Large International Cohort Research Articles

Successful Models of Virtual Experiential Education Initiatives in Global Health for International Students.

Background: Experiential learning activities help students prepare for their future careers by providing opportunities for hands‑on practice experiencing real‑world scenarios. Innovations in technology can facilitate experiential learning and cross‑cultural connections for large groups of students in multiple global settings through a virtual platform. However, designing these opportunities with diverse groups of students for a virtual environment can be challenging. Objective: The purpose of this paper is to highlight three examples of innovative virtual experiential learning initiatives that were developed and implemented by the Global Health Program of the Association of Pacific Rim Universities (APRU), a non‑profit network of 60+ leading research universities in the Asia‑Pacific. Findings: We have leveraged the expertise of our wide network to enhance student learning through the purposeful design of virtual educational experiences centered around pedagogical approaches that emphasize active learning, self‑reflection, and knowledge exchange with people from other cultures and disciplines. The annual global health joint virtual courses, the annual APRU Virtual Global Health Case Competition, and the APRU Mini Certificate foster meaningful engagement with other students and experts in the field, expanding the lens of students to foster an increased awareness and appreciation of the diversity of perspectives represented in an international network such as APRU. These allow students to practice real‑world application of knowledge gained in a traditional didactic classroom setting. Conclusions: The benefits of virtual experiential learning to students greatly outweigh the challenges in the design and implementation of such programs. While relatively short‑term, these virtual initiatives have had a demonstrable impact on student participants. Such programs can enhance student learning and provide cost‑effective ways to allow large international cohorts to experience global experiential learning.

Childhood socioeconomic position relates to adult decision-making: Evidence from a large cross-cultural investigation.

Early exposure to poverty may have profound and enduring impacts on developmental trajectories over the lifespan. This study investigated potential links between childhood socioeconomic position, recent economic change, and temporal discounting in a large international cohort (N = 12,951 adults from 61 countries). Temporal discounting refers to the tendency to prefer smaller immediate rewards over larger rewards delivered after a delay, and connects to consequential outcomes including academic achievement, occupational success, and risk-taking behaviors. Consistent with multiple theories about the impacts of stress exposure, individuals who reported lower socioeconomic positions in childhood exhibited greater temporal discounting in adulthood compared to peers who did not. Furthermore, an interaction emerged between childhood socioeconomic position and recent economic change, such that the steepest temporal discounting was found among those from lower childhood socioeconomic positions who also recently experienced negative economic change as a result of the COVID pandemic. These associations remained significant even when accounting for potentially confounding factors like education level and current employment. Findings provide new evidence that childhood socioeconomic position relates to greater temporal discounting and steeper devaluation of future rewards later in adulthood, particularly in response to contemporaneous economic change. This suggests childhood socioeconomic position may have longer-term impacts on developmental trajectories. Speculatively, childhood socioeconomic position may shape adult behavior through increased life stress, diminished access to resources, and lower perceived trust and reliability in social systems. These findings underscore the long-term implications of socioeconomic gaps, cycles of disadvantage and economic marginalization.

Platelet count has a U-shaped association with mortality in hemodialysis patients

Our previous manuscript showed that thrombocytopenia predicts all-cause mortality in Chinese hemodialysis (HD) patients. Based on the role of platelets in coagulation, clot formation, and systemic inflammation, we speculate that high platelets increase risk of thrombo-embolic events, hence the mortality. However, research evidence is currently lacking. Therefore, we utilized data from a very large international cohort study to explore the association of platelet counts with mortality and cardiovascular (CV) death in hemodialysis (HD) patients. International data from 396 facilities enrolled in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012–2015) were analyzed. Participants were divided into 3 groups according to their platelet counts (low: <100, normal: 100–300, high: >300*109). Associations between platelet counts and all-cause and CV mortality were analyzed using Cox regression, adjusted for confounders. There were 13,631 patients with median age of 65 years old. Males accounted for 61.2%. Mean platelet count was 205*109/L overall and ranged from 173 *109/L in China to 227 *109/L in Sweden. Overall, 2,348 (17.2%) patients died and 1017 (7.5%) died from CV disease. Both low (HR:1.48, 95% CI 1.21–1.80, p < 0.001) and high (HR:1.17, 95% CI 1.00- 1.35, p = 0.044) platelet counts were associated with higher all-cause mortality after adjustment for covariates; results for CV death were consistent. Platelet count has a U-shaped association with all-cause and CV mortality in HD patients, and thus may be used as an outcome predictor that is readily available among HD patients.

