Investigating mechanisms underlying the development of paralysis symptom in a model of MS

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder with approximately 80 % of patients suffering from pain and 50 % from paralysis. Using a rodent model for MS, experimental autoimmune encephalomyelitis (EAE), researchers have predominately investigated paralysis/motor disease as the clinical symptom of EAE with fewer studying MS/EAE pain. However, in EAE, all mice exhibit a pain like phenotype and only a subset progresses to paralysis. Despite extensive research characterizing the disease pathology, the etiology that contributes to the range of pain and motor symptom occurrence in MS remains understudied. This is the first study to dissect MS symptom pathophysiology, using the non-PTX EAE model, in mice that experience mechanical hypersensitivity (pain-like phenotype) with and without paralysis. We found that mechanical hypersensitivity experienced by mice with or without paralysis is comparable between the two groups, irrespective of sex. In addition, there is a significant increase in the activation and infiltration of immune cells, demyelination, and heightened protein expression of B cell chemoattractant CXCL13 within the spinal cord of mice exhibiting mechanical hypersensitivity and paralysis, compared to mice only experiencing mechanical hypersensitivity

Assessing cardiovascular disease risk and social determinants of health: A comparative analysis of five risk estimation instruments using data from the Eastern Caribbean Health Outcomes Research Network

BACKGROUND: Accurate assessment of cardiovascular disease (CVD) risk is crucial for effective prevention and resource allocation. However, few CVD risk estimation tools consider social determinants of health (SDoH), despite their known impact on CVD risk. We aimed to estimate 10-year CVD risk in the Eastern Caribbean Health Outcomes Research Network Cohort Study (ECS) across multiple risk estimation instruments and assess the association between SDoH and CVD risk. METHODS: Five widely used CVD risk estimation tools (Framingham and WHO laboratory, both laboratory and non-laboratory-based, and ASCVD) were applied using data from ECS participants aged 40-74 without a history of CVD. SDoH variables included educational attainment, occupational status, household food security, and perceived social status. Multivariable logistic regression models were used to compare differences in the association between selected SDoH and high CVD risk according to the five instruments. FINDINGS: Among 1,777 adult participants, estimated 10-year CVD risk varied substantially across tools. Framingham non-lab and ASCVD demonstrated strong agreement in categorizing participants as high risk. Framingham non-lab categorized the greatest percentage as high risk, followed by Framingham lab, ASCVD, WHO lab, and WHO non-lab. Fifteen times more people were classified as high risk by Framingham non-lab compared with WHO non-lab (31% vs 2%). Mean estimated 10-year risk in the sample was over 2.5 times higher using Framingham non-lab vs WHO non-lab (17.3% vs 6.6%). We found associations between food insecurity, those with the lowest level compared to the highest level of education, and non-professional occupation and increased estimated CVD risk. INTERPRETATION: Our findings highlight significant discrepancies in CVD risk estimation across tools and underscore the potential impact of incorporating SDoH into risk assessment. Further research is needed to validate and refine existing risk tools, particularly in ethnically diverse populations and resource-constrained settings, and to develop race- and ethnicity-free risk estimation models that consider SDoH

Consumer-grade wearable devices in arrhythmia diagnostics for clinicians: where we are and where we are going

Atrial arrhythmias, including atrial fibrillation (AF), are a major contributor to cardiovascular morbidity and mortality. Early detection and effective management are critical to mitigating adverse outcomes such as stroke, heart failure, and overall mortality. Wearable devices have emerged as promising tools for monitoring, detecting, and managing atrial arrhythmias near-continuously. This comprehensive analysis explores these wearable technologies\u27 current role and capabilities for clinicians\u27 daily practice. Despite challenges related to data accuracy, privacy, patient compliance, and integration with healthcare systems, ongoing advancements hold significant promise for the future. Continued research and development are essential to fully realize the potential of wearables in improving clinical outcomes for patients with atrial arrhythmias

Tracking bla transmission through transposable elements in uropathogenic and commensal E. coli

