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BACKGROUND: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t 1/2eff and terminal half-life (t 1/2z ) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). METHODS: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T 1/2eff was estimated using within-participant accumulation ratios. T 1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. RESULTS: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t 1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t 1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t 1/2eff and t 1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. CONCLUSIONS: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t 1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

OBJECTIVES: There is growing interest in assessing patient quality of life (QOL) following treatment of sinonasal tumors, including inverted papilloma (IP). We aimed to elucidate the natural history of postoperative QOL outcomes in IP patients treated with surgery. METHODS: Cases of sinonasal IP treated surgically at 4 tertiary academic rhinology centers were retrospectively reviewed. SNOT-22 scores were used to evaluate QOL preoperatively and postoperatively (1, 3, 6, 12 months). Repeated-measures ANOVA assessed for differences in mean scores over time. Linear regression identified factors associated with QOL longitudinally. RESULTS: 373 patients were analyzed. Mean preoperative SNOT-22 score was 20.6 ± 20.4, which decreased to 16.3 ± 18.8 (p = 0.041) and 11.8 ± 15.0 (p  0.05). When analyzed by SNOT-22 subdomains, nasal, sleep, and otologic/facial subdomain scores (all p  0.05). CONCLUSIONS: QOL outcomes related to IP resection are largely driven by nasal, sleep, and otologic/facial subdomains, though patients appear to experience enduring improvement as early as 3 months postoperatively. Recurrent disease is a major driver of negative QOL. LEVEL OF EVIDENCE: 4 Laryngoscope, 135:579-585, 2025.

BACKGROUND: Nonthermal, pulsed shortwave (radiofrequency) therapy (PSWT) is a nonpharmacologic, noninvasive modality that limited evidence suggests provides analgesia. Its potential favorable risk-benefit ratio stems from its lack of side effects and significant medical risks, applicability to any anatomic location, long treatment duration, and ease of application by simply affixing it with tape. Even with a relatively small treatment effect, PSWT might contribute to a multimodal analgesic regimen, similar to acetaminophen. However, widespread clinical use is hindered by a lack of systematic evidence. The current randomized, controlled pilot study was undertaken to determine the feasibility and optimize the protocol for a subsequent definitive investigation and estimate the treatment effect of PSWT on postoperative pain and opioid consumption. METHODS: Within the recovery room following primary knee and hip arthroplasty, cholecystectomy, hernia repair, and non-mastectomy breast surgery, we applied 1-3 PSWT devices (Model 088, BioElectronics Corporation, Frederick, Maryland) over the surgical bandages. Participants were randomized to 28 days of either active or sham treatment in a double-masked fashion. The outcomes of primary interest were the cumulative opioid consumption and the mean of the average and worst daily pain measured with the Numeric Rating Scale over the first 7 postoperative days. RESULTS: During the first 7 postoperative days, oxycodone consumption in participants given active treatment (n = 55) was a mean (SD) of 21 mg (24) versus 17 mg (26) in patients given sham (n = 57): difference 4 (95% CI, -5 to 13), p = 0.376. During this same period, the average daily pain intensity in patients given active treatment was 2.4 (1.6) versus 2.6 (1.7) in sham: difference -0.2 (95% CI -0.8 to 0.5), p = 0.597. Concurrently, the worst/maximum pain for the active group was 4.6 (2.0) versus 4.7 (2.1) in sham: difference -0.1 (95% CI -0.8 to 0.7), p = 0.888. No device-related systemic side effects or serious adverse events were identified. CONCLUSIONS: Pulsed shortwave (radiofrequency) therapy did not reduce pain scores and opioid requirements to a statistically significant or clinically relevant degree during the initial postoperative week in this pilot study. These results must be replicated with a subsequent study before being considered definitive. Data from this preliminary study may be used to help plan future trials.

Throughout the COVID-19 pandemic, underserved populations, such as racial and ethnic minority communities, were disproportionately impacted by illness and death. Ensuring people from diverse backgrounds have the ability to participate in clinical trials is key to advancing health equity. We sought to analyze the spatial variability in locations of COVID-19 trials sites and to test associations with demographic correlates. All available and searchable COVID-19 studies listed on ClinicalTrials.gov until 04/04/2022 and conducted in the United States were extracted at the trial-level, and locations were geocoded using the Microsoft Bing API. Publicly available demographic data were available at the county level for national analysis and the census tract level for local analysis. Independent variables included eight racial and ethnic covariates, both sexes, and twelve age categories, all of which were population-normalized. The county-level, population-normalized count of study site locations, by type, was used as the outcome for national analysis, thereby enabling the determination of demographic associations with geospatial availability to enroll as a participant in a COVID-19 study. Z-scores of the Getis-Ord Gi statistic were used as the outcome for local analysis in order to account for areas close to those with clinical study sites. For both national (p

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) has been rising at an alarming rate in the USA, and EOCRC disproportionately affects racial/ethnic minorities. Here, we construct comprehensive profiles of EOCRC DNA methylomes at base-pair resolution for a cohort of Hispanic and African American patients. RESULTS: We show the epigenetic landscape of these EOCRC patients differs from that of late-onset colorectal cancer patients, and methylation canyons in EOCRC tumor tissue preferentially overlapped genes in cancer-related pathways. Furthermore, we identify epigenetic alterations in metabolic genes that are specific to our racial/ethnic minority EOCRC cohort but not Caucasian patients from TCGA. Top genes differentially methylated between these cohorts included the obesity-protective MFAP2 gene as well as cancer risk susceptibility genes APOL3 and RNASEL. CONCLUSIONS: In this study, we provide to the scientific community high-resolution DNA methylomes for a cohort of EOCRC patients from underrepresented populations. Our exploratory findings in this cohort highlight epigenetic mechanisms underlying the pathogenesis of EOCRC and nominate novel biomarkers for EOCRC in underrepresented populations.

BACKGROUND: Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state functional magnetic resonance imaging. We hypothesized that a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future. METHODS: The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the HCP-EP (Human Connectome Project for Early Psychosis) (n = 183) to identify links between connectivity and ACPT performance. We then analyzed data from the NAPLS2 (North American Prodrome Longitudinal Study 2) (n = 345), a multisite prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and control participants. RESULTS: Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p < .005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n = 17). This finding was not observed in nonconverters (n = 196) or control participants (n = 132). CONCLUSIONS: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of individuals with psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships.