Aquaporin-4 Immunoglobulin G-seropositive Neuromyelitis Optica Spectrum Disorder MRI Characteristics: Data Analysis from the International Real-World PAMRINO Study Cohort.

Background Patients with neuromyelitis optica spectrum disorder (NMOSD) are often seropositive for antibodies against aquaporin-4 (AQP4). The importance of MRI monitoring in this disease requires evaluation. Purpose To profile MRI features from a large international cohort with AQP4 immunoglobulin G (IgG)-seropositive NMOSD (from the Parallel MRI in NMOSD [PAMRINO] study) and to evaluate and confirm existing knowledge regarding the incidence, location, and longitudinal development of characteristic lesions in the central nervous system associated with AQP4-IgG-seropositive NMOSD. Materials and Methods In this retrospective study (from August 2016 to January 2019), MRI and clinical data were collected from 17 NMOSD expert sites in 11 countries across four continents. Clinical features and lesions identified at cross-sectional and longitudinal MRI were assessed. No formal statistical tests were used to compare observations; however, means, SDs, and 95% CIs are reported when evaluating lesion frequencies. Results Available T1-weighted and T2-weighted MRI scans in patients with AQP4-IgG-seropositive NMOSD (n = 525) were read. Among the 525 patients, 320 underwent cerebral MRI examinations with T2-weighted hyperintense cerebral (264 of 320; 82.5%), cerebellar (44 of 320; 13.8%), and brainstem (158 of 321 [49.2%], including one lesion observed at cervical spinal cord [SC] MRI) lesions. Lesions in the optic nerves, analyzed from 152 MRI examinations, were mainly found in the central (81 of 92; 88%) and posterior (79 of 92; 86%) sections (bilaterally in 39 of 92; 42%). Longitudinally extensive transverse myelitis was the predominant SC lesion pattern (upper compartment from 322 MRI examinations, 133 of 210 [63.3%]; and lower compartment from 301 MRI examinations, 149 of 212 [70.3%]). However, nonlongitudinal extensive transverse myelitis lesions were also observed frequently (105 of 210; 50.0%) in the cervical SC. Clinical data (n = 349; mean age, 44 years ± 14 [SD]; 202 female patients) and acute lesions at contrast-enhanced (CE) MRI (n = 58, performed within 30 days of the last attack) were evaluated. CE lesions were detected in the cerebrum (eight of 13; 62%), optic nerves (14 of 19; 74%), or chiasm (three of four; 75%) within 15 days of any relapse. In the upper SC (29 of 44; 66%), CE lesions were frequently observed up to 20 days after a clinical myelitis event. Conclusion A high incidence of abnormal brain MRI examinations and nonlongitudinal extensive SC lesions was found in patients in PAMRINO with AQP4-IgG-seropositive NMOSD. © RSNA, 2024 Supplemental material is available for this article.

Endovascular therapy in patients with acute intracranial non-terminal internal carotid artery occlusion (ICA-I).

Acute intracranial occlusion of the internal carotid artery (ICA) can be distinguished into (a) occlusion of the terminal ICA, involving the proximal segments of the middle or anterior cerebral artery (ICA-L/-T) and (b) non-terminal intracranial occlusions of the ICA with patent circle of Willis (ICA-I). While patients with ICA-L/-T occlusion were included in all randomized controlled trials on endovascular therapy (EVT) in anterior large vessel occlusion, data on EVT in ICA-I occlusion is scarce. We thus aimed to evaluate effectiveness and safety of EVT in ICA-I occlusions in comparison to ICA-L/-T occlusions. A large international multicentre cohort was searched for patients with intracranial ICA occlusion treated with EVT between 2014 and 2023. Patients were stratified by ICA occlusion pattern, differentiating ICA-I and ICA-L/-T occlusions. Baseline factors, technical (modified thrombolysis in cerebral infarction (mTICI) scale) and functional outcomes (modified Rankin scale [mRS] at 3 months) as well as rates of (symptomatic) intracranial hemorrhage ([s]ICH) were analyzed. Of 13,453 patients, 1825 (13.6%) had isolated ICA occlusion. ICA-occlusion pattern was ICA-I in 559 (4.2%) and ICA-L/-T in 1266 (9.4%) patients. Age (years: 74 vs 73), sex (female: 45.8% vs 49.0%) and pre-stroke functional independency (pre-mRS ⩽ 2: 89.9% vs 92.2%) did not differ between the groups. Stroke severity was lower in ICA-I patients (NIHSS at admission: 14 [7-19] vs 17 [13-21] points). EVT was similarly successful with respect to technical (mTICI2b/3: 76.1% (ICA-I) vs 76.6% (ICA-L/-T); aOR 1.01 [0.76-1.35]) and functional outcome (mRS ordinal shift cOR 1.01 [0.83-1.23] in adjusted analyses. Rates of ICH (18.9% vs 34.5%; aOR 0.47 [0.36-0.62] and sICH (4.7% vs 7.3%; aOR 0.58 [0.35-0.97] were lower in ICA-I patients. EVT might be performed safely and similarly successful in patients with ICA-I occlusions as in patients with ICA-L/-T occlusions.

