Search

BackgroundThe Everyday Cognition scale (ECog-39) scores are associated with future cognitive decline. We investigated whether the 12-item ECog (ECog-12), which is being collected in Alzheimer's Disease Neuroimaging Initiative (ADNI)4, can predict progression.MethodsBaseline self (PT)- and study partner (SP)-ECog-12 data were extracted from the 39-item version collected in the ADNI. Weibull analysis examined the relationship between baseline ECog-12 and future clinical progression (change in Clinical Dementia Rating Sum of Boxes [CDR-SB] scores and diagnostic conversion).ResultsHigher PT- and SP-ECog-12 scores were associated with faster CDR-SB worsening, with hazard ratios in cognitively unimpaired (CU) 3.34 and 9.61, mild cognitive impairment (MCI) 1.44 and 2.82, and dementia 0.93 and 1.82. They were associated with conversion from CU to MCI 3.01 and 6.24 and MCI to dementia 1.61 and 3.07.DiscussionSP-ECog-12 provided a higher prognostic value for predicting clinical progression, so this can help identify and monitor patients at risk in research and health-care settings.HighlightsThe 12-item Everyday Cognition scale (ECog-12) data obtained from both raters increased diagnostic conversion risk from cognitively unimpaired to mild cognitive impairment (MCI) and from MCI to dementia. ECog-12, rated by study partners, was associated with an increased risk of Clinical Dementia Rating Sum of Boxes worsening in all diagnostic groups. Our results provide novel information about the specific scoring outputs and rater types (participant vs. study partner) of ECog-12 that can facilitate screening, prioritization, and longitudinal monitoring of the clinical progression of participants in Alzheimer's Disease Neuroimaging Initiative 4 and other Alzheimer's disease clinical studies, clinical trials, and in health-care settings.

Hypertrophic cardiomyopathy (HCM) afflicts humans, cats, pigs, and rhesus macaques. Disease sequelae include congestive heart failure, thromboembolism, and sudden cardiac death (SCD). Sarcomeric mutations explain some human and cat cases, however, the molecular basis in rhesus macaques remains unknown. RNA-Seq of the LV tissues of five HCM-affected and seven healthy control rhesus macaques was employed for differential transcriptomic analyses. DNA from 15 severely HCM-affected and 21 healthy geriatric rhesus macaques were selected for whole-genome sequencing. A genome-wide association study (GWAS) of disease status and SCD outcome was performed. 614 down- and 1,065 upregulated differentially expressed genes (DEGs) were identified between groups. The top DEG (MAFF) was overexpressed in affected animals (log2FoldChange = 4.71; PAdjusted-value = 1.14E-133). Channelopathy-associated enriched terms were identified in ~ 57% of downregulated DEGs providing transcriptomic evidence of hypertrophic and arrhythmic disease processes. For GWAS, no putative variant withstood segregation. Polygenic modeling analysis resulted in poor prediction power and burden testing could not explain HCM by an association of multiple variants in any gene. Neither single nor compound genetic variant(s), or identified polygenic profile, suggest complex genotype-phenotype interactions in rhesus macaques. Brought forth is an established dataset of robustly phenotyped rhesus macaques as an open-access resource for future cardiovascular disease genetic studies.

Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by 'debulking' of high-risk PCa; however, using androgen deprivation therapy (ADT) at this point risks castration resistant PCa (CRPC) clonal proliferation. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated potassium-sparing diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated ERK1/2 and inhibited survival. Amiloride combined with lapatinib significantly increased apoptosis at relatively low doses of both drugs but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with using ADT as NAT in HSPC.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID₅₀/mL, respectively. The vRNA assay differentiated between acutely infected (n = 10) and infection-naïve patients (n = 33) with an AUC of 0.9818, sensitivity of 90%, and specificity of 100%. The antigen assay similarly differentiated these patient populations with an AUC of 1.000. The BAb assay detected BAbs with an LOD of 39 pg/mL and distinguished acutely infected (n = 35), vaccinated with prior infection (n = 13), and vaccinated infection-naïve patients (n = 13) from pre-pandemic (n = 81) with AUC of 0.9481, 1.000, and 0.9962, respectively. The NAb assay detected NAbs with a LOD of 31.6 Unit/mL and differentiated between COVID-19 recovered or vaccinated patients (n = 31) and pre-pandemic controls (n = 60) with an AUC 0.923, sensitivity of 87.10%, and specificity of 86.67%. Our combo assay represents a significant technological advancement to simultaneously address SARS-CoV-2 infection and immunity, and it lays the foundation for tackling potential future pandemics.

OBJECTIVE: Summaries of health research can be a complementary way to return value to participants. We assess how research participants engage with summaries via email communication and how this can be improved. MATERIALS AND METHODS: We look at correlations between demographic subgroups and engagement in a longitudinal dataset of 305 626 participants (77% are classified as underrepresented in biomedical research) from the All of Us Research Program. We compare this against engagement with other program communications and use impact evaluations (N = 421 510) to measure the effect of tailoring communication by (1) eliciting content preferences, (2) Spanish focused content, (3) informational videos, and (4) article content in the email subject line. RESULTS: Between March 2020 and October 2021, research summaries reached 67% of enrolled participants, outperforming other program communication (60%) and return of results (31%), which have a high uptake rate but have been extended to a subset of eligible participants. While all demographic subgroups engage with research summaries, participants with higher income, educational attainment, White, and older than 45 years open and click content most often. Surfacing article content in the email subject line and Spanish focused content had negative effects on engagement. Video and social media content and eliciting preferences led to a small directional increase in clicks. DISCUSSION: Further individualization of tailoring efforts may be needed to drive larger engagement effects (eg, delivering multiple articles in line with stated preferences, expanding preference options). Our findings are likely a conservative representation of engagement effects, given the coarseness of our click rate measure. CONCLUSIONS: Health research summaries show promise as a way to return value to research participants, especially if individual-level results cannot be returned. Personalization of communication requires testing to determine whether efforts are having the expected effect.

