International Centers Research Articles

Histomorphological changes in the organs of the immune system of broiler chickens when using drug Betulin

Currently, much attention is paid to maintaining the health of poultry and in this regard, the role of the immune system can hardly be overestimated. Specific protective reactions are carried out by immunocompetent cells that are located in the central and peripheral organs of the immune system. The purpose of the research was to study histomorphological changes in the thymus and Bursa fabricii of broiler chickens when using the phytodrug Betulin. The histomorphological changes in the central organs of the immune system (thymus and fabricius sac) of broiler chickens when using Betulin have been presented in the article. Betulin is a natural pentacyclic triterpenoid of the lupan series. It is found in a large number of plants (hazel, calendula, licorice), but it does not occur in free form. On an industrial scale, it is extracted from birch bark – the outer layer of the bark of white birch (Betula alba), hanging (Betula pendula). Its biological activity has been confirmed in the course of scientific research in more than forty international scientific centers. The effectiveness of using triterpene compounds as direct regulators of the activity of the body’s enzymatic systems has been demonstrated. The research was carried out in the veterinary department of poultry at Siberian Scientifi c and Research Institute of Poultry – a branch of the Federal State Budget Scientific Institution “Omsk Agrarian Scientific Center” on broiler chickens of the cross Sibiryak. The chickens of the experimental groups were used Betulin from 7–21 days, the 1st experimental group at a dose of 2,5 mg/kg of live weight, the 2nd – 5,0 mg/kg, the 3rd – 10,0 mg/kg and the 4th – 15,0 mg/kg of live weight. The poultry of the control group did not receive the phytodrug Betulin. Vaccination of chickens was carried out at the age of 7 days against Newcastle disease viruses and infectious bronchitis of chickens, at 14 days against infectious bursal disease. It was found on the base histological studies that Betulin in doses of 10,0 and 15,0 mg/kg of live weight stimulated the proliferation of lymphocytes and differentiation of the central organs of the immune system of broiler chickens.

CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History

To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date. Multicenter retrospective cohort study. Forty-seven patients (37 families) with likely disease-causing CERKL variants. Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers. Visual function, retinal imaging, and characteristics were evaluated and correlated. The mean age at the first visit was 29.6± 13.9 years, and the mean follow-up time was 9.1± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up. The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

#3670 THE ROLE OF CALCINEURIN INHIBITORS IN MONOGENIC PEDIATRIC STEROID RESISTANT NEPHROTIC SYNDROME: A RETROSPECTIVE, MULTICENTER STUDY

Abstract Background and Aims Response to calcineurin inhibitors (CNI) is associated with a significant improvement in long-term kidney survival of children with non-genetic steroid resistant nephrotic syndrome (SRNS). On the contrary, these agents are considered non-efficacious in monogenic SRNS and are contraindicated according to the latest International Pediatric Nephrology Association (IPNA) Clinical Practice Recommendations for SRNS. However, there is evidence suggesting that remission with CNI therapy in this subgroup of children with SRNS is possible, but no studies to date have assessed this question in a systematic way. We aimed to study the incidence of response to CNI in children with monogenic SRNS, factors predictive of remission and the effect of treatment on kidney survival. Method Retrospective cohort study of children 0–18 years with genetically confirmed SRNS treated with a CNI for at least 3 months. Demographic, clinical, genetic, biochemical, histopathologic and treatment data were collected at various time points; at clinical diagnosis, 6, 12, 24 months from CNI onset, and last available follow-up. Pathogenicity of all reported variants was assessed by a dedicated geneticist according to the American College of Medical Genetics guidelines and only patients with a pathogenic genotype were included in the analysis[1]. Patients were classified according to their response to CNI as complete, partial or non-responders based on the IPNA Clinical Practice Recommendations for SRNS[2]. Results 141 patients from 37 international paediatric nephrology centers were included in the study. At 6 months from CNI initiation and at last visit, 27.6% and 22.5%, respectively, demonstrated either complete or partial response (“at least partial response”). Median observation time between CNI initiation and last visit was 42.1 months (IQR 20.1–65.6) and was comparable between patients with no response and at least partial response (42.3 vs 41.6 months; P>0.05). No serious adverse effects mandating treatment discontinuation were reported. Children demonstrating at least partial response at 6 months had a lower risk of progression to kidney failure at last visit versus non-responders (hazard ratio [95%CI] 0.25, [0.10–0.62]; P = 0.003). Subgroup analysis of patients with a follow-up of at least 2 years revealed similar results with a hazard ratio of 0.35 (95%CI 0.14–0.91; P = 0.03). Of the various clinical, biochemical, genetic, histopathologic and treatment parameters tested in a multivariable logistic regression model only higher serum albumin at CNI onset was associated with higher likelihood of response at 6 months (odds ratio [95% CI] 1.16, [1.08–1.24]; P < 0.001). Conclusion Our findings suggest that CNI use could be considered in monogenic SRNS and that achievement of response in this setting can alter an otherwise dismal long-term kidney outcome.