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.

Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

The prognostic impact of intra-procedural mitral valve gradient following transcatheter edge-to-edge repair for primary mitral regurgitation

Abstract Background/Introduction The impact of intra-procedural mitral valve gradient following transcatheter edge-to-edge repair (TEER) in primary mitral regurgitation (MR) is a matter of controversial debates. Purpose The aim of this study was to investigate the prognostic impact of intra-procedural mean mitral valve gradient (MPG) in patients with primary MR undergoing TEER. Methods The PRIME-MR registry included consecutive patients with primary MR undergoing TEER from 2008-2022 at 27 international sites. Clinical outcomes were assessed according to intra-procedural mean MPG measured at the end of the procedure by transesophageal echocardiography. The evolution of mean MPG from intra-procedural to discharge and follow-up was documented. Baseline characteristics and clinical outcomes of patients were investigated according to intra-procedural mean MPG using a cut-off of 5mmHg (low MPG: ≤5mmHg, high MPG: &amp;gt;5mmHg). The prognostic impact of intra-procedural mean MPG was evaluated in multivariable Cox regression analysis. The primary endpoint was 2-year all-cause mortality or heart failure (HF) hospitalization. Results Intra-procedural MPG was available in 1,516 patients (median age 82 years [IQR 76.0, 86.0], 55.1% male). Patients with high intra-procedural MPG presented with less atrial fibrillation and less severe MR but were more symptomatic at baseline than patients with low MPG. Moreover, patients with high intra-procedural MPG had higher baseline MPG and smaller LV dimensions (LVEDV and LVESV). The rate of patients with mean MPG &amp;gt;5mmHg increased from intra-procedural (18.3%) to discharge (31.3%), while remaining stable thereafter (1-year follow-up: 30.9%; last follow-up: 29.6%). At 1-year follow-up the rate of patients presenting with New York Heart Association (NYHA) functional class I or II did not differ between patients with low (82.3%) and high MPG (83.6%, p=0.93). Kaplan-Meier analysis according to mean MPG showed no difference between patients with low and high MPG for the primary endpoint (32.4% vs. 42.1%, p=0.12), as well as for the single endpoints of all-cause mortality (22.3% vs. 27.7%, p=0.47) and HF hospitalization (17.6% vs. 27.5%, p=0.087) through 2 years (Figure 1). Unadjusted spline analyses were provided to depict the prognostic impact of continuous intra-procedural MPG (Figure 2). Following multivariable Cox regression neither MPG &amp;gt;5mmHg (HR 0.91, 95%-CI 0.56-1.49, p=0.72), nor continuous MPG (HR 1.05, 95% CI 0.96-1.15, p=0.28) were independently associated with adverse clinical outcomes. Conclusions Based on a large international cohort of patients with primary MR undergoing TEER, intra-procedural mean MPG did not significantly affect clinical and functional outcomes at 2 years. The long-term impact of elevated post-procedural MPG warrants further investigation.Figure 1Figure 2

Generalizability of SELECT to a contemporary cohort of cardiac surgical patients: analysis of the TRICS III Randomized Trial