Cheek swabs, heterogeneous samples consisting primarily of buccal epithelial cells, are widely used in pediatric DNA methylation studies and biomarker creation. However, the decrease in buccal proportion with age in adults remains unexamined in childhood. We analyzed cheek swabs from 4626 typically developing children 2-months to 20-years-old. Estimated buccal proportion declined throughout childhood with both increasing chronological and predicted epigenetic age. However, buccal proportion did not associate with age throughout adolescence. Variability in buccal proportion increased with age through the entire developmental range. These trends held inversely true for neutrophil proportions. Correcting for buccal proportion attenuated the weak association with PedBE age acceleration to non-significance during initial estimation. Notably, correcting for buccal proportion attenuated the association of PedBE age acceleration with obsessive-compulsive disorder and strengthened the association with diurnal cortisol slope. Thus, the age-related change in childrens oral cells is a crucial consideration for cell type-sensitive research.

BackgroundDespite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.MethodsComprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.ResultsWhile TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.ConclusionsGlioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 μg or 6 μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The studys aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50 % neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N = 82, 95 % CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N = 83, 95 % CI 29·03-44·15), 18·85 (VAXZEVRIA; N = 82, 95 % CI 15·10-23·54), and for subjects age ≥ 60 years was 37·27 (COVIVAC 3 μg; N = 42, 95 % CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N = 40, 95 % CI 35·46-70·76), 16·11 (VAXZEVRIA; N = 40, 95 % CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95 % CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95 % CI 1·98-5·32) for subjects age ≥ 60 years. On day 197, the age-specific ratios were 1·11 (95 % CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0 %, COVIVAC 6 μg 23·2 %, VAXZEVRIA 31·2 %); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194.

PURPOSE: While treatment modalities for Maisonneuve fractures involving the proximal third of the fibula are established, no studies to date have reported outcomes associated with syndesmotic-only fixation of middle third fibular shaft fractures. The purpose of this study was to evaluate outcomes associated with syndesmotic-only fixation in the treatment of Maisonneuve fractures involving the middle third of the fibula. METHODS: A retrospective review was conducted on 257 cases of syndesmotic ankle instability with associated fibular fractures at a level 1 trauma center between 2013 and 2023. Patients were divided into cohorts based on fibular fracture location in the proximal, middle, or distal third of the fibula. The Chi-square test of independence, two-sample t-test, and analysis of variance were used to compare outcome measures between cohorts. RESULTS: Sixty-six patients were identified including 48% (n = 32) with proximal third fibular fractures, 20% (n = 13) with middle third fibular fractures, and 32% (n = 21) with distal third fibular fractures. Rates of infection, loss of reduction, wound healing complications, and reoperation did not vary significantly between cohorts. Functional outcome measures including range of motion, time to weight-bearing, and tibiofibular/medial clear space measurements at final follow-up were similar across cohorts. CONCLUSION: Patients with Maisonneuve fractures involving the middle third of the fibula demonstrated positive outcomes with syndesmotic fixation alone, with no documented cases of infection, loss of reduction, or wound healing issues. By demonstrating maintenance of anatomic reduction and low rates of complications, our results support the use of syndesmotic-only fixation in the treatment of middle third Maisonneuve fractures.

BackgroundCancer survivors are at increased risk for cardiometabolic comorbidities following cancer treatment, which may be further exacerbated by cannabis and alcohol use. We aimed to examine the direct relationships of cannabis, alcohol, and the co-use of both substances with cardiometabolic risk factors and to explore disparities by race/ethnicity and sex.MethodsCross-sectional data were extracted from adult cancer survivors in the "All of Us" from 2018 to 2022. Cannabis use was defined as occasional or frequent/regular cannabis use (vs. never) in the past 3 months and hazardous alcohol intake (AUDIT-C >3 for females; AUDIT-C >4 for males) versus nonhazardous in the past year, respectively. Co-use was defined as participants who engaged in regular cannabis and hazardous alcohol intake. We identified binary cardiovascular, immune, and metabolic system biomarkers, with high values defined by clinically established cutoffs or >75th percentile. We used multivariable logistic regression adjusting for sociodemographic and clinical factors.ResultsIn our sample (N = 7,054), 7.6% were Hispanic, 6.2% were Black, and 86.2% were White cancer survivors. Less than 5% of Hispanic and White survivors reported substance co-use compared with 7% of Black survivors. Compared with never-users, co-users were 1.58 (95% confidence interval, 1.14-2.19) more likely to have high blood pressure. No significant associations were found between co-use and immune biomarkers or sex differences.ConclusionsCo-use of cannabis and hazardous alcohol may worsen high blood pressure in survivors, who are at higher risk for cardiometabolic comorbidities.ImpactThe study investigates substance use and cardiometabolic biomarkers, urging much research on their effects on cancer survivors.

In recent years, Brazils non-White (Brown and Black) population became a numerical majority for the first time since the 19th century. Although we know this change was mostly due to racial reclassification, we do not know how such changes are related to skin color, the primary marker of race in Brazil. Using data from six Latin American Public Opinion Project (LAPOP), or Americas Barometer, surveys from 2010 to 2023, we examine how changes in racial self-identification (White, Brown, or Black) are related to respondent skin color (light, medium, or dark). We ask how the association between self-identified race and skin color changed over the 13-y period and to what extent these trends varied by educational level. We found a darkening of racial identification over time, especially among those with medium and dark skin, who increasingly identified as Black. Brazilians with light skin increasingly identified as Brown, but this was partly explained by changes in interviewer reporting of skin color in the same period. We found only minor evidence that education level was related to changing racial classification over time. Our findings further understanding of recent trends in racial reclassification, which may reflect growing Black consciousness and the extension of racial quotas to both Brown and Black Brazilians in federal universities and public sector jobs.