OBJECTIVE: Higher truncated-to-native apolipoprotein (apo) C-I proteoform ratios (C-I/C-I) are associated with favorable cardiometabolic risk profiles, but their relationship with longitudinal changes in insulin resistance (IR) and incident diabetes is unknown. RESEARCH DESIGN AND METHODS: Plasma apoC-I proteoforms were measured by mass spectrometry immunoassay at baseline in 4,742 nondiabetic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 524 participants with prediabetes in the Actos Now for Prevention of Diabetes (ACT NOW) study. The primary outcome was incident diabetes (fasting glucose [FG] ≥7.0 mmol/L or hypoglycemic medication use in MESA; FG ≥7.0 mmol/L or 2-h glucose ≥11.1 mmol/L in an oral glucose tolerance test [OGTT] in ACT NOW). Secondary outcomes were changes in FG and HOMA-IR in MESA, and OGTT-glucose area under the curve (AUCglucose) and Matsuda insulin sensitivity index (ISI) in ACT NOW. RESULTS: In MESA, a higher C-I/C-I was associated with lower risk of diabetes (n = 564 events; HR 0.87 [95% CI 0.79, 0.95] per SD; P = 0.0036; median follow-up, 9 years), and smaller increases (follow-up adjusted for baseline) in FG (-0.5%; P < 0.0001) and HOMA-IR (-2.9%; P = 0.011) after adjusting for baseline clinical and demographic covariates, including plasma triglycerides and HDL cholesterol. Total apoC-I concentrations were not associated with changes in FG, HOMA-IR, or incident diabetes. In ACT NOW, higher C-I/C-I was associated with smaller increases in AUCglucose (-1.8%; P = 0.0052), greater increases in ISI (7.2%; P = 0.0095), and lower risk of diabetes (n = 59 events; 0.66 [95% CI 0.48, 0.91]; P = 0.004; median follow-up, 2.5 years) after adjusting for treatment group and diabetes risk factors, including plasma lipids. CONCLUSIONS: Our results indicate that apoC-I truncation may contribute to changes in glucose levels, IR, and risk of diabetes.

BACKGROUND: While water, sanitation, and hygiene (WASH) interventions can reduce diarrheal disease, many large-scale trials have not found the expected health gains for young children in low-resource settings. Evidence-based guidance is needed to improve interventions and remove barriers to diarrheal disease reduction. OBJECTIVES: We aimed to estimate how sensitive WASH intervention effectiveness was to underlying contextual and intervention factors in the WASH Benefits (WASH-B) Bangladesh cluster-randomized controlled trial. METHODS: The investigators measured diarrheal prevalence in children enrolled in the WASH-B trial at three time points approximately 1 year apart (n=17,187 observations). We developed a susceptible-infectious-susceptible model with transmission across multiple environmental pathways and evaluated each of four interventions [water (W), sanitation (S), hygiene (H), and nutrition (N) applied individually and in combination], compliance with interventions, and the impact of individuals not enrolled in the study. Leveraging a set of mechanistic parameter combinations fit to the WASH-B Bangladesh trial using a hybrid Bayesian sampling-importance resampling and maximum-likelihood estimation approach, we simulated trial outcomes under counterfactual scenarios to estimate how changes in six WASH factors (preexisting WASH conditions, disease transmission potential, intervention compliance, intervenable fraction of transmission, intervention efficacy, and community coverage) impacted intervention effectiveness. RESULTS: Increasing community coverage had the greatest impact on intervention effectiveness (e.g., median increases in effectiveness of 34.0 and 45.5 percentage points in the WSH and WSHN intervention arms when increasing coverage to 20%). The effect of community coverage on effectiveness depended on how much transmission was along pathways not modified by the interventions. Intervention effectiveness was reduced by lower levels of preexisting WASH conditions or increased baseline disease burden. Individual interventions had complementary but not synergistic effects when combined. DISCUSSION: To realize the expected health gains, future WASH interventions must address community coverage and transmission along pathways not traditionally covered by WASH. The effectiveness of individual-level WASH improvements is reduced more the further the community is from achieving the coverage needed for herd protection. https://doi.org/10.1289/EHP15200.

Developmental delays have been associated with metabolic disturbances in children. Previous research in the childhood autism risk from genetics and the environment (CHARGE) case-control study identified neurodevelopment-related plasma metabolites in children, suggesting disturbances in the energy-related tricarboxylic acid (TCA) cycle and 1-carbon metabolism (1CM). Here, we investigated associations between children's neurodevelopmental outcomes and their mothers' plasma metabolite profiles in a subset of mother-child dyads from CHARGE, including those with autism spectrum disorder (ASD, n = 209), Down syndrome (DS, n = 76), idiopathic developmental delay (iDD, n = 64), and typically developed (TD, n = 185) controls. Multiple linear regression revealed associations between child neurodevelopmental outcomes and maternal plasma metabolites related to the TCA cycle, 1CM, and lipid metabolism. Despite profound metabolic disturbances in children with DS reported previously, few of these differences were observed in the mothers, which might reflect differences in gene dosage between children with DS and their euploid mothers. Notably differences in maternal metabolism related to ASD and iDD followed similar patterns of disturbance in previously reported metabolic signatures in children but were generally smaller in magnitude. Similar patterns of metabolic disturbances observed in mothers and their children with ASD or iDD could reflect shared genetic, mitochondrial, and/or environmental risk factors.

The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer's disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aβ-PET showed significant associations between the Aβ42/38 ratio and memory. Further, associations between the Aβ42/38 ratio and learning scores were stronger in males and in Aβ-PET-negative individuals. In contrast, no significant associations were detected between the Aβ42/40 ratio and any learning measure. These studies implicate the Aβ42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aβ38 fragment as an important biomarker in the AD field.

