Large Multicenter Research Articles

Large Italian Multicenter Study on Prognostic Value of Baselines Variables in mCRPC Patients Treated with 223RaCl2: Ten Years of Clinical Experience

Large Italian Multicenter Study on Prognostic Value of Baselines Variables in mCRPC Patients Treated with 223RaCl2: Ten Years of Clinical Experience

Operational feasibility and reproducibility of serial echocardiographic parameters of left ventricular remodelling and function for evaluation of drug efficacy in multicentre clinical trial settings

Abstract Background Operational feasibility and reproducibility of echocardiographic (Echo) parameters are essential for planning interventional trials with surrogate imaging endpoints. Existing data from large cohort studies performed at institutions with high expertise in Echo may not be representative of the multicentre clinical trial settings where substantial variability in local standards and equipment exists. Purpose To assess feasibility of standardized Echo data acquisition, measurability, and reproducibility of key Echo endpoints in a large multicentre clinical trial. Methods ENDEAVOR was a phase 2b/3 multicentre, international, placebo-controlled trial investigating the effects of mitiperstat on symptoms and function in participants with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%. Echo was used for efficacy assessment at 3 time points (baseline, 16 and 24 weeks). Echo data were acquired according to the study protocol at sites with various equipment and expertise and analysed centrally by an academic core laboratory. Key Echo metrics were LVEF, LV global longitudinal strain (GLS), LV mass, E/E’ and left atrial volume (LAV). LVGLS was measured from three apical views (4, 2, and 3-chamber) by 2DSTRAIN TomTec software. All images were evaluated for image quality using the scale from 1 (Very poor) to 5 (Excellent) and measured by a single reader. Results 711 participants at 142 sites in 18 countries were randomised in ENDEAVOR trial (mean age 72.4y, mean BMI 30.5kg/m2). A total of 2052 Echo exams were analysed: 735 at baseline, 661 at 16 and 656 at 24 weeks. Majority were of excellent to good (1282/62%) or adequate (732/36%) image quality. Doppler images and apical 4ch view were the most feasible to acquire, while apical 2ch view was the most challenging (Fig, A). LVEF, LV mass, E/E’ and LAV were measurable in most studies (88-96%), however fewer studies were interpretable for LVGLS (61% at baseline to 70% at week 24). When matching echo exams at 2 or 3 visits were analysed, the number of interpretable matches dropped more significantly for LVGLS (to 47% for 2 and 41% for 3 time points), while the proportion of interpretable matches for standard echo endpoints remained acceptable (>83% and >75%, respectively). A total of 82 scans were re-read for reproducibility. Most of the echo endpoints demonstrated good or excellent reproducibility, with LVGLS showing better reproducibility than LVEF (Fig, B). Conclusions We report feasibility of Echo data acquisition, measurability, and reproducibility of key parameters of LV remodelling and function in a large multicentre, international, placebo-controlled clinical trial in HF and EF>40%. These data will help to inform future trial design to drive drug development decision making.

Prevalence and management of hypertension in Turner syndrome: data from the International Turner Syndrome (I-TS) registry.

Cardiovascular disease is the most common cause of death in Turner syndrome (TS) for which arterial hypertension has a direct influence and is a key modifiable risk factor. To investigate the prevalence and patterns of hypertension diagnosis and management in adult patients with TS who are registered in a large international multicentre database (TS-HTN study). Retrospective multicentre observational study of patients aged ≥18 years included in the I-TS (International-TS) registry (2020-2022), using registry and participating centre-collected data. Twelve international centres participated, including 182 patients with a median age of 28 years (IQR 23-37.2). Arterial hypertension was recorded in 13.2% (n = 24). The median age at hypertension diagnosis was 27 years (range 10-56), with 92% aged less than 50 years at diagnosis. The majority (75%) were classified as primary hypertension (n = 18). In binomial regression analysis, higher body mass index was the only parameter significantly associated with the occurrence of hypertension (B = 1.487, P = 0.004). Among patients with aortic disease (n = 9), 50% had systolic BP ≥ 130 mmHg and 66.6% had diastolic BP ≥ 80 mmHg during the last clinic review. Angiotensin-converting enzyme inhibitors were the most common (n = 16) medication prescribed, followed by angiotensin receptor blockers (n = 6), beta-blockers (n = 6) and calcium channel blockers (n = 6). Arterial hypertension is common in TS and occurs at a young age. Overweight/obesity was a notable risk factor for hypertension. The frequency of suboptimal BP control among high-risk patients highlights the importance of increased awareness and TS-specific consensus guidance on management.

