Rambam Health Care Campus

Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented with acute heart failure and isolated cardiomyopathy or myocarditis, between 2021 and 2023 at a single tertiary care center. A total of nine patients were included; age range: 5 days-11 years (median 42 days). Eight patients (88.8%) presented in the first year of life. The turnaround time for the ES results was 5-14 days (median 9 days). The diagnostic yield was 5/9 (55.5%), confirming primary cardiomyopathy. The majority had dominant disorders (ACTC1, MYBCP3, TNNI3, and NKX2-5), with two (22.2%) occurring de novo. One patient had a recessive condition (MYBPC3). In three patients (33.3%) who rapidly deteriorated during hospitalization, ES results had a major impact on immediate medical management. In most patients, the diagnosis led to the avoidance of further metabolic workup, cardiac magnetic imaging and vitamin treatment. In two families with no prior history of cardiomyopathy, at-risk relatives were advised to initiate cardiac surveillance. Overall the results show high clinical impact due to a shorter time to diagnosis, a high diagnostic yield, an improved therapeutic approach, in addition to the facilitation of genetic counseling for family planning and cascade testing of relatives at risk.

To describe the clinical and laboratory findings, disease course, and treatment effectiveness of a large, genetically homogenous group of patients with deficiency of adenosine deaminase 2 (DADA2), and to identify factors associated with disease-related damage. We conducted a retrospective cohort study that included 45 patients with DADA2 vasculitis with long-term follow-up. Information was collected from patients' charts, including demographic information, clinical presentations, laboratory findings, and treatment. The extent of disease-related damage was determined based on the Vasculitis Damage Index. In this large homogenous cohort, we found that a young age at disease onset and periodic illness that included recurrent episodes of fever, myalgia, and abdominal pain were associated with disease-related damage. Patients with severe DADA2 disease responded favorably to tumor necrosis factor inhibitors (TNFi). Early age of onset and the periodic nature of the disease warrant prompt initiation of TNFi treatment to prevent later complications and severe disease progression.

Abstract Most clinical large language model (LLM) benchmarks rely on clean, concise vignettes that do not reflect the noisy, long-form documentation typical of real clinical records. How LLM performance degrades under realistic chart conditions remains poorly characterised. Here we test whether structured retrieval workflows protect National Institutes of Health Stroke Scale (NIHSS) scoring accuracy under systematic context stress. Using 100 de-identified acute stroke cases and a fully crossed 4 x 4 x 3 x 3 condition matrix (144 conditions per case), we vary context acquisition method, document length, distractor load and critical-information position across four Gemini models (57,047 retained runs). Structured retrieval reduces mean absolute error (MAE) from 4.58 to 2.96 points relative to non-agentic baselines (mean gain 1.62 MAE points; 95% CI 1.57–1.67; 35% relative reduction), with consistent gains across all 36 stress combinations. Lower-cost models show disproportionately larger gains (2.76 versus 0.45 MAE points). Tool-retrieved pipelines outperform retrieval-augmented generation in 33 of 36 combinations. These findings indicate that retrieval architecture, rather than model scale alone, is a tractable lever for robust, equitable clinical LLM deployment.

The aim of this trial was to evaluate whether intravenous sodium ferric gluconate could provide benefit beyond transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis. Between 1 October 2020 and 1 July 2023, we conducted an investigator-initiated, single-center, randomized, single-blind, placebo-controlled trial enrolling patients electively admitted for TAVI due to severe symptomatic aortic stenosis. Patients were randomly assigned to receive intravenous sodium ferric gluconate or a placebo before the procedure and were followed for up to 3 months. After screening, 44 patients were included: 20 patients randomized to intravenous sodium ferric gluconate complex treatment and 24 patients to placebo. There was no difference in the baseline-adjusted 6-min walk distance between the two treatment arms (P = 0.215). Quality-of-life measures such as Kansas City Cardiomyopathy Questionnaire score and New York Heart Association class did not differ between the treatment arms. Treatment with intravenous sodium ferric gluconate did not provide clinical benefit beyond TAVI in patients with severe aortic stenosis.Clinical Trial Registration: ClinicalTrials.gov NCT04797832.