Time to progression of disease and outcomes with second-line BTK inhibitors in relapsed/refractory mantle cell lymphoma

AbstractTime to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton’s tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.

International Validation of Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) Score in Heart Failure.

Current European heart failure (HF) Guidelines suggests the use of risk score: among them, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has demonstrated to be one of the most accurate. However, the risk scores are still poorly implemented in clinical practice, also due to lack of strong evidence regarding their external validation in different populations. Thus, the current study was designed as an external validation test of the MECKI score in an international multicentre setting. The study cohort consisted of patients diagnosed with HF with reduced ejection fraction (HFrEF) across international centres (not Italian), retrospectively recruited. Collected data included demographics, HF aetiology, laboratory testing, ECG, echocardiographic findings, cardiopulmonary exercise testing (CPET) results as described in the original MECKI score publication. 1042 patients across 8 international centres (7 European and 1 Asian) were included and followed up from 1998 till 2019. Patients were divided according to the calculated MECKI scores into 3 subgroups: (i) MECKI score <10%; (ii) 10-20%; (iii) ≥20%. Survival analysis comparison among the 3 MECKI score subgroups showed a worse prognosis in patients with higher MECKI score value: median event-free survival times were 4396 days for MECKI score <10%; 3457 days for 10-20%; 1022 days for ≥20% (p<0.0001). ROC curves and the AUC curves were like those reported in the original internal validation studies. In patients diagnosed with HFrEF, the power of the MECKI score was confirmed in terms of prognosis and risk stratification, supporting its implementation as advised by the HF Guidelines.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

تأثير مراكز الأبحاث في المفاوضات السياسيّة بشأن حل الصراعات والنزاعات المفاوضات الفلسطينيّة-الإسرائيليّة أنموذجًا

The study aims to shed light on the impact of research centers on political negotiations related to resolving conflicts, with a focus on their influential role in the Palestinian-Israeli negotiations. The study dealt with practical examples of influential roles played by international, regional, Palestinian and Israeli research centers in those negotiations, and suggested a practical vision for establishing a research center specialized in negotiation affairs, to serve the Palestinian issue and its resistance project. The study used the descriptive analytical approach. The study's results: that research centers play an important role in negotiations to resolve the conflict, and that Western and Israeli centers have a major role in the Palestinian-Israeli negotiations and influencing their results, and the role of Arab and Palestinian centers was characterized by weakness in playing such roles. The study recommended: The need to improve and pay attention to what the research centers produce, and to open effective channels between the Palestinian centers with each other, and with other Arab and international centers, in order to support the Palestinian issue in all international forums.

The impact of coronary calcium score as an addition to myocardial perfusion imaging in altering clinical management (ICCAMPA trial)

Introduction: AimMyocardial perfusion imaging (MPI) is a key tool for the identification and risk stratification of patients with coronary artery disease. The use of a coronary calcium score further adds to prognostic data above MPI alone. In this study, our aim was to evaluate the extent to which the use of a coronary artery calcium (CAC) score, when co-reported with MPI, impacts changes in clinical management in patients without a history of coronary artery disease (CAD) undergoing functional imaging. MethodsThis is a multicenter international study which incorporated a standardized questionnaire to evaluate changes in clinician management after MPI results were given with and without the additional information of a CAC score. Calcium scoring on a SPECT-CT system was performed via a semiquantitative Shemesh score (0-12) with a 0-3 score from the left main, left anterior descending, left circumflex, and right coronary arteries. CT of the chest was read independently, and non-coronary findings were reported alongside the CAC score. ResultsA total of 281 patients were enrolled across 3 international centers (Brazil, Australia, New Zealand). Of the 281 patients, 133 (47%) had management altered after the clinician was made aware of the CAC score. The impact of the CAC in changing clinical management was significant, particularly in patients with a negative MPI (P < 0.0001), but also in MPI-positive patients (P = 0.0021). The most common management change was the addition or intensification of statin therapy. ConclusionThe addition of the CAC component to MPI yielded significant management changes in nearly half of all patients undergoing MPI for suspected CAD. This trend was observed across all centers in the three countries involved and was particularly evident in patient with a negative MPI.