PURPOSE: There is a lack of systematic solutions to manage supportive care issues in racial/ethnic minorities (REM) receiving treatment for cancer. We developed and implemented an electronic patient-reported outcome (ePRO)-driven symptom management tool led by oncology pharmacists in a majority-minority cancer center located in Southern California. This study was designed to evaluate the implementation outcomes of our multilevel intervention. METHODS: This was a prospective, pragmatic, implementation study conducted between July 2021 and June 2023. Newly diagnosed adult patients with cancer receiving intravenous anticancer therapies completed symptom screening using ePRO that consists of the Patient-Reported Outcomes Measurement Information System measures at each infusion visit during the study. ePRO results were presented to an oncologist pharmacist for personalized symptom management and treatment counseling. The RE-AIM framework was used to guide implementation outcomes. Differences in symptom trajectories and clinical outcomes between groups were tested using generalized estimating equations. RESULTS: We screened 388 patients of whom 250 were enrolled (acceptance rate: 64.4%), with 564 assessments being completed. The sample consisted of non-Hispanic White (NHW, 42.4%), Hispanic/Latinx (H/L, 30.8%), and non-Hispanic Asian (20.4%), with one (21.6%) of five participants preferring speaking Spanish. Compared with NHW, H/L participants had greater odds of reporting mild to severe pain interference (odds ratio [OR], 1.91 [95% CI, 1.18 to 3.08]; P = .008) and nausea and vomiting (OR, 2.08 [95% CI, 1.21 to 3.58]; P = .008), and higher rates of urgent care utilization (OR, 1.92 [95% CI, 1.04 to 3.61]; P = .04) within 30 days. Nausea and vomiting (n = 131, 23.2%), pain (n = 91, 16.1%), and fatigue (n = 72, 12.8%) were most likely to be intervened, with 90% of the participants expressing satisfaction across all visits. CONCLUSION: Our multilevel ePRO-driven intervention led by oncology pharmacists helps facilitate symptom assessments and management and potentially reduce health disparities among REM.

BackgroundTrachoma programs use the indicator trachomatous inflammation--follicular (TF) to monitor indication for and response to treatment for trachoma at the district level. Alternative indicators, including serologic markers, are increasingly being evaluated for trachoma surveillance. We evaluated seroprevalence of IgG antibodies to the Pgp3 antigen in two districts in Maradi, Niger thought to have low TF prevalence.MethodsData were collected as part of the baseline assessment of the Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) trial in September 2021. A random sample of 80 communities was selected from Mayahi and Guidan Roumdji districts, both of which had TF prevalence

BACKGROUND AND OBJECTIVES: Iron deficiency (ID) poses a prevalent concern among blood donors, especially impacting young donors, premenopausal females and frequent donors. In alignment with recommendations to address ID, routine ferritin testing was implemented in a hospital-based donor centre. MATERIALS AND METHODS: Data set, encompassing 26 164 ferritin values from 16 464 blood donors over 33 months, were analysed retrospectively. Ferritin levels were assessed concerning donor characteristics such as sex, age, ethnicity and donation frequency. RESULTS: Ferritin testing revealed age, sex and ethnicity variations, emphasising the heightened risk of ID in young females meeting all donation criteria under 23 year of age who demonstrated the lowest mean baseline ferritin (41% [CI: 34%-48%]

High-grade or grade 3 epithelial neuroendocrine neoplasms (G3 NEN) are now divided into grade 3 well-differentiated neuroendocrine tumor (G3 NET) and neuroendocrine carcinoma (NEC), both defined by Ki-67 > 20% and/or > 20 mitoses per 2 mm2. NET and NEC are thought to be distinct tumors with different genetic profiles: NEC classically harbors co-alteration of TP53 and RB1, whereas NET genetics are site-dependent with frequent alterations in MEN1, ATRX, DAXX, and TSC1/2 in pancreatic NETs. Progression from NET to NEC is considered rare and is not well described. While both TP53 and RB1 alterations were initially thought to be rare in NET, recent work has demonstrated the former in up to 35% of high-grade G3 NET and the latter in rare high-grade NEN that progressed from NET. Here, we describe the clinical, pathologic, and molecular features associated with tumor evolution in a series of five patients that had low-grade NET that progressed to high-grade NEN with co-alteration of RB1 and TP53, similar to NEC. Morphology of the high-grade neoplasms remained well-differentiated in some cases despite RB1/TP53 co-alteration and had some NEC-like features in other cases. All five patients died of disease, with a mean overall survival of 41 months from the first metastatic disease and 12 months from acquisition of RB1/TP53 co-alteration. Our data demonstrate that low-grade NET can progress via the acquisition of both TP53 and RB1 alteration, similar to NEC, but whether this represents a transformation from NET to NEC remains unclear.

Stress can have profound impacts on memory. However, the directionality of stress effects on memory varies widely across studies, some showing enhancement while others showing impairment. This variability has been attributed to the Yerkes-Dodson Law, which proposes a U-shaped pattern such that too little or too much stress may be associated with cognitive dysfunction. The impact of stress on memory may also depend on what aspects of memory are being measured (e.g., emotional content, gist vs. detail) and how stress is measured (e.g., physiological measures, self-report). Here, we aimed to examine how self-reported perceived stress in the current moment was associated with memory performance. We used an emotional memory task designed to tap into potential gist versus detail trade-offs of stress impacting memory (e.g., target recognition, lure discrimination). Participants (ages 18-35) reported their current level of perceived stress. We replicated prior work showing impaired emotional relative to neutral lure discrimination in young adults in support of a gist versus detail trade-off in emotional memory. However, those with low and high current perceived stress showed better emotional lure discrimination compared to those with moderate current perceived stress. These results are in line with the Yerkes-Dodson Law but suggest that the directionality of the impact of stress on memory may depend on the type of memory measured. Low and high current perceived stress was associated with greater detailed memory, especially for emotional information, which may be maladaptive given gist vs. detail trade-offs in emotional memory.

BACKGROUND: Cardiometabolic diseases are risk factors for COVID-19 severity. The extent that cardiometabolic health represents a modifiable factor to mitigate the short- and long-term consequences from SARS-CoV-2 remains unclear. Our objective was to evaluate the associations between intraindividual variability of cardiometabolic health indicators and COVID-19 related hospitalizations and post-COVID conditions (PCC) among a relatively healthy population. METHODS: This retrospective, multi-site cohort study was a post-hoc analysis among individuals with cardiometabolic health data collected during routine blood donation visits in 24 US states (2009-2018) and who responded to COVID-19 questionnaires (2021-2023). Intraindividual variability of blood pressure (systolic, diastolic), total circulating cholesterol, and body mass index (BMI) were defined as the coefficient of variation (CV) across all available donation timepoints (ranging from 3 to 74); participants were categorized into CV quartiles. Associations were evaluated by multivariable binomial regressions. RESULTS: Overall, 3344 participants provided 42,090 donations (median 9 [IQR 5, 17]). The median age was 48 years (38, 56) at the first study donation. 1.2% (N = 40) were hospitalized due to COVID-19 and 15.5% (N = 519) had PCC. Higher BMI variability was associated with greater risk of COVID-19 hospitalization (4th quartile aRR 4.15 [95% CI 1.31, 13.11], p = 0.02; 3rd quartile aRR 3.41 [95% CI 1.09, 10.69], p = 0.04). Participants with higher variability of BMI had greater risk of PCC (4th quartile aRR 1.29 [95% CI 1.02, 1.64]; p = 0.04). Intraindividual variability of blood pressure (systolic, diastolic) and total circulating cholesterol were not associated with COVID-19 hospitalization or PCC risk (all p > 0.05). From causal mediation analysis, the association between the highest quartiles of BMI variability and PCC was not mediated by hospitalization (p > 0.05). CONCLUSIONS: Higher intraindividual variability of BMI was associated with COVID-19 hospitalization and PCC risk. Our findings underscore the need for further elucidating mechanisms that explain these associations and importance for consistent maintenance of body weight.