Survival Benefit From Corticosteroids in Severe Alcohol-associated Hepatitis Attributed to Clinical and Treatment Differences in a Large Multicenter Cohort.

Corticosteroids are recommended by multiple society guidelines for the treatment of severe alcohol-associated hepatitis (AH). However, their use remains controversial due to inconsistent studies regarding their survival benefit. This was a retrospective cohort study of first-time hospitalizations for severe AH (Maddrey discriminant function ≥ 32) admitted to the Veterans Health Administration between January 3, 2005, and December 5, 2020, (i) evaluating the effect of corticosteroid therapy on all-cause survival, (ii) characterizing the clinical and psychosocial factors associated with corticosteroid use, and (iii) determining the effect of duration of corticosteroid therapy on all-cause survival among treatment-responsive patients (Lille score < 0.45). During the study period, 2,618 patients were admitted with severe AH, of whom 1,083 (41.37%) received corticosteroids. Although corticosteroids were significantly associated with improved all-cause survival in the unadjusted model ( P = 0.022), no survival benefit was observed in the adjusted model after accounting for baseline and admission characteristics (adjusted hazard ratio [aHR] = 1.01, P = 0.818). Psychiatry consultation was the only factor evaluated that was protective against mortality (aHR = 0.67, P < 0.001). Among the 428 patients (49.7%) responsive to corticosteroids, duration of therapy was not associated with overall survival on unadjusted ( P = 0.696) or adjusted models (aHR = 1.12, P = 0.710 for a ≥28-day course compared with a ≤7-day reference). Despite being recommended by clinical guidelines for severe AH, corticosteroids have low utilization with no survival benefit after accounting for differences in patient characteristics and practice patterns. Among patients with treatment response per the Lille score, no difference was observed in overall survival between shorter and longer durations of corticosteroid therapy.

Outcomes of Follicular Lymphoma with Leukemic Phase in the Modern Era: Results from a Large Multicenter Study

Outcomes of Follicular Lymphoma with Leukemic Phase in the Modern Era: Results from a Large Multicenter Study

Sex Differences in Colonoscopy Indications and Findings: Results from a Large Multicenter Database.

Background: Sex-based differences are common among diseases. We aimed to investigate the differences in colonoscopy indications and its findings between males and females. Methods: A large, multi-center, cross-sectional, retrospective study included all colonoscopies performed between 2016 and 2021 in seven endoscopy departments. The indications and findings of the procedures were compared between males and females. Results: A total of 151,411 (52.6%) women and 136,519 (47.4%) men were included, aged 56.54 ± 12.9 years and 56.59 ± 12.7. Cecal intubation was similar (95.6% vs 95.5%, p = 0.251). More females had excellent or good bowel preparation compared to males (71.4% vs 65.6%). Colonoscopy due to abdominal pain, constipation, diarrhea, and anemia was higher in females compared to males (15% vs 9.9%, 3.9% vs 2.2%, and 7.6% vs 4.9%, p < 0.001, respectively), while positive FOBT, rectal bleeding and post-polypectomy surveillance and screening were more common indications among males (9.5% vs 7.8%, 10.7% vs 7.8%, and 10.8% vs 7.1%, respectively). On colonoscopy, males were found to have significantly higher colorectal cancer and polyps (0.5% vs 0.4% and 35.1% vs 24.6%). Polyp detection rates were lower in females across all indications, whereas diverticulosis rates were higher in males. However, a clinically significant difference regarding diverticulosis was observed only in patients with anemia as the indication. Conclusions: Notable differences exist between males and females in terms of the indications and findings on colonoscopy. This highlights the need for identifying the factors contributing to these differences and the developing sex-specific approaches for the diagnosis and management of gastrointestinal diseases.