AIM: To investigate the nucleotide sequences associated with transposable elements carrying bla allelic variants as potential markers for the transmission of antimicrobial resistance genes between domestic animals, humans and the environment. MATERIALS & METHODS: We conducted whole-genome sequencing and analyzed the nucleotide sequences of most abundant bla allelic variants (bla, bla, and bla) in commensal Escherichia coli (n = 20) from household members in Quito and uropathogenic E. coli (UPEC) (n = 149) isolated from nine clinics in Quito, Ecuador. RESULTS: The Ecuadorian commensal E. coli and UPEC displayed identical nucleotide sequences surrounding the bla gene and the synteny was similar to those found in other parts of the world; however phylogenetic analysis indicated that the genetic environments in Ecuadorian isolates were unique. CONCLUSION: These findings suggest that the nucleotide sequences flanking the bla genes may be useful for resolving ARG transmission pathways, especially inter-regional analyses

Optimizing Large Language Models in Radiology and Mitigating Pitfalls: Prompt Engineering and Fine-tuning

Large language models (LLMs) such as generative pretrained transformers (GPTs) have had a major impact on society, and there is increasing interest in using these models for applications in medicine and radiology. This article presents techniques to optimize these models and describes their known challenges and limitations. Specifically, the authors explore how to best craft natural language prompts, a process known as prompt engineering, for these models to elicit more accurate and desirable responses. The authors also explain how fine-tuning is conducted, in which a more general model, such as GPT-4, is further trained on a more specific use case, such as summarizing clinical notes, to further improve reliability and relevance. Despite the enormous potential of these models, substantial challenges limit their widespread implementation. These tools differ substantially from traditional health technology in their complexity and their probabilistic and nondeterministic nature, and these differences lead to issues such as hallucinations, biases, lack of reliability, and security risks. Therefore, the authors provide radiologists with baseline knowledge of the technology underpinning these models and an understanding of how to use them, in addition to exploring best practices in prompt engineering and fine-tuning. Also discussed are current proof-of-concept use cases of LLMs in the radiology literature, such as in clinical decision support and report generation, and the limitations preventing their current adoption in medicine and radiology. RSNA, 2025 See invited commentary by Chung and Mongan in this issue

We Were Still Left in the Back Field, Not Knowing : Pediatric Cancer Patients and Parents Describe Obstacles to Prognostic Communication

PURPOSE: Patient/parent perceptions of poor-quality prognostic disclosure have not been well described, and these data offer important lessons to shape clinical practice and communication skills training. In this study, we aimed to characterize patient/parent negative experiences with prognostic communication to inform future efforts to improve how clinicians disclose prognosis. PATIENTS AND METHODS: Semistructured interviews were conducted with a purposeful sample of pediatric cancer patients (n = 25) and parents (n = 40) across different timepoints in the progressive illness course extending into bereavement. Interviews were audio-recorded, transcribed, and de-identified for rapid qualitative analysis, in which multiple analysts used a standardized episode summary template to extract raw data specific to patient/parent narratives about prognostic disclosure experiences. Analysts engaged independently and collaboratively as a team in reflexive memo writing to identify negative experiences with prognostic communication, followed by team discussion to generate concepts and synthesize those concepts into themes. RESULTS: More than half of participants (59%) described negative experiences with prognostic disclosure, with parents highlighting distressing communication experiences more often than patients (parents: 32/40, 80% vs. patients: 6/25, 24%). Across patient/parent narratives, three main themes underpinned the perception of poor-quality prognostic communication: (1) insufficient information, (2) overwhelming or contradictory information, and (3) absence of person-centered connection. CONCLUSION: Many patients/parents perceived prognostic disclosure to be suboptimal and identified specific features underpinning poor-quality prognostic communication. These findings will inform future collaborative research with patients, parents, and multidisciplinary clinicians to codesign an intervention that individualizes prognostication to align with patient/parent preferences for receiving information and fostering connection

The LvL UP trial: Protocol for a sequential, multiple assignment, randomised controlled trial to assess the effectiveness of a blended mobile lifestyle intervention