Abstract Background The SELECT trial reported a significant reduction in cardiovascular (CV) outcomes with semaglutide amongst patients without diabetes who had pre-existing CV disease and a body-mass index (BMI) of 27 or greater. Patients undergoing cardiac surgery represent a high-risk subset of those with established CV disease, and may benefit from treatment with semaglutide. Purpose This study evaluated the generalizability of SELECT to a contemporary international cohort of cardiac surgical patients, and assessed whether differences between SELECT-eligible and non-eligible patients translated to altered risks of CV outcomes. Methods Present data was gathered from the TRICS III trial, a multicentre, randomized trial of restrictive versus liberal red-cell transfusion thresholds amongst 5243 cardiac surgical patients with a EuroSCORE I of ≥6. The proportion of cardiac surgical patients eligible for SELECT was determined by applying its selection criteria to the TRICS III cohort. Finally, baseline characteristics and outcomes stratified by SELECT eligibility were compared. Results A total of 4887 patients from the TRICS III cohort had available data for analysis, of which 452 (9.2%) were deemed to have been eligible for the SELECT trial. A comparison of baseline characteristics between SELECT-eligible and non-eligible patients are presented in Table 1; while SELECT-eligible patients were more likely to have preserved left ventricular function (71.7% vs. 61.0%), EuroSCORE I values were comparable between the two groups (7.8±2.1 vs. 7.9±1.9). The rate of a 3-point MACCE of Death, MI or stroke in the present cohort of SELECT-eligible patients undergoing cardiac surgery (16.6%) was numerically higher than those enrolled in SELECT receiving semaglutide (8.1%) or placebo (10.0%), despite the shorter follow-up (6 months vs. 39.8 months). Six month outcomes following cardiac surgery were similar regardless of SELECT eligibility (Figure 1); no difference in risk of outcomes was documented for the 3-point MACCE [SELECT Eligible vs. Non-eligible – 16.6% vs. 14.5%; OR 1.17 (0.9-1.53); P=0.24] and the TRICS III primary composite of Death, MI, Stroke, or New-Onset Renal Failure with Dialysis [17.0% vs. 17.0%; OR 1.0 (0.77-1.29); P=0.98]. There was a trend towards higher rates of MI at 6 months amongst SELECT-eligible patients, but this difference failed to reach statistical significance [8.5% vs. 6.3%; OR 2.0 (0.96-1.39); P=0.08). Conclusions In this large international cohort of contemporary cardiac surgical patients, nearly 10% would have met eligibility for SELECT. SELECT-eligible patients undergoing cardiac surgery in TRICS III had a numerically higher rate of MACCE than those enrolled in SELECT, highlighting the high risk nature of this patient subgroup. However, amongst SELECT-eligible and non-eligible patients undergoing cardiac surgery, no significant difference in CV outcomes was uncovered.

Development and Validation of a Clinical Score to Predict Epilepsy After Cerebral Venous Thrombosis

One of 10 patients develop epilepsy in the late phase after cerebral venous thrombosis (CVT) diagnosis but predicting the individual risk is difficult. To develop and externally validate a prognostic score to estimate the individual risk of post-CVT epilepsy. This observational cohort study included both retrospective and prospective patients enrolled from 1994 through 2022. For development of the DIAS3 score, data from the International CVT Consortium (n = 1128), a large international hospital-based multicenter CVT cohort, were used. For validation, data from 2 independent multicenter cohorts, the ACTION-CVT (n = 543) and the Israel CVT study (n = 556), were used. Of 2937 eligible, consecutively enrolled adult patients with radiologically verified CVT, 710 patients with a history of epilepsy prior to CVT, follow-up less than 8 days, and missing late seizure status were excluded. The prediction score (DIAS3) was developed based on available literature and clinical plausibility and consisted of 6 readily available clinical variables collected during the acute phase: decompressive hemicraniectomy, intracerebral hemorrhage at presentation, age, seizure(s) in the acute phase (excluding status epilepticus), status epilepticus in the acute phase, and subdural hematoma at presentation. Time to a first late seizure, defined as occurring more than 7 days after diagnosis of CVT. Of 1128 patients included in the derivation cohort (median age, 41 [IQR, 30-53] years; 805 women [71%]), 128 (11%) developed post-CVT epilepsy during a median follow-up of 12 (IQR, 3-26) months. According to the DIAS3 score, the predicted 1-year and 3-year risk of epilepsy in individual patients ranged from 7% to 68% and 10% to 83%, respectively. Internal and external validation showed adequate discrimination in the derivation cohort (1 year and 3 years: C statistic, 0.74; 95% CI, 0.70-0.79) and the 2 independent validation cohorts, (ACTION-CVT) 1 year: C statistic, 0.76; 95% CI, 0.67-0.84; 3 years: C statistic, 0.77; 95% CI, 0.66-0.84; and Israel CVT study 1 year: C statistic, 0.80; 95% CI, 0.75-0.86. Calibration plots indicated adequate agreement between predicted and observed risks. The DIAS3 score (freely available online) is a simple tool that can help predict the risk of post-CVT epilepsy in individual patients. The model can improve opportunities for personalized medicine and may aid in decision-making regarding antiseizure medication, patient counseling, and facilitation of research on epileptogenesis in CVT.

