Cyclin-dependent kinase 4/6 inhibitors (CDKIs) improves survival when added to endocrine therapy in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, their complex schedule, side effects, and cost contribute to non-adherence.The EAQ221CD is a two-arm randomized controlled trial that evaluates the effectiveness of the CONnected CUstomized Treatment Platform (CONCURxP), a mobile health intervention, versus enhanced usual care (EUC) on CDKI adherence among 390 patients with breast cancer and a new CDKI prescription. Participants use a smart pouch (Wisebag) to monitor real-time adherence. CONCURxP arm patients: (1) receive text reminders for missed or extra doses; (2) receive text message surveys inquiring reasons for missed or extra doses; and (3) have access to their adherence history on a study web portal. Missed or double doses trigger alerts to the oncology team. Patients citing cost as a barrier are referred to a national non-profit financial navigation program. EUC arm patients receive educational materials on side effect management. Patients complete surveys at baseline, 3, 6, and 12 months after randomization. Our objectives are to: (1) compare 12-month CDKI adherence measured using Wisebag (primary outcome) between the two arms; (2) compare patient-reported outcomes at 12-months between the two arms, including symptom burden, quality of life, patient-provider communication, self-efficacy for managing symptoms, and financial worry; and (3) use mixed methods to describe patients' experience with the CONCURxP intervention. Our multilevel intervention will provide actionable results to improve adherence, health outcomes, and patients' experience.NCT06112613.

Multi-tracer positron emission tomography (PET), which assesses key neurological biomarkers such as tau pathology, neuroinflammatory, β -amyloid deposition, and glucose metabolism, plays a vital role in diagnosing neurological disorders by providing complementary insights into the brain's molecular and functional state. Acquiring multi-tracer PET scans remains challenging due to high costs, radiation exposure, and limited tracer availability. Recent studies have attempted to synthesize multi-tracer PET images from structural MRI. However, these approaches typically either rely on direct mappings to individual tracers or lack distributional constraints, leading to inconsistencies in image quality across tracers. To this end, we propose a normalized diffusion framework (NDF) to generate high-quality multi-tracer PET images from a single MRI through a distribution-guided class-conditioned weighted diffusion model. Specifically, a diffusion model conditioned on MRI and tracer-specific class labels is trained to synthesize PET images of multiple tracers, and a pre-trained normalizing flow model refines these outputs by mapping them into a shared distribution space. This mapping ensures that the subject-specific high-level features across different PET tracers are preserved, resulting in more consistent and accurate synthesis. Experiments on a total of 425 subjects with multi-tracer PET scans demonstrate that our NDF outperforms current state-of-the-art methods, indicating its potential for advancing multi-tracer PET synthesis.

Introduction Corticospinal tract lesion load (CST-LL) is a biomarker used for studying motor outcomes after stroke. However, the optimal method for calculating this metric is unknown. Methods This is a cross-sectional study of a large ischemic stroke cohort from the ENIGMA Stroke Recovery Consortium (n = 221; mean age = 59.8 years, 56% male) to compare 4 lesion load metrics across 3 CST templates. We then validate these findings in another large, independent stroke cohort (n = 125; mean age = 64.6 years, 54% male). Results: Results indicate that variance in behavioral outcome was best explained using the maximum weighted cross-sectional overlap between lesion and the CST (Max-WLL), and when using an age-appropriate normative CST template (generated from the HCP Aging study). This was true both when the outcome was motor impairment, measured using the Fugl-Meyer Upper Extremity scale (FMUE, relative explained variance (REV) = 58.9%), and when it was global function, measured using the Barthel Index (BI, REV = 60%). In the validation cohort, FMUE results were replicated (REV = 47.6%). Conclusion: The findings indicate that Max-WLL, which represents the proportion of transected CST fibers, most accurately captures CST injury as it relates to motor and functional outcomes after stroke. Additionally, results suggest the importance of an age-appropriate template, a key consideration given that stroke is largely a disease of the elderly. Together, these findings provide an independently validated tool to optimize future research examining CST injury after stroke.

A 13-year-old male competitive club soccer player with a history of bilateral Osgood-Schlatter disease over the past 6 months reported unusually high fatigue and right heel pain after a match. Over the next 4 days, fever developed and persisted despite antipyretics. Right heel pain, warmth, and redness increased until weight-bearing was not tolerated. Subsequent imaging and blood work eventually lead to a calcaneal osteomyelitis diagnosis. A bone biopsy procedure and a 6-week course of antibiotics were completed. The rehabilitation and conditioning plan, which was successful, was based on assessment findings and targeted a return to sport 12 weeks postsurgery. Interprofessional collaboration was key for the diagnosis and effective medical treatment. Rehabilitation and conditioning protocol development was challenging as (1) no postsurgical rehabilitation protocol for a patient with calcaneal osteomyelitis wishing to return to sport has been described and (2) the impact of postinjury rehabilitation on training load is poorly documented.