BACKGROUND: Blended mobile health (mHealth) interventions - combining self-guided and human support components - could play a major role in preventing non-communicable diseases (NCDs) and common mental disorders (CMDs). This protocol describes a sequential, multiple assignment, randomised trial aimed at (i) evaluating the effectiveness and cost-effectiveness of LvL UP, an mHealth lifestyle intervention for the prevention of NCDs and CMDs, and (ii) establishing the optimal blended approach in LvL UP that balances effective personalised lifestyle support with scalability. METHODS: LvL UP is a 6-month mHealth holistic intervention targeting physical activity, diet, and emotional regulation. In this trial, young and middle-aged Singaporean adults at risk of developing NCDs or CMDs will be randomly allocated to one of two initial conditions (\u27LvL UP\u27 or \u27comparison\u27). After 4 weeks, participants categorised as non-responders from the LvL UP group will be re-randomised into second-stage conditions: (i) continuing with the initial intervention (LvL UP) or (ii) additional motivational interviewing (MI) support sessions by trained health coaches (LvL UP + adaptive MI). The primary outcome is mental well-being. Secondary outcomes include anthropometric measurements, resting blood pressure, blood metabolic profile, health status, and health behaviours (physical activity, diet). Outcomes will be measured at baseline, 6 months (post-intervention), and 12 months (follow-up). DISCUSSION: In addition to evaluating the effectiveness of LvL UP, the proposed study design will contribute to increasing evidence on how to introduce human support in mHealth interventions to maximise their effectiveness while remaining scalable. TRIAL REGISTRATION: The LvL UP Pilot trial was prospectively registered with ClinicalTrials.gov (NCT06360029)

The Association Between Atopic Dermatitis and Select Disease Events in Adults in the United States: A Retrospective Cohort Study in the Optum Electronic Health Records Database

INTRODUCTION: Previous studies have reported positive associations between atopic dermatitis (AD) and select disease events; however, definitive conclusions are lacking. The aim of this study was to characterize demographic and clinical characteristics of patients with and without AD and estimate crude incidence rates (IRs) and adjusted hazard rate ratios (HRRs) of select disease events in these cohorts. METHODS: This retrospective observational analysis used Optum® Market Clarity Electronic Health Records, a US administrative healthcare database. Adults with and without AD between 2016 and 2021 with ≥ 12 months of database activity prior to index date (based on diagnosis or first treatment) were included. Each patient with AD was matched on age and index date with five patients without AD. The AD cohort was stratified by treatment prescribed within 30 days of AD diagnosis: no AD treatment; topical corticosteroids (TCS)/topical calcineurin inhibitors (TCI) only ( TCS/TCI only ); phototherapy with/without TCS/TCI ( phototherapy ); and systemic therapy, including oral corticosteroids with/without phototherapy and with/without TCS/TCI ( systemics ). Crude IRs and adjusted HRRs of infections, malignancies, cardiovascular events, mental health outcomes, asthma, fracture, and death across patient subgroups were estimated. RESULTS: The total cohort comprised 161,646 adults. Among the 25,915 patients with AD, 8384 (32.35%), 13,459 (51.94%), 366 (1.41%), and 3706 (14.30%) were included in the no AD treatment, TCS/TCI only, phototherapy, and systemics subgroups, respectively. Crude IRs/1000 patient-years were higher among patients with AD versus those without AD for serious infections (38.35 vs. 19.21), major adverse cardiovascular events (16.51 vs. 11.82), venous thromboembolism (11.12 vs. 6.89), malignancies (excluding nonmelanoma skin cancer; 17.51 vs. 15.25), and depression (63.50 vs. 44.18); similar trends were observed after controlling for potential confounding variables. When stratified by treatment, IRs and HRRs of these events were generally higher in patients in the systemics subgroup versus other treatment subgroups. CONCLUSIONS: Overall, certain disease event rates were higher in the population with AD versus the population without AD, with a trend towards higher rates among patients prescribed systemic therapies compared with those prescribed TCS/TCI only. This study further informs the relationship between AD and the risk of select disease events

Endoscopic papillectomy versus surgical ampullectomy for adenomas and early cancers of the papilla: a retrospective Pancreas2000/European Pancreatic Club analysis