BACKGROUND: Although leisure time physical activity (LTPA) is a beneficial factor for cardiovascular disease (CVD) mortality, relationships between occupational physical activity (OPA) and CVD mortality are inconclusive. We aimed to examine prospective associations of OPA with CVD mortality using a large representative sample of adult workers in the United States (US), and explore how socioeconomic status (SES) may influence these associations. METHODS: This cohort study included US workers (≥ 18 years) participating in the 1988 National Health Interview Survey (NHIS) and passively followed until December 31, 2019. Time (minutes/week) on strenuous OPA (e.g., lifting, pushing, or pulling heavy objects) was assessed at baseline by a questionnaire and categorized into 4 groups [i.e., none, low, medium, and high]. CVD mortality was identified by International Classification of Diseases, Tenth Version (ICD-10) and collected by the National Death Index database. We examined the association of OPA with CVD mortality using multivariable Cox proportional hazard regressions, controlling for age, sex, race/ethnicity, marital status, education, annual household income, occupation type, and pre-existing cardiometabolic disorders. RESULTS: In 28,604 participants (46.2% women; mean age 37.86 years), adjusted hazard ratios (95% CIs) of none, low, medium, and high OPA groups were 1.39 (1.01-1.91), 1.00 (reference), 1.18 (0.83-1.66) and 1.58 (1.12-2.22) for CVD mortality. The associations were stronger in workers with low education level (i.e., high school or less) [estimates of none, low, medium, and high OPA groups were 1.74 (1.09-2.78, P = 0.02), 1.00, 1.49 (0.92-2.42), and 1.87 (1.16-3.00)] or annual household income

BACKGROUND: Increasing syphilis infection rates are a concerning issue worldwide. Blood donation screening is an opportunity to monitor the burden of asymptomatic infections, providing information on contemporary factors associated with infection and public health insights into transmission. METHODS: Blood donations collected at five Brazilian blood centers between January 2020 and February 2022 were screened with treponemal or non-treponemal assays according to local protocols, followed by alternate Enzyme-Linked Immunosorbent Assay (ELISA); samples with reactive or indeterminate results in the alternate ELISA were further tested with the rapid plasma reagin (RPR), and categorized as RPR-positive or RPR-negative. RPR-positive donations were also grouped according to RPR titers (

Uncovering rates at which susceptible individuals become infected with a pathogen, i.e., the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology is considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, has not been assessed. Using 26 y of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence were 1.75 to 4.05 times higher than case-derived FOI. Seroprevalence-derived was moderately correlated with case-derived FOI (correlation coefficient = 0.47) with slightly lower estimates. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.

BACKGROUND: 2022 survey data showed 29% of Veterans utilized Veterans Affairs (VA) paid health care at a non-VA facility, 6% higher than in 2021. Despite an increase in the number of Veterans accessing care in the community via the MISSION Act Community Care Program (CCP), there is limited information on the quality of mental health care delivered to Veterans in these settings. Further, Veterans report barriers to quality care, including poor communication between CCP and VA providers, which can result in negative patient outcomes. We aimed to evaluate the feasibility and acceptability of using electronic screening, eScreening, as part of a process involving remote symptom screening, symptom monitoring, and clinically driven communication from VA to CCP providers, for Veterans accessing mental health treatment in CCP settings. METHODS: Veterans (n = 150) diagnosed with major depressive disorder, an anxiety disorder, post-traumatic stress disorder, and/or an adjustment disorder referred to mental health care in CCP between August-November 2021 were eligible to participate. Veterans received an eScreening link to complete an initial web-based assessment and three follow-up assessments spaced 4-6 weeks apart over the course of their treatment. Quantitative assessment data was largely characterized using descriptive statistics and included patient-reported outcome (PRO) measures (PTSD and depression), health-related quality of life/functioning, community care information (e.g., number of sessions attended), and satisfaction with the eScreening technology. Qualitative interview data was also collected from participating Veterans and CCP providers to better understand experiences with eScreening. RESULTS: Findings support the feasibility and acceptability of using eScreening to administer and monitor PROs for Veterans accessing mental health treatment in CCP. Of the Veterans who provided eScreening satisfaction ratings (Ns = 45-55), 89% had no technical difficulties; 78% felt comfortable entering personal information; and 83% were neutral or positive about ease of use. Focus group interviews revealed strong support from Veterans, who stated the software was easy to use; they felt comfortable completing PRO measures; and they appreciated having their symptoms monitored. Similarly, providers indicated eScreening had a positive impact on communication, collaboration of care, and transparency. CONCLUSIONS: Technologies like eScreening represent a promising tool to support the mental health care Veterans receive when they access CCP.

Emerging research suggests that the gut microbiome plays a crucial role in stress. We assess stress-microbiome associations in two samples of healthy adults across three stress domains (perceived stress, stressful life events, and biological stress /Respiratory Sinus Arrhythmia; RSA). Study 1 (n = 62; mean-age = 37.3 years; 68% female) and Study 2 (n = 74; mean-age = 41.6 years; female only) measured RSA during laboratory stressors and used 16S rRNA pyrosequencing to classify gut microbial composition from fecal samples. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to predict functional pathways of metagenomes. Results showed differences in beta diversity between high and low stressful life events groups across both studies. Study 1 revealed differences in beta diversity between high and low RSA groups. In Study 1, the low perceived stress group was higher in alpha diversity than the high perceived stress group. Levels of Clostridium were negatively associated with RSA in Study 1 and levels Escherichia/Shigella were positively associated with perceived stress in Study 2. Associations between microbial functional pathways (L-lysine production and formaldehyde absorption) and RSA are discussed. Findings suggest that certain features of the gut microbiome are differentially associated with each stress domain.

Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization of CSF immune cells. CSF derives from and borders central nervous system (CNS) tissue, allowing for comprehensive accounting of cell types along with their relative abundance and immunologic profiles relevant to CNS diseases. Using integration techniques applied to publicly available datasets in combination with our own studies, we generated a compendium with 139 subjects encompassing 135 CSF and 58 blood samples. Healthy subjects and individuals across a wide range of diseases, such as multiple sclerosis (MS), Alzheimers disease, Parkinsons disease, COVID-19, and autoimmune encephalitis, were included. We found differences in lymphocyte and myeloid subset frequencies across different diseases as well as in their distribution between blood and CSF. We identified what we believe to be a new subset of AREG+ dendritic cells exclusive to the CSF that was more abundant in subjects with MS compared with healthy controls. Finally, transcriptional cell states in CSF microglia-like cells and lymphoid subsets were elucidated. Altogether, we have created a reference compendium for single-cell transcriptional profiling encompassing CSF immune cells useful to the scientific community for future studies on neurologic diseases.

A salience map is a topographic map that has inputs at each x,y location from many different feature maps and summarizes the combined salience of all those inputs as a real number, salience, which is represented in the map. Of the more than 1 million Google references to salience maps, nearly all use the map for computing the relative priority of visual image components for subsequent processing. We observe that salience processing is an instance of substance-invariant processing, analogous to household measuring cups, weight scales, and measuring tapes, all of which make single-number substance-invariant measurements. Like these devices, the brain also collects material for substance-invariant measurements but by a different mechanism: salience maps that collect visual substances for subsequent measurement. Each salience map can be used by many different measurements. The instruction to attend is implemented by increasing the salience of the to-be-attended items so they can be collected in a salience map and then further processed. Here we show that, beyond processing priority, the following measurement tasks are substance invariant and therefore use salience maps: computing distance in the frontal plane, computing centroids (center of a cluster of items), computing the numerosity of a collection of items, and identifying alphabetic letters. We painstakingly demonstrate that defining items exclusively by color or texture not only is sufficient for these tasks, but that light-dark luminance information significantly improves performance only for letter recognition. Obviously, visual features are represented in the brain but their salience alone is sufficient for these four judgments.