The multiple-transferable resistance protein (MtrR) is a transcriptional repressor of the mtrCDE-encoded drug efflux pump and Type IV pilus biosynthesis (pilM), and an activator of penicillin-binding protein 1 (ponA) expression in Neisseria gonorrhoeae. Previously published microarray data suggested that MtrR is also an activator of ltgA expression in the gonococcus. LtgA is a lytic transglycosylase responsible for approximately half of recycled peptidoglycan fragments and released peptidoglycan-derived cytotoxins, which cause ciliary damage and induce specific inflammatory responses. The fragments generated by LtgA during peptidoglycan remodeling can either be recognized by the permease AmpG for uptake into the bacterial cytoplasm and recycled for new cell wall growth and general metabolism or released into the external milieu. Therefore, we sought to define the capacity of MtrR to regulate LtgA expression in gonococci. We show that MtrR binds to the ltgA promoter region in a concentration-dependent manner, and that this binding results both in increased ltgA mRNA transcription and LtgA protein levels during exponential growth. Deletion of mtrR in N. gonorrhoeae decreased peptidoglycan monomer release from growing cells and increased autolysis. These results suggest that MtrR regulation of ltgA impacts peptidoglycan-derived cytotoxin release and autolysis in the gonococcus. This study suggests a central role of MtrR in coordinating aspects of the cellular envelope that may contribute to gonococcal pathogenesis.

Introduction Access to medications for opioid use disorder (MOUD) varies across racial and ethnic groups. As the largest payer for MOUD, Medicaid has potential to ensure access for all enrollees. We aimed to quantify recent trends and state variation in MOUD use by race and ethnicity in Medicaid. Methods Using a distributed research network, we conducted a cross-sectional study of 11 states' Medicaid data from 2016 to 2020. Among enrollees diagnosed with opioid use disorder (OUD), we measured the percent receiving MOUD (overall; and methadone, buprenorphine, naltrexone, separately), continuity of MOUD for ≥180 days, and claims-based overdose event rates. We estimated logistic regression models in each state with fixed effects for year, race/ethnicity, and year and race/ethnicity interaction terms to examine changes in demographic differences in outcomes over time, adjusting for patient characteristics. We pooled estimates using random effects meta-analyses. Results Of the 542,414 enrollees with OUD in 2020, 430,891 (79.4%) were non-Hispanic white, 77,952 (14.4%) were non-Hispanic Black, 17,094 (3.2%) were Hispanic, and 16,477 (3.0%) had other race or ethnicity. MOUD use increased among enrollees in all racial and ethnic groups over time. The share of non-Hispanic white enrollees diagnosed with OUD receiving MOUD increased from 52.3% to 68.8% from 2016 to 2020 while the percent of non-Hispanic Black enrollees receiving MOUD from 37.2% to 49.7% during that period. Differences were widest for buprenorphine versus methadone or naltrexone. In adjusted analyses, Hispanic and Non-Hispanic Black enrollees were less likely to receive MOUD (adjusted odds ratios (AOR) = 0.67 [95 CI 0.49–0.91] and AOR = 0.41 [95 CI 0.33–0.52], respectively) compared to non-Hispanic white enrollees in 2016. Differences in receipt of MOUD did not change from 2016 to 2020. Non-Hispanic Black enrollees were less likely to have continuous MOUD relative to non-Hispanic white enrollees (AOR = 0.68 [95 CI 0.61–0.77)]. Overdose events peaked in 2017 for all racial and ethnic groups and were highest for Hispanic enrollees in 2020. Conclusion MOUD increased among all racial and ethnic groups in 11 state Medicaid programs from 2016 to 2020. Yet, racial and ethnic differences in MOUD persisted, especially for buprenorphine. Our findings can inform Medicaid efforts to improve access to MOUD for all enrollees affected by OUD.