OBJECTIVE: Ampullary neoplastic lesions can be resected by endoscopic papillectomy (EP) or transduodenal surgical ampullectomy (TSA) while pancreaticoduodenectomy is reserved for more advanced lesions. We present the largest retrospective comparative study analysing EP and TSA. DESIGN: Of all patients in the database, lesions with prior interventions, benign histology advanced malignancy (T2 and more), patients with hereditary syndromes and those undergoing pancreatoduodenectomy were excluded. All remaining cases as well as a subgroup of them, after propensity-score matching (nearest-neighbour-method) based on age, gender, anthropometrics, comorbidities, size and histological subtype, were analysed. The median follow-up was 21 months (IQR 10-47) after the primary intervention. Primary outcomes were rates of complete resection (R0) and complications. Groups were compared by Fisher\u27s exact or χ test, Mann-Whitney-U-test and log-rank test for survival. RESULTS: Of 1673 patients in the database, 1422 underwent EP and 251 TSA. Of them, 23.2% were excluded for missing or inconclusive data and 19.8% of patients for prior interventions or hereditary syndromes. Final histology showed in 24.2% of EP and 14.8% of TSA patients a histology other than adenoma or adenocarcinoma while advanced cancers were recorded in 10.9% of EP and 36.6% of TSA patients. Finally, 569 EP and 63 TSA were included in the overall analysis, with a higher rate of more advanced cases and higher R0 resection rates in the TSA groups (90.5% vs 73.1%; p\u3c0.01), with additional ablation in the EP group in 14.4%. Severe adverse event rates were 3.2% (TSA) vs 1.9% (EP). Recurrence after histological R0 resection was 16% (EP) vs 3.2% (TSA; p=0.01), and additional therapy for R1 resection was applied in 67% of the 159 cases. Propensity-score-based matching identified 62 pairs of EP/TSA patients with comparable baseline patient and lesion characteristics. The initial R0-rate was 72.6% (EP) compared with 90.3% (TSA, p=0.02) with recurrences found in 8% (EP) vs 3.2% (TSA; p=0.07); reinterventions were more frequent in the EP group. Overall survival was comparable. CONCLUSIONS: The rate of patients with poor indications due to non-neoplastic disease or advanced cancer is still high for both EP and TSA; multiple retreatments were necessary for EP. Although EP can be considered an appropriate primary therapy for certain ampullary adenomas, case selection for both therapies (especially with regard to the best step-up approach) should be studied further

Investigating Intensity and Percentage of p53 Nuclear Expression in Prostate Cancer: Findings from a Cohort of U.S. Military Veterans

BACKGROUND: Next-generation sequencing has revealed TP53 alterations in localized prostate cancer (PCa), suggesting growing clinical potential for p53 immunohistochemistry (IHC). Prior research supports the use of IHC for the detection of p53 overexpression to predict the presence of TP53 alterations known to be associated with adverse outcomes. However, to reach a consensus definition of p53 overexpression in PCa, further insights are needed. This study aimed to compare two fundamental approaches of evaluating p53 expression across a variety of specimens regarding PCa progression. METHODS: This study included 84 patients (75% self-identified as African American) diagnosed with PCa between 1996 and 2021 at the DC VA Medical Center. Representative sections of core biopsies, radical prostatectomies, transurethral prostate resections, and metastatic deposits were examined. p53 nuclear expression was scored according to the highest intensity observed (0, 1+, 2+, 3+) and the percentage (0%, \u3c1%, 1-5%, \u3e5%) of tumor cells expressing any level of intensity in the aggregate tumor area. All slides were reviewed by two independent pathologists. Pertinent clinical data were collected. RESULTS: A total of 34 patients (40%) exhibited p53 nuclear expression, of which 18 (21%) showed the maximum (3+) intensity. The presence of maximum intensity, regardless of percentage, was found to be associated with Grade Group (p \u3c 0.001), higher PSA at biopsy (p \u3c 0.001), BCR (p \u3c 0.001) and metastasis (p \u3c 0.001). Importantly, maximum p53 intensity was identified only in patients who developed metastatic disease. CONCLUSIONS: Maximum (3+) p53 nuclear intensity of any percentage is highly associated with disease progression in PCa, suggesting that optimal determination of p53 overexpression should incorporate intensity