Citations

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals’ tolerance levels for progressive blood loss.

We highlight the complex management considerations in a patient with cerebral amyloid angiopathy who developed venous thromboembolism, explicitly navigating the balance between risks of thromboembolism and bleeding with anticoagulation therapy. This case highlights a man in his 70s who presented to the emergency department with an acute right frontal intracerebral haemorrhage secondary to cerebral amyloid angiopathy with an acute segmental pulmonary embolism managed with an inferior vena cava (IVC) filter. During hospitalisation, the patient developed a large expansile thrombus extending inferior from the IVC filter to the right popliteal vein. This necessitated the initiation of anticoagulation therapy, beginning with unfractionated heparin, transitioning to enoxaparin and ultimately to apixaban. He was treated with 3 months of anticoagulation with no haemorrhagic complications. The patient’s successful outcome underscored the potential for safe and effective anticoagulation management in this complex clinical scenario.

ABSTRACT Premature physeal closure occurs following trauma, cancer, or infection. Current treatments have poor success rates. With recent pediatric donor tissue availability, physeal allograft transfer (PAT) can now be considered. The purpose of this study was to study the safety and feasibility of PAT in a large animal model. The aim of this study is to gather foundational data to inform future studies into the efficacy of PAT. Physeal defects were created in the distal femur of nine female domestic swine and treated with PAT from two male donor pigs, cementation, or bone autograft. Viability was assessed. After 3 months, physes were visualized using CT and MRI. Integration, tissue composition, donor DNA presence, and microscopic appearance were evaluated. Physeal allografts demonstrated 93% viability after procurement and preservation. All animals reached the 3‐months study endpoint without gross deformations. No physeal bars formed in any group. Cystic changes were seen in experimental and control femurs. All groups showed disorganized tissue architecture without growth plate recapitulation. High allografts viability and structural integrity after procurement support the potential of this treatment. Although no gross deformities were found, transferred physes demonstrate poor integration and incomplete repair. The lack of physeal bar formation in the control group limits the reliability of the animal model for studying physeal allograft transfer. Lastly, this study was designed as a feasibility study and lacks power to compare treatment effects statistically. The efficacy of PAT for preventing growth arrest remains undetermined.

Abstract Over 50% of older adults in the US take ≥5 medications, with prevalence reaching 76.8% in the emergency department (ED) setting. However, little is known about their medication self-efficacy (the ability to understand and follow medication regimens), which may influence adherence and adverse drug events when new prescriptions are added during ED visits. Our objective was to determine whether polypharmacy and potentially inappropriate medication (PIM) are associated with self-efficacy. We performed a logistic regression analysis using 5-site multicenter ED survey data linked to electronic health records from patients aged ≥65 years with baseline ED visits during 2019-2021. The predictors were polypharmacy (≥5 medications) and PIM use (≥1 high-risk medication, GEMRx criteria) of prescriptions taken within 1 year of the ED visit. The outcome was low medication self-efficacy (< 11 points MUSE-taking score) assessed at the ED visit. Covariates included insurance, education, marital status, race/ethnicity, caregiver support, dementia status, and frailty. Among 921 patients, 249 (27.0%) had polypharmacy and 66 (7.2%) had PIM use. Low medication self-efficacy was reported by 76 (37.8%) with polypharmacy and 26 (12.9%) with PIM use versus 125 (62.2%) and 40 (5.6%) without. Both polypharmacy (aOR 6.12, 95% CI 2.05-18.22, p = 0.001) and PIM use (aOR 33.65, 95% CI 5.81-214.35, p < 0.001) were associated with greater adjusted odds of low medication self-efficacy. Frailty modified this association, with weaker effects in more frail patients (OR 5.51, 95% CI 2.57-11.8, p = 0.003). These findings suggest that the ED is an important setting to identify older adults who may struggle with medication use.

