, as DLI increased from 6 to 18 mol·m‒2·d‒1, while sweet basil fresh mass MDTopt increased from 32.6 to 35.5°C as DLI increased from 6 to 11 mol·m‒2·d‒1. Purple basil was greener [hue angle (h°) = 99° to 138°] when MDT was ~35°C regardless of DLI, but when MDT was lower (~25°C), basil was more purple (h° = 335°) at a DLI of 18.7 compared to 5.0 mol·m‒2·d‒1 (h° = 98°). Taken together, MDT and DLI can have a large impact on plant growth, development, and color and can be manipulated to achieve desired characteristics.

Preliminary assessment of three quantitative approaches for estimating time-since-deposition from autofluorescence and morphological profiles of cell populations from forensic biological samples.

Determining when DNA recovered from a crime scene transferred from its biological source, i.e., a sample's 'time-since-deposition' (TSD), can provide critical context for biological evidence. Yet, there remains no analytical techniques for TSD that are validated for forensic casework. In this study, we investigate whether morphological and autofluorescence measurements of forensically-relevant cell populations generated with Imaging Flow Cytometry (IFC) can be used to predict the TSD of 'touch' or trace biological samples. To this end, three different prediction frameworks for estimating the number of day(s) for TSD were evaluated: the elastic net, gradient boosting machines (GBM), and generalized linear mixed model (GLMM) LASSO. Additionally, we transformed these continuous predictions into a series of binary classifiers to evaluate the potential utility for forensic casework. Results showed that GBM and GLMM-LASSO showed the highest accuracy, with mean absolute error estimates in a hold-out test set of 29 and 21 days, respectively. Binary classifiers for these models correctly binned 94-96% and 98-99% of the age estimates as over/under 7 or 180 days, respectively. This suggests that predicted TSD using IFC measurements coupled to one or, possibly, a combination binary classification decision rules, may provide probative information for trace biological samples encountered during forensic casework.

Sex-specific lung inflammation and mitochondrial damage in a model of electronic cigarette exposure in asthma.

The prevalence of electronic cigarette (EC) use among adult with asthma has continued to increase over time, in part due to the belief of being less harmful than smoking. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. In the present project, we tested the hypothesis that EC use contributes to respiratory damage and worsening inflammation in the lungs of patients with asthma. To define the consequences of EC exposure in established asthma, we used a mouse model with/without preexisting asthma for short-term exposure to EC aerosols. C57/BL6J mice were sensitized and challenged with a DRA (dust mite, ragweed, Aspergillus fumigates, 200 µg/mL) mixture and exposed daily to EC with nicotine (2% nicotine in 30:70 propylene glycol: vegetable glycerin) or filtered air for 2 wk. The mice were evaluated at 24 h after the final EC exposure. After EC exposure in asthmatic mice, lung inflammatory cell infiltration and goblet cell hyperplasia were increased, whereas EC alone did not cause airway inflammation. Our data also show that mitochondrial DNA (mtDNA) content and a key mtDNA regulator, mitochondrial transcription factor A (TFAM), are reduced in asthmatic EC-exposed mice in a sex-dependent manner. Together, these results indicate that TFAM loss in lung epithelium following EC contributes to male-predominant sex pathological differences, including mitochondrial damage, inflammation, and remodeling in asthmatic airways.NEW & NOTEWORTHY Respiratory immunity is dysregulated in preexisting asthma, and further perturbations by EC use could exacerbate asthma severity. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. We found that EC has unique biological impacts in lungs and potential sex differences with loss of TFAM, a key mtDNA regulator, in lung epithelial region from our animal EC study.

Gradients of response latencies and temporal precision of auditory neurons extend across the whole inferior colliculus.