The RAINBO MMRd-GREEN trial (GCIG/DGOG/ENGOT-EN142): A phase III trial on the addition of adjuvant durvalumab to radiotherapy in patients with high-risk MMRd endometrial cancer.

TPS5633 Background: The molecular class of endometrial cancer (EC) is both prognostic and predictive in high-risk EC (HREC). The TransPORTEC research consortium showed that patients with MMRd HREC did not benefit from adjuvant chemotherapy added to radiotherapy. MMRd tumors are particularly sensitive to immunotherapy. We hypothesize that adjuvant durvalumab added to standard radiotherapy will increase recurrence-free survival (RFS) in patients with MMRd HREC. Methods: MMRd-GREEN is an international, open-label, randomized phase III trial and part of the RAINBO program (NCT05255653). Eligible patients will be allocated (1:1) to adjuvant durvalumab 1500 mg once every 4 weeks for 1 year combined with radiotherapy or standard radiotherapy alone. The primary endpoint is RFS at 3 years. Secondary endpoints are pelvic, vaginal and distant RFS, EC-specific survival, overall survival, treatment-related toxicity, health-related quality of life and exploratory translational research . Main inclusion criteria include histologically confirmed stage IB/II with (substantial) lymph-vascular space invasion (LVSI) or stage IIIA-C MMRd EC, after hysterectomy and bilateral salpingo-oophorectomy (regardless of lymphadenectomy or sentinel lymph node biopsy) without macroscopic residual disease. Molecular classification must be performed according to the WHO 2020 algorithm. The target accrual is 316 patients, accounting for a total drop-out rate of 12%. This sample size yields 80% power to detect a 13% increase in the 3-year RFS (hazard ratio 0.58) as a result of the addition of durvalumab, with an accrual duration of 48 months and follow-up period of 30 months. No interim analysis is planned; an independent data monitoring committee will routinely monitor recurrences and adverse events. Enrollment: Since August 2022, the trial is open for recruitment in the Netherlands and per February 10th 2023, the first 3 patients have been enrolled. Activation of more international centers is ongoing. Clinical trial information: NCT05255653 .

Factors Affecting C5 Viability and Demographic Variability in Two Brachial Plexus Centers.

A retrospective study of 200 consecutive patients with complete brachial plexus injuries at two international centers (Mayo Clinic in the United States and Chang Gung Memorial Hospital in Taiwan) was performed. Demographic information, concomitant injuries, mechanism, and details of the injury were determined, and kinetic energy (KE) and Injury Severity Score were calculated. C5 nerve root was evaluated by preoperative imaging, intraoperative exploration, and/or intraoperative neuromonitoring. A spinal nerve was considered viable if it was grafted during surgery. Complete five-nerve root avulsions of the brachial plexus were present in 62% of US and 43% of Taiwanese patients, which was significantly different. Increasing age, the time from injury to surgery, weight, body mass index of patient, motor vehicle accident, KE, Injury Severity Score, and presence of vascular injury significantly increased the risk of C5 avulsion. Motorcycle (≤150cc) or bicycle accident decreased the risk of avulsion. Significant differences were found between demographic variables between the two institutions: age of injury, body mass index, time to surgery, vehicle type, speed of injury, KE, Injury Severity Score, and presence of vascular injury. The rate of complete avulsion injury was high in both centers. Although there are a number of demographic differences between the United States and Taiwan, overall the KE of the accident increased the risk of C5 avulsion.

Diagnostic accuracy of optical flow ratio: an individual patient-data meta-analysis.