Background/Objectives: Colombia has implemented a tiered tax on sugar-sweetened beverages (SSBs), reaching 20% for high-sugar products by 2025. To inform evaluations of this policy, we estimated taxed and untaxed beverage intake prior to implementation and examined differences across sociodemographic groups. Methods: We analyzed 24 h dietary recall data from the 2015 National Survey of the Nutritional Situation of Colombia (ENSIN; n = 11,877 adults aged 18–64), which uses a stratified, multistage cluster sampling design covering all regions of the country. Beverages were categorized by 2025 tax thresholds: untaxed (<5 g added sugar/100 mL), taxed (≥5 g), and high-sugar taxed (≥9 g). Intake (mL, kcal) was estimated per capita and per consumer using survey-weighted two-part models, adjusting for sociodemographic characteristics. Results: Eighty-four percent of adults consumed taxed beverages, with per capita intake of 209 kcal (95% CI: 203–216) and 481 mL (95% CI: 464–497). Sixty-three percent consumed high-sugar taxed beverages, with intake of 134 kcal (95% CI: 130–139) and 292 mL (95% CI: 282–303) per capita. Untaxed beverages accounted for 109 kcal (95% CI: 106–112) and 837 mL (95% CI: 793–882) per capita. Across categories, the highest per capita kcal intakes were from untaxed dairy/milk substitutes (67 kcal, 95% CI: 64–69), any taxed fruit/vegetable juices (61 kcal, 95% CI: 55–66), and any taxed sodas/carbonated beverages (47 kcal, 95% CI: 44–50). Males consumed more taxed beverages of any type (255 kcal, 95% CI: 247–264) than females (174 kcal, 95% CI: 165–182). Conclusions: Prior to its SSB tax, Colombians had a high consumption of SSBs that would be subject to the tax. Future research should assess how consumption changed in response to the tax.

Components of the insulin processing and secretion pathways remain incompletely understood. Here, we examined a genome-wide association study (GWAS) signal for plasma proinsulin levels. Lead GWAS variant rs150781447-T encodes an Arg279Cys substitution in TBC1 domain family member 30 (TBC1D30), but no role for this protein in insulin processing or secretion has been established previously. This study aimed to evaluate whether TBC1D30 drives the GWAS association signal by determining whether TBC1D30 is involved in proinsulin secretion and, if so, to examine the effects of variant alleles and potential mechanisms.Using CRISPR/Cas9 genome editing to create double-strand breaks and prime editing to install substitutions in INS1 832/13 insulinoma cells, we generated clonal cell lines with altered TBC1D30, as well as homozygous and heterozygous lines carrying the lead GWAS variant. We characterised lines by Sanger sequencing, quantitative PCR and ELISAs to measure glucose-stimulated proinsulin and insulin secretion. We also tested the effects of TBC1D30 knockdown on proinsulin and insulin secretion in human islets. We further assessed TBC1D30's contribution to secretory pathways by examining the effects of altered gene function on intracellular proinsulin and insulin content and insulin localisation, and by identifying potential proteins that interact with TBC1D30 using affinity purification mass spectrometry.Compared with mock-edited cells, cell lines with reduced TBC1D30 expression or altered Rab GTPase-activating protein (RabGAP) domain had significantly more secreted proinsulin, 1.8- and 2.6-fold more than controls, respectively. Similarly, cells expressing the variant substitution demonstrated increased proinsulin secretion. Cell lines with a partial deletion of a critical functional domain showed 1.8-fold higher expression of Tbc1d30 and at least 2.0-fold less secreted proinsulin. Cells with altered RabGAP domain sequence also demonstrated, to a lesser extent, changes in secreted insulin levels. TBC1D30 knockdown in human islets resulted in increased insulin secretion with no significant effect on proinsulin secretion. The effects of altered TBC1D30 on mislocalisation of insulin, intracellular proinsulin and insulin content and the identities of interacting proteins are consistent with a role for TBC1D30 in proinsulin and insulin secretion.These findings suggest that effects on TBC1D30 are responsible for the GWAS signal and that TBC1D30 plays a critical role in the secretion of mature insulin.

Data heterogeneity is a challenging issue for modern statistical data analysis. There are different types of data heterogeneity in practice. In this article, we consider potential structural changes and complicated tail distributions. There are various existing methods proposed to handle either structural changes or heteroscedasticity. However, it is difficult to handle them simultaneously. To overcome this limitation, we consider statistically and computationally efficient change point detection and localization in high-dimensional quantile regression models. Our proposed framework is general and flexible since the change points and the underlying regression coefficients are allowed to vary across different quantile levels. The model parameters, including the data dimension, the number of change points, and the signal jump size, can be scaled with the sample size. Under this framework, we construct a novel two-step estimation of the number and locations of the change points as well as the underlying regression coefficients. Without any moment constraints on the error term, we present theoretical results, including consistency of the change point number, oracle estimation of change point locations, and estimation for the underlying regression coefficients with the optimal convergence rate. Finally, we present simulation results and an application to the S&amp;P 100 dataset to demonstrate the advantage of the proposed method. Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work