Citations

Abstract TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer’s disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7 . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43–depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease

ABSTRACT Intratumor heterogeneity arises from ongoing somatic evolution complicating cancer diagnosis, prognosis, and treatment. Here we present TEATIME (es t imating e volution a ry events t hrough s i ngle-ti m epoint s e quencing), a novel computational framework that models tumors as mixtures of two competing cell populations: an ancestral clone with baseline fitness and a derived subclone with elevated fitness. Using cross-sectional bulk sequencing data, TEATIME estimates mutation rates, timing of subclone emergence, relative fitness, and number of generations of growth. To quantify intratumor fitness asymmetries, we introduce a novel metric—fitness diversity—which captures the imbalance between competing cell populations and serves as a measure of functional intratumor heterogeneity. Applying TEATIME to 33 tumor types from The Cancer Genome Atlas, we revealed divergent as well as convergent evolutionary patterns. Notably, we found that immune-hot microenvironments constraint subclonal expansion and limit fitness diversity. Moreover, we detected temporal dependencies in mutation acquisition, where early driver mutations in ancestral clones epistatically shape the fitness landscape, predisposing specific subclones to selective advantages. These findings underscore the importance of intratumor competition and tumor-microenvironment interactions in shaping evolutionary trajectories, driving intratumor heterogeneity. Lastly, we demonstrate that TEATIME-derived evolutionary parameters and fitness diversity offer novel prognostic insights across multiple cancer types.

Objective Reference values of regional cerebral oxygen saturation (rScO 2 ) in preterm neonates across gestational age (GA) groups remain undefined. This study aimed to establish rScO 2 references for neonates born before 32 weeks of gestation. Design A prospective observational cohort study. Setting Large tertiary neonatal referral centre in Croatia. Patients Preterm neonates without major comorbidities born between 2018 and 2022 with normal cranial ultrasound findings. Interventions rScO 2 was assessed with near-infrared spectroscopy (NIRS) using neonatal sensors. Main outcome measures The primary analysis provided rScO 2 reference ranges for the entire preterm neonatal cohort, followed by stratified analyses based on GA: extremely preterm , <28.0 weeks; very preterm , 28.0–30.0 weeks; and very preterm , 30.1–32.0 weeks. Quantile regression was used to estimate the selected rScO 2 percentiles (5th, 10th, 50th, 90th and 95th) from 6 to 72 hours after birth. Results 114 neonates with median (IQR) GA of 29.9 (29.1–31.5) weeks were included: 22% were EP <28w , 29% were VP 28–30w and 49% were VP >30–32w . The median rScO 2 was 75.6% at 6 hours, 79.5% over the first 24 hours and exceeding 80% in the subsequent 48 hours. When analysed separately, notable differences emerged across prematurity categories, with the highest median rScO 2 observed in the VP >30–32w group. Supplementary analyses, comparing rScO 2 values across the three GA groups, revealed significant differences at 48 and 72 hours. The majority of the estimated rScO 2 fifth percentiles between 6 and 72 hours were in the range ≥60%, with a single lowest estimate of 56.3% at 6 hours in the EP <28w group. Thus, for all subgroups, the estimated fifth percentile of rScO 2 was above the brain hypoxic threshold. Conclusions The use of age-appropriate neonatal NIRS sensors provided the rScO 2 reference values for very and extremely preterm neonates without major comorbidities 6–72 hours after birth.