Optical flow ratio (OFR) is a novel method for the fast computation of fractional flow reserve (FFR) from optical coherence tomography. We aimed to evaluate the diagnostic accuracy of OFR in assessing intermediate coronary stenosis using wire-based FFR as the reference. We performed an individual patient-level meta-analysis of all available studies with paired OFR and FFR assessments. The primary outcome was vessel-level diagnostic concordance of the OFR and FFR, using a cut-off of ≤0.80 to define ischaemia and ≤0.90 to define suboptimal post-percutaneous coronary intervention (PCI) physiology. This meta-analysis was registered in PROSPERO (CRD42021287726). Five studies were finally included, providing 574 patients and 626 vessels (404 pre-PCI and 222 post-PCI) with paired OFR and FFR from 9 international centres. Vessel-level diagnostic concordance of the OFR and FFR was 91% (95% confidence interval [CI]: 88%-94%), 87% (95% CI: 82%-91%), and 90% (95% CI: 87%-92%) in pre-PCI, post-PCI, and overall, respectively. The overall sensitivity, specificity, and positive and negative predictive values were 84% (95% CI: 79%-88%), 94% (95% CI: 92%-96%), 90% (95% CI: 86%-93%), and 89% (95% CI: 86%-92%), respectively. Multivariate logistic regression indicated that a low pullback speed (odds ratio [OR] 7.02, 95% CI: 1.68-29.43; p=0.008) was associated with a higher risk of obtaining OFR values at least 0.10 higher than FFR. Increasing the minimal lumen area was associated with a lower risk of obtaining an OFR at least 0.10 lower than FFR (OR 0.39, 95% CI: 0.18-0.82; p=0.013). This individual patient data meta-analysis demonstrated a high diagnostic accuracy of OFR. OFR has the potential to provide an improved integration of intracoronary imaging and physiological assessment for the accurate evaluation of coronary artery disease.

Решение международного коммерческого арбитража и основания для его отмены: сравнительно-правовой анализ регулирования в России и Сингапуре

The purpose of the article is to conduct a comparative analysis of the processes for issuing, amending and supplementing awards by institutional international commercial arbitrations in the Russian Federation and Singapore, as well as reviewing the legal regulation of the setting aside the arbitral awards and current trends in judicial practice in this area in these states. The mechanism of returning an arbitral award by state courts for consideration within the framework of arbitration is analyzed in the article. This paper examines the provisions of the national legislation of the Russian Federation and Singapore governing the issues of international commercial arbitration, as well as the regulations of institutional arbitration organizations represented by the International Commercial Arbitration Court at the Chamber of Commerce and Industry of the Russian Federation and Singapore International Arbitration Center; analyzes the unified norms of international law, as well as the practice of state courts and international commercial arbitration centers of the Russian Federation and Singapore. The process of an arbitral award issuing in the institutional international arbitrations of the Russian Federation and Singapore has a number of features that may indirectly affect the outcome of the dispute. The legislation of Singapore also contains additional (compared to generally accepted) grounds for the setting aside an arbitral award — fraudulent or corrupt motives; violation of the fundamental principle of natural justice, while specific approaches to the essence of these grounds were developed by judicial practice. Of particular interest is the developed pro-arbitration active position of the state court of Singapore regarding the possibility of returning an arbitration dispute from the state court to arbitration, as well as the criteria for such return.

Characterizing KRAS allele variants within biliary tract cancers.