635P Pain impacts quality of life, psychological disorders and exercise in a large international cohort of patients with facioscapulohumeral muscular dystrophy

635P Pain impacts quality of life, psychological disorders and exercise in a large international cohort of patients with facioscapulohumeral muscular dystrophy

Abstract B013: Host phenotype profiling predicts progression to resection in neoadjuvant pancreatic cancer

Abstract Introduction Neoadjuvant chemotherapy offers a modest survival benefit in pancreatic cancer. Current methods for assessing response to chemotherapy are limited to CA19-9 and post- treatment imaging. However, these methods are not without caveats and focus heavily on tumour biology and staging the tumour, without consideration of host biology or staging the host. We sought to explore the relationship between host biology and outcomes in neoadjuvantly- treated pancreatic cancer, and determine the utility of host phenotype profiling as a tool for predicting chemotherapy response and subsequent progression to resection. Methods Host phenotype profiling was performed by measuring body composition (BC) pre- and post- neoadjuvant chemotherapy in a large international pancreatic cancer cohort (n = 301). Patients with resectable or borderline resectable disease were included if they received chemotherapy with neoadjuvant intent. BC was determined with contrast-enhanced CT scans by measuring single-slice L3 cross-sectional area. Results There were significant differences in BC change from baseline to post-treatment between resected (n = 174) and non-resected patients (n = 127). Patients who did not progress to resection exhibited greater loss in all BC compartments vs those who progressed to resection (muscle area -3.4 vs -0.7, visceral fat -10.1 vs -2.1, subcutaneous fat -12.0 vs -1.4, all p &amp;lt; 0.001, median percentage change per 100 days). We used these values to define a adverse and favourable host phenotypes, which significantly correlated with progression to resection (58.8% adverse phenotype, 74.3% favourable phenotype, p &amp;lt; 0.001). The independence of this effect was confirmed in a logistic regression model with well-established clinico-pathological variables including CA19-19 rise (adverse phenotype OR of non-resection 4.57, 95% CI 1.55-13.48, p = 0.006). Conclusion Host phenotype profiling represents a useful addition to an otherwise limited toolbox of methods for assessing treatment response and selecting for surgery in neoadjuvant pancreatic cancer. Clinicians will be familiar with the subjective “gut feeling” of identifying patients in the clinic who are unlikely to be candidates for surgery, and we demonstrate an objective measurement of this. Early identification of patients on an adverse trajectory may highlight those who would benefit from early intervention such as prehabilitation, salvage change of chemotherapy regimen, or nutritional optimization to switch the phenotype from adverse to favourable and reverse adverse host biology. Citation Format: Adam Bryce, Stephan Dreyer, Ross Dolan, Fieke Froeling, Dario Solinas, Alice Cattelani, Antonio Pea, David Chang. Host phenotype profiling predicts progression to resection in neoadjuvant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B013.

Improved Risk Prediction in Human Papillomavirus-Associated Endocervical Adenocarcinoma Through Assessment of Binary Silva Pattern-based Classification: An International Multicenter Retrospective Observational Study Led by the International Society of Gynecological Pathologists (ISGyP).