PURPOSE: To compare the assessment of clinically relevant retinal and choroidal lesions as well as optic nerve pathologies using a novel three-wavelength ultra-widefield (UWF) scanning laser ophthalmoscope with established retinal imaging techniques for ophthalmoscopic imaging. METHODS: Eighty eyes with a variety of retinal and choroidal lesions were assessed on the same time point using Topcon color fundus photography (CFP) montage, Optos red/green (RG), Heidelberg SPECTRALIS MultiColor 55-color montage (MCI), and novel Optos red/green/blue (RGB). Paired images of the optic nerve, retinal, or choroidal lesions were initially diagnosed based on CFP imaging. The accuracy of the imaging was then evaluated in comparison to CFP using a grading scale ranging from -1 (losing imaging information) to +1 (gaining imaging information). RESULTS: Eighty eyes of 43 patients with 116 retinal or choroidal pathologies, as well as 59 eyes with optic nerve imaging using CFP, MCI, RG, and RGB, were included in this study. Across all subgroups, RGB provided significantly more accurate clinical imaging with CFP as ground truth and compared to other modalities. This was true comparing RGB to both RG (P = 0.0225) and MCI (P < 0.001) overall. Although RGB provided more accurate clinical information overall, it was inferior to RG for melanocytic choroidal lesions (P = 0.011). CONCLUSIONS: RGB can be considered as a useful tool to detect characteristics of central, midperipheral, and peripheral retinal lesions. Regarding melanocytic choroidal lesions, RGB was inferior to RG, and MCI was inferior to both RG and RGB modalities due to color changes. TRANSLATIONAL RELEVANCE: Traditional retinal ultra-widefield imaging uses two wavelengths. Here, we evaluated three wavelengths for ultra-widefield imaging. We examined new optics (basic science) effect on patient imaging (clinical care).

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels. In addition, transplant recipients exhibit decreased plasmablasts and transitional B cells, and increased senescent T cells. Blood and nasal transcriptional profiling demonstrate unexpected upregulation of innate immune signaling pathways and increased levels of several proinflammatory serum chemokines. Severe disease in transplant recipients, however, is characterized by a less robust induction of pro-inflammatory genes and chemokines. Together, our study reveals distinct immune features and altered viral dynamics in solid organ transplant recipients.

BACKGROUND: Practical biomarkers for endotypic characterization of chronic rhinosinusitis (CRS) remain elusive, hindering clinical utility. Eosinophil peroxidase (EPX) is an enzyme released by activated eosinophils. The objective of this study was to evaluate a clinic EPX assay as a marker of eosinophilic CRS. METHODS: Subjects with and without CRS presenting to a tertiary care rhinology clinic were prospectively enrolled, and nasal cytology brushings were collected from the middle meatus during in-clinic nasal endoscopy. ELISA assay was used to quantify EPX levels, and a customized multiplex immunoassay was used to quantify inflammatory cytokine mediators. Findings were correlated with clinical data. RESULTS: Forty-two subjects were enrolled, including 31 CRS subjects and 11 controls. Median EPX levels were 125.0 ng/mL (standard deviation [SD] 1745.8) and 6.5 ng/mL (SD 99.0) for CRS group and controls, respectively (p = 0.003). EPX levels were associated with history of asthma (p = 0.015), allergies (p = 0.028), polyps (p = 0.0006), smell loss (p = 0.006), and systemic eosinophilia or elevated immunoglobulin E (p ≤ 0.0001). Twenty-eight subjects from both the CRS and control groups had prior pathology for comparison, with histologic confirmation of local tissue eosinophilia (>10 eosinophils/hpf) in 11 subjects. This subgroup had a median EPX level of 967.5 ng/mL compared to 10.6 ng/mL in 17 subjects without local tissue eosinophilia (p = 0.0008). EPX levels were positively correlated to interleukin-5 levels (p = 0.0005). CONCLUSION: EPX levels can be measured via well-tolerated in-clinic collection of nasal mucus. EPX levels are associated with clinical markers of type 2 inflammation and tissue eosinophilia and may provide a valuable diagnostic tool to delineate eosinophilic CRS.

BackgroundData comparing the performance of sex-specific to overall (non-sex-specific) high-sensitivity cardiac troponin (hs-cTn) cut-points for diagnosing acute coronary syndrome (ACS) are limited. This study aims to compare the safety and efficacy of sex-specific versus overall 99th percentile high-sensitivity cardiac troponin T (hs-cTnT) cut-points.MethodsWe conducted a secondary analysis of the STOP-CP cohort, which prospectively enrolled emergency department patients ≥ 21 years old with symptoms suggestive of ACS without ST-elevation on initial electrocardiogram across eight U.S. sites (January 25, 2017-September 6, 2018). Participants with both 0- and 1-h hs-cTnT measures less than or equal to the 99th percentile (sex-specific 22 ng/L for males, 14 ng/L for females; overall 19 ng/L) were classified into the rule-out group. The safety outcome was adjudicated cardiac death or myocardial infarction (MI) at 30 days. Efficacy was defined as the proportion classified to the rule-out group. McNemar's test and a generalized score statistic were used to compare rule-out and 30-day cardiac death or MI rates between strategies. Net reclassification improvement (NRI) index was used to further compare performance.ResultsThis analysis included 1430 patients, of whom 45.8% (655/1430) were female; the mean ± SD age was 57.6 ± 12.8 years. At 30 days, cardiac death or MI occurred in 12.8% (183/1430). The rule-out rate was lower using sex-specific versus overall cut-points (70.6% [1010/1430] vs. 72.5% [1037/1430]; p = 0.003). Among rule-out patients, the 30-day cardiac death or MI rates were similar for sex-specific (2.4% [24/1010]) vs. overall (2.3% [24/1037]) strategies (p = 0.79). Among patients with cardiac death or MI, sex-specific versus overall cut-points correctly reclassified three females and incorrectly reclassified three males. The sex-specific strategy resulted in a net of 27 patients being incorrectly reclassified into the rule-in group. This led to an NRI of -2.2% (95% CI -5.1% to 0.8%).ConclusionsSex-specific hs-cTnT cut-points resulted in fewer patients being ruled out without an improvement in safety compared to the overall cut-point strategy.