4088 Background: Biliary tract cancers (BTC) are aggressive malignancies with a poor 5-year survival rate and growing incidence globally. KRAS mutations (mut) in BTC are associated with a poor prognosis; however, PD-L1 inhibition with Durvalumab may lead to an improved survival with KRAS mut (TOPAZ-1 trial). It is important to understand the genomic landscape and immunophenotype of KRAS mut in BTC given the advent of immunotherapeutics and small molecular inhibitors targeting KRAS mut. Methods: A retrospective pooled analysis was performed from the following patient databases: Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, along with the publicly accessible cBioPortal for Cancer Genomics that includes the American Association for Cancer Research Project Genie cancer registry of real-world data assembled between 19 leading international cancer centers. Any overlapping cases were excluded. Patients included had a diagnosis of a BTC and completed molecular testing from January 2017 to December 2022. Cohort demographics, KRAS allelic variants, concurrent genetic aberrations, and immune biomarkers (PD-L1, TMB, MSI and gLOH) were summarized. Log-rank, Wilcoxon, and Kaplan-Meier tests were conducted for survival analysis. Results: 5,813 BTC patients were included, and 1000 patients (17.2%) had a KRAS mutation. The prevalence of KRAS mut was higher in extra-hepatic cholangiocarcinoma (EH-CCA) (36.1%) and perihilar (PH)-CCA (28.6%) than in intra-hepatic (IH)-CCA (11.82%) and gallbladder cancer (GBC) (7.6 %). The most common KRAS allelic variant was G12D, and the most common co-mutation was TP53, except in PH-CCA, which was G12V and SMAD4, respectively. In this cohort, race was primarily White (73%). The most prevalent variant in North America was G12D, while G12V and Q61H were more prevalent with genomic African American and genomic East Asian descent, respectively. For patients with KRAS mut, GBC had the most PD-L1 high positivity (17%) compared to IH-CCA (7%) and EH-CCA (3%), along with the most MSI-H phenotypes and the highest mean and median TMB compared to other sites, especially in G12V and Q61H variant patients. Genomic loss of heterozygosity was low among all groups. In the survival analysis, patients with the G12V allele subtype had the lowest OS at 17.8 months, followed by Q61H (22.8 months) and G12D (25.1 months) (p = 0.022). Survival analysis with KRAS co-mut ( TP53, SMAD4, CDK2NA, or additional KRAS mut) was not significant (p = 0.7). In a co-variance analysis of KRAS variants and tumour site, there was no difference in IH-CCA and GBC but lower OS in Q61H variants in PH-CCA and G12V variants in EH-CCA (p = 0.0081). Conclusions: This large series adds to the growing body of comprehensive genomic and immune landscape data of KRAS mut in BTC and will be of value in planning specific therapies in this heterogeneous group. Immune profiling studies are ongoing to further describe the immunophenotype of this subset.

0431 Different physiological characteristics of obstructive sleep apnea symptom subtypes across international sleep centers

Abstract Introduction Obstructive Sleep Apnea (OSA) is a widespread and heterogeneous sleep disorder. Studies have identified reproducible subtypes of OSA based on patient-reported symptoms that have different cardiovascular outcomes. Prior data showed similar apnea-hypopnea index (AHI) across subtypes; however, other physiological characteristics have not been comprehensively compared among these subtypes. Methods 1,285 participants from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC) with moderate-severe OSA (AHI≥15) were included. Differences in traditional and novel physiological traits were compared among the Disturbed Sleep (n=183 [14.2%]), Minimally Symptomatic (n=581 [45.2%]), and Excessively Sleepy (n=521 [40.5%]) subtypes using analysis of covariance (ANCOVA) adjusted for age, sex, BMI and race/ethnicity. Measures included AHI and other respiratory event indices, hypoxic burden, oxygen characteristics, sleep/wake amounts, electroencephalogram (EEG) spectral characteristics, including metrics related to the odds ratio product (ORP; a validated index of sleep depth ranging from 0.0 [deep sleep] to 2.5 [full wakefulness]), arousal intensity, and heart rate response to arousal. Results Compared to other subtypes, the Disturbed Sleep subtype demonstrated increased wakefulness (more wake time [p&amp;lt; 0.001] and wake after sleep onset [p=0.001]), higher beta frequency EEG power (14.33-20.0 Hz [p=0.025] and 20.33-35.0 Hz [p=0.004]), and less deep sleep (higher average [p=0.001] and NREM-specific [p=0.044] ORP, less time with ORP from 0.50-0.75 [p=0.004] and 0.75-1.00 [p=0.015], and more time from 2.20-2.25 [p=0.017] and 2.25-2.50 [p=0.0005]). The Excessively Sleepy subtype had more severe hypoxemia, including greater hypoxic burden (p=0.002) and lower average SpO2 (p=0.002) and minimum SpO2 (p=0.0002) compared to other subtypes. Conclusion Differences in physiological characteristics, including ORP-related traits, were observed among symptom subtypes. Results suggest that characteristics indicative of increased wakefulness may distinguish those with the Disturbed Sleep subtype, whereas more severe hypoxemia may characterize the Excessively Sleepy subtype. Future investigations into underlying molecular causes of symptom subtypes, particularly the Excessively Sleepy, are warranted given evidence of associations with outcomes such as cardiovascular disease. Support (if any) SAGIC Investigators (Ayas N, Chen NH, Cistulli P, de Chazal P, Gislason TG, Han F, Hirsch-Allen AJ, Keenan BT, Li QY, Magalang UJ, Maislin G, Mazzotti DR, McArdle N, Mindel J, Pack AI, Penzel T, Schwab RJ, Singh B, Sutherland K); NIH P01 HL094307

