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Aim: A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy.Methods: Pre- and post-contrast T1-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans. Univariate and multivariate Cox regression analyses were used to test the influence of contrast-enhancing tumor volume, total cellularity, mean Cyt and mean ECF at baseline, immediately post-treatment and the pre- and post-treatment rate of change in volume and cellularity on overall survival (OS).Results: Smaller Cyt and larger ECF after treatment were significant predictors of OS, independent of tumor volume and other clinical prognostic factors (HR = 3.23 × 10-6, p

Uptake of COVID-19 vaccine booster doses is an important public health topic of study to prevent morbidity and mortality in underserved U.S. populations. However, limited research exists on COVID-19 vaccine booster use and willingness - including its associated factors - among Asian Americans (AA): the fastest growing racial group in the U.S. This study collected survey data from 447 AA adults from three large AA subgroups: Chinese, Korean, and Filipino. Data were collected as part of a community-driven county-wide needs assessment conducted in collaboration with AA community organizations in Riverside County, California. Data indicated that nearly 24% of AA participants received at least four doses of the COVID-19 vaccine, with 36% expressing definite willingness to receive future booster doses. Participants reported experiencing an average of 1.6 instances of racial discrimination across their lifetime. Ordered logistic regression and marginal effects analysis revealed ethnicity, education, racial discrimination, preexisting health conditions, and the number of prior COVID-19 vaccine doses received significantly predicted willingness to receive future vaccine doses. The study suggests that key social factors such as racial discrimination may play an important role in influencing public health efforts to promote vaccine uptake in diverse Asian American populations.

Dentists are well-positioned to discuss oral health issues related to Human Papillomavirus (HPV) and recommend the HPV vaccine to their patients, mainly because the HPV virus causes oropharyngeal cancers.. We assessed Los Angeles (LA) County dentists opinions on discussing HPV-related oral health issues and recommending the HPV vaccine to their patients. We tested if opinions differed between dentists whose primary patient population was only adults versus children and adults. We mailed a 19-item survey to 2000 randomly sampled LA County dentists for this cross-sectional study. The primary outcome variable was a summary opinion score of 7 opinion statements. We ran descriptive, bivariate comparisons and adjusted linear regression models. Overall, 261 dentists completed the survey. A majority (58.5%) worried they would lose patients if they recommended the vaccine; 49% thought dentists were not appropriate to educate, counsel, or advise on HPV-related issues; 42% were concerned about the safety of the vaccine; and 40% did not feel comfortable recommending the vaccine. The mean summary opinion score was 21.4 ± 5.4 for the total sample. Regression analysis showed no differences in opinions between dentists whose primary patient population was only adults versus children and adults (Coefficient = 0.146, p = 0.83). Overall, the responding dentists were not very favorable about discussing oral health-related HPV issues and recommending the HPV vaccine to their patients. Additionally, the overall opinions were similar between dentists whose primary patient population was only adults versus children and adults.

Substantial evidence indicates that medical mistrust, resulting from experiences with discrimination and marginalisation, is a determinant of health disparities in minority populations. However, this research is largely limited to the US and other industrialised countries. To broaden our understanding of the role of medical mistrust on health-care decision making, we conducted a study on healthcare experiences and perceptions in a rural, underserved indigenous community in northwest Namibia (n = 86). Mixing semi-structured interview questions with the medical mistrust index (MMI), we aim to determine the relevance of the MMI in a non-industrialised population and compare index scores with reports of healthcare experiences. We find that medical mistrust is a salient concept in this community, mapping onto negative healthcare experiences and perceptions of discrimination. Reported healthcare experiences indicate that perceived incompetence, maltreatment and discrimination drive mistrust of medical personnel. However, reporting of recent healthcare experiences are generally positive. Our results indicate that the concept of medical mistrust can be usefully applied to communities in the Global South. These populations, like minority communities in the US, translate experiences of discrimination and marginalisation into medical mistrust. Understanding these processes can help address health disparities and aid in effective public health outreach in underserved populations.

PurposeThis study sought to understand family functioning surrounding weight in Mexican American women with obesity.MethodsSemi-structured in-depth interviews were conducted with mothers and adult daughters (N = 116).ResultsThematic analysis identified five themes. 1) The communication process drives perception of supportive messages. Messages perceived as non-supportive consist of directives as interventions, confirmation of faults, and critical compliments whereas supportive consist of compliments, encouragement, empathetic listening, and disclosure. 2) Acculturation differences interfere with intergenerational alliance. Differences involve dissonance in communication, behavioural expectations, and weight-related practices. 3) Maladaptive conflict responses contribute to relational strain. These responses include avoidance, withdrawal, and defensiveness. 4) Role transformations alter the generational hierarchical relationship. Daughters serve as role models, caregivers, or collaborators. 5) Low communal coping heightens psychological distress. It does so by challenging family roles, increasing social isolation, and compromising social support.ConclusionObesity interventions for Mexican American women may benefit from targeting relational skills to improve family functioning.