INTRODUCTION: We used an implementation science framework to investigate perceived health inequities in preventive health care initiatives in rural communities in the Philippines. We also identified health equity-focused quality improvement strategies. METHODS: Three health care providers and 12 barangay clinic patients were interviewed. RESULTS: Patient interviews showed that social determinants of health, respect, and attitudes toward health care providers affected patient empowerment to engage in self-management for noncommunicable diseases (NCDs). Health care providers identified six challenges in managing NCDs: (a) inefficient work processes; (b) staffing shortages; (c) insufficient access to low-cost medications; (d) inadequate primary preventive health education from the schools; (e) health care not considered a priority; and (f) lack of local government support. DISCUSSION: Inadequate preventive health care and education intensify health access and resource inequities in rural communities in the Philippines. A multi-sectoral plan may improve rural health infrastructure and education toward improving health care access and decreasing care disparities.

Participation in technical/research internships may improve undergraduate graduation rates and persistence in science, technology, engineering, and mathematics (STEM), yet little is known about the benefits of these activities a) for community college students, b) when hosted by national laboratories, and c) beyond the first few years after the internship. We applied Social Cognitive Career Theory (SCCT) to investigate alumni perspectives about how CCI at Lawrence Berkeley National Laboratory (LBNL) impacted their academic/career activities. We learned that alumni had low confidence and expectations of success in STEM as community college students. Participation in CCI increased their professional networks, expectations of success, and STEM skills, identity, and self-efficacy/confidence. Hispanic/Latinx alumni recalled the positive impact of mentors who prioritized personal connections, and women valued "warm" social environments. We propose several additions to the SCCT model, to better reflect the supports and barriers to STEM persistence for community college students.

Despite recommendations in the US National Research Action Plan on Long COVID, gender identity is rarely reported in research and surveillance used to guide public health programming and clinical care. We analyzed data from a cross-sectional study of COVID-19 in a nationwide sample of transgender and nonbinary (TNB) people (N = 2,134). Participants were surveyed between June 14, 2021 and May 1, 2022. Data were restricted to 817 participants who reported confirmed or suspected COVID-19 to estimate the prevalence of long COVID, defined as symptoms persisting for ≥ 3 months. Ten percent of participants with a history of COVID-19 reported symptom duration consistent with long COVID, ranging from 4.8% to 12.9% across gender identities. Long COVID was most common in transmasculine and nonbinary people assigned female sex at birth. There was no evidence of an association with reported hormone therapy, supporting current recommendations that prioritize gender-affirming care during treatment for long COVID. As a condition which profoundly impacts health and productivity, long COVID is likely to exacerbate existing disparities. Principles of equity demand that we reduce barriers to prevention, diagnosis, and care for long COVID, and ensure that research and surveillance are inclusive of TNB people and disaggregate findings by gender identity.

People living with HIV are at higher risk of heart failure and associated left atrial remodeling compared to people without HIV. Mechanisms are unclear but have been linked to inflammation and premature aging. Here we obtain plasma proteomics concurrently with cardiac magnetic resonance imaging in two independent study populations to identify parallels between HIV-related and aging-related immune dysfunction that could contribute to atrial remodeling and clinical heart failure. We discover a plasma proteomic signature that may in part reflect or contribute to HIV-associated atrial remodeling, many features of which are associated with older age and time to incident heart failure among an independent community-based cohort without HIV. This proteomic profile was statistically enriched for immune checkpoint proteins, tumor necrosis factor signaling, ephrin signaling, and extracellular matrix organization, identifying possible shared pathways in HIV and aging that may contribute to risk of heart failure.

Working memory (WM) plays a crucial role in human cognition. Previous candidate and genome-wide association studies have reported many genetic variations associated with WM. However, little research has examined genetic basis of WM by using transcriptome, even though it reflects gene function more directly than does the genome. Here we propose a new approach to exploring the genetic mechanisms of WM by integrating connectome, transcriptome, and genome data in a high-quality dataset comprising 481 Chinese healthy adults. First, relevance vector regression was used to define WM-related brain regions. Second, genes differentially expressed within these regions were identified using the Allen Human Brain Atlas (AHBA) dataset. Finally, two independent datasets were used to validate these genes' contributions to WM. With this method, we identified 24 novel genes and 20 of them were confirmed in the large-scale datasets of ABCD and UK Biobank. These novel genes were enriched in the cellular component of collagen-containing extracellular matrix and the CCL18 signaling pathway. Our method offers an effective approach to integrating multimodal gene discovery and demonstrates the superiority of expression data. This new method and the newly identified genes deserve more attention in the future.

This study investigates baseline differences in couples enrolled in the "It Takes Two" HIV prevention intervention for transgender women and their partners, comparing in-person participation pre-COVID-19 and digital participation during the pandemic. Among 52 couples (40% in-person, 60% digital), bivariate analyses revealed that in-person participants were more likely to be African American, have cisgender male partners, report higher unemployment, incarceration histories, greater relationship stigma, and lower relationship quality. The findings highlight the limitations of digital modalities in engaging transgender women of color and those with structural vulnerabilities. The study emphasizes that reliance on digital methods in HIV research jeopardizes the inclusion of those lacking technological access and literacy, especially communities disproportionately impacted by HIV. Researchers must incorporate hybrid or in-person options and engage communities to ensure equity and inclusion, thus overcoming barriers and ensuring comprehensive population reach in HIV prevention studies.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in 85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

BACKGROUND: The ALLEGRO phase 2b/3 study investigated the efficacy and safety of ritlecitinib in patients with alopecia areata (AA). OBJECTIVE: To describe the impact of ritlecitinib on patient-reported hair loss using the Alopecia Areata Patient Priority Outcomes (AAPPO) instrument and evaluate the relationship between clinically meaningful hair regrowth and improvements in patient-reported impacts. METHODS: In ALLEGRO-2b/3, patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg daily loading dose), 10 mg, or placebo for 24 weeks and then continued ritlecitinib or switched from placebo to ritlecitinib 200/50 or 50 mg for 24 weeks. The AAPPO instrument evaluated improvement in hair loss, emotional symptoms (ES), and activity limitations (AL) from weeks 4 to 48 (secondary endpoint). Mean changes in ES and AL domain scores and individual items at weeks 24 and 48 were calculated for Severity of Alopecia Tool (SALT) score ≤ 20 responders and nonresponders (exploratory endpoint). RESULTS: Overall, 718 patients were randomized. At week 24, 5-36% of patients receiving ritlecitinib 10-200/50 mg reported improvement in scalp hair loss versus 9% receiving placebo. The results for eyebrow, eyelash, and body hair loss were similar. Mean change from baseline in ES and AL scores at weeks 24 and 48 was small and similar between groups. Mean change was larger for individual hair loss and ES items at weeks 24 and 48 in SALT score ≤ 20 responders versus nonresponders. CONCLUSIONS: The AAPPO instrument demonstrated the beneficial impact of ritlecitinib on patient-reported hair growth, which was consistent with improvements in clinician-reported outcomes. CLINICAL TRIAL REGISTRATION: NCT03732807. INFOGRAPHIC.