Objectives To estimate the proportion and correlates of self-reported financial difficulty among patients with multiple myeloma (MM) or chronic lymphocytic leukaemia (CLL). Setting Sixty-six US community and minority oncology practices affiliated with the National Cancer Institute Community Oncology Research Programme (NCORP). Participants A total of 521 patients (=18 years) with MM or CLL consented and 416 responded to a survey (completion rate=79.8%). Respondents had a MM diagnosis (74.0%), an associate degree or higher (53.4%), were White (89.2%), insured (100%) and treated with clinician-administered drugs (68.0%). Study design Observational, theoretical model and protocol-based patient survey administered between May 2019 and June 2020. Primary and secondary outcome measures Financial difficulty was assessed using a single-item measure, the EORTC QLQC30: Has your physical condition or medical treatment caused you financial difficulties in the past year? and using an any-or-none composite measure of 22 items assessing financial difficulty, worries and the use of cost-coping strategies. Multivariable logistic regression models assessed the association of financial difficulty with diagnosis, socioeconomic and treatment characteristics. Results About 16.8% reported experiencing financial difficulty using the single-item measure and 60.3% using the composite measure. Most frequently endorsed items in the composite measure were financial worry about having to pay large medical bills related to cancer and difficulty paying medical bills. Financial difficulty using the single-item measure was associated with having MM vs CLL (adjusted OR (aOR), 0.34; 95% CI, 0.13 to 0.84; p=0.02), having insurance other than Medicare (aOR, 2.53; 95% CI, 1.37 to 4.66; p=0.003), being non-White (aOR, 2.21; 95% CI, 1.04 to 4.72; p=0.04) and having a high school education or below (aOR, 0.36; 95% CI, 0.21 to 0.64; p=0.001). Financial difficulty using the composite measure was associated with having a high school education or below (aOR, 0.62; 95% CI, 0.41 to 0.94; p=0.03). Conclusions US patients with MM and CLL report financial difficulty, especially those with low socio-economic status. Interventions are needed to mitigate patients financial difficulty. Trial registration number NCT03870633 .

ABSTRACTIntroduction and ObjectiveProcedural therapies for overactive bladder (OAB) most often include intradetrusor onabotulinumtoxinA (BTX) injections, sacral neuromodulation (SNM), and percutaneous tibial nerve stimulation (PTNS). Despite their proven efficacy, real‐world data on therapy continuation and crossover rates between these modalities remain limited. This study aimed to evaluate longitudinal patterns of treatment continuation and therapy crossover among women receiving procedural OAB treatments.MethodsWe conducted a multi‐institutional retrospective cohort study of women with idiopathic OAB who underwent index BTX, SNM, or PTNS between 2014 and 2022. Patients were identified using electronic medical records, and follow‐up data were collected through December 31, 2023. The primary outcomes included duration of maintenance treatments and crossover to another procedural therapy for OAB. Kaplan–Meier survival analysis estimated rates of continued treatment, and a log‐rank test assessed differences in crossover rates among treatment groups.ResultsA total of 506 women met inclusion criteria: 266 (52.6%) received BTX, 114 (22.5%) underwent SNM, and 126 (24.9%) received PTNS. Ongoing treatment rates were lowest for PTNS, with only 17.1% maintaining therapy between 3 and 5 years and 26.1% crossing over to another procedure within 3 years. Among BTX patients, 65.2% underwent repeat treatment within 3 years, and 9.5% of patients crossed over to another procedure within 3 years. Of those with 5 or more years of follow‐up, 39.1% of patients continued with BTX procedures in the 3–5‐year follow‐up timeframe. Among SNM patients, the cumulative revision rates were 7.6% at 1 year and 10.9% at 2 years. 13.1% of patients crossed over from SNM to another procedure within 3 years (the vast majority to BTX).ConclusionsPTNS had the lowest ongoing therapy rates and the highest crossover rates. BTX and SNM demonstrated similar crossover rates. These findings underscore the importance of individualized patient counseling and treatment selection based on expectations of therapy persistence. Future research should focus on optimizing patient selection, improving long‐term adherence strategies, and evaluating novel or combined therapeutic approaches for OAB management.

ABSTRACTBackgroundMetabolic dysfunction‐associated steatotic liver disease (MASLD) affects over one third of the global population and is closely linked to gastrointestinal, oncological, and cardiovascular diseases. As the most common cause of steatotic liver disease (SLD), MASLD is often referred to as “fatty liver” in general health information searches. With the Internet becoming a primary source of healthcare information, this study aimed to evaluate global and regional public interest in steatotic liver disease using Google Trends data from January 2004 to December 2024.MethodsA comprehensive analysis was performed using Google Trends with the search term “fatty liver disease.” Interest levels were quantified using Google Trends indices, and temporal patterns were evaluated using average annual percent change (AAPC). Regional variations were assessed to identify geographic hotspots of public interest.ResultsGlobal interest in MASLD demonstrated significant growth (AAPC: 6.77%, 95% Confidence interval [CI]: 5.33–8.23), with a 264% increase from 2004 to 2024. Peak interest was observed in August 2024 (index: 100) compared to the lowest point in June 2007. Iran showed the highest country‐specific search volume (index: 100), while within the United States, West Virginia demonstrated the greatest relative interest (index: 100). Key topics associated with MASLD included “liver,” “symptoms,” “disease,” and “therapy.”ConclusionsSubstantial growth in global public interest in MASLD, with distinct temporal and geographical patterns, provides insights to develop targeted awareness campaigns and educational interventions, particularly in regions with low search volumes. Future research should examine the relationship between online search patterns and clinical outcomes in MASLD.