Development and Validation of Prediction Models and Risk Calculators for Posthepatectomy Liver Failure and Postoperative Complications Using a Diverse International Cohort of Major Hepatectomies.

The study aim was to develop and validate models to predict clinically significant posthepatectomy liver failure (PHLF) and serious complications [a Comprehensive Complication Index (CCI)>40] using preoperative and intraoperative variables. PHLF is a serious complication after major hepatectomy but does not comprehensively capture a patient's postoperative course. Adding the CCI as an additional metric can account for complications unrelated to liver function. The cohort included adult patients who underwent major hepatectomies at 12 international centers (2010-2020). After splitting the data into training and validation sets (70:30), models for PHLF and a CCI>40 were fit using logistic regression with a lasso penalty on the training cohort. The models were then evaluated on the validation data set. Among 2192 patients, 185 (8.4%) had clinically significant PHLF and 160 (7.3%) had a CCI>40. The PHLF model had an area under the curve (AUC) of 0.80, calibration slope of 0.95, and calibration-in-the-large of -0.09, while the CCI model had an AUC of 0.76, calibration slope of 0.88, and calibration-in-the-large of 0.02. When the models were provided only preoperative variables to predict PHLF and a CCI>40, this resulted in similar AUCs of 0.78 and 0.71, respectively. Both models were used to build 2 risk calculators with the option to include or exclude intraoperative variables ( PHLF Risk Calculator; CCI>40 Risk Calculator ). Using an international cohort of major hepatectomy patients, we used preoperative and intraoperative variables to develop and internally validate multivariable models to predict clinically significant PHLF and a CCI>40 with good discrimination and calibration.

International cohort of 382 children with lupus nephritis - presentation, treatment and outcome at 24months.

Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients. We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10years in 23 international centers. The mean age at onset was 11years 9months and 72.8% were females. Fifty-seven percent and 34% achieved complete and partial remission at 24-month follow-up, respectively. Patients with LN class III achieved complete remission more often than those with classes IV or V (mixed and pure). Only 89 of 351 patients maintained stable complete kidney remission from the 6th to 24th months of follow-up. eGFR ≥ 90ml/min/1.73m2 at diagnosis and biopsy class III were predictive of stable kidney remission. The youngest and the oldest age quartiles (2y-9y,5m) (14y, 2m-18y,2m) showed lower rates of stable remission (17% and 20.7%, respectively) compared to the two other age groups (29.9% and 33.7%), while there was no difference in gender. No difference in achieving stable remission was found between children who received mycophenolate or cyclophosphamide as induction treatment. Our data show that the rate of complete remission in patients with LN is still not high enough. Severe kidney involvement at diagnosis was the most important risk factor for not achieving stable remission while different induction treatments did not impact outcome. Randomized treatment trials involving children and adolescents with LN are needed to improve outcome for these children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Comparison of Left Bundle Branch Area Pacing and Biventricular Pacing in Candidates for Resynchronization Therapy