While viewing a visual stimulus, we often cannot tell whether it is inherently memorable or forgettable. However, the memorability of a stimulus can be quantified and partially predicted by a collection of conceptual and perceptual factors. Higher-level properties that represent the "meaningfulness" of a visual stimulus to viewers best predict whether it will be remembered or forgotten across a population. Here, we hypothesize that the feelings evoked by an image, operationalized as the valence and arousal dimensions of affect, significantly contribute to the memorability of scene images. We ran two complementary experiments to investigate the influence of affect on scene memorability, in the process creating a new image set (VAMOS) of hundreds of natural scene images for which we obtained valence, arousal, and memorability scores. From our first experiment, we found memorability to be highly reliable for scene images that span a wide range of evoked arousal and valence. From our second experiment, we found that both valence and arousal are significant but weak predictors of image memorability. Scene images were most memorable if they were slightly negatively valenced and highly arousing. Images that were extremely positive or unarousing were most forgettable. Valence and arousal together accounted for less than 8% of the variance in image memorability. These findings suggest that evoked affect contributes to the overall memorability of a scene image but, like other singular predictors, does not fully explain it. Instead, memorability is best explained by an assemblage of visual features that combine, in perhaps unintuitive ways, to predict what is likely to stick in our memory.

PURPOSE: Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have been noted to face increased cancer incidence. Yet, the impact of concomitant renal dysfunction on acute outcomes following elective surgery for cancer remains to be elucidated. METHODS: All adult hospitalizations entailing elective resection for lung, esophageal, gastric, pancreatic, hepatic, or colon cancer were identified in the 2016-2020 National Inpatient Sample. Based on stage of renal dysfunction, CKD patients were sub-classified as CKD1-3, CKD4-5, or ESRD (others: Non-CKD). Multivariable regression models were developed to assess the association of comorbid CKD/ESRD with in-hospital mortality, perioperative complications, and resource utilization. RESULTS: Of ~515,145 patients, 32,195 (6.2%) had CKD (5.1% CKD1-3, 0.7% CKD4-5, 0.5% ESRD). The incidence of CKD among patients undergoing cancer resection increased from 5.3% in 2016 to 7.3% in 2020 (P

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, so together may provide a more complete picture of sleep health, while illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p

Short-term motor adaptation to novel movement dynamics has been shown to involve at least two concurrent learning processes: a slow process that responds weakly to error but retains information well and a fast process that responds strongly to error but has poor retention. This modeling framework can explain several properties of motion-dependent motor adaptation (e.g., 24 h retention). An important assumption of this computational framework is that learning is only based on the experienced movement error, and the effect of noise (either internally generated or externally applied) is not considered. We examined the respective error sensitivity by quantifying adaptation in three subject groups distinguished by the noise added to the motion-dependent perturbation. We assessed the feedforward adaptive changes in motor output and examined the adaptation rate, retention, and decay of learning. Applying a two-state modeling framework showed that the applied noise during training mainly affected the fast learning process, with the slow process largely unaffected; participants in the higher noise groups demonstrated a reduced force profile following training, but the decay rate across groups was similar, suggesting that the slow process was unimpaired across conditions. Collectively, our results provide evidence that noise significantly decreases motor adaptation, but this reduction may be due to its influence over specific learning mechanisms. Importantly, this may have implications for how the motor system compensates for random fluctuations, especially when affected by brain disorders that result in movement tremor (e.g., essential tremor).

INTRODUCTION: As pharmacological strategies remain limited for relieving fatigue and associated cognitive symptoms, integrative modalities such as traditional Chinese medicine (TCM) could be explored as therapeutic strategies in cancer survivors. Here, we evaluate and report the efficacy and safety of a TCM concoction, modified Xiang Bei Yang Rong Tang (XBYRT), on quality of life (QOL), cancer-related fatigue (CRF), and cognitive symptoms, compared to placebo. METHODS: In a single-centered, randomized, double-blinded, placebo-controlled pilot trial conducted from 2019 to 2022, fatigued cancer survivors ≥21 years old were recruited to receive the XBYRT intervention or placebo (5% diluted) once daily for the duration of 8 weeks. Patient-reported outcomes for QOL, CRF, cognition, blood samples for biomarker testing, and adverse events were collected at baseline (T0), 4 weeks (T1), 8 weeks (T2), and 10 weeks (T3) after baseline. Linear regression was performed to evaluate differences between groups at T2 and T3. RESULTS: A total of 1502 patients were screened, with 672 patients considered eligible. Of the eligible, 15 XBYRT and 13 placebo subjects with similar mean ages (58.5 vs 58.4) were recruited. Both groups were predominantly Chinese (93% vs 62%), breast cancer patients (87% vs 62%), and diagnosed with stage 2 cancer (60% vs 46%). Although no significant difference was found in QOL between groups, the XBYRT group exhibited improved emotional fatigue at T3 (P = .045) and higher BDNF levels at T2 (P = .047) and T3 (P = .029). After baseline adjustment, XBYRT was associated with better perceived cognitive impairment at T2 (P = .011) and T3 (P = .017), as well as overall perceived cognitive function at T3 (P = .028). XBYRT is well tolerated, with grade 3 adverse events reported in three XBYRT (20%) and two placebo (15%) subjects. CONCLUSION: In this pilot study, XBYRT as an integrative therapy is safe and generates encouraging improvements in cognitive and fatigue symptoms. Difficulties with recruitment limited the generalizability of trial findings, thus findings should be verified through a larger, multi-centered trial.

Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24-2.20), neutrophils (HR = 1.49, 1.13-1.97), and eosinophils (HR = 1.59, 1.18-2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications.

Accumulating evidence indicates that unpredictable signals in early life represent a unique form of adverse childhood experiences (ACEs) associated with disrupted neurodevelopmental trajectories in children and adolescents. The Questionnaire of Unpredictability in Childhood (QUIC) was developed to assess early life unpredictability [1], encompassing social, emotional, and physical unpredictability in a childs environment, and has been validated in three independent cohorts. However, the importance of identifying ACEs in diverse populations, including non-English speaking groups, necessitates translation of the QUIC. The current study aims to translate and validate a Spanish language version of the QUIC (QUIC-SP) and assess its associations with mental and physical health. Spanish-speaking participants (N = 285) were recruited via the online market crowdsourcing platform, Amazon Mechanical Turk (MTurk), and completed an online survey that included the QUIC-SP and validated Spanish language assessments of physical and mental health. The QUIC-SP demonstrated excellent psychometric properties and similar mean scores, endorsement rates, and internal reliability to the English language version, thus establishing its validity among Spanish-speaking adults. Higher QUIC-SP scores, indicating greater unpredictability in early life, predicted increased symptoms of anxiety, anhedonia, depression, and poorer physical health. Given significant racial and ethnic disparities in health, the QUIC-SP may serve as a valuable tool to address the public health consequences of ACEs among Spanish-speaking populations.

PURPOSE: To assess outcomes of Descemet stripping endothelial keratoplasty (DSEK) in eyes with custom artificial iris (CAI) implantation. METHODS: This is a retrospective, interventional, consecutive, surgical case series of patients who underwent DSEK after CAI implantation between 2010 and 2021 at 2 referral centers. Primary safety measures were loss of corrected distance visual acuity (CDVA), increase in intraocular pressure (IOP), development or progression of glaucoma, and intraoperative and postoperative complications. Efficacy measures were graft survival at year 1 and improvement in cosmesis at postoperative month 3. In general, measures were compared between baseline and postoperative year 1 while any complication was reported for the full follow-up period. RESULTS: Thirty-nine eyes of 39 patients were identified. 64.1% of eyes had acquired aniridia from trauma. The mean follow-up interval was 27.7 months (range 12.2-117.4). Median CDVA improved from logMAR 1.0 to 0.7 at year 1 ( P = 0.0047). At the final follow-up, permanent loss of CDVA occurred in 25.6% of eyes, of which 90% was due to glaucoma. The most common postoperative complication was IOP elevation (66.7% of eyes). Graft survival at postoperative year 1 was 82.0% (95% confidence interval, 66.3-91.4). Secondary graft failure occurred in 28.2% of eyes at a mean duration of 39.7 months (SD 27.9 months) after DSEK. Cosmesis improved among 87.2% of eyes at postoperative month 3. CONCLUSIONS: DSEK is an effective procedure for addressing corneal edema in eyes with a CAI, but a majority develop elevated IOP and graft survival is shorter than in eyes without a CAI.

Some interventions for smoking cessation such as quit smoking aids show sex-specific effects on outcomes, but behavioral interventions such as mindfulness-based interventions (MBIs) for smoking cessation lack formal reporting of sex-intervention tests of interaction to date. To address this gap, we conducted a secondary analysis of a RCT dataset (N = 213), recruiting participants from California, to statistically test a sex-intervention interaction effect on complete 7-day point prevalence abstinence (PPA), proportion of days abstinent, and daily cigarettes smoked. Smoking was assessed using the timeline follow back method spanning the four weeks following a daily 14-day app-based intervention and a planned smoking quit date immediately following the intervention phase. All models adjusted for baseline nicotine dependence. The study groups had comparable sex proportions (MBI: 56 % female; control: 55 % female) and the ratio of outcome assessment completion by group was not dependent on sex. Adjusted analyses revealed a significant sex-intervention interaction effect for daily cigarettes smoked ([female coded 1]: two-way interaction effect IRR = 0.59, 95 % CI: 0.46-0.77, p

OBJECTIVE: To study the association between dietary patterns and subgingival microbiota. METHODS: Participants (n = 651) who were enrolled in the Oral Infections, Glucose Intolerance, and Insulin Resistance Study (ORIGINS) with subgingival plaque sampling (n = 890 plaques) and a dietary assessment were included. 16S rRNA gene amplicon sequences of subgingival plaque from sites with either probing depth

As clinical evaluations of neuromuscular disorders such as hypertonia mostly rely on perception-based scales, the imprecise subjective ratings make it difficult to accurately monitor treatment progress. To promote objective evaluation, this work used a multi-modal sensing glove in a double-blind study to enable sensitive monitoring of medication effects across 19 participants. The biomechanical measurements from the sensing glove effectively distinguished patient cohorts receiving a baclofen treatment or a placebo with 95% confidence. Consistent monitoring over a two-month period was demonstrated, closely tracking variations in individual responses to treatment. The biomechanical changes were correlated to neural activities as recorded by electromyography, verifying the medication effects. The sensing glove is shown to be a reliable tool for point-of-care settings to facilitate precise evaluation of hypertonia, essential for tailoring individual treatment choices and timely management of chronic symptoms.

BackgroundLong COVID patients present with a myriad of symptoms that can include fatigue, exercise intolerance and post exertional malaise (PEM). Long COVID has been compared to other post viral syndromes, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where a reduction in day 2 cardiopulmonary exercise test (CPET) performance of a two-day CPET protocol is suggested to be a result of PEM. We investigated cardiopulmonary and perceptual responses to a two-day CPET protocol in Long COVID patients.Methods15 Long COVID patients [n=7 females; mean (SD) age: 53(11) yr; BMI = 32.2(8.5) kg/m2] performed a pulmonary function test and two ramp-incremental CPETs separated by 24 hr. CPET variables included gas exchange threshold (GET), peak oxygen uptake (V̇O2peak) and peak work rate (WRpeak). Ratings of perceived dyspnoea and leg effort were recorded at peak exercise using the modified 0-10 Borg Scale. PEM (past six months) was assessed using the modified DePaul Symptom Questionnaire (mDSQ). One-sample t-tests were used to test significance of mean difference between days (p0.05).ConclusionPEM symptoms in Long COVID patients, in the absence of differences in two-day CPET responses separated by 24 hours, suggests that PEM is not due to impaired recovery of exercise capacity between days.