Evaluations of interventions to promote fathers involvement in family life typically focus on whether or not the intervention has a positive impact. Some evaluations also attempt to describe mediators that explain how the intervention is linked to specific outcomes. An evaluation of TRUE Dads, a Randomized Clinical Trial of a couples-based fatherhood intervention for low-income families, reported results that addressed these two issues. Reporting new analyses, the present study addresses a question asked in only a very few fatherhood intervention studies: Are there moderator variables that define characteristics of participants who benefit most or least from the intervention? A total of 46 potential moderators of 2 significant intervention outcomes - reductions in personal distress and in negative evaluations of the parents relationship with each other - were selected from a 5-domain risk/protective model of family functioning (Cowan & Cowan, 2018. Journal of Family Theory & Review, 92, 111) and from a set of demographic variables associated with these outcomes. An additional 24 potential moderators were tested on 4 outcomes that did not have direct intervention effects. Only 6 of the 70 moderator tests were statistically significant. The intervention provided greater reductions in parents personal distress when fathers had more economic resources, co-parents had higher levels of education, and the parents were living in the same household on entering the study. There were greater reductions in negative aspects of their couple or co-parenting relationship when the parents at enrollment described more difficulties in the parent-child relationship, fathers were more involved in the childrens daily care and were living in the household with their child. No other moderators were found. The results support the conclusion that TRUE Dads was equally effective for a relatively wide range of participants. This search for potential moderators of TRUE Dads outcomes is presented as an example of a needed direction in the evaluation of fatherhood interventions.

Examining institutional data from seven cohorts of students intending to major in biology across five research-intensive institutions, this work analyzes opportunity gaps-defined as the difference between the grade received by students from the dominant and nondominant sociodemographic groups in institutions of higher education-at the course-section level across mathematics, physics, biology, and chemistry disciplines. From this analysis, we find that the majority of course sections have large opportunity gaps between female and male students, students who are Black, Latino/a/e/x, or indigenous to the United States and its territories and students who are White or Asian, first-generation and non-first-generation students, and low-income and non-low-income students. This work provides a framework to analyze equity across institutions using robust methodology, including: using multiple approaches to measure grades, quantile regression rankscores which adjust for previous academic performance, and cluster analysis. Recommendations are provided for institutions to identify faculty who have equitable course sections, automate equity analyses, and compare results to other institutions to make a change toward more equitable outcomes.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity. However, the incidence and long-term risk of hypoglycemia after surgery in patients without diabetes remains unclear. This study aimed to investigate the prevalence of hypoglycemia following RYGB surgery in patients with obesity and without diabetes. METHODS: A retrospective cohort study was conducted using the TriNetX database. The study population included 15,085 patients with obesity (BMI ≥ 30 kg/m2) who underwent RYGB surgery and 3,200,074 non-surgical controls, all without a history of diabetes or GLP-1 receptor agonist use. Propensity score matching was performed to balance baseline characteristics. The primary outcome was the incidence of hypoglycemia, defined by ICD-10-CM codes or laboratory values (glucose ≤ 70 mg/dL). Cox regression analysis was employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: In the overall study population, the risk of hypoglycemia was significantly higher in the RYGB group (18.70%, n = 2,810) compared to the control group (3.80%, n = 120,923; HR 4.3, 95% CI 4.14-4.46, p

Aim: We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study.Materials & methods: Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of MET, AXL, RET, NTRK, DDR2, KDR, PDGFRA, KIT or CBL received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR).Results: In total, 113 patients were enrolled following a median of 3 (range 1-18) prior systemic regimens. Altered RET (n = 31), CBL (n = 31) and MET (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with RET-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; p = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the RET-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts.Conclusion: Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.

Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer's disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2-7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer's Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.

IntroductionIn a nested case-control study, we examined how cerebral perfusion relates to cognitive status and amyloid in the oldest-old (i.e., 90 years of age and older).MethodsStudy participants included 113 dementia-free older adults (76 cognitively normal [CN]; 37 cognitively impaired, no dementia [CIND]) from the 90+ Study (mean age = 92.9, SD = 2.4). We quantified regional perfusion from arterial spin labeling-MRI (magnetic resonance imaging) and amyloid deposition from florbetapir-positron emission tomography (PET) in a region comprising the posterior cingulate and precuneus (PCC+PCu), and additionally quantified perfusion in other regions important for cognitive decline (medial temporal lobe, inferior parietal lobe, and orbitofrontal cortex).ResultsParticipants with CIND displayed lower perfusion in the PCC+PCu relative to participants who were CN, but there was no statistically significant difference between the groups in amyloid burden in this region. In addition, participants with CIND exhibited lower inferior parietal and higher orbitofrontal perfusion.DiscussionCerebral perfusion is related to cognitive status in the oldest-old independent of amyloidosis.HighlightsCerebral perfusion and amyloid positron emission tomography (PET) were measured in older adults: 90 years of age and older. Perfusion but not amyloid differed between cognitively impaired and normal groups. Frontal and parietal regions linked to cognitive decline had altered perfusion. Perfusion is related to cognitive status in the oldest-old independent of amyloid.

IntroductionLimbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria were updated in 2023. We evaluated this updated staging using National Alzheimer's Coordinating Center data.MethodsWe examined associations of LATE-NC stages with cognition and other neuropathologic changes (NCs), and with cognition while accounting for other NCs, using multilevel regression models.ResultsOf 1352 participants, 502 (37%) had LATE-NC (23% stage 1a, 6% stage 1b, 58% stage 2, 13% stage 3). LATE-NC stages were associated with cognition, hippocampal sclerosis of aging (HS-A), Alzheimer's disease NC (ADNC), Lewy bodies (LBs), and hippocampal atrophy. While stage 1b was associated with cognition and HS-A consistent with other stages, it was not associated with ADNC or LBs. All LATE-NC stages remained significantly associated with worse cognition when accounting for other NCs.DiscussionThe updated LATE-NC staging criteria capture variations in early TDP-43 pathology spread which are consequential for cognition and associations with other NCs.HighlightsWe applied the updated limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria to data from the National Alzheimer's Coordinating Center. LATE-NC stage 1b was identified in 22% of participants with stage 1. In contrast to other LATE-NC stages, stage 1b was not associated with Alzheimer's disease neuropathologic change (ADNC) or Lewy bodies. Stages 1a and 1b were significantly associated with dementia and memory impairment. Stages 1b+ were more strongly tied to dementia than all other neuropathologic changes except high likelihood ADNC.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

INTRODUCTION: The Alzheimers Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimers disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment. METHODS: URPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board). RESULTS: As of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4s ≥ 50% URP representation goal for new enrollees but may not represent final enrollment. DISCUSSION: Findings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity. HIGHLIGHTS: The Alzheimers Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.

Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimers disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal fluid soluble platelet-derived growth factor receptor-β (CSF sPDGFRβ, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. Its possible that increased levels of sPDGFRβ in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured significant associations between BOLD FC strength among seed-target regions and sPDGFRβ values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRβ as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC, and while the hippocampus exhibited an interaction effect using CDR score, this was an exploratory analysis that we feel can lead to further research. Ultimately, we found that BBB breakdown, as measured by CSF sPDGFRβ, is associated with neural networks, and decreased functional connections.

BACKGROUND: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the region-level neuroanatomical properties of the orbitofrontal cortex (OFC), but not posteromedial cortex (PMC). Informed by a growing body of research indicating that examining the morphology of specific cortical folds (sulci) can produce unique insights into behavioral outcomes, the present study modeled the association between ERI and the morphology of sulci within OFC and PMC, which is a finer scale than previously conducted. METHODS: Analyses were conducted in a transdiagnostic sample of 118 adult individuals with a broad range of psychiatric syndromes. First, we manually defined over 4,000 sulci across 236 cerebral hemispheres. Second, we implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI. Third, we tested whether effects were specific to OFC sulci, sulcal depth, and ERI (as compared to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity). RESULTS: The LASSO regression revealed bilateral associations of ERI with the depths of eight OFC sulci. These effects were strongest for OFC sulci, sulcal depth, and ERI in comparison to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker. CONCLUSIONS: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.

Children born with congenital upper limb absence exhibit consistent and distinguishable levels of biological control over their affected muscles, assessed through surface electromyography (sEMG). This represents a significant advancement in determining how these children might utilize sEMG-controlled dexterous prostheses. Despite this potential, the efficacy of employing conventional sEMG classification techniques for children born with upper limb absence is uncertain, as these techniques have been optimized for adults with acquired amputations. Tuning sEMG classification algorithms for this population is crucial for facilitating the successful translation of dexterous prostheses. To support this effort, we collected sEMG data from a cohort of N = 9 children with unilateral congenital below-elbow deficiency as they attempted 11 hand movements, including rest. Five classification algorithms were used to decode motor intent, tuned with features from the time, frequency, and time-frequency domains. We derived the congenital feature set (CFS) from the participant-specific tuned feature sets, which exhibited generalizability across our cohort. The CFS offline classification accuracy across participants was 73.8% ± 13.8% for the 11 hand movements and increased to 96.5% ± 6.6% when focusing on a reduced set of five movements. These results highlight the potential efficacy of individuals born with upper limb absence to control dexterous prostheses through sEMG interfaces.

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging.

AimsAnxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders.MethodsWe included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders.ResultsAnxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k-11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD n=47 , BIP n=33 , SCZ n=71 , ADHD n=20 , and ASD n=5 . Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci.ConclusionsAnxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

Background and objectiveWe characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.MethodsWe first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA.Key findings and limitationsPSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax.Conclusions and clinical implicationsPSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging.

IntroductionCerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease.MethodsA total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-.ResultsSAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.DiscussionThese results highlight the interplay between amyloid and α-syn and their association with disease progression.HighlightsSeed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Comorbid cannabis use disorder (CUD) is disproportionately high in people with bipolar disorder (BD) and has been associated with worsening of BD symptoms. However, many people with BD report regularly using cannabis to ameliorate symptoms, including sleep disturbances. Sleep and circadian rhythm disturbances are hallmark features of BD that often precede the onset of mood symptoms. Genetic studies indicate that circadian disruption may predispose individuals towards both problematic cannabis use and BD, rather than cannabis use directly impacting BD symptoms. To further disentangle these hypotheses, we aimed to investigate the relationship between chronotype, cannabis use disorder (CUD) and BD mood symptoms. Data from 212 participants with BD I from the Pharmacogenomics of Bipolar Disorder study dataset were analyzed for this study. Participants were stratified by those diagnosed with co-morbid CUD and BD symptom variables, including the mean number of mood episodes per year and age of mood symptom onset for both depression and mania symptoms. The Basic Language Morningness scale (BALM) was used to assess chronotype. There was no interaction between morningness levels and CUD on BD symptoms, however both lower morningness and CUD were independently associated with earlier age of mood symptom onset. However, patients who reported initiating cannabis use post mood symptom onset had an earlier mood symptom age of onset compared to those who reported initiating cannabis use prior to mood symptom onset. These findings could provide further evidence that circadian rhythm disruption could be an underlying factor that predisposes individuals toward both CUD and BD.

IntroductionEvaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities.MethodsWe analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE).ResultsHigher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect.DiscussionOur findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health.HighlightsDementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations.