S2033 Cardiovascular Disease Risk and Overall Mortality in Patients With Hepatitis C Infection and Depression: A Large Multicenter Cohort Study

S2033 Cardiovascular Disease Risk and Overall Mortality in Patients With Hepatitis C Infection and Depression: A Large Multicenter Cohort Study

S1055 Does Starting PPIs Increase the Risk of Complications in IBD Patients on Biologics or Immunomodulators?: A Large Multicenter Cohort Study

S1055 Does Starting PPIs Increase the Risk of Complications in IBD Patients on Biologics or Immunomodulators?: A Large Multicenter Cohort Study

Predicting Early AKI in Two Large Multicenter Pediatric Critical Care Datasets

Predicting Early AKI in Two Large Multicenter Pediatric Critical Care Datasets

S1998 The Impact of COVID-19 on Alcohol Related Morbidity and Mortality: A Large Multicenter Study

S1998 The Impact of COVID-19 on Alcohol Related Morbidity and Mortality: A Large Multicenter Study

Measurement properties of the Inclusion Body Myositis Functional Rating Scale

ObjectivesTo evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS).MethodsData from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in...

MHC Class II Deficiency: Clinical, Immunological, and Genetic Insights in a Large Multicenter Cohort

BackgroundMajor Histocompatibility Complex Class II (MHC-II) deficiency, a combined immunodeficiency, results from loss of Human Leukocyte Antigen class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation (HSCT) stands as the sole curative approach, though factors influencing patient outcomes remain insufficiently explored. ObjectiveOur aim was to elucidate the clinical, immunological, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates. MethodsIn this multicenter retrospective analysis, we gathered data from 35 patients diagnosed with MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes. ResultsPredominant symptoms observed were pneumonia (n=29, 82.9%), persistent diarrhea (n=26, 74.3%), and severe infections (n=26, 74.3%). The RFXANK gene mutation (n=9) was the most frequent, followed by mutations in RFX5 (n=8), CIITA (n=4), and RFXAP (n=2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared to those with RFX5 mutations (p=0.0008 and p=0.0006, respectively), alongside a more significant diagnostic delay (p=0.020). A notable founder effect was observed in 5 patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n=10), showing a significantly higher proportion in individuals with HSCT (n=8, 80%). Early demise (p=0.006) and higher CD8+ T-cell counts were observed in patients with the RFX5 mutations compared to RFXANK-mutant patients (p=0.006 and p=0.009, respectively). ConclusionThe study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency.

Machine Learning and External Validation of the IDENTIFY Risk Calculator for Patients with Haematuria Referred to Secondary Care for Suspected Urinary Tract Cancer

BackgroundThe IDENTIFY study developed a model to predict urinary tract cancer using patient characteristics from a large multicentre, international cohort of patients referred with haematuria. In addition to calculating an individual’s cancer risk, it proposes thresholds to stratify them into very-low-risk (<1%), low-risk (1–<5%), intermediate-risk (5–<20%), and high-risk (≥20%) groups. ObjectiveTo externally validate the IDENTIFY haematuria risk calculator and compare traditional regression with machine learning algorithms. Design, setting, and participantsProspective data were collected on patients referred to secondary care with new haematuria. Data were collected for patient variables included in the IDENTIFY risk calculator, cancer outcome, and TNM staging. Machine learning methods were used to evaluate whether better models than those developed with traditional regression methods existed. Outcome measurements and statistical analysisThe area under the receiver operating characteristic curve (AUC) for the detection of urinary tract cancer, calibration coefficient, calibration in the large (CITL), and Brier score were determined. Results and limitationsThere were 3582 patients in the validation cohort. The development and validation cohorts were well matched. The AUC of the IDENTIFY risk calculator on the validation cohort was 0.78. This improved to 0.80 on a subanalysis of urothelial cancer prevalent countries alone, with a calibration slope of 1.04, CITL of 0.24, and Brier score of 0.14. The best machine learning model was Random Forest, which achieved an AUC of 0.76 on the validation cohort. There were no cancers stratified to the very-low-risk group in the validation cohort. Most cancers were stratified to the intermediate- and high-risk groups, with more aggressive cancers in higher-risk groups. ConclusionsThe IDENTIFY risk calculator performed well at predicting cancer in patients referred with haematuria on external validation. This tool can be used by urologists to better counsel patients on their cancer risks, to prioritise diagnostic resources on appropriate patients, and to avoid unnecessary invasive procedures in those with a very low risk of cancer. Patient summaryWe previously developed a calculator that predicts patients’ risk of cancer when they have blood in their urine, based on their personal characteristics. We have validated this risk calculator, by testing it on a separate group of patients to ensure that it works as expected. Most patients found to have cancer tended to be in the higher-risk groups and had more aggressive types of cancer with a higher risk. This tool can be used by clinicians to fast-track high-risk patients based on the calculator and investigate them more thoroughly.

