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Importance Although 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established cross-sectional biomarker of brain metabolism in dementia with Lewy bodies (DLB), the longitudinal change in FDG-PET has not been characterized. Objective To investigate longitudinal FDG-PET in prodromal DLB and DLB, including a subsample with autopsy data, and report estimated sample sizes for a hypothetical clinical trial in DLB. Design, Setting, and Participants Longitudinal case-control study with mean (SD) follow-up of 3.8 (2.3) years. Cases were recruited consecutively between 2007 and 2022 at a referral center and among the population. Patients with probable DLB or mild cognitive impairment with Lewy bodies (MCI-LB) were included. Individuals without cognitive impairment were included from a population-based cohort balanced on age and sex for comparison. All participants completed at least 1 follow-up assessment by design. Exposure Patients with MCI-LB and DLB. Main Outcomes and Measures Rate of change in FDG-PET was assessed as standardized uptake value ratios (SUVr). Clinical progression was assessed with the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Results Thirty-five patients with probable DLB, 37 patients with MCI-LB, and 100 individuals without cognitive impairment were included. The mean (SD) age of the DLB and MCI-LB groups combined (n = 72) was 69.6 (8.2) years; 66 patients (92%) were men and 6 (8%) were women. At follow-up, 18 participants (49%) with MCI-LB had progressed to probable DLB. Patients with MCI-LB had a faster decline in FDG-SUVr, compared with that of participants without cognitive impairment, in the posterior cingulate, occipital, parietal, temporal, and lateral frontal cortices. The same regions showed greater metabolic decline in patients with DLB than in participants without cognitive impairment, with the addition of anterior-middle cingulate, insula, and medial frontal orbital cortices. Rates of change in FDG-PET in these brain regions were combined into a region of interest (ROI) labeled longitudinal FDG-PET LB meta-ROI. The rate of change in FDG-SUVr in the meta-ROI correlated with the rate of change in CDR-SB, and sample size estimates were reported for potential clinical trials in DLB. Findings were confirmed in the subsample with neuropathologic confirmation (n = 20). Conclusions and Relevance This study found that brain hypometabolism begins to evolve during the prodromal stages of DLB with changes paralleling symptomatic progression. These data may inform clinical practice and trials planning to use FDG-PET for biologic staging, monitoring disease progression, and potentially assessing treatment response.

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

Abstract Aims Pulmonary regurgitation (PR) after reparative intervention for congenital heart disease has been studied extensively. However, the burden, distribution of causes, and outcome of PR in adults is unknown. The study aimed to evaluate the prevalence, types, and outcomes of moderate/severe PR in adults in the community setting. Methods and results A total of 398 adult residents of Olmsted County who had clinically indicated echocardiography 2004–2023 at Mayo Clinic, Rochester, and had moderate or severe PR were identified retrospectively. The median age was 77 years, 48% were females, and 61 (51%) had severe PR. The age- and sex-adjusted US prevalence was 0.11% (vs. 0.67% for ≥moderate tricuspid regurgitation). Moderate/severe PR was due to pulmonary hypertension in 77%, congenital/iatrogenic in 11%, primary pulmonary valve disease in 2% (88% due to carcinoid), and idiopathic isolated in 10%. In contrast, severe PR was due to congenital/iatrogenic disease in 52%, pulmonary hypertension in 39%, primary PR in 5%, and isolated idiopathic in 3%. The all-cause mortality rate per 100 person-year was 73 in primary (mostly carcinoid) PR, 16 in pulmonary hypertension–related PR (not different vs. propensity-matched patients without PR), and 6 in isolated idiopathic PR (not different vs. matched patients without PR). Conclusion Moderate or severe PR had a lower prevalence vs. TR. The most frequent cause was pulmonary hypertension for ≥moderate PR and congenital/iatrogenic for severe PR. Mortality in patients with acquired ≥moderate PR appeared to be related to the underlying cause, with no excess mortality compared with matched patients without PR. Whether specifically severe PR confers excess mortality requires future investigation.