INTRODUCTION: Locus of control (LoC) refers to ones expectation that life outcomes and (mis)fortune are driven largely by ones own actions or abilities (internal LoC) or by external factors (e.g., powerful others, chance; external LoC). There is a large literature demonstrating an association between internal LoC and positive mental health outcomes. However, this research is conducted mostly in high-income, Global North settings, with limited consideration of cross-cultural variability. This short report explores how LoC relates to mental health when considered in a less-studied context: in a setting of stark structural violence and in relation to supernatural agents. METHODS: I conducted a community-based survey in rural Haiti (n = 322) that assessed sent spirit-related locus of control (LoC-S) and mental health. RESULTS: Among individuals experiencing higher levels of daily stressors, depressive and anxiety symptoms were high regardless of LoC-S. However, for individuals facing low-to-moderate daily stressors, external LoC-S (believing one does not have control in relation to sent spirits) was associated with lower depressive and anxiety symptoms, though this interaction did not hold for anxiety after controlling for covariates. Though initially a nonintuitive finding, I contextualize this outcome in relation to ethnographic work in Haiti, showing that the ability to explain misfortune via the supernatural world can serve as a form of blame displacement. CONCLUSION: In a context where extreme structural violence means that individuals realistically have little control over their lives, an external LoC better reflects lived experience, helping explain the association with better mental health outcomes.

Rationale: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. Objectives: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. Methods: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. Measurements and Main Results: Among 2,255 participants with 6,978 plasma samples, pyrazinamide displayed sevenfold exposure variability (151-1,053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in therapeutic windows of 231-355 mg · h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1,000 mg would have permitted an additional 13.1% (n = 96) of participants allocated to the control and 9.2% (n = 70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared with the current weight-banded dosing. Conclusions: Flat dosing of pyrazinamide at 1,000 mg/d would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registered with www.clinicaltrials.gov (NCT02410772).

ObjectiveTo systematically review Medicaid policies state-by-state for gender-affirming surgery coverage.Data sources and study settingPrimary data were collected for each US state utilizing the LexisNexis legal database, state legislature publications, and Medicaid manuals.Study designA cross-sectional study evaluating Medicaid coverage for numerous gender-affirming surgeries.Data collection/extraction methodsWe previously reported on state health policies that protect gender-affirming care under Medicaid coverage. Building upon our prior work, we systematically assessed the 27 states with protective policies to determine coverage for each type of gender-affirming surgery. We analyzed Medicaid coverage for gender-affirming surgeries in four domains: chest, genital, craniofacial and neck reconstruction, and miscellaneous procedures. Medicaid coverage for each type of surgery was categorized as explicitly covered, explicitly noncovered, or not described.Principal findingsAmong the 27 states with protective Medicaid policies, 17 states (63.0%) provided explicit coverage for at least one gender-affirming chest procedure and at least one gender-affirming genital procedure, while only eight states (29.6%) provided explicit coverage for at least one craniofacial and neck procedure (p = 0.04). Coverage for specific surgical procedures within these three anatomical domains varied. The most common explicitly covered procedures were breast reduction/mastectomy and hysterectomy (n = 17, 63.0%). The most common explicitly noncovered surgery was reversal surgery (n = 12, 44.4%). Several states did not describe the specific surgical procedures covered; thus, final coverage rates are indeterminate.ConclusionsIn 2022, 52.9% of states had health policies that protected gender-affirming care under Medicaid; however, coverage for various gender-affirming surgical procedures remains both variable and occasionally unspecified. When specified, craniofacial and neck reconstruction is the least covered anatomical area compared with chest and genital reconstruction.

Building on decades of scholarship critiquing scientist representation in classrooms and textbooks, the present study characterizes the lifetime experiences of undergraduate students regarding their perceptions of scientists and science identity. Informed by the theoretical framework of Cultural Learning Pathways (CLP), we conducted 31 semistructured interviews with undergraduates who completed six Scientist Spotlights (scientistspotlights.org), which are inclusive curricular supplements that feature counterstereotypical scientists. Despite decades of progress in curricular representation, our results revealed almost all students (94%, n = 29) recounted exposure to predominantly (if not exclusively) stereotypical scientists across social institutions (e.g., media, K12, universities, healthcare environments) throughout their lifetime, which limited their Scopes of Possibility to pursue science. All students (100%, n = 31) reported that Scientist Spotlights enhanced Scopes of Possibility for themselves and others from marginalized backgrounds to pursue science. Last, almost all students (97%, n = 30) shared characteristics they hoped to see when imagining Scopes of Possibility, emphasizing the need for a concerted effort to increase representation of counterstereotypical scientists across science curriculum and social institutions more broadly.

Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm arising from follicular dendritic cells (FDC) of lymphoid follicles. While the majority of FDC sarcoma cases arise within lymph nodes, approximately 30% manifest in extranodal sites. Only 4 prior occurrences of intra-parotid FDC sarcomas have been documented. We are reporting a rare case of FDC of the parotid gland in a 65-year-old male with a questionable history of B-cell lymphoma. The patient underwent a right total parotidectomy and bilateral neck dissection. A diagnosis of follicular dendritic cell (FDC) sarcoma was made, with one positive intra-parotid node. The malignant cells expressed the characteristic markers for FDC sarcoma but with positivity of the melanocytic marker PRAME. This is a case of FDC sarcoma with an unusual extranodal localization in the parotid gland. Immunohistochemistry was useful in making a diagnosis although the positivity for the melanocytic marker PRAME was unusual and unreported before.

OBJECTIVE: To identify organizational service features associated with positive patient ratings of primary care within primary care clinics tailored to accommodate persons with ongoing and recent experiences of homelessness (PEH). DATA SOURCES AND STUDY SETTING: PEH receiving primary care in 29 United States Veterans Health Administration homeless-tailored clinics were surveyed about their primary care experience using the validated Primary Care Quality-Homeless (PCQ-H) survey. Characteristics of the clinics were assessed through surveys of clinic staff using a new organizational survey developed through literature review, site visits, statistical analysis, and consensus deliberation. STUDY DESIGN: Cross-sectional examination of patients ratings of care based on surveys of patients, and of clinic characteristics, analyzed with Classification and Regression Tree (CART) analysis, a form of machine learning. DATA COLLECTION METHODS: Patient surveys (n = 3394) were obtained from a random sample of enrolled patients by both mail and telephone by an external survey contractor. Staff (n = 52 from 29 clinics) were interviewed by telephone. PRINCIPAL FINDINGS: This analysis identified service features that impact patient experience favorably, including aspects of patient-centeredness, team identity, strong external leadership support, and service that reach beyond traditional primary care clinic confines. Results varied according to the patient experience scale analyzed. Individual characteristics of PEH, such as degree of social support, general health, and unsheltered status, were also correlated with how they rate care. CONCLUSIONS: Organizational characteristics correlate with ratings of primary care from patients with recent and ongoing homelessness. Primary care programs serving homeless individuals can assure better care based on who they hire, how they foster team identity, what services they provide, and the strength of leadership support to protect a homeless-focused mission.