BackgroundCardiac resynchronization therapy (CRT) with biventricular pacing (BVP) is a well established therapy in patients with reduced left ventricular ejection fraction (LVEF), heart failure, and wide QRS or expected frequent ventricular pacing. Left bundle branch area pacing (LBBAP) has recently been shown to be a safe alternative to BVP. ObjectivesThe aim of this study was to compare the clinical outcomes between BVP and LBBAP among patients undergoing CRT. MethodsThis observational study included patients with LVEF ≤35% who underwent BVP or LBBAP for the first time for Class I or II indications for CRT from January 2018 to June 2022 at 15 international centers. The primary outcome was the composite endpoint of time to death or heart failure hospitalization (HFH). Secondary outcomes included endpoints of death, HFH, and echocardiographic changes. ResultsA total of 1,778 patients met inclusion criteria: 981 BVP, 797 LBBAP. The mean age was 69 ± 12 years, 32% were female, 48% had coronary artery disease, and mean LVEF was 27% ± 6%. Paced QRS duration in LBBAP was significantly narrower than baseline (128 ± 19 ms vs 161 ± 28 ms; P < 0.001) and significantly narrower compared to BVP (144 ± 23 ms; P < 0.001). Following CRT, LVEF improved from 27% ± 6% to 41% ± 13% (P < 0.001) with LBBAP compared with an increase from 27% ± 7% to 37% ± 12% (P < 0.001) with BVP, with significantly greater change from baseline with LBBAP (13% ± 12% vs 10% ± 12%; P < 0.001). On multivariable regression analysis, the primary outcome was significantly reduced with LBBAP compared with BVP (20.8% vs 28%; HR: 1.495; 95% CI: 1.213-1.842; P < 0.001). ConclusionsLBBAP improved clinical outcomes compared with BVP in patients with CRT indications and may be a reasonable alternative to BVP.

Prognostic factors in undifferentiated uterine sarcoma: a subanalysis of the SARCUT study.

The aim of this study was to analyze the prognostic factors related to the recurrence rate and overall survival of patients with undifferentiated uterine sarcoma. An international multicenter study involving 43 international centers, the SARCUT study, collected 966 uterine sarcoma cases; among them 39 cases corresponded to undifferentiated uterine sarcoma and where included in the present subanalysis. The risk factors related to the oncological outcomes where analyzed. The median age of the patients was 63 (range 14-85) years. Seventeen (43.5%) patients presented FIGO stage I. The 5-year overall survival (OS) was 15.3% and 12-months disease-free survival (DFS) 41%. FIGO stage I was significantly associated with a better prognosis. In addition, patients who received adjuvant radiotherapy showed significant longer disease-free survival compared to those without adjuvant radiotherapy (20.5 vs. 4.0months, respectively; p = 0.04) and longer overall survival (34.7 vs. 18.2months, respectively; p = 0.05). Chemotherapy administration was associated with shorter DFS (HR 4.41, 95% CI 1.35-14.43, p = 0.014). Persistent disease after primary treatment (HR = 6.86, 95% CI 1.51-31.09, p = 0.012) and FIGO stage IV (HR 4.12, 95%CI 1.37-12.44, p = 0.011) showed significant worse prognosis for OS. FIGO stage seems to be the most important prognostic factor in patients with undifferentiated uterine sarcoma. Adjuvant radiotherapy seems to be significantly associated also to a better disease-free and overall survival. On the contrary, the role of chemotherapy administration remains unclear since was associated to a shorted DFS.

Asymptomatic Allograft Fibrosis in Pediatric Liver Transplantation: Potential Clinical Implications.

Asymptomatic Allograft Fibrosis in Pediatric Liver Transplantation: Potential Clinical Implications.

Impact of body mass index on the difficulty and outcomes of laparoscopic left lateral sectionectomy

IntroductionCurrently, the impact of body mass index (BMI) on the outcomes of laparoscopic liver resections (LLR) is poorly defined. This study attempts to evaluate the impact of BMI on the peri-operative outcomes following laparoscopic left lateral sectionectomy (L-LLS). MethodsA retrospective analysis of 2183 patients who underwent pure L-LLS at 59 international centers between 2004 and 2021 was performed. Associations between BMI and selected peri-operative outcomes were analyzed using restricted cubic splines. ResultsA BMI of >27kg/m2 was associated with increased in blood loss (Mean difference (MD) 21 mls, 95% CI 5–36), open conversions (Relative risk (RR) 1.13, 95% CI 1.03–1.25), operative time (MD 11 min, 95% CI 6–16), use of Pringles maneuver (RR 1.15, 95% CI 1.06–1.26) and reductions in length of stay (MD -0.2 days, 95% CI -0.3 to −0.1). The magnitude of these differences increased with each unit increase in BMI. However, there was a “U” shaped association between BMI and morbidity with the highest complication rates observed in underweight and obese patients. ConclusionIncreasing BMI resulted in increasing difficulty of L-LLS. Consideration should be given to its incorporation in future difficulty scoring systems in laparoscopic liver resections.