ABSTRACT A prevailing model holds that human cytomegalovirus (HCMV) spreads cell-to-cell spread upon initial culturing from clinical specimens and that de novo mutations in the UL128-131 genes reduce expression of glycoprotein complex gH/gL/UL128-131 (pentamer) relative to gH/gL/gO (trimer), which in turn enhances virion infectivity and favors cell-free spread. The clone Merlin-BAC (ME) expresses far more pentamer than trimer and is highly cell-associated, whereas clone TB40-BAC4 (TB) expresses mostly trimer and spreads predominantly cell-free. A single G>T polymorphism in TB relative to ME was shown to impair UL128 mRNA splicing, reducing pentamer expression and enhancing infectivity and cell-free spread. However, enhanced cell-free spread of ME due to pentamer suppression did not come at the expense of efficient cell-to-cell spread, and cell-to-cell spread of TB was especially poor despite highly infectious intracellular virus. Most of the nucleotide diversity in the HCMV genome is due to 17 genes that have up to 14 alleles each, and TB and ME match at only two of the 17. Here, we report a set of recombinant HCMV generated by coinfecting cells with TB and ME. Trimer:pentamer ratio and virion infectivity largely aligned with the TB or ME UL128, with “TB-like” recombinants displaying more trimer and higher infectivity and “ME-like” recombinants displaying more pentamer and lower infectivity. Strikingly, some recombinants had shifts in preference for cell-free vs cell-to-cell spread without predicted changes to trimer:pentamer ratio or virion infectivity, demonstrating uncoupling of these phenotypes. IMPORTANCE The emerging picture of HCMV genetic diversity in vivo prompts a reevaluation of how in vitro -characterized phenotypes, such as the abundance of different viral envelope glycoproteins, virion infectivity, and tendency toward cell-free or direct cell-to-cell spread, reflect viral characteristics in vivo . Laboratory examination of HCMV phenotypes has included a limited sampling of the apparent in vivo genetic diversity. A widely held model that directly links cell-free and cell-to-cell spread characteristics to glycoprotein display and virion infectivity also presumes that HCMV is predominantly cell-associated in vivo . These have implications for intervention strategies, such as calling into question the therapeutic benefit of neutralizing antibodies. Our finding that spread characteristics can be uncoupled from glycoprotein display and virion infectivity suggests a model that includes both cell-free and cell-associated spread as bona fide wild-type phenotypes for different allelic haplotypes. This model would allow a broader examination of neutralizing antibodies as correlates of protection.

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well‐structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point‐in‐time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70233 . The Concise Guides provide expert‐curated recommendations of ‘Gold Standard’ selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid‐2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

ABSTRACT Background Sampling techniques have poor accuracy for classifying biliary strictures as benign or malignant. Previously, a cholangioscopy artificial intelligence (AI) outperfromed sampling techniques based solely on analysis of previously recorded cholangioscopy footage. The aim of this trial was to compare the performance of a real-time cholangioscopy AI to both sampling techniques and human observers for the task of biliary stricture classification. Methods A cholangioscopy AI computer connected directly to a cholangioscope console. The computer analyzed the cholangioscopy video stream during procedures for suspected biliary strictures. The primary outcome of the study was comparison of the performance of cholangioscopy AI to sampling techniques – brush cytology and transpapillary forceps biopsy – for biliary stricture classification. Secondary outcomes included comparison of the AI classification performance to that of human observers (separated into junior-level and experienced-level cohorts) who reviewed the cholangioscopy footage. Results A total of 41 patients were enrolled in the trial and had biliary strictures analyzed by cholangioscopy AI. For the classification of strictures, the AI had greater classification accuracy than standard sampling techniques (87.8% versus 67.4%; p = 0.043). Additionally, the cholangioscopy AI was significantly more accurate for biliary stricture classification than both junior-level (87.8% versus 61.5%; p = 0.001) and experienced endoscopists (87.8% versus 63.15%; p = 0.011). Conclusions This trial demonstrates that sampling techniques and human assessment of biliary strictures are flawed and there may be a benefit to the use of a cholangioscopy AI system to aid in biliary stricture classification.