Recent genetic studies have revealed that hemimegalencephaly (HME) is a multi-system disorder associated with germline or mosaic variants within the PI3K-mTOR-GATOR1 signaling pathways. Patients with HME typically develop drug-resistant epilepsy necessitating extensive evaluation, hemispherectomy, and long-term management. We describe the role of a multidisciplinary team (MDT) for the diagnosis and management of recent patients with HME at UCLA who underwent hemispherectomy. Genetic evaluation identified nine patients with the following variants: NPRL3 x2 germline, PIK3CA mosaicism x4, MTOR mosaicism x1, AKT3 mosaicism x1, unknown x1. Each patients MDT comprised 4-9 specialties. One child with a MTOR variant had persistent epilepsy after hemispherectomy, but addition of everolimus resulted in an 80% decrease in seizure frequency. Another child with hemihypertrophy and PIK3CA mosaic variant was offered targeted PIK3CA inhibitor treatment, alpelisib, for overgrowth. A third child with germline NPRL3 variant inherited from their unaffected mother resulted in a sibling being diagnosed with the variant who later developed seizures secondary to focal cortical dysplasia. The implementation of a MDT offers essential guidance for families affected by HME, encompassing prognostication, surveillance, and therapeutic strategies. Identifying the etiology of HME can facilitate the development of targeted treatments and enable timely genetic counseling. PLAIN LANGUAGE SUMMARY: Hemimegalencephaly (HME) is a complex brain disorder caused by genetic changes. It often leads to severe epilepsy that doesnt respond to standard treatments and frequently requires surgery. In this case series, nine patients with HME were identified and found to have genetic mutations in key growth-regulating genes. A multidisciplinary team model was developed to facilitate patients care. For example, one patients seizures improved with surgery, another with a new targeted medication, and another received treatment for symptoms of overgrowth. This team approach provides comprehensive care for patients and can lead to efficient care coordination and implementation of novel therapies.

Few studies have measured components of stress responses in real time-an essential step in designing just-in-time interventions targeting moments of risk. Using ecological momentary assessment (EMA), we characterised stress response components to everyday stressors, including reactivity (the response following a stressor), recovery (the return towards baseline), and pile-up (the accumulation of stressors) (RRPs) by quantifying the dynamics of response indicators (i.e., subjective stress, negative affect, and perseverative cognition). To determine the utility of these novel measures in capturing and characterising acute moments of the stress response, this study evaluated the proportion of variance in RRPs attributed to (1) between-person, (2) between-days, and (3) within-day (momentary) levels. Healthy adults (n = 123; aged 35-65, 79% women, 91% non-Hispanic White) participated in a 14-day study assessing stress response via EMA 6 times a day. RRPs were constructed from 10,065 EMA reports. Multilevel models with moments nested within days nested within persons were used to partition variance in the RRPs. Reactivity and recovery indicators captured the most variation within-days (i.e., across moments; range 76%-80% and 87%-89%, respectively), with small amounts of variance between-person. For pile-up, variation was mostly observed between-days (range 60%-63%) and between-persons (range 27%-31%). In contrast, raw measures of stress response reflected substantial between-person (range 32%-54%) and within-day (range 34%-53%) variance. These results demonstrated that a person-specific approach to measuring stress response components (i.e., RRPs) can capture the dynamic within-person variation in stress response, as it occurs in real time, making it well-suited for use in novel just-in-time interventions targeting moments of risk.

Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is an agnostic method for broad-based diagnosis of central nervous system (CNS) infections. Here we analyzed the 7-year performance of clinical CSF mNGS testing of 4,828 samples from June 2016 to April 2023 performed by the University of California, San Francisco (UCSF) clinical microbiology laboratory. Overall, mNGS testing detected 797 organisms from 697 (14.4%) of 4,828 samples, consisting of 363 (45.5%) DNA viruses, 211 (26.4%) RNA viruses, 132 (16.6%) bacteria, 68 (8.5%) fungi and 23 (2.9%) parasites. We also extracted clinical and laboratory metadata from a subset of the samples (n = 1,164) from 1,053 UCSF patients. Among the 220 infectious diagnoses in this subset, 48 (21.8%) were identified by mNGS alone. The sensitivity, specificity and accuracy of mNGS testing for CNS infections were 63.1%, 99.6% and 92.9%, respectively. mNGS testing exhibited higher sensitivity (63.1%) than indirect serologic testing (28.8%) and direct detection testing from both CSF (45.9%) and non-CSF (15.0%) samples (P

Stimulus-response habits benefit behavior by automatizing the selection of rewarding actions. However, this automaticity can come at the cost of reduced flexibility to adapt behavior when circumstances change. The goal-directed system is thought to counteract the habit system by providing the flexibility to pursue context-appropriate behaviors. The dichotomy between habitual action selection and flexible goal-directed behavior has recently been challenged by findings showing that rewards bias both action and goal selection. Here, we test whether reward reinforcement can give rise to habitual goal selection much as it gives rise to habitual action selection. We designed a rewarded, context-based perceptual discrimination task in which performance on one rule was reinforced. Using drift-diffusion models and psychometric analyses, we found that reward facilitates the initiation and execution of rules. Strikingly, we found that these biases persisted in a test phase in which rewards were no longer available. Although this facilitation is consistent with the habitual goal selection hypothesis, we did not find evidence that reward reinforcement reduced cognitive flexibility to implement alternative rules. Together, the findings suggest that reward creates a lasting impact on the selection and execution of goals but may not lead to the inflexibility characteristic of habits. Our findings demonstrate the role of the reward learning system in influencing how the goal-directed system selects and implements goals.