Haemoglobin values, transfusion practices, and long-term outcomes in critically ill patients with traumatic brain injury: a secondary analysis of CENTER-TBI

Haemoglobin (Hb) thresholds and red blood cells (RBC) transfusion strategies in traumatic brain injury (TBI) are controversial. Our objective was to assess the association of Hb values with long-term outcomes in critically ill TBI patients. We conducted a secondary analysis of CENTER-TBI, a large multicentre, prospective, observational study of European TBI patients. All patients admitted to the Intensive Care Unit (ICU) with available haemoglobin data on admission and during the first week were included. During the first seven days, daily lowest haemoglobin values were considered either a continous variable or categorised as < 7.5 g/dL, between 7.5–9.5 and > 9.5 g/dL. Anaemia was defined as haemoglobin value < 9.5 g/dL. Transfusion practices were described as “restrictive” or “liberal” based on haemoglobin values before transfusion (e.g. < 7.5 g/dL or 7.5–9.5 g/dL). Our primary outcome was the Glasgow outcome scale extended (GOSE) at six months, defined as being unfavourable when < 5. Of 1590 included, 1231 had haemoglobin values available on admission. A mean Injury Severity Score (ISS) of 33 (SD 16), isolated TBI in 502 (40.7%) and a mean Hb value at ICU admission of 12.6 (SD 2.2) g/dL was observed. 121 (9.8%) patients had Hb < 9.5 g/dL, of whom 15 (1.2%) had Hb < 7.5 g/dL. 292 (18.4%) received at least one RBC transfusion with a median haemoglobin value before transfusion of 8.4 (IQR 7.7–8.5) g/dL. Considerable heterogeneity regarding threshold transfusion was observed among centres. In the multivariable logistic regression analysis, the increase of haemoglobin value was independently associated with the decrease in the occurrence of unfavourable neurological outcomes (OR 0.78; 95% CI 0.70–0.87). Congruous results were observed in patients with the lowest haemoglobin values within the first 7 days < 7.5 g/dL (OR 2.09; 95% CI 1.15–3.81) and those between 7.5 and 9.5 g/dL (OR 1.61; 95% CI 1.07–2.42) compared to haemoglobin values > 9.5 g/dL. Results were consistent when considering mortality at 6 months as an outcome. The increase of hemoglobin value was associated with the decrease of mortality (OR 0.88; 95% CI 0.76–1.00); haemoglobin values less than 7.5 g/dL was associated with an increase of mortality (OR 3.21; 95% CI 1.59–6.49). Anaemia was independently associated with long-term unfavourable neurological outcomes and mortality in critically ill TBI patients.Trial registration: CENTER-TBI is registered at ClinicalTrials.gov, NCT02210221, last update 2022–11–07.

Treatment of Chronic Pouchitis With JAK Inhibitors: Results from A Large Multicenter Database.