INTRODUCTION: Amid the spread of the novel coronavirus (COVID-19), racially and economically marginalized communities experienced a disproportionate burden of disease and social consequences (e.g., unemployment, increased exposure). This study seeks to understand strategies that these communities employed to cope with unequal burdens of the pandemic. METHODS: We utilized qualitative data collected between 2020 and 2021 from a mobile mapping platform designed to facilitate real-time, geocoded data collection on individuals experiences and perceptions of their neighborhoods. Reports were iteratively coded by an academic researcher and community partner. We employed an inductive approach to analysis, which allowed findings to emerge organically without constraint of researcher hypotheses. RESULTS: A total of 19 respondents (14 under the age of 45, 16 non-White, 15 with less than half a year of emergency savings) provided 236 qualitative reports. Participants described innovative strategies for exchanging resources as a means of informally networking and building community, the importance of tailored programming (e.g., for specific racial/ethnic groups) in fostering belonging and comfort, and the importance of two specific dimensions of services-interactions with service providers and the quality of goods or services-in providing dignified care. DISCUSSION: Amidst exacerbated racial and economic disparities emerging from the COVID-19 pandemic, our study highlights the need for investment in mutual aid, the importance of tailored services and support, and promoting dignity in social services. As other macro-level social stressors become more prevalent as the pandemic continues, these findings can inform how we examine and address them.

OBJECTIVE: To determine the budget impact of implementing multidisciplinary complex pain clinics (MCPCs) for Veterans Health Administration (VA) patients living with complex chronic pain and substance use disorder comorbidities who are on risky opioid regimens. DATA SOURCES AND STUDY SETTING: We measured implementation costs for three MCPCs over 2 years using micro-costing methods. Intervention and downstream costs were obtained from the VA Managerial Cost Accounting System from 2 years prior to 2 years after opening of MCPCs. STUDY DESIGN: Staff at the three VA sites implementing MCPCs were supported by Implementation Facilitation. The intervention cohort was patients at MCPC sites who received treatment based on their history of chronic pain and risky opioid use. Intervention costs and downstream costs were estimated with a quasi-experimental study design using a propensity score-weighted difference-in-difference approach. The healthcare utilization costs of treated patients were compared with a control group having clinically similar characteristics and undergoing the standard route of care at neighboring VA medical centers. Cancer and hospice patients were excluded. DATA COLLECTION/EXTRACTION METHODS: Activity-based costing data acquired from MCPC sites were used to estimate implementation costs. Intervention and downstream costs were extracted from VA administrative data. PRINCIPAL FINDINGS: Average Implementation Facilitation costs ranged from $380 to $640 per month for each site. Upon opening of three MCPCs, average intervention costs per patient were significantly higher than the control group at two intervention sites. Downstream costs were significantly higher at only one of three intervention sites. Site-level differences were due to variation in inpatient costs, with some confounding likely due to the COVID-19 pandemic. This evidence suggests that necessary start-up investments are required to initiate MCPCs, with allocations of funds needed for implementation, intervention, and downstream costs. CONCLUSIONS: Incorporating implementation, intervention, and downstream costs in this evaluation provides a thorough budget impact analysis, which decision-makers may use when considering whether to expand effective programming.

Uptake of pre-exposure prophylaxis medication (PrEP) to prevent HIV among people who inject drugs (PWID) remains extremely low in the United States. West Virginia's rising HIV incidence and highest drug overdose rate in the nation makes it an important locus for opioid use and HIV risk interaction. In this pilot study we pioneered the use of Cultural Theory among PWID to understand HIV-related risk perception arising from four contrasting modes of social organization. Carried out during an HIV outbreak, we explored PrEP uptake qualitatively as a window onto risk perception. Of the 26 interviewees, 18 were HIV- and despite the medication's free availability from the health center where recruitment took place, none had taken PrEP, half considering they were not at risk. Intimate couples who showed characteristics of 'enclaves' considered the boundary around themselves protective against HIV, creating a safe space or 'invisible risk group'. Higher HIV risk was perceived among those who were housed compared to those living homeless. Beliefs about the causation of the local HIV outbreak and the validity of scientific research corresponded with characteristics of the contrasting modes of social organization and the approach is promising for informing public health interventions among PWID.

BACKGROUND AND PURPOSE: The efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG) were demonstrated in the CHAMPION MG study (NCT03920293). This analysis aimed to characterize the latency to onset of a clinically meaningful therapeutic effect for ravulizumab. METHODS: Post hoc analysis of data collected for up to 60 weeks from CHAMPION MG was performed to assess the timing of response to ravulizumab. Response was analyzed based on reductions of ≥2 and ≥3 points (minimal clinically important differences [MCIDs]) in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores, respectively, and on more rigorous reductions of ≥3 and ≥5 points, respectively. Time to first response was assessed using the Kaplan-Meier product-limit method. RESULTS: The median (95% confidence interval) time to first response was 2.1 (2.1-2.6) and 4.1 (2.3-10.0) weeks for reductions of ≥2 and ≥3 points in MG-ADL total score, respectively (n = 139), and 4.1 (2.1-10.0) and 18.3 (11.0-33.4) weeks for reductions of ≥3 and ≥5 points in QMG total score, respectively (n = 134). Cumulative response rates at Week 60 (data cut-off) were 88% and 82% for ≥2- and ≥3-point MG-ADL score reductions, respectively, and 86% and 59% for ≥3- and ≥5-point QMG score reductions, respectively. CONCLUSIONS: The median times to MCID with ravulizumab treatment in patients with AChR Ab+ gMG were ~2 weeks and ~4 weeks based on MCID MG-ADL and QMG total score reductions, respectively.