Neural responses to acoustic stimulation have long been studied throughout the auditory system to understand how sound information is coded for perception. Within the inferior colliculus (IC), a majority of the studies have focused predominantly on characterizing neural responses within the central region (ICC), as it is viewed as part of the lemniscal system mainly responsible for auditory perception. In contrast, the responses of outer cortices (ICO) have largely been unexplored, though they also function in auditory perception tasks. Therefore, we sought to expand on previous work by completing a three-dimensional (3-D) functional mapping study of the whole IC. We analyzed responses to different pure tone and broadband noise stimuli across all IC subregions and correlated those responses with over 2,000 recording locations across the IC. Our study revealed there are well-organized trends for temporal response parameters across the full IC that do not show a clear distinction at the ICC and ICO border. These gradients span from slow, imprecise responses in the caudal-medial IC to fast, precise responses in the rostral-lateral IC, regardless of subregion, including the fastest responses located in the ICO. These trends were consistent at various acoustic stimulation levels. Weaker spatial trends could be found for response duration and spontaneous activity. Apart from tonotopic organization, spatial trends were not apparent for spectral response properties. Overall, these detailed acoustic response maps across the whole IC provide new insights into the organization and function of the IC.NEW & NOTEWORTHY Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.

Development and use of machine learning models for prediction of male sling success A proof-of-concept institutional evaluation.

INTRODUCTION: For mild to moderate male stress urinary incontinence (SUI), transobturator male slings remain an effective option for management. We aimed to use a machine learning (ML )-based model to predict those who will have a long-term success in managing SUI with male sling. METHODS: All transobturator male sling cases from August 2006 to June 2012 by a single surgeon were reviewed. Outcome of interest was defined as 'cure': complete dryness with 0 pads used, without the need for additional procedures. Clinical variables included in ML models were: number of pads used daily, age, height, weight, race, incontinence type, etiology of incontinence, history of radiation, smoking, bladder neck contracture, and prostatectomy. Model performance was assessed using area under receiver operating characteristic curve (AUROC), area under precision-recall curve (AUPRC), and F1-score. RESULTS: A total of 181 patients were included in the model. The mean followup was 56.4 months (standard deviation [SD ] 41.6). Slightly more than half (53.6%, 97/181) of patients had procedural success. Logistic regression, K-nearest neighbor (KNN ), naive Bayes, decision tree, and random forest models were developed using ML. KNN model had the best performance, with AUROC of 0.759, AUPRC of 0.916, and F1-score of 0.833. Following ensemble learning with bagging and calibration, KNN model was further improved, with AUROC of 0.821, AUPRC of 0.921, and F-1 score of 0.848. CONCLUSIONS: ML-based prediction of long-term transobturator male sling is feasible. The low numbers of patients used to develop the model prompt further validation and development of the model but may serve as a decision-making aid for practitioners in the future.

Long-Term Impact of Daily E-cigarette Exposure on the Lungs of Asthmatic Mice.

INTRODUCTION: Although the greater popularity of electronic cigarettes (EC) among asthmatics is alarming, there is limited knowledge of the long-term consequences of EC exposure in asthmatics. AIMS AND METHODS: Mild asthmatic C57/BL6J adult male and female mice were established by intranasal insufflation with three combined allergens. The asthmatic and age and sex-matched' naïve mice were exposed to air, nicotine-free (propylene glycol [PG]/vegetable glycerin [VG]-only), or PG/VG+Nicotine, 4 hours daily for 3 months. The effects of EC exposure were accessed by measuring cytokines in bronchoalveolar lavage, periodic acid-schiff (PAS) staining, mitochondrial DNA copy numbers (mtCN), and the transcriptome in the lung. Significance was false discovery rate <0.2 for transcriptome and 0.05 for the others. RESULTS: In asthmatic mice, PG/VG+Nicotine increased PAS-positive cells and IL-13 compared to mice exposed to air and PG/VG-only. In naïve mice exposed to PG/VG+Nicotine and PG/VG-only, higher INF-γ was observed compared to mice exposed only to air. PG/VG-only and PG/VG+Nicotine had significantly higher mtCN compared to air exposure in asthmatic mice, while the opposite pattern was observed in non-asthmatic naïve mice. Different gene expression patterns were profoundly found for asthmatic mice exposed to PG/VG+Nicotine compared to PG/VG-only, including genes involved in mitochondrial dysfunction, oxidative phosphorylation, and p21-activated kinase (PAK) signaling. CONCLUSIONS: This study provides experimental evidence of the potential impact of nicotine enhancement on the long-term effects of EC in asthmatics compared to non-asthmatics. IMPLICATIONS: The findings from this study indicate the potential impact of EC in asthmatics by addressing multiple biological markers. The long-term health outcomes of EC in the susceptible group can be instrumental in supporting policymaking and educational campaigns and informing the public, healthcare providers, and EC users about the underlying risks of EC use.