The early initiation of binge-drinking and biological sex are critical risk factors for the development of affective disturbances and cognitive decline, as well as neurodegenerative diseases including Alzheimers disease. Further, a history of excessive alcohol consumption alters normal age-related changes in the pattern of protein expression in the brain, which may relate to an acceleration of cognitive decline. Here, we aimed to disentangle the interrelation between a history of binge-drinking during adolescence, biological sex and normal aging on the manifestation of negative affect, cognitive decline and associated biochemical pathology. To this end, adolescent male and female C57BL/6J mice (PND 28-29) underwent 30 days of alcohol binge-drinking using a modified drinking-in-the-dark (DID) paradigm. Then, mice were assayed for negative affect, sensorimotor gating and cognition at three developmental stages during adulthood-mature adulthood (6 months), pre-middle age (9 months) and middle age (12 months). Behavioural testing was then followed by immunoblotting to index the protein expression of glutamate receptors, neuropathological markers [Tau, p (Thr217)-Tau, p (Ser396)-Tau, BACE, APP, Aβ], as well as ERK activation within the entorhinal cortex, prefrontal cortex and amygdala. Across this age span, we detected only a few age-related changes in our measures of negative affect or spatial learning/memory in the Morris water maze and all of these changes were sex-specific. Prior adolescent binge-drinking impaired behaviour only during reversal learning in 9-month-old females and during radial arm maze testing in 12-month-old females. In contrast to behaviour, we detected a large number of protein changes related to prior binge-drinking history, several of which manifested as early as 6 months of age, with the prefrontal cortex particularly affected at this earlier age. While 6-month-old mice exhibited relatively few alcohol-related protein changes within the entorhinal cortex and amygdala, the number of alcohol-related protein changes within the entorhinal cortex increased with age, while the 12-month-old mice exhibited the largest number of protein changes within the amygdala. Approximately a third of the alcohol-related protein changes were sex-selective. Taken together, the results of our longitudinal study using a murine model of binge-drinking indicate that a prior history of heavy alcohol consumption, beginning in adolescence, is sufficient to induce what we presume to be latent changes in protein indices of cellular activity, glutamate transmission and neuropathology within key brain regions governing cognition, executive function and emotion that appear to precede the onset of robust behavioural signs of dysregulated affect and cognitive impairment.

Male infertility has been a primary cause of global infertility, affecting 8-12% of couples worldwide. Previous studies have shown that semen quality decreases with advanced aging with an increased presence of inflammatory cells. In this study, we examined changes in the epigenome across a diverse cohort that includes both fertile and infertile men. We also compare the age-associated changes in semen to those observed in buccal swabs in order to characterize differences in epigenetic aging across diverse tissues. We found that variations in the semen methylome associated with aging are linked to inflammatory genes. Many age-associated sites are demethylated with advanced aging and are associated with the activation of inflammatory pathways. By contrast, we do not observe age-associated changes in inflammatory genes in buccal swab methylomes, which instead are characterized by changes to bivalent promoters. Our findings highlight the potential of epigenetic markers as indicators of male reproductive health.

We report general acceptance (61.0%) of an mpox vaccine in the Democratic Republic of the Congo among 5,226 survey respondents. Healthcare workers and respondents in historic mpox-endemic regions had higher acceptance rates. These data highlight the need for increased community engagement and sensitization before widespread deployment of mpox vaccines.

Implantation of penile prosthesis is considered when conservative measures fail or are unacceptable to patients wishing treatment for erectile dysfunction. In the United States (US), inflatable penile prostheses are more often used than malleable penile prostheses (MPP). Outside the US, the reverse is true because third-party reimbursement is not available, and MPP is considerably cheaper. Two American manufacturers make MPP; presently, a new manufacturer, Rigicon (Ronkonkoma NY), has recently begun to sell its MPP worldwide. Patient information forms submitted to the manufacturer between March 1, 2019, and December 8, 2022, were used to conduct an initial safety study for 605 first-time patients implanted with Rigicon10® by 46 physicians in 15 countries with a mean follow-up of 21.6 months. It has the same configuration of trimmable, paired silicone rods containing a twisted stainless-steel wire for bendability. However, it is available in six widths with hydrophilic coating compared to three widths offered by competitors. Revision or explantation was needed in 6 of 605 patients (0.99%) with half of those being removed for dissatisfaction (0.50%). Two (0.33%) suffered device infection and one (0.16%) required removal for erosion. Kaplan-Meiers statistical analysis showed three-year implant survival from revision = 99.2%. It demonstrated a comparable safety record with less than 1.00% of patients requiring reoperation.

Neurons in the locus coeruleus (LC) have been traditionally viewed as a homogenous population. Recent studies begin to reveal their heterogeneity at multiple levels, ranging from molecular compositions to projection targets. To further uncover variations of neuronal properties in the LC, we took a genetic-based tagging approach to identify these neurons. Our data revealed diverse spike waveforms among neurons in the LC region, including a considerable fraction of narrow-spiking units. While all wide-spiking units possessed the regular waveform polarity (negative-positive deflection), the narrow units can be further divided based on opposing waveform polarities. Under anesthesia, wide units emitted action potential at a higher rate than the narrow units. Under wakefulness, only one subtype of narrow units exhibited fast-spiking phenotype. These neurons also had long latencies to optogenetic stimulation. In-situ hybridization further supported the existence of a small population of putative GABAergic neurons in the LC core. Together, our data reveal characteristic differences among neurons in the LC region, and suggest that a fraction of electrophysiologically-identified narrow-spiking neurons can be fast-spiking interneurons, and their fast-spiking feature is masked by anesthesia.

The protozoan parasite Trypanosoma brucei evades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically switching expression of the VSG using a large genomic repertoire of VSG-encoding genes1-6. Recent studies of antigenic variation in vivo have focused near exclusively on parasites in the bloodstream6-8, but research has shown that many, if not most, parasites reside in the interstitial spaces of tissues9-13. We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq7, a high-throughput sequencing approach for profiling VSGs expressed in populations of T. brucei. Here we show that tissues, not the blood, are the primary reservoir of antigenic diversity during both needle- and tsetse bite-initiated T. brucei infections, with more than 75% of VSGs found exclusively within extravascular spaces. We found that this increased diversity is correlated with slower parasite clearance in tissue spaces. Together, these data support a model in which the slower immune response in extravascular spaces provides more time to generate the antigenic diversity needed to maintain a chronic infection. Our findings reveal the important role that extravascular spaces can have in pathogen diversification.