INTRODUCTION: Energy-reducing spinal cord stimulation (SCS) approaches have the potential to impact patient experience with rechargeable and non-rechargeable SCS devices through reducing device recharge time or enhancing device longevity. This prospective, multi-center study evaluated the safety, effectiveness, and actual energy usage of differential target multiplexed (DTM) endurance therapy, a reduced energy DTM SCS derivative. METHODS: Subjects who reported an overall pain visual analog score (VAS) of ≥6/10 cm and an Oswestry Disability Index score of 21-80 out of 100 at baseline with moderate to severe chronic, intractable back and/or leg pain were eligible. Evaluation visits occurred at 1, 3, 6, and 12 months post-device activation. The primary objective was to characterize change in overall pain intensity, as measured by VAS, from baseline to 3-month visit. RESULTS: Fifty-seven subjects enrolled at 12 US sites from November 2020 through June 2021, 35 were implanted with a rechargeable SCS device, and 27 completed the 12-month visit. Subjects experienced a 50.4% mean reduction in overall pain from baseline at the 3-month follow-up that was sustained through 12 months. Additional outcomes including changes in overall, back, and leg pain intensity, quality of life, disability, therapy satisfaction, safety, and current battery usage are shown through 12-month follow-up. CONCLUSION: The use of DTM endurance SCS therapy in this study resulted in reductions in pain relief through 12 months, demonstrating that energy-reducing stimulation patterns can provide clinical benefit. Clinically effective, reduced energy SCS derivatives have the potential to impact patient experience through either reduced recharge requirements or increased device longevity.

BACKGROUND: Obesity is an independent risk factor for complications after abdominal hernia repair. Glucagon-like-peptide-1 (GLP-1) receptor agonists are gaining popularity as pharmacologic weight loss adjuncts and may help patients reach weight loss goals for surgery. We examine our early experience utilizing GLP-1 agonists versus lifestyle modifications alone to achieve weight loss in patients before elective hernia repair. METHODS: This single-center, retrospective review identified obese patients who underwent elective hernia repair from 2014 to 2023. Patients were asked to achieve a BMI ≤ 33 kg/m2 before surgery. Patients who lost weight with GLP-1 therapy in addition to lifestyle changes were compared to a control cohort that achieved similar preoperative weight loss without GLP-1 therapy. Primary outcome was mean time from GLP-1 agonist initiation and initial surgery clinic visit to surgery. Secondary outcomes were 30-day morbidity, mortality, and reoperation rates, and hernia recurrence. RESULTS: Forty-six patients with ventral/incisional, flank, umbilical, parastomal, inguinal, and hiatal hernias were identified (GLP-1 N = 24, control N = 22). 81.8% (N = 18) of controls had a ventral/incisional hernia, compared to 45.8% (N = 11) of GLP-1 patients (p = 0.03). Mean BMI at GLP-1 agonist initiation was similar to mean BMI at initial clinic visit for controls (38.1 ± 4.9 vs 38.2 ± 2.7 kg/m2, p = 0.66). Preoperative mean percentage total weight loss (14.9 ± 7.5 vs 12.4 ± 6.9 kg, p = 0.39) and mean BMI reduction (6.0 ± 3.8 vs 4.9 ± 2.3 kg/m2, p = 0.43) were similar between groups. The mean time from GLP-1 agonist initiation to surgery was significantly shorter than initial clinic visit to surgery for controls (6.3 ± 4.0 vs 14.7 ± 17.6 months, p = 0.03). There was no statistically significant difference in time from initial clinic visit to surgery between groups (7.6 ± 4.4 vs 14.7 ± 17.6 months, p = 0.06). There was no significant difference in 30-day morbidity between groups (8.3 vs 27.3%, p = 0.13). CONCLUSION: GLP-1 agonists accelerate preoperative weight loss for obese hernia patients without negatively impacting postoperative outcomes.

PurposeTo compare the diagnostic utility of metagenomic deep sequencing (MDS) to cytology, flow cytometry and gene rearrangement by PCR in ocular samples of patients with suspected vitreoretinal lymphoma (VRL).MethodsPatients with suspected VRL underwent ocular sampling of one or both eyes at the Emory Eye Center from September 2017 to June 2022. Ocular samples were evaluated with MDS and conventional diagnostics. MDS was performed at the Ralph and Sophie Heintz Laboratory at the F.I. Proctor Foundation. Relevant demographic and clinical data were retrospectively collected from medical records. Patients were diagnosed with VRL based on clinical assessment and conventional diagnostic testing.ResultsThis study included 13 patients with suspected VRL who underwent diagnostic vitrectomy, including 1 patient who had an additional subretinal biopsy. Six patients (46.2%) were diagnosed with VRL. Among patients diagnosed with VRL, MDS detected pathogenic mutations in 5 out of 6 patients (83.3%) while cytology was positive for VRL in 4 out of 6 patients (66.7%), flow cytometry in 4 out of 4 patients (100.0%) and PCR in 4 out of 4 patients (100.0%). MDS detected mutations in MYD88 in 2 out of 6 patients diagnosed with VRL. In 7 patients (53.8%) not diagnosed with VRL, MDS detected pathogenic lymphoma mutations in 2 patients (28.6%).DiscussionMDS detected pathogenic mutations in five out of six patients diagnosed with VRL, including in two patients with negative cytology, demonstrating its potential to improve diagnostic rates of VRL as an adjunctive test.

This article focuses on an empirical setting that upends the clinician-patient dyadic norm: group medical visits (GMVs), in which multiple patients gather in the same space for medical care, health education and peer support. Our grounded theory analysis draws on participant observation and interviews (N = 53) with patients and staff of GMVs at four safety-net healthcare organisations in the United States. We delineate (1) how group medical visits provide health-focused social networks that facilitate the mobilisation of social capital, (2) how the organisationally embedded relationships that comprise group visits are made possible through extended time that is part of the GMV field and (3) how clinicians have opportunities rarely found in other settings to learn from patients, using knowledge accrued from GMV networks to advance their own skills, thereby converting social capital into provider cultural health capital. GMVs provide a rich empirical site for understanding the ways in which organisational arrangements can shape opportunities for patients and clinicians to cultivate and mobilise social capital and cultural health capital, and in doing so, materially shift experiences of receiving and providing healthcare.

ObjectiveTo examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes.Research design and methodsIn a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods.ResultsAverage glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy.ConclusionsGlucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies. AIMS: This study investigated memantines impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis. RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline. DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.

ObjectivePatients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils.DesignIn this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet).ResultFaecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days.ConclusionsWe found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.