Lay Summary This retrospective study assessed the use of Janus kinase inhibitors in treating chronic pouchitis. While showing relative safety, Janus kinase inhibitors demonstrated effectiveness in &amp;lt;50% of cases, cautioning against their use as first-line agents. Larger randomized trials are recommended for further investigation.

Clinical Impact of Digitalis Therapy in a Large Multicenter Cohort of CRT-Recipients.

(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large, observational study in recipients of cardiac resynchronization therapy (CRT). (2) Methods: Consecutive patients receiving a CRT-defibrillator in three European tertiary referral centers were enrolled and followed-up for a mean 37 months ± 28 months. Digitalis use was assessed at the time of CRT implantation. A multivariate Cox-regression model and propensity score matching were used to determine all-cause mortality as the primary endpoint. CRT-response (defined as improvement of ≥1 NYHA class), echocardiographic improvement (defined as improvement of LVEF of ≥ 5%) and incidence of ICD shocks and rehospitalization were assessed as secondary endpoints in a subgroup of patients. (3) Results: The study comprised 552 CRT-recipients with standard indications, including 219 patients (40%) treated with digitalis. Compared to patients without digitalis, they had more often atrial fibrillation, poorer LVEF and a higher NYHA class (all p ≤ 0.002). Crude analysis of all-cause mortality demonstrated a similar relative risk of death for patients with and without digitalis (HR = 1.14; 95% CI 0.88-1.5; p = 0.40). After adjustment for independent predictors of mortality, digitalis therapy did not alter the risk for death (adjusted HR = 1.04; 95% CI 0.75-1.45; p = 0.82). Furthermore, in comparison to 286 propensity-score-matched patients, mortality was not affected by digitalis intake (propensity-adjusted HR = 1.11; 95% CI 0.72-1.70; p = 0.64). A CRT-response was predominant in digitalis non-users, concerning both improvement of HF symptoms and LVEF (NYHA p < 0.01; LVEF p < 0.01), while patients on digitalis had more often ventricular tachyarrhythmias requiring ICD shock (p = 0.01); although, rehospitalization for cardiac reasons was significantly lower among digitalis users compared to digitalis non-users (HR = 0.58; 95% C. I. 0.40-0.85; p = 0.01). (4) Conclusions: Digitalis therapy had no effect on mortality, but was associated with a reduced response to CRT and increased susceptibility to ventricular arrhythmias requiring ICD shock treatment. Although, digitalis administration positively altered the likelihood for cardiac rehospitalization during follow-up.

The Burden of Stroke in Neonates Undergoing Congenital Heart Surgery: A Large Multicenter Analysis

BackgroundStroke affects surgical decision making and outcomes of neonatal cardiac surgery (CHS). We sought to assess the burden of stroke in this population from a large multicenter database. MethodsWe analyzed neonates undergoing CHS with cardiopulmonary bypass from the Pediatric Health Information System database (2004-2022). The cohort was divided into the stroke group, which included preoperative/postoperative ischemic, hemorrhagic subtypes, and grade III to IV intraventricular hemorrhages, and compared in-hospital and follow-up outcomes to a nonstroke group. ResultsA perioperative stroke occurred in 800 of 14,228 neonates (5.6%). The stroke group was more likely to have hypoplastic left heart syndrome (HLHS; 30.5% vs 20.7%), born preterm (19.4% vs 11.7%), low birth weight (17.8% vs 11.9%), and require extracorporeal membrane oxygenation (ECMO; 48.8% vs 13.8%; all P < .001). Outcomes comparing stroke vs no stroke were mortality, 33.1% vs 8.9%; nonhome discharge, 12.5% vs 6.9%; length of stay, 41 vs 24 days; and hospitalization costs, $354,521 vs $180,489 (all, P < .05). Stroke increased the odds of mortality by 2-fold (odds ratio, 2.20; 95% CI, 1.75-2.77; P < .001) after adjusting for ECMO, prematurity among other significant factors. On follow-up, the stroke group had a higher incidence of hydrocephalus (9.5% vs 1.3%), cerebral palsy (6.2% vs 1.3%), and autism spectrum disorder (7.1% vs 3.5%), and survivors of the index admission had higher 1- and 5-year mortality (5.3% and 11.3% vs 3.3% and 5.9%, respectively; all P < .05). ConclusionsNeonatal CHS patients born prematurely, diagnosed with HLHS, or those requiring ECMO are disproportionately affected by stroke. The occurrence of stroke is marked by significantly higher mortality. Future research should seek to identify factors leading to stroke to increase rescue after stroke and for improvement of long-term outcomes.