AbstractBackgroundDementia with Lewy bodies (DLB) frequently co‐occurs with Alzheimer’s disease (AD) pathologies, exacerbating disease progression. Biophysical models of diffusion imaging data, such as Neurite Orientation Dispersion and Density Imaging (NODDI), may reveal novel insights into the neurobiological substrates of AD on cortical and white matter microstructural injury.MethodA cohort of 57 DLB patients on the DLB spectrum (33 clinically probable DLB and 14 prodromal DLB) and 57 cognitively unimpaired (CU) controls underwent NODDI and PET imaging with [18F]‐Flortaucipir and [11C]‐PiB (Table 1). NODDI parameters were derived from white matter tracts and grey matter regions using the JHU “Eve” and Mayo Clinic Adult Lifespan Template atlases, respectively. Conditional logistic models were used to compare these parameters between the two groups, accounting for the 1:1 matching on age and sex. The associations of tau and amyloid‐β with NODDI parameters across the white matter tracts were examined with linear regressions. A region‐by‐region approach was adopted to evaluate the relationships of tau and amyloid‐β with grey matter NODDI, adjusting for age, APOE, and local grey matter volumes.ResultDLB spectrum patients exhibited extensive white matter abnormalities relative to CU, including lower fractional anisotropy, higher mean diffusivity (MD), and lower tissue‐weighted neurite density (tNDI). In grey matter, these deficits were paralleled with higher MD and lower tNDI and ODI, primarily in the temporoparietal and posterior cortices. Regression models revealed significant associations of elevated [18F]‐Flortaucipir uptake with deficits in temporal and limbic white matter tracts and a temporal‐lobe pattern of higher MD and lower tNDI in the cortex (Figure 1). No associations were observed with [11C]‐PiB in the DLB spectrum.ConclusionThese findings demonstrated an in vivo relationship between tau deposition and neurite deficits that spatially aligned with the canonical AD “cortical signature” of neurodegeneration in both white matter tracts and grey matter regions in DLB. Our study underscores the detrimental impact of AD pathology in DLB and provides a rationale for further investigations into the underlying mechanisms of AD in DLB. Future longitudinal studies tracking the progression of these changes could inform therapeutic strategies for DLB in the presence of AD pathologies

INTRODUCTION: Patients with ulcerative colitis (UC) and prior biologic failure may have reduced or delayed efficacy with subsequent advanced therapies. This analysis evaluated the efficacy and safety of ozanimod during the True North (TN) study and its open-label extension (OLE) in biologic-exposed patients with UC. METHODS: TN was a randomized, placebo-controlled 52-week trial (10-week induction, 42-week maintenance period). Eligible patients could enter the OLE. Clinical outcomes were assessed at TN week (W) 10 and W52 and OLE W46 and W94. Symptomatic efficacy was evaluated through induction and in the OLE until W94. Safety was assessed. RESULTS: This analysis included 376 biologic-exposed patients. In the placebo-controlled cohort, more ozanimod-treated patients achieved clinical response than placebo at W10 regardless of the number or type of prior biologics; patients who used 1 vs ≥2 prior biologics achieved higher efficacy rates. Efficacy rates were higher at W52 than W10 and were similar across subgroups regardless of the number or type of prior biologics. Significantly greater proportions of ozanimod vs placebo patients achieved symptomatic response by W5 ( P = 0.0173) and symptomatic remission by W10 ( P = 0.0207). Among biologic-exposed TN W10 ozanimod nonresponders who entered the OLE, 61% achieved symptomatic response with an extra 10 weeks of ozanimod treatment. Ozanimod efficacy was durable for ∼3 years of continuous treatment in biologic-exposed W52 clinical responders who entered the OLE. No new safety signals were observed. DISCUSSION: Ozanimod was effective and safe in biologic-exposed patients with UC, but these patients may require more time to respond to treatment. Clinical trial registry website and trial numbers: ClinicalTrials.gov, numbers NCT02435992 and NCT02531126.