This study investigated whether earlier menopause is associated with reduced later-life cognitive performance and brain structure in a population-based cohort. It is among a few studies examining both cognition and neuroimaging within the same postmenopausal sample, and the first to test whether gray matter volume mediates the relationship between menopause timing and cognitive performance within the same sample. We analyzed data from the Cambridge Centre of Neuroscience and Aging, including 747 postmenopausal women who underwent cognitive testing. A subset was additionally tested with a fluid intelligence test and structural brain scans. Multiple linear regression models evaluated the association between menopause age, cognitive performance, and gray matter volume, controlling for chronological age, education, depressive symptoms, and physical activity. Earlier menopause was associated with lower cognitive performance ( t717 =2.2, P =0.028) and fluid intelligence ( t153 =1.59, P =0.026). Structural imaging analyses (n=182) revealed that earlier menopause was associated with decreased total gray matter volume ( t182 =0.152, P =0.024). Exploratory mediation analysis showed that total gray matter volume partially mediated the relationship between age at menopause and cognitive performance ( P =0.006). In this population-based cohort, earlier menopause was associated with both lower cognitive performance and reduced gray matter volume, suggesting a potential mechanism linking earlier menopause to cognitive decline. However, the cross-sectional nature of this study prevents causal conclusions, and longitudinal research is needed to establish causal links and explore potential targeted interventions.

BackgroundPreeclampsia (PE), a multisystem and complex disorder diagnosed when maternal hypertension manifests after 20 weeks of gestation with proteinuria, is one of the direct causes of maternal morbidity and mortality, in addition to bleeding and infection. Despite its critical impact, effective preventive dietary interventions are scarce. Oxidative stress and microvascular damage are central to PE pathophysiology. Extra virgin olive oil (EVOO), particularly early harvested EVOO (EVOOEH), is rich in antioxidant compounds and may mitigate these issues.MethodsThis randomized, single-masked (investigator and data analysis) interventional pilot study protocol will enroll 156 high-risk pregnant women (8 to 16 weeks of gestation) at Barzilai University Medical Center. Participants will be allocated to two parallel arms: the EVOOEH arm (n=78), receiving 42 mL/day (three tablespoons) of EVOOEH in addition to general Ministry of Health (MOH) dietary recommendations for 4 weeks; and the Control arm (n=78), receiving MOH dietary recommendations only. Low-dose aspirin prophylaxis will be co-administered, if indicated. Adherence will be monitored via phone calls and assessment of maternal whole blood and plasma hydroxytyrosol (HT) at recruitment and approximately four weeks post-intervention initiation. Primary outcomes are incidence of gestational diabetes mellitus (GDM), PE, Cesarean section, preterm birth, and small for gestational age (SGA) newborns. Secondary outcomes include post-intervention maternal 1-hour glucose challenge test (GCT) and serum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF), as well as maternal blood pressure, gestational age at delivery, and newborn percentile. Blood samples will be analyzed for serum 25-hydroxyvitamin D [25(OH)D], sFlt-1/PlGF ratio and HT. Statistical analysis will include use of JMP Pro software, with compared by chi-squared or Fisher’s exact tests for categorical variables and Student’s t-tests or Wilcoxon rank-sum tests for continuous variables when appropriate. Multivariate analyses will be performed for significant variables.DiscussionThis pilot study will provide crucial insights into the potential of EVOOEH as a dietary intervention for reducing PE risk in high-risk pregnancies, addressing a significant gap in current preventive strategies. This protocol study findings can inform larger-scale trials and contribute to evidence-based nutritional recommendations for PE prevention.Trial RegistrationThis study was registered on ClinicalTrials.gov (NCT06759545).

Intraoperative radiotherapy (IORT) offers single-session treatment during breast-conserving surgery (BCS). Outcomes depend heavily on patient selection and tumor characteristics. To assess local recurrence (LR) and prognosis using the 2024 American Society for Radiation Oncology (ASTRO) risk classification in IORT-treated patients. This multicenter retrospective study analyzed 358 IORT cases (356 patients) treated between 2014 and 2018 using the Zeiss INTRABEAM system. Cases were classified per the 2024 ASTRO partial-breast irradiation guidelines. The primary endpoint was local recurrence-free survival (LRFS); secondary endpoints included overall survival (OS) and mastectomy-free survival (MFS). The median age was 66 years (range 48-80); all tumors were invasive with a median tumor size of 10 mm. At a median follow-up of 7.1 years, LR occurred in 14/358 cases (3.9%) at a median of 5.2 years post-diagnosis. Five- and 8-year LRFS were 98.3% and 94.8%, respectively; 5- and 8-year OS were 99.4% and 97.7%; MFS at 8 years was 98.2%. Cases that were classified as "conditionally recommended" or "conditionally not recommended" had significantly higher LR than the "suitable" group (8.5% vs. 2.7%; HR 3.25, 95% CI 1.05-10.08, p = 0.041). Exploratory analysis showed that cases with ≥2 conditional criteria carried a markedly higher risk than those with 0-1 (21.4% vs. 3.2%; Firth-penalized Cox HR 8.26, 95% CI 2.06-26.06, p = 0.005). In appropriately selected patients, IORT achieves local control consistent with contemporary series. The 2024 ASTRO risk classification effectively identifies high-risk cases, supporting its use for risk-adapted candidate selection.

Abstract Background: Chronic pain, subjective cognitive decline (SCD) and psychosocial distress (PD) are reported by > 40-60 % of patients recovering from breast cancer (BC). We previously reported that adverse childhood experiences (ACEs) are associated with increased pain and SCD before treatment. The effect of ACEs on pain and SCD during follow up has not been explored. Methods: We are conducting a prospective study to assess if ACEs increase chronic adverse effects in patients with localized BC and identify mediating mechanisms. Patients with stage I-III BC, age 18-75 without a history of prior cancer are recruited before starting (neo)adjuvant oncological treatment and assessed every 6 months by validated questionnaires, including ACEs, the brief pain inventory, FACT-COG and FACT-ES (measuring PD). Blood samples for inflammatory biomarkers are stored. This sub-study tested if ACEs are associated with pain, measured as a composite of pain intensity and interference, SCD and PD 6 months after treatment initiation, and with changes in these symptoms over time. Results: This sub-study included 116 patients with data collected 6 months from treatment initiation. Missing data ranged from 0.9% (n = 1) in ACEs to 9.5% (n = 11) in PD at 6 months and were imputed using the expectation maximization algorithm, as data were missing completely at random, Little's MCAR test (229) = 242.51, p = .258. Of study participants, 68.1% were treated with chemotherapy, 62.9% had an academic degree, and 97.4% were employed prior to diagnosis. Univariate analysis did not detect an association between demographic or treatment factors and outcomes at 6 months (p’s > .14). Correlation analyses indicated that a higher number of ACEs was associated with more pain, SCD, and PD across time points (r range = .19 - .31, ps = < .048). A repeated-measures MANCOVA followed by Univariate analyses was conducted to examine changes over time in pain, SCD, and PD. Analyses included the number of ACEs (as a covariate), chemotherapy status (between-subjects variable), and time (within-subjects variable). The multivariate effect of time was significant, indicating that patients’ functioning declined over the 6 months, [Wilk’s lambda = .95, F (3,111) = 6.80, p < .001, partial η2 = .16]. Specifically, pain [F (1,113) = 4.59, p = .034, partial η2 = .04] and SCD [F (1,113) = 16.14, p < .001, partial η2 = .13], but not PD [F (1,113) = 3.24, p = .074, partial η2 = .03], increased between baseline and 6 months. ACEs had a significant main effect, F (3,111) = 4.81, p = .003, partial η2 = .12. , and a higher number of ACEs was associated with worse pain, higher SCD, and higher PD on both timepoints [F pain (1,113) = 13.43, p = .009, partial η2 = .11; F SCD (1,113) = 6.97, p = .009, partial η2 = .06; and F PD (1,113) = 7.96, p = .006, partial η2 = .07]. The interaction between time and ACEs was not significant (p = .210) As expected, the interaction between time and chemotherapy was significant [F (3,111) = 3.50, p = .018, partial η2 = .09; Univarite F’s (1, 113) > 4.14, p’s < 0.019, partial η2’s > .03]. Conclusion: Increasing numbers of ACEs predicts poor functioning of BC patients in terms of pain, SCD, and PD across the first 6 months post-diagnosis. Citation Format: A. Alpert, E. Sher-Cenzor, M. Makarov, A. Shai. The association between adverse childhood events and pain, subjective cognitive decline and psychosocial distress over time in patients treated for early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-07.