BACKGROUND: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. METHODS: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. RESULTS: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p

BACKGROUND: Renal dysfunction is a common complication following liver transplantation (LT). This study aimed to determine whether a comprehensive assessment of kidney function using nineteen serum and urinary biomarkers (BMs) within the first 48 h post-LT could enhance the prediction of severe acute kidney injury (AKI) and the need of kidney replacement therapy (KRT) during the first postoperative week. METHODS: Blood and urine (U) samples were collected during the pre- and postoperative periods. Nineteen BMs were evaluated to assess kidney health in the first 48 h after LT. Classification and regression tree (CART) cross-validation identified key predictors to determine the best BM combination for predicting outcomes. RESULTS: Among 100 LT patients, 36 developed severe AKI, and 34 required KRT within the first postoperative week. Preoperative assessment of U neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) predicted the need for KRT with 75% accuracy. The combined assessment of U osmolality (OSM), U kidney injury molecule 1 (KIM-1), and tissue inhibitor of metalloproteinase (TIMP-1) within 48 h post-LT predicted severe AKI with 80% accuracy. U-OSM alone, measured within 48 h post-LT, had an accuracy of 83% for predicting KRT need, outperforming any BM combination. CONCLUSIONS: Combined BM analysis can accurately predict severe AKI and KRT needs in the perioperative period of LT. U-OSM alone proved to be an effective tool for monitoring the risk of severe AKI, available in most centers. Further studies are needed to assess its impact on AKI progression postoperatively.Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB) and identifier NCT02095431.

PURPOSE: Patients with invasive lobular carcinoma (ILC) face high rates of positive margins and completion mastectomy, which can be improved with the use of specific techniques, such as oncoplastic surgery. However, prior studies have shown that type of breast cancer surgery performed is also associated with patient factors such as elevated body mass index (BMI). Thus, this study investigates whether BMI impacts the type of surgical interventions in patients with ILC. METHODS: A retrospective analysis of 705 patients with stage I-III ILC from an institutional database was conducted. Patients were stratified by BMI (underweight, normal weight, overweight, obese). Pearsons Chi-square, ANOVA, and multivariable logistic regression were used to evaluate the relationship between BMI and surgical procedures. RESULTS: Breast-conserving surgery (BCS) was the initial operation in 60% of patients, with no significant difference by BMI. Among those undergoing BCS, patients with obese BMI were significantly more likely to undergo oncoplastic surgery (46.9% vs. 7.7%, 37.3%, and 33.6% for underweight, normal, and overweight, respectively, p = 0.032). Obese BMI patients undergoing mastectomy were less likely to have reconstruction compared to those with underweight, normal weight, and overweight BMI (44.2% vs. 50%, 71.1%, and 64.1%, p = 0.002). CONCLUSION: Overweight/obese BMI patients with ILC underwent different surgical interventions compared to those with lower BMI. While initial BCS rates were similar, overweight/obese patients had higher oncoplastic surgery rates in BCS and lower reconstruction rates in mastectomy. Further research is needed to understand BMIs impact on surgical decisions and outcomes in ILC.

Measures of life outlook in older adults have been investigated in connection to pain, as both pain management and outlook are important factors of successful aging. We hypothesized that higher pain is associated with lower optimism among community-dwelling older adults. We utilized data from the UC San Diego Successful Aging Evaluation (SAGE), a prospective longitudinal cohort study initiated in 2010, to evaluate the relationship between pain and optimism in 378 community-dwelling adults aged ≥50 years. We used the revised Life Orientation Test (LOT-R) to measure optimism and three pain subscales-PROMIS Pain Interference, PROMIS Pain Intensity, and MOS 36-Item Short-Form Health Survey (SF-36)-as pain measures. Regression analyses reveal negative relationships between pain and optimism for all three pain scales, with regression coefficients of -0.277 (p

Cytomegalovirus (CMV) infection and reactivation in solid organ transplant (SOT) recipients increases the risk of viremia, graft failure and death. Clinical studies of CMV serostatus indicate that donor positive recipient negative (D+/R-) patients have greater viremia risk than D-/R-. The majority of patients are R+ having intermediate serologic risk. To characterize the long-term impact of CMV infection and assess viremia risk, we sought to measure the effects of CMV on the recipient immune epigenome. Specifically, we profiled DNA methylation in 156 individuals before lung or kidney transplant. We found that the methylome of CMV positive SOT recipients is hyper-methylated at loci associated with neural development and Polycomb group (PcG) protein binding, and hypo-methylated at regions critical for the maturation of lymphocytes. In addition, we developed a machine learning-based model to predict the recipient CMV serostatus after correcting for cell type composition and ancestry. This CMV episcore measured at baseline in R+ individual stratifies viremia risk accurately in the lung transplant cohort, and along with serostatus the CMV episcore could be a potential biomarker for identifying R+ patients at high viremia risk.