Endocervical adenocarcinomas (EACs) are a group of malignant neoplasms associated with diverse pathogenesis, morphology, and clinical behavior. As a component of the International Society of Gynecological Pathologists International Endocervical Adenocarcinoma Project, a large international retrospective cohort of EACs was generated in an effort to study potential clinicopathological features with prognostic significance that may guide treatment in these patients. In this study, we endeavored to develop a robust human papillomavirus (HPV)-associated EAC prognostic model for surgically treated International Federation of Gynecology and Obstetrics (FIGO) stage IA2 to IB3 adenocarcinomas incorporating patient age, lymphovascular space invasion (LVSI) status, FIGO stage, and pattern of invasion according to the Silva system (traditionally a 3-tier system). Recently, a 2-tier/binary Silva pattern of invasion system has been proposed whereby adenocarcinomas are classified into low-risk (pattern A/pattern B without LVSI) and high-risk (pattern B with LVSI/pattern C) categories. Our cohort comprised 792 patients with HPV-associated EAC. Multivariate analysis showed that a binary Silva pattern of invasion classification was associated with recurrence-free and disease-specific survival (P < 0.05) whereas FIGO 2018 stage I substages were not. Evaluation of the current 3-tiered system showed that disease-specific survival for those patients with pattern B tumors did not significantly differ from that for those patients with pattern C tumors, in contrast to that for those patients with pattern A tumors. These findings underscore the need for prospective studies to further investigate the prognostic significance of stage I HPV-associated EAC substaging and the inclusion of the binary Silva pattern of invasion classification (which includes LVSI status) as a component of treatment recommendations.

737. ETHNIC, GENDER AND TUMOR-SPECIFIC ASSESSMENT OF BODY COMPOSITION IS CRITICAL FOR CLINICAL RELEVANCE IN PATIENTS UNDERGOING THERAPY FOR ESOPHAGEAL

Abstract Background Growing evidence has supported a role for body composition in predicting survival in patients undergoing esophagectomy. A contemporary meta-analysis of published data (n=44 studies) conducted for this study confirmed an association between reduced muscle mass at diagnosis and worse overall survival (HR 1.72, 95%CI 1.49-1.97). Variation in methods of assessing and defining parameters of body composition remain however an important barrier to the wider adoption in routine clinical practice. This is particularly pertinent in esophageal cancer due to known sex, biological and geographical difference in tumor subtypes. This study seeks to define baseline variation in body composition parameters and to report their association with 90-day and overall survival in a large international cohort of patients undergoing esophagectomy for cancer. Methods Patients who underwent esophagectomy in fourteen high-volume centers between January 2007 to December 2019 were eligible for inclusion. Survival data were included up until June 2022. Skeletal muscle, visceral and subcutaneous adipose tissues within CT images, acquired at the time of diagnosis, were analyzed in accordance with a standardized protocol. Results 1716 patients were recruited to this study from three global regions: North America (n=386;22.5%), Europe (n=940;54.8%) and Asia (n=390;22.7%). Patients were predominantly male (79.5%) and adenocarcinoma was the most common histological subtype (66.6%). Wide variation of skeletal muscle (17.1-83.5cm2), visceral adiposity (0.2-170.1cm2) and subcutaneous adiposity (0.2-216.8cm2) was observed at presentation. Characteristics significantly associated with levels of muscle and adiposity were global region, sex, age, and histological subtype (P&amp;lt;0.001) (Figure 1). Compared to adenocarcinoma, squamous cell carcinoma was associated with significantly lower levels of muscle and adiposity, a finding that was independent of global region, sex, and age using a multivariable linear regression model (p&amp;lt;.0001). Median follow-up was 71.3 (95%CI 69.1-73.5) months with a median overall survival of 60.9 (95%CI 53.0-68.9) months. Reduced skeletal muscle and an excess of total adiposity at the time of diagnosis was associated with worse 90-day mortality and long-term survival. An interactive online survival prediction tool was developed to provide personalized survival estimates based on relevant predictors including skeletal muscle, total adiposity at diagnosis and other tumor and patient specific variables. Conclusions This is the first and largest study to adopt standardized methods to define international variation in parameters of body composition in esophageal cancer patients. Findings corroborate the potential role of body composition as a method of prognostication in esophageal cancer and presents a on-line tool for convenient integration into clinical practice.

Dual Mobility Trapeziometacarpal Joint Arthroplasty: A Survey on Variations in Surgical Techniques and Patient Management.