Abstract The use of radionuclides for targeted radiopharmaceutical therapy (RPT) is a rapidly evolving field in nuclear medicine and oncology. With the integration of imaging and therapy, therapeutic nuclear medicine has made remarkable progress in recent years. One particularly promising area of research is the use of α-emitting radionuclides, which possess unique physical properties that provide notable advantages, including the ability to target single tumor cells with high precision. Although the only targeted α therapy (TAT) currently approved by the United States Food and Drug Administration is 223Ra-dichloride for the treatment of castration-resistant prostate cancer with skeletal metastases, a search on clinicaltrials.gov yields a significant number of early- and late-stage clinical trials utilizing 223-Ra, 225-Ac, 211-At, 212-Pb, and 227-Th are in progress, indicating that more TATs are on the horizon. As the prevalence of use for TAT increases, it is important to consider the logistics of TAT administration and the requirements for radiation safety and patient discharge. This review aims to provide a comprehensive overview of the advancements, relevant clinical trials, and logistical considerations associated with targeted α RPT in oncology.

Introduction The Care Hotel is a virtual medicine hybrid model of care implemented at the Mayo Clinic to increase use of enhanced recovery protocols, address hospital capacity and reduce medical costs. This voluntary accommodation offers patients a comfortable environment to receive nursing care postoperatively with in-person daytime monitoring and 24-hour virtual telemonitoring in a hotel setting. This study aims to evaluate postoperative outcomes in patients admitted to the Care Hotel after mastectomy with immediate tissue expander reconstruction compared to standard overnight admission. Methods A retrospective review of the electronic medical record was conducted for patients who underwent mastectomy with immediate tissue expander reconstruction prior to (1/2019–1/2020) and after (7/2021–7/2023) the implementation of the Care Hotel. Postoperative outcomes, including 48-hour ED visit, 48-hour readmission, and 30-day infection, hematoma, seroma, admission, and return to operating room were collected. Results There were 61 patients with 108 tissue expander reconstructions in the hospital admission group and 122 patients with 212 tissue expander reconstructions in the Care Hotel group. The average length of hospital stay was 1.2 days while the average Care Hotel stay was 1.4 days. There were four 48-hour ED visits with 1 admission for 12 hours of observation in the Care Hotel group. There was no statistically significant difference in 30-day infection, seroma, hematoma, readmission, need for IR drain procedure or return to operating room between the groups. Conclusions This investigation demonstrates the safety of postoperative virtual telemonitoring and should encourage providers to utilize virtual visit technology in the immediate postoperative time-period.

Abstract Motivation Understanding kinship relationships is fundamental to genetic research, particularly in the context of genetic linkage studies and population genetics. Pedigree design and analysis are a prerequisite for these investigations. The legacy kinship2 CRAN package has been a cornerstone in this area; however, the need for handling larger and more complex datasets necessitates an updated, flexible, and user-friendly toolset. To address this issue, we present Pedixplorer, a novel Bioconductor package designed to enhance kinship analyses with modern functionality and usability, especially in large multigeneration complex pedigrees with inbreeding loops, which are frequently seen in domestic animal breeding. Results Pedixplorer builds upon the robust foundation of kinship2, integrating Bioconductor standards and most recent programming practices. Its core component is the S4 Pedigree object, facilitating efficient representation of complex pedigrees. The new functions enable automatic querying, filtering, and trimming of large pedigrees, while the graphical functions have been rewritten for better customization in pedigree visualizations. Additionally, Pedixplorer offers a comprehensive Shiny application, accessible both locally and via a dedicated website, allowing non-R users to easily create, filter, and customize pedigrees. Availability and implementation The Pedixplorer package is freely available at: https://www.bioconductor.org/packages/release/bioc/html/Pedixplorer.html with additional documentation at https://louislenezet.github.io/Pedixplorer. A user-friendly web application is available at: https://pedixplorer.univ-rennes.fr.