INTRODUCTION: A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. METHODS: A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. RESULTS: Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann-Whitneys test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p

BackgroundOral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings.MethodsHIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentrations in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies.ResultsAmong 17 274 participants, there were 101 cases with new HIV-1 diagnosis (.77 per 100 person-years; 95% confidence interval [CI]: .63-.94). In 78 cases with resistance data, 18 (23%) had M184I or V, 1 (1.3%) had K65R, and 3 (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of

Liquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers. In this study, we analyze orphan non-coding RNAs (oncRNAs) from serum samples of 1050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls. We demonstrate that our multi-task generative AI model, Orion, surpasses commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieves an overall sensitivity of 94% (95% CI: 87%-98%) at 87% (95% CI: 81%-93%) specificity for cancer detection across all stages, outperforming the sensitivity of other methods on held-out validation datasets by more than  ~ 30%.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells (the HIV reservoir) which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people living with HIV (PLWH) treated during acute infection, we developed a mathematical model to predict reservoir decay from peripheral CD4 + T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t1/2 ~ 2.83 weeks; week 5-24: t1/2 ~ 15.4 weeks) that extended out to 1 year. These estimates were ~5-fold faster than prior decay estimates among chronic treated PLWH. Defective DNA had a similar biphasic pattern, but data were more variable. Predicted intact and defective decay rates were faster for PLWH with earlier timing of ART initiation, higher initial CD4 + T cell count, and lower pre-ART viral load. In this study, we advanced our limited understanding of HIV reservoir decay at the time of ART initiation, informing future curative strategies targeting this critical time.

Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general populations yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m2, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p

The Zika virus (ZIKV) epidemic in Latin America (2015-2016) has primarily been studied in urban centers, with less understanding of its impact on smaller rural communities. To address this gap, we analyzed ZIKV seroepidemiology in 6 rural Ecuadorian communities (2018-2019) with varying access to a commercial hub. Seroprevalence ranged from 19% to 54%, measured by nonstructural protein 1 blockade of binding enzyme-linked immunosorbent assay. We observed a decline in ZIKV seroprevalence between 2018 and 2019 that was greater among younger populations, suggesting that the attack rates in the 2015-2016 epidemic were significantly higher than our 2018 observations. These data indicate that the 2015-2016 epidemic included significant transmission in rural and more remote settings. Our observations of high seroprevalence in our area of study highlights the importance of surveillance and research in rural areas lacking robust health systems to manage future Zika outbreaks and vaccine initiatives.

Human leukocyte antigen (HLA) class I/killer cell immunoglobulin-like receptor (KIR) genotypes influence human immunodeficiency virus type 1 (HIV-1) disease progression and viral load, but their role in primary infection is uncertain. Inconsistent results from previous studies suggest that the inoculum size and transmission route-parenteral versus sexual-may influence this association. We conducted a genome-wide association study in a population of people with HIV-1 and HIV-1-exposed seronegative individuals exposed to the virus through the sexual route. Our data do not support any role of the HLA/KIR system in susceptibility to sexually transmitted HIV-1 infection. The genetics basis of HIV-1 viral load and disease progression are distinct from the genetics of HIV resistance, a paradox worth exploring.

BACKGROUND: Lipid-lowering therapy (LLT) plays a central role in managing atherosclerotic cardiovascular disease (ASCVD) risk, but its underuse is reported in over 40% of the qualified population in the United States. Studies on factors, particularly actionable factors associated with guideline-directed LLT are limited. METHODS: This study evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA) on their qualification for LLT at exam 5 (2010-2012) according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on cholesterol management. Participants were categorized as on-LLT or off-LLT at the following exam (2016-2018). Multi-variable relative risk (RR) models were used to analyze between LLT usage and factors prior to 2013, including age, gender, race/ethnicity, education level and medical insurance, income, smoking, body mass index (BMI), diabetes, hypertension, and presence of coronary artery calcium (CAC). RESULTS: Among the 2114 participants qualified for LLT at exam 5 with an average age of 70.7, 1,129 (53.4%) were on LLT while 985 (46.6%) were off LLT at exam 6. Black participants were less likely to be on LLT compared to the reference white participants (RR 0.80, 95% confidence interval CI 0.71-0.90). Higher BMI showed borderline significant association with LLT. Comorbidities of diabetes and hypertension were positively associated with LLT use (RR 1.39 and 1.23, 95% CI 1.27-1.52 and 1.10-1.36, respectively). CAC score > 0 as an indicator of subclinical ASCVD was strongly associated with LLT too, independent of other demographic or comorbidity factors (RR 1.38, 95% CI 1.21-1.56). CONCLUSIONS: This study identifies key factors influencing LLT use among MESA participants. Black participants were less likely to be on LLT, highlighting healthcare disparities. CAC presence was strongly associated with LLT use, suggesting that CAC measurement could be an actionable factor to improve adherence to LLT guidelines.