Background: Dual mobility total joint arthroplasty is gaining popularity for trapeziometacarpal joint (TMCJ) arthritis, with evolving indications, surgical technique and rehabilitation. The aim of this study was to obtain detailed insight into the variations in indications, surgical technique and rehabilitation for TMCJ arthroplasty with dual mobility implants, across a large international cohort of surgeons. The secondary aim was to analyse if there were differences in TMCJ arthroplasty between highly and less experienced surgeons. Methods: An anonymised online survey was developed and distributed to the international hand surgery community of surgeons performing TMCJ arthroplasty. Responses were summarised, and a sub-analysis comparing indications, contra-indications, surgical technique, implant placement, rehabilitation and complications between highly and less experienced surgeons was performed. Results: Of the 203 included respondents, 59 were considered highly experienced. Most respondents perform TMCJ arthroplasty under regional anaesthesia (84%), via a dorsolateral approach (78%) and with image-guidance for cup placement (84%). However, there is considerable variation in handling of scaphotrapeziotrapezoidal (STT) arthritis, cup positioning landmarks, postoperative immobilisation, first extensor compartment release and revision techniques. Highly experienced surgeons performed TMCJ arthroplasty for a larger proportion of their patients undergoing surgery for TMCJ arthritis, and a trapezium smaller than 8 mm or STT-OA was less frequently considered a contra-indication. Highly experienced surgeons preferred freehand osteotomy of the metacarpal and allowed office workers to return to work earlier. Conclusions: This survey shows that there is considerable variation in (contra)indications, surgical technique and rehabilitation amongst surgeons performing TMCJ arthroplasty, but only a few differences between highly and less experienced surgeons were identified. This data provides a reference for surgeons who want to familiarise themselves with increasingly popular procedure and may help surgeons already performing TMCJ arthroplasty to identify potential topics for future research to optimise its outcome. Level of Evidence: Level V (Therapeutic).

Sport and longevity: an observational study of international athletes.

The human lifespan is influenced by various factors, with physical activity being a significant contributor. Despite the clear benefit of exercise on health and longevity, the association between different types of sports and lifespan is yet to be considered. Accordingly, we aimed to study this association in a large international cohort of former athletes using a robust linear regression model. We collected data on athletes from public sources, accumulating a total of 95,210 observations, 95.5% of which were accounted for by males. The dataset represented athletes born between 1862 and 2002 from 183 countries across 44 sports disciplines. We calculated the change in lifespan by measuring the difference in age between athletes and the corresponding reference populations, while accounting for variations caused by sex, year of death, and country. The results revealed that various sports impacted lifespan differently, with male athletes being more likely to experience benefits from sports than female athletes. Among male athletes, pole vaulting and gymnastics were linked to the highest extension in lifespan (8.4years, 95% CI [6.8, 9.9] and 8.2years, 95% CI [7.4, 9], respectively), while volleyball and sumo wrestling were the most negatively associated with lifespan (- 5.4years, 95% CI [- 7, - 3.8]; - 9.8years, 95% CI [- 11, - 8.6], respectively). The association between lifespan and popular team sports in males was positive for cricket, rowing, baseball, water polo, Australian rules, hurling, lacrosse, field hockey, minimal for rugby, canoeing and kayaking, basketball, gridiron football, and football (soccer), and negative for handball and volleyball. Racquet sports (i.e., tennis and badminton) exhibited a consistent and positive association in both male and female athletes, as shown by an extended lifespan of up to 5.7years in males (95% CI [5, 6.5]) and 2.8years in females (95% CI [1.8, 3.9]). Although lacking conclusive evidence, we theorize that the observed results may be attributed to the aerobic and anaerobic characteristics of each sport, with mixed sports yielding the maximum benefits for the lifespan. While results from female athletes should be cautiously interpreted, our study highlights the complex interplay between sports and lifespan and contributes to the growing body of knowledge on the multifaceted relationship between physical activity and human longevity.

Autoantibodies and damage in patients with idiopathic inflammatory myopathies: A longitudinal multicenter study from the MYONET international network

ObjectiveTo study the trajectories of changes in damage over time and explore associations with autoantibody defined subgroups using a large international cohort of patients with idiopathic inflammatory myopathies (IIM). MethodsData from the MYONET registry, including patients who were tested for autoantibodies and had at least one assessment of damage using the Myositis Damage Index (MDI), were analyzed. Patients were sub-grouped according to their autoantibody profiles (myositis-specific, myositis-associated, or seronegative). The index date was defined as the time point for the first registered MDI assessment. The longitudinal trajectories of damage with autoantibody status as the main predictor were analyzed using linear mixed models. ResultsA total of 757 adult patients were included in this study. Each year of disease duration since diagnosis had an estimated MDI score increase of 0.16 units for the seronegative group (reference). Compared with the seronegative group as reference, patients with dermatomyositis-specific autoantibodies developed less damage per year of follow-up since diagnosis (average 0.08 less score, P = 0.04), whereas patients with anti-PM/Scl autoantibodies developed more damage per year of follow-up since diagnosis (average 0.28 higher score, P = 0.03) independent of sex and age at diagnosis. The seronegative subgroup and the immune-mediated necrotizing myopathy autoantibody subgroup had the strongest correlation between severity of muscle damage and HAQ-DI scores at five years of follow-up, rho=0.84, P < 0.001 and rho=0.72, P < 0.001, respectively. ConclusionOur study is the first to describe patterns and trajectories of change in damage over time in relation to autoantibody defined subgroups in a large international multicenter cohort of patients with IIM. Patients with anti-PM/Scl scored a greater extent of damage, whereas patients with dermatomyositis-specific antibodies had less damage than seronegative patients. Severity in muscle damage had moderate to strong correlation with functional disability among the IMNM and seronegative subgroups with lower correlations for the other subgroups. These findings suggest that autoantibodies may be useful predictors of long-term damage.