The Clinical and Radiological Outcomes of the Multimodal Use of the Woven EndoBridge Device: A Large Multicenter Study

The Woven EndoBridge (WEB) is a device used for intrasaccular flow diversion, designed for the elimination of wide-necked bifurcation aneurysms from the circulation. In this study, we aim to assess the safety and efficacy of the WEB and its uses in treating aneurysms of different morphologies and locations. In a retrospective analysis, we compiled a comprehensive dataset from patients treated with the WEB device across three major Australian neurovascular centers from May 2017 to September 2023. The case series encompassed a spectrum of aneurysm types, including wide-necked bifurcation, sidewall, and irregularly shaped aneurysms, as well as cases previously managed with alternative therapeutic strategies. This study additionally encompasses cases where aneurysms were managed using the WEB device in combination with supplementary endovascular devices. The study included 169 aneurysms in 161 patients. The rate of satisfactory aneurysm occlusion was 85.6%, with 86.7% of patients maintaining good functional status at their most recent follow-up. The procedure exhibited a low mortality rate of 0.6% and a thromboembolic complication rate of 7.1% (n= 12/161). There were no instances of postoperative re-rupture and the procedure-related hemorrhage rate was low (1.2%, n= 2/169), aligning with the literature regarding the safety and efficacy of the WEB device. Our multicenter trial reinforces the WEB device's role as an effective and safe modality for intracranial aneurysm management, supporting its expanded application beyond wide-necked bifurcation aneurysms. Further prospective studies are required to delineate its evolving role fully.

Large Multicenter Study Assessing the Accuracy of Molecular Testing for Cytologically Indeterminate Thyroid Nodules

Large Multicenter Study Assessing the Accuracy of Molecular Testing for Cytologically Indeterminate Thyroid Nodules

Lack of Association of TLR1 and TLR5 Coding Variants with Mortality in a Large Multicenter Cohort of Melioidosis Patients.

Melioidosis, infection caused by Burkholderia pseudomallei, is characterized by robust innate immune responses. We have previously reported associations of TLR1 single nucleotide missense variant rs76600635 with mortality and of TLR5 nonsense variant rs5744168 with both bacteremia and mortality in single-center studies of patients with melioidosis in northeastern Thailand. The objective of this study was to externally validate the associations of rs76600635 and rs5744168 with bacteremia and mortality in a large multicenter cohort of melioidosis patients. We genotyped rs76600635 and rs5744168 in 1,338 melioidosis patients enrolled in a prospective parent cohort study conducted at nine hospitals in northeastern Thailand. The genotype frequencies of rs76600635 did not differ by bacteremia status (P = 0.27) or 28-day mortality (P = 0.84). The genotype frequencies of rs5744168 did not differ by either bacteremia status (P = 0.46) or 28-day mortality (P = 0.10). Assuming a dominant genetic model, there was no association of the rs76600635 variant with bacteremia (adjusted odds ratio [OR], 0.75; 95% CI, 0.54-1.04, P = 0.08) or 28-day mortality (adjusted OR, 0.96; 95% CI, 0.71-1.28, P = 0.77). There was no association of the rs5744168 variant with bacteremia (adjusted OR, 1.24; 95% CI, 0.76-2.03, P = 0.39) or 28-day mortality (adjusted OR, 1.22; 95% CI, 0.83-1.79, P = 0.21). There was also no association of either variant with 1-year mortality. We conclude that in a large multicenter cohort of patients hospitalized with melioidosis in northeastern Thailand, neither TLR1 missense variant rs76600635 nor TLR5 nonsense variant rs5744168 is associated with bacteremia or mortality.