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

BACKGROUND: Time and money are limited resources to pursue quality improvement (QI) goals. Computer simulation using Monte Carlo methods may help focus resources towards the most efficacious interventions to pursue. METHODS: This observational, cross-sectional study analysed the length of stay (LOS) for adult American Society of Anesthesiologists (ASA) 1-3 patients in the postanaesthesia care unit (PACU) at a major academic medical centre. Data were collected retrospectively from 1 April 2023 to 31 March 2024. Statistical analysis with Monte Carlo methods simulated the per cent reduction in PACU LOS following the elimination of postoperative nausea and vomiting (PONV), hypothermia (initial temperature

Tools for rapid identification of novel and/or emerging viruses are urgently needed for clinical diagnosis of unexplained infections and pandemic preparedness. Here we developed and clinically validated a largely automated metagenomic next-generation sequencing (mNGS) assay for agnostic detection of respiratory viral pathogens from upper respiratory swab and bronchoalveolar lavage samples in

BACKGROUND: Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3 days or more). METHODS: LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported. RESULTS: 294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2 days, vs 28.3 days with caspofungin, and mean ICU LoS was 16.1 vs 21.6 days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1 days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5-6 days earlier. CONCLUSIONS: Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting. TRIAL REGISTRATION: NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016).

STUDY OBJECTIVES: Post hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal. METHODS: We studied sleep architecture in adults with chronic insomnia disorder from two randomized phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg). We analyzed sleep-wake transition probabilities, EEG spectra, and sleep spindle properties including density, dispersion, and slow oscillation phase coupling. The wake EEG similarity index (WESI) was determined using a machine learning algorithm analyzing the spectral profile of the EEG. RESULTS: At month 3, daridorexant 50 mg decreased wake-to-wake transition probabilities (p

Kinesiophobia, the fear of movement, can significantly impede an individuals ability to engage in daily activities. This fear often stems from past traumatic experiences or witnessing others in pain, leading to an increased fear of injury. This study aimed to evaluate the psychometric properties of the Persian version of the Tampa Scale for Kinesiophobia among Iranian post-surgery patients. A methodological study conducted in 2023 involved a sample of 400 post-surgery patients selected through convenience sampling. The translated scale underwent psychometric evaluation, including network analysis, exploratory and confirmatory factor analysis for construct validity, as well as assessments for convergent and discriminant validity. Internal consistency of the scale was also assessed. The mean age of the participants was 44.38 (SD = 13.49) years and the majority of them (77.8%) were women. Exploratory factor analysis with Promax rotation identified two factors explaining 60.28% of the variance, comprising 17 items. The final model was confirmed after necessary adjustments in confirmatory factor analysis. Both convergent and discriminant validity were established, and alpha and omega coefficients of the subscales were above 0.7. The Persian version of the Tampa Scale for Kinesiophobia showed robust psychometric properties among Iranian post-surgery patients, serving as a valuable tool for evaluating and addressing kinesiophobia in this population. These findings enhance the understanding and management of kinesiophobia within the Iranian healthcare context.

INTRODUCTION: The central biochemical cause of gout is hyperuricemia (elevated serum urate levels). Ultrasound features of monosodium urate (MSU) crystal deposition are common in people with asymptomatic hyperuricemia. However, it is unclear whether this is a precondition for the development of gout. This study aims to determine whether ultrasound imaging evidence of MSU crystal deposition predicts development of symptomatic gout over 5 years, in people who already have an increased risk of gout due to elevated serum urate concentrations (≥8 mg/dL). METHODS AND ANALYSIS: This is a prospective, international, multicentre study. The study population comprises over 250 participants with asymptomatic hyperuricemia (serum urate ≥8.0 mg/dL). After the baseline assessments, participants are followed for 5 years or until the development of gout, defined by the 2015 American College of Rheumatology/European Alliance of Associations for Rheumatology gout classification criteria. Baseline assessments include anthropomorphic measures, laboratory tests, questionnaires, blood and urine specimen collection, plain radiographs of the feet and standardised ultrasound scans of the lower limbs, scored according to the Outcomes in Rheumatology (OMERACT) gout ultrasound scoring system. The primary outcomes are the development of gout and time course for development of gout in people with and without ultrasound evidence of MSU crystal deposition. Exploratory analyses will examine clinical, genetic and biological factors associated with development of MSU crystal deposition and gout. ETHICS AND DISSEMINATION: This study protocol was approved by the New Zealand Ministry of Health Southern Health and Disability Ethics Committee (MEC/05/10/130/AM16) on 18 December 2018. The findings from this study will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000915156.

Under compassionate use, chimeric antigen receptor (CAR) T cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIMs). Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T cell therapy (CABA-201) in the RESET-Myositis phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was observed. Creatine kinase levels decreased, and muscular strength improved post-infusion. Peripheral B cells were depleted rapidly following infusion, and the subject achieved peripheral B cell aplasia by day 15 post-infusion. Peripheral B cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline, whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4+ effector memory T cells and exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.

BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

BACKGROUND: Dark-field radiography imaging exploits the wave character of x-rays to measure small-angle scattering on material interfaces, providing structural information with low radiation exposure. We explored the potential of dark-field imaging of bone microstructure to improve the assessment of bone strength in osteoporosis. METHODS: We prospectively examined 14 osteoporotic/osteopenic and 21 non-osteoporotic/osteopenic human cadaveric vertebrae (L2-L4) with a clinical dark-field radiography system, micro-computed tomography (CT), and spectral CT. Dark-field images were obtained in both vertical and horizontal sample positions. Bone microstructural parameters (trabecular number, Tb.N; trabecular thickness, Tb.Th; bone volume fraction, BV/TV; degree of anisotropy, DA) were measured using standard ex vivo micro-CT, while hydroxyapatite density was measured using spectral CT. Correlations were assessed using Spearman rank correlation coefficients. RESULTS: The measured dark-field signal was lower in osteoporotic/osteopenic vertebrae (vertical position, 0.23 ± 0.05 versus 0.29 ± 0.04, p

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32-72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14-40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

BACKGROUND: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. METHODS: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. RESULTS: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. CONCLUSIONS: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. TRIAL REGISTRATION NUMBER: NCT04510129.

BACKGROUND: We previously showed worse outcomes among lower socioeconomic status (SES) groups following metabolic/bariatric surgery (MBS). In light of healthcare changes in response to COVID-19, this study aims to evaluate post-pandemic MBS outcomes and determine if prior socioeconomic disparities persisted in the post-COVID era. METHODS: A retrospective chart review of patients undergoing primary Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) between 2015 and 2022 was performed. Patients were stratified into pre- and post-COVID groups. Post-COVID cohort was further stratified into high (HT) and low (LT) tier status based on Distressed Communities Index, a geocoded composite measure of SES. Preoperative characteristics and postoperative outcomes were compared between pre- and post-COVID cohorts, as well as between post-COVID HT and LT groups. RESULTS: Of 709 patients, 82.9% were pre-COVID and 17.1% were post-COVID. Post-COVID cohort had greater rate of public insurance (46% vs. 37%, p

OBJECTIVE: The aim of this study was to analyze the origins of prostatic arteries (PAs) in the Korean population and compare them with those reported in the literature. MATERIALS AND METHODS: From April 2018 to February 2024, 108 male (mean age ± standard deviation: 71.6 ± 9.7 years) with lower urinary tract symptoms (n = 102) or refractory hematuria (n = 6) underwent prostatic artery embolization (PAE). Computed tomography and angiography images were retrospectively reviewed. The branching pattern of the internal iliac artery (IIA) was classified according to the Yamaki system. The origin of the PA was categorized using the de Assis definition, and the incidence of each type was recorded. A systematic literature review was conducted and the most common types of PA were investigated. RESULTS: PAE was successfully implemented on 211 of the 216 pelvic sidewalls. PA cannulation failed in five sidewalls due to a steno-occlusive state. The most common IIA type was type A, in which the IIA was divided into the superior gluteal artery and gluteal-pudendal trunk (77%). Of 226 PAs analyzed, including 15 in 211 sidewalls exhibiting dual PAs, the most common PA origin was the internal pudendal artery (type IV, 35%), followed by the superior vesical (type I, 25%) and obturator (type III, 21%) arteries. Anterior division of IIA (type II) was less common (10%). Type V (uncommon origins) occurred in 8% of cases, including five distal internal pudendal arteries, four quadfurcations, three inferior gluteal arteries, three trifurcations, two medial femoral circumflex arteries, and two rectal arteries. Two of the five patients with surgically or endovascularly altered anatomy were successfully treated via PAs originating from the medial femoral circumflex arteries. Globally, type I is the most common PA type. CONCLUSION: In the Korean population, the most common IIA pattern and PA origin were types A and IV, respectively.

PURPOSE: Women with obesity are more likely to experience bothersome urinary and sexual symptoms, but the long-term effect of metabolic and bariatric surgery (MBS) on these outcomes is poorly understood. We aimed to describe how MBS longitudinally impacted womens urinary and sexual health. METHODS: Patients who underwent MBS at the University of California, San Francisco Medical Center (UCSF) between 2009 and 2021 participated in a survey examining sexual health, pelvic organ prolapse (POP), and urinary health using three validated questionnaires: a modified version of the Female Sexual Function Index (FSFI), the Pelvic Organ Prolapse Distress Inventory 6 (POPDI-6), and the Urinary Distress Inventory 6 (UDI-6). All questions asked referenced two time points: before surgery and at the time of survey. Logistic regression identified predictors of symptom improvement. RESULTS: Of 162 participants contacted, 118 (73%) had complete survey data. Mean body mass index (BMI) decreased from 52.4 ± 12.6 to 36.3 ± 9.7 kg/m2 (p