BRCA1/2 Mutations and Breast/Ovarian Cancer Risk: A New Insights Review.

Breast and ovarian cancers are significant global health concerns, and understanding their genetic underpinnings is essential for effective prevention and cure. This narrative review provides a comprehensive analysis of studies conducted between 1994 and June 2024, focusing on the link between specific mutations in the breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) and the associated risks of both breast and ovarian cancers. It encompasses the findings of various works, including observational studies and molecular profiling analyses. Conducted on large international cohorts, these studies present compelling evidence of the relationship between different BRCA1 and BRCA2 mutations and the varying risks of breast and ovarian cancer. Furthermore, this review highlights the significance of nonsense-mediated decay mutations and their impact on cancer risk, particularly concerning the age of breast cancer onset. The implications of these findings are far-reaching, offering valuable information for risk assessment and decision-making in managing individuals who carry BRCA1 or BRCA2 mutations. The molecular subtyping profile BluePrint is discussed as a potential tool for enhancing clinical care by aiding the selection of appropriate treatment options, such as endocrine therapy or chemotherapy, based on the tumor's molecular characteristics. In conclusion, we establish a robust link between specific BRCA1 and BRCA2 gene mutations and increased susceptibility to breast and ovarian cancers. These mutations impact cancer onset age and severity, underscoring the need for targeted testing and screening. The current study enhances cancer detection, prevention, and cure strategies.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

International differences in the selection and outcome of minimally invasive and open distal pancreatectomy: A transatlantic analysis

BackgroundThe efficacy and safety of minimally invasive distal pancreatectomy have been confirmed by randomized trials, but current patient selection and outcome of minimally invasive distal pancreatectomy in large international cohorts is unknown. This study aimed to compare the use and outcome of minimally invasive distal pancreatectomy in North America, the Netherlands, Germany, and Sweden. MethodsAll patients in the 4 Global Audits on Pancreatic Surgery Group (GAPASURG) registries who underwent minimally invasive distal pancreatectomy or open distal pancreatectomy during 2014–2020 were included. ResultsOverall, 20,158 distal pancreatectomies were included, of which 7,316 (36%) were minimally invasive distal pancreatectomies. Use of minimally invasive distal pancreatectomy varied from 29% to 54% among registries, of which 13% to 35% were performed robotically. Both the use of minimally invasive distal pancreatectomy and robotic surgery were the highest in the Netherlands. Patients undergoing minimally invasive distal pancreatectomy tended to have a younger age (Germany and Sweden), female sex (North America, Germany), higher body mass index (North America, the Netherlands, Germany), lower comorbidity classification (North America, Germany, Sweden), lower performance status (Germany), and lower rate of pancreatic adenocarcinoma (all). The minimally invasive distal pancreatectomy group had fewer vascular resections (all) and lower rates of severe complications and mortality (North America, Germany). In the multivariable regression analysis, country was associated with severe complications but not with 30-day mortality. Minimally invasive distal pancreatectomy was associated with a lower risk of 30-day mortality compared with open distal pancreatectomy (odds ratio 1.633, 95% CI 1.159–2.300, P = .005). ConclusionsConsiderable disparities were seen in the use of minimally invasive distal pancreatectomy among 4 transatlantic registries of pancreatic surgery. Overall, minimally invasive distal pancreatectomy was associated with decreased mortality as compared with open distal pancreatectomy. Differences in patient selection among countries could imply that countries are in different stages of the learning curve.

†Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort

†Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort