Hadassah

IntroductionArtificial rupture of membranes (AROM) is a common intervention during delivery, usually done in order to expedite delivery. Studies to determine optimal timing of AROM according to cervical dilation were inconclusive. However, other important factors, which are known to be associated with timing of delivery were ignored. One of these factors is fetal head station (FHS). We sought to investigate the association between FHS during AROM and time to delivery and other obstetrical outcomes.Material and methodsA retrospective cohort study encompassing data from labors during a 12-year period were analyzed. All cases of singleton, term pregnancy with documented AROM time were included. The study population was stratified by parity.ResultsThis study cohort included 45,898 singleton, term vaginal delivery parturients with time stamp at time of AROM and delivery. Stratification by parity yielded 11,947 primiparas (26%) and 33,951 multiparas (74%). Across all sub-cohorts, as fetal head station decreased at AROM the duration from ROM to delivery was shorter. This trend seems to be stronger for multiparas than primiparas. Rates of cesarean delivery, postpartum hemorrhage, neonatal intensive care unit admission, and low 5-min Apgar scores were also negatively associated with decrease in fetal head station at AROM across all cervical dilations.ConclusionLower fetal head station at AROM is associated with shorter time to delivery as well as lower rates of cesarean delivery, postpartum hemorrhage, NICU admission, and 5-min Apgar ≤ 7. Fetal head station should be considered alongside cervical dilation during AROM. Our findings underscore the necessity for personalized timing of AROM, especially in multiparous women, to enhance maternal and neonatal health outcomes.

Abstract The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.

Abstract Purpose: To evaluate 25-year national trends in pediatric intensive care utilization, patient outcomes, rehospitalizations, and regional resource distribution in Israel. Methods: Retrospective, population-based cohort study of all acute pediatric (0–17 years) hospitalizations in Israel from January 1, 1999, to December 31, 2023 (≈ 180 000 admissions), excluding neonatal and maternity ICU stays. We linked the National Hospital Discharge Register with pediatric ICU bed capacity data and Central Bureau of Statistics population estimates. Outcomes included age-adjusted ICU admission rates, in-hospital and one-year post-discharge mortality, rehospitalization at 7, 30, and 365 days, and pediatric ICU beds per 100 000 children. Trends were assessed in five-year intervals using SAS 9.4. Results: The proportion of hospitalizations involving ICU care increased from 3.3–6.5%. In-hospital mortality among ICU patients declined from 3.8–1.4% (63.2% relative reduction), and one-year post-discharge mortality decreased from 3.0–1.9% (36.7% relative reduction). One-year rehospitalization occurred in 46% of ICU survivors versus 29% of non-ICU patients (20% vs 3% requiring subsequent ICU). Between 2018 and 2023, national pediatric ICU bed capacity rose by 23%, yet regional bed-to-population ratios varied up to 2.6-fold. Conclusions: Over 25 years, Israeli pediatric ICU utilization and capacity nearly doubled, accompanied by marked reductions in mortality. However, persistently high rehospitalization rates and pronounced regional disparities underscore the need for structured post-ICU follow-up, standardized admission criteria, equitable resource allocation, and further research to clarify drivers of ICU utilization and long-term outcomes. Limitations include reliance on administrative data lacking individual illness-severity measures.

Abstract Objective To assess inter-specialty differences in the management of febrile neonates receiving prostaglandin E1 (PGE1) for duct-dependent congenital heart disease. Study Design A cross-sectional, web-based survey was distributed to 800 neonatologists and pediatric cardiac intensivists in North America, Europe, and the Middle East. Respondents (n=526) were queried regarding their management of a clinical vignette involving a febrile neonate on PGE1, including decisions about sepsis work-up, antibiotic administration, and lumbar puncture. Data were analyzed using chi-square tests and multivariate logistic regression. Result Pediatric cardiac intensivists were significantly more likely to initiate full sepsis work-up and antibiotic therapy (65.6% vs. 38.7%, p<0.001). Specialty was the only significant predictor of antibiotic administration (OR=3.07, 95% CI: 1.76–4.40, p<0.001). No significant differences were found in lumbar puncture practices. Conclusion Significant inter-specialty variation exists in the management of febrile neonates on PGE1, highlighting the need for evidence-based guidelines to standardize care and optimize antimicrobial stewardship.

Abstract Background Critically-ill patients are at increased risk for cytomegalovirus (CMV) reactivation, associated with adverse clinical outcomes. Given the surge in intensive care unit (ICU) admissions during the COVID-19 pandemic and the continued burden of critical illness associated with the ongoing circulation of SARS-CoV-2, we sought to resolve risk factors for CMV reactivation and disease within the broader ICU patient population including those with and without COVID-19, to identify common and potentially distinct contributors to CMV reactivation and disease in this vulnerable setting. Methods This prospective study included 160 adult ICU (78 COVID-19, and 82 concomitant non-COVID-19