Natural disasters trigger complex chains of events within human societies1. Immediate deaths and damage are directly observed after a disaster and are widely studied, but delayed downstream outcomes, indirectly caused by the disaster, are difficult to trace back to the initial event1,2. Tropical cyclones (TCs)-that is, hurricanes and tropical storms-are widespread globally and have lasting economic impacts3-5, but their full health impact remains unknown. Here we conduct a large-scale evaluation of long-term effects of TCs on human mortality in the contiguous United States (CONUS) for all TCs between 1930 and 2015. We observe a robust increase in excess mortality that persists for 15 years after each geophysical event. We estimate that the average TC generates 7,000-11,000 excess deaths, exceeding the average of 24 immediate deaths reported in government statistics6,7. Tracking the effects of 501 historical storms, we compute that the TC climate of CONUS imposes an undocumented mortality burden that explains a substantial fraction of the higher mortality rates along the Atlantic coast and is equal to roughly 3.2-5.1% of all deaths. These findings suggest that the TC climate, previously thought to be unimportant for broader public health outcomes, is a meaningful underlying driver for the distribution of mortality risk in CONUS, especially among infants (less than 1 year of age), people 1-44 years of age, and the Black population. Understanding why TCs induce this excess mortality is likely to yield substantial health benefits.

BACKGROUND: Type 2 diabetes is a major public health concern in the United States and worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease. OBJECTIVE: The aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Womens Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes. DESIGN: Participants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the United States. DII/E-DII scores were calculated from a self-administered food frequency questionnaire at baseline that included 122 food items, of which 12 are representative of Hispanic eating patterns. PARTICIPANTS/SETTINGS: Participants included 3,849 postmenopausal women who self-identified as Hispanic that were recruited for the WHI from 1993 to 1998 at 40 US clinical centers. MAIN OUTCOME MEASURES: The outcome was incident diabetes. STATISTICAL ANALYSIS PERFORMED: Cox regression models were used to assess the association between DII/E-DII and incident diabetes. Models were adjusted for age at baseline, lifestyle-related risk factors, known type 2 diabetes mellitus (T2DM) risk factors, and neighborhood socioeconomic status. Interaction was tested between the DII/E-DII scores and obesity. RESULTS: The incidence of diabetes was 13.1% after a median follow-up of 13 years. Higher E-DII scores were associated with a higher risk of incident diabetes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04-1.14). There was no interaction between E-DII scores and obesity (P = 0.73). CONCLUSIONS: Pro-inflammatory diets, as measured by higher E-DII scores, were associated with a higher risk of incident diabetes. Future research is needed for understanding how the inflammatory potential of diets can be decreased.

PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

PURPOSE: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. PATIENTS AND METHODS: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity. RESULTS: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors. CONCLUSIONS: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

BackgroundThe cumulative, health system-wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real-world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system-wide survival impact of ICIs.MethodsWe identified all patients receiving PD-1/PD-L1 or CTLA-4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non-ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer-related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life-years gained system-wide were calculated from the difference in adjusted 5-year restricted mean survival times.ResultsThere were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54-0.58, p

BACKGROUND: Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location. METHODS: The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint regression analysis. RESULTS: From 1999 to 2022, a total of 273,761 CAD and obesity-related deaths were recorded in the United States. The AAMR increased consistently from 1999 to 2018 (APC: 4.3, 95% confidence interval (CI): 3.4-4.9) and surged thereafter till 2022 (APC: 11.4; 95% CI: 7.7-19.1). During the COVID-19 pandemic (2020-2022), AAMR almost doubled that of the rest of the study period. Additionally, the AAMR for males was nearly twice that of females. Non-Hispanic (NH) Blacks or African Americans displayed the highest AAMR, followed by NH Whites, Hispanic or Latino, and other NH populations. AAMRs showed minimal variation by census regions. Rural areas exhibited a higher AAMR (AAMR: 5.9, 95% CI: 5.8-5.9) than urban areas (AAMR: 4.4, 95% CI: 4.4-4.5). CONCLUSIONS: We observed increasing trends in CAD and obesity-related deaths throughout the study period reaching a peak during the COVID-19 pandemic.

BACKGROUND: Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. METHODS: Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction. FINDINGS: We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. INTERPRETATION: This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis. FUNDING: This work was supported by the US NIH and FAPESP.

BACKGROUND: Although mindfulness-based interventions (MBIs) are widely used in clinical and nonclinical settings, there has been little systematic study of their potential risks. To address this gap, we examined differences in psychological and physical worsening among participants in the usual care and intervention conditions of a 3-group, randomized pragmatic trial (Learning to Apply Mindfulness to Pain [LAMP]) that tested the effectiveness of 2 approaches to delivering MBIs to patients with chronic pain. METHODS: The sample consisted of 374 male and 334 female patients with chronic pain enrolled in the LAMP trial who completed a 10-week follow-up survey, 61% of whom had a mental health diagnosis. Psychological and physical worsening was assessed by a checklist asking whether participants experienced specific symptoms since beginning the study. We used multivariable logistic regression models with imputed data to determine whether predicted probabilities of increased symptoms differed between usual care and the 2 MBIs. RESULTS: Participants in usual care were more likely to report experiencing increased psychological and physical worsening than were those in the MBIs, including an increase in disturbing memories; sadness, anxiousness, and fatigue; isolation and loneliness; and feeling more upset than usual when something reminded them of the past. CONCLUSIONS: MBIs do not appear to cause harm, in terms of increased symptoms, for this population of patients with chronic pain and high levels of mental health comorbidities. CLINICAL TRIAL REGISTRATION: Preregistration with an analysis plan at www.ClinicalTrials.gov: NCT04526158. Patient enrollment began December 4, 2020.