Abstract Background: Immunotherapy is a cornerstone in the treatment of early stage, high-risk triple-negative breast cancer (TNBC), leading to improved pathological complete response rates and overall survival. However, a substantial proportion of patients experience immune-related adverse events (irAEs), which can be severe or even life-threatening. At present, there are no validated biomarkers capable of predicting the risk of high-grade irAEs among breast cancer patients undergoing immunotherapy. While therapeutic efficacy is largely dictated by tumor-intrinsic characteristics, evidence from studies in non-small cell lung cancer (NSCLC) suggests that irAE susceptibility is significantly influenced by the host’s baseline immune status. Advances in immunological profiling have enabled the quantification of immune system function by leveraging the physiological decline in immune competence that accompanies aging. These metrics—collectively referred to as immune age—offer a clinically meaningful assessment of immune system integrity that surpass chronological age in their clinical predictive value. Methods: Peripheral serum samples were collected from 145 treatment-naıve patients with stage I-III breast cancer (age range: 28-75 years). Baseline serum concentrations of 96 inflammatory proteins were quantified using the Olink inflammation panel. To derive immune age, we trained an elastic net linear regression model with cross-validation to predict chronological age from inflammatory protein profiles in post-surgical, treatment-naıve samples (n = 57), minimizing tumor-induced immune perturbation. The trained model was then applied to the full cohort to compute immune age. Immune age acceleration was defined as the difference between immune age and chronological age. Among 33 TNBC patients treated with perioperative pembrolizumab and chemotherapy, we compared immune age acceleration at baseline between those who did and did not develop high-grade (grades 3-4) irAEs. Results: The immune-age model accurately predicted chronological age in both training (post-surgery) and test (pre-surgery) cohorts, with Pearson correlation coefficients of 0.783 and 0.628, respectively. Immune age was positively associated with increased levels of inflammatory markers including CXCL9 and CCL11 (BH-adjusted P = 0.014 and P = 0.008, respectively), consistent with known hallmarks of immune aging. Across all measured inflammatory proteins, correlations with immune age were significantly stronger than with chronological age (paired t-test, P = 2.5 × 10−10), highlighting the superior capacity of immune age to capture individual baseline inflammatory status. Immune age acceleration followed a normal distribution centered around zero with a standard deviation of 4.7 years, reflecting the high inter-individual variability in the rates of immune aging. Among TNBC patients treated with perioperative pembrolizumab (n = 33), 13 (39.4%) developed grade 3-4 irAEs. Patients who developed high-grade irAEs exhibited significantly higher immune age acceleration at baseline (prior to treatment) compared to those who did not develop irAEs (t-test, P = 0.025), while chronological age showed no significant association with irAE development (median age: 44.0 vs. 46.9 years; P = 0.26). Conclusion: Immune age acceleration is associated with increased risk of severe irAEs in early-stage TNBC and may serve as a novel predictive biomarker. This immune-aging framework offers a host-centric approach to stratify risk prior to immunotherapy initiation, with potential implications for personalized surveillance and toxicity mitigation strategies. Citation Format: A. Alpert, M. Makarov, S. Mor, D. Aran, A. Shai. Immune Age Acceleration as a Biomarker for Immune-Related Adverse Events in Early Triple-Negative Breast Cancer Treated with Perioperative Pembrolizumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD1-10.