AbstractObjective(s)To evaluate the otolaryngology surgical capacity in Harare, Zimbabwe by analyzing procedural volumes across four hospitals, one private and three public, from 2019 to 2022.MethodsA retrospective review of hand‐written surgical case logs was conducted at Harare Eye, Ear, Nose, and Throat Institute (HEENT), Parirenyatwa Group of Hospitals (PGH), Sally Mugabe Children's Hospital (SMCH), and Sally Mugabe Adult's Hospital (SMAH). Patient age and surgical intervention for all otolaryngology surgeries performed in the operating room from 2019 to 2022 were recorded. Procedures were categorized into six groups: head and neck malignancy, laryngeal surgery, oropharyngeal surgery, otologic surgery, rhinology/sinus surgery, and other. Data were analyzed using descriptive statistics to identify trends in surgical volume and types of procedures across hospitals.ResultsA total of 2626 procedures were recorded: 1470 at HEENT, 377 at PGH, 625 at SMCH, and 154 at SMAH. Of these, 39.5% were performed on pediatric patients and 60.5% on adult patients. The most common procedures were adenotonsillectomy/adenoidectomy/tonsillectomy (38.9%), diagnostic endoscopies (10.4%), and endoscopic sinus surgery (8.3%). HEENT performed the highest volume and widest range of procedures. HEENT had higher surgical volumes across all groups of procedure, except for laryngeal surgery.ConclusionThis study found disparities in otolaryngology surgical capacity between a private hospital, HEENT, and three public tertiary hospitals—SMCH, SMAH, and PGH, the largest hospital in the country—in Harare, Zimbabwe. Additionally, it highlights areas for targeted interventions in capacity building. This study establishes a foundation for understanding otolaryngologic surgical capacity in the country, supporting international collaboration, guiding future research, and serving as a model for similar assessments in other LMICs.Level of evidenceLevel VI.

Abstract Generation of a protective and long-lasting immune memory is central to effective vaccination strategies and healthy aging. However, age-associated changes in immune cells, particularly T cells, impair immune memory generation and maintenance rendering older adults vulnerable to infectious diseases. Here, we investigated signatures of age-related memory T cell dysfunction and uncovered molecular determinants of a protective, persistent T cell memory in older individuals. We leveraged the contrasting T cell memory elicited in younger (<30 years) and older adults (>55 years) by vaccination against varicella zoster virus (VZV). Using ex vivo peptide stimulation of peripheral blood mononuclear cells of vaccine recipients several years after vaccination, we collected antigen-specific CD4+ and CD8+ T cells for high-dimensional spectral flow cytometry and tri-modal single-cell sequencing analyses. We found that older vaccine recipients predominantly suffer from a quantitatively and qualitatively impaired CD8+ T cell memory response compared to younger adults receiving the same vaccine type. Conversely, comparisons of two VZV vaccine strategies with contrasting efficacies in older adults demonstrated that a CD4+ T cell response rich in self-renewing Th17-like and low in regulatory T cells overcomes the age-associated T cell memory defect and associates with a durable, protective T cell memory. Collectively, we propose that vaccine strategies targeted towards older adults benefit from a Th17-focused CD4+ T cell memory response. Our results not only uncover traits of immune cell dysfunction with aging, but also inform vaccination efforts tailored towards healthy aging.

ABSTRACT Introduction Lack of social support negatively impacts medical trainees' wellness. Programmes to educate medical trainees and their support persons (SPs) have been developed to improve resident wellness, but implementation of these programmes at other institutions remains unclear. We aimed to demonstrate the feasibility of implementing the Family Anesthesia Experience (FAX) programme across multiple institutions and to assess the programme's utility. Methods FAX includes didactics on wellness, burnout, substance use disorder and institutional resources; a panel of senior residents and their SPs; and small‐group simulations of airway management, common procedures and a high‐fidelity intraoperative code. We assessed the programme qualitatively using semistructured interviews of 20 first year anaesthesiology residents and 20 SPs. Data analysis was performed via a content analysis approach. Results Twelve anaesthesiology programmes of varying size and geographic locations implemented FAX with minor adaptations. Minimal direct costs were incurred for the virtual programme. Participants enjoyed the event overall. Content analysis showed that FAX improved SPs' understanding of residency and communication between SPs and residents, had minimal impact on SPs' stress, reduced residents' interpersonal stress with SPs and modified perceptions on wellness and burnout. We developed a conceptual model in which we propose SPs' understanding and empathy for their residents would improve through FAX, which may improve communication with and support for residents. Conclusion We demonstrated that FAX can be implemented at varying anaesthesiology residency programmes. Family‐oriented educational events like FAX may be an effective approach to improve SPs' understanding of a resident's role, thereby increasing social support for residents.

Abstract Chemotherapy regimens for triple-negative breast cancer (TNBC) combine agents without knowing which agents drive response. Consequently, predictors derived from multi-agent regimens cannot be assumed to generalize to individual drugs or other regimens, motivating development of treatment-matched predictors. Here, we used TNBC patient-derived xenografts (PDXs) treated with carboplatin, docetaxel, or the combination to deconvolute drug-specific responses and identify associated molecular features. Combination treatment rarely improved upon the best single agent, with enhanced responses in only 13% of PDXs and antagonism in a comparable fraction. Proteogenomic analyses identified high cytokeratin-5 (KRT5) as a general marker of chemotherapy responsiveness and KRT5 immunohistochemistry discriminated responsive PDXs (AUROC, 0.83). To train treatment-specific predictors, we integrated these data with independent PDX and clinical cohorts with responses assessed after anthracycline-free platinum, taxane, or platinum-taxane therapy, ensuring response corresponded to the modeled treatment. Four feature selection strategies yielded largely nonoverlapping biomarker panels converging on treatment-relevant pathways. On independent test data, RNA-based predictors of complete response (CR) to platinum-based (carboplatin or cisplatin) and taxane-based (docetaxel or paclitaxel) chemotherapy achieved AUROCs of 0.80 and 0.86, respectively. For platinum-taxane regimens (carboplatin plus docetaxel or paclitaxel), proteomic-guided feature selection generated a 10-biomarker, protein- informed RNA predictor of pathologic complete response (pCR) that outperformed RNA-only feature selection and achieved an AUROC of 0.85 in an independent clinical cohort, while retaining practicality as an RNA-based assay. Treatment-matched integration of multi-omic PDX and clinical datasets provides a framework for chemotherapy-specific predictors with clinically relevant performance, supporting biomarker-guided precision selection and treatment optimization for patients with TNBC. Statement of significance Integration of multi-omic data from patient-derived xenografts with treatment-matched clinical cohorts yielded three retrospectively validated predictors of platinum, taxane, and platinum+taxane response, enabling biomarker-guided chemotherapy selection for patients with triple-negative breast cancer.

Abstract Objectives Patients with hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) experience a wide array of symptoms and system disorders. This study aimed to identify whether differences occurred in 115 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD. Methods In this study we analysed self-reported data from an EDS Clinic intake questionnaire in patients diagnosed with hEDS, HSD or no hypermobile conditions. Results From 1 November 2019 to 7 March 2024, the EDS Clinic saw 2088 patients. Using the 2017 diagnostic criteria, 66.5% were diagnosed with HSD (n = 1389), 20.3% with hEDS (n = 423), 10.6% with historic HSD (H-HSD) or localized HSD (L-HSD) (n = 256) (hypermobile controls) and 2.6% were not diagnosed with hEDS, HSD, H-HSD or L-HSD (n = 55) (controls). Symptoms/comorbidities that occurred with high prevalence in both hEDS and HSD included joint pain (hEDS 82.0%, HSD 88.9%), allergy (hEDS 77.0%, HSD 77.0%), subluxations (hEDS 71.2%, HSD 72.6%), brain fog (hEDS 70.0%, HSD 74.7%), headache (hEDS 68.1%, HSD 69.1%), anxiety (hEDS 60.3%, HSD 69.3%), depression (hEDS 52.2%, HSD 58.0%), migraine (hEDS 53.7%, HSD 52.5%), nausea (hEDS 54.6%, HSD 59.5%) and constipation (hEDS 53.0%, HSD 57.2%). In contrast, 9/115 (8%) symptoms/comorbidities were self-reported significantly more often in hEDS but 42/115 (37%) in HSD. hEDS patients reported more symptoms that suggest a defect in collagen, such as dislocation, hernias and rectal prolapse, while HSD patients reported more joint, muscle, allergy, neurological, gastrointestinal, sleep and psychological symptoms/comorbidities. Conclusion Although we found an overlap in some symptoms and comorbidities self-reported by hEDS/HSD patients, such as allergy/atopy, headache/migraine and gastrointestinal symptoms, our findings suggest key differences exist between the two diagnoses, suggesting that hEDS and HSD may be distinct conditions.