IntroductionThe potential utility of subjective cognitive decline (SCD) as an early risk marker of Alzheimer's disease and related dementias is under consideration. We examined associations between SCD and cognitive change among middle-aged and older Hispanic/Latino adults living in the United States.MethodsThe short-form Everyday Cognition Scale (ECog-12) was assessed to generate global, executive function, and memory-related SCD scores. We used survey generalized regressions to model the change in learning, memory, verbal fluency, executive function, and global cognitive performance over 7 years as a function of SCD (at Visit 2).ResultsThe mean age was 56.37 ± 8.10 years at Visit 1 (n = 6225). Higher ECog-12 was associated with greater decline in global cognitive performance (ECog-12 global: B = -0.17, standard error [SE] = 0.02; ECog-12 executive: B = -0.15, SE = 0.02; ECog-12 memory: B = -0.14, SE = 0.02, p's

BACKGROUND: Worsening renal function (WRF) is common in hospitalized patients being treated for acute heart failure. However, discriminating clinically significant WRF remains challenging. In patients hospitalized with acute heart failure, we evaluated if blood and urine biomarkers of cardiac and kidney dysfunction were associated with adverse outcomes. METHODS: We identified 175 of 927 participants in the AKINESIS study (Acute Kidney Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) who met criteria for stage 1 or 2 Kidney Disease: Improvement Global Outcomes acute kidney injury during the first 3 days of hospitalization. We measured 24 blood and urine biomarkers from specimens collected within 24 hours of meeting acute kidney injury criteria. The primary composite outcome consisted of worsening WRF (higher acute kidney injury stage), need for dialysis, or death at 30 days. Biomarkers association with the composite outcome was assessed with logistic regression by tertiles and area under the curve (AUC). RESULTS: Of the 175 participants, 32 (18%) developed the primary composite outcome. Only history of chronic kidney disease was significantly different between those with and without the composite outcome. The highest tertile of plasma Gal-3 (galectin-3) and urine epidermal growth factor were associated with increased odds of the composite outcome compared with the lowest tertile in unadjusted analyses. After adjusting for serum creatinine, systolic blood pressure, and blood urea nitrogen, only the highest tertile of Gal-3 was associated with greater odds of the composite outcome (odds ratio, 4.6 [95% CI, 1.4-16.0). Gal-3 had the highest AUC (0.70 [95% CI, 0.58-0.82]), while epidermal growth factor had a lower AUC (0.63 [95% CI, 0.53-0.74]). Notably, urine biomarkers of kidney tubule injury were not associated with the composite outcome. CONCLUSIONS: Tubular injury does not occur in most patients with acute heart failure experiencing WRF, consistent with the functional mechanisms of WRF in this patient population. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT01291836?term=NCT01291836&rank=1; Unique identifier: NCT01291836.

BACKGROUND: The pandemic rapidly expanded telemedicine, which has persisted as a widely available primary care modality. The uptake of telemedicine among people with dementia specifically in the primary care setting, who have more complex care needs but also benefit from more accessible primary care, is unknown. OBJECTIVE: Among people with dementia, assess uptake of telemedicine-based primary care in the post-pandemic period and determine associations with key socio-demographic characteristics. DESIGN: Retrospective observational study. SUBJECTS: People with dementia at UCSF and Kaiser Permanente Northern CA (KPNC) with at least one primary care encounter in pre- (3/1/2019-2/29/2020) or post-COVID (3/1/2021-2/28/2022) periods, post-COVID sample: N= 419 individuals (UCSF), N=18,037 (KPNC). MAIN MEASURES: Encounter modality: in-person, video telemedicine, or telephone telemedicine. Focal socio-demographic characteristics: age, limited English proficiency, socioeconomic status, driving distance to clinic, and caregiver at encounter. KEY RESULTS: There was a large increase in telemedicine among people with dementia in the post-pandemic period at both sites. At KPNC, those with only in-person primary care visits shrunk from 60.47% (pre) to 26.95% (post). At UCSF, the change was even greater: 98.99% to 35.08%. Across both sites, the only measure significantly associated with use of telemedicine was greater driving distance from home to clinic. At KPNC, those over age 90 were most likely to use telemedicine while patients with limited English proficiency and those with a caregiver at the encounter used telemedicine at lower levels. The relationships were similar at UCSF but not statistically significant. CONCLUSIONS: Telemedicine use is high for people with dementia in the primary care setting in the post-pandemic period. Those with longer drives to clinic and the oldest patients were most likely to use telemedicine, likely due to challenges traveling to appointments. Still, not all people with dementia used telemedicine equally-particularly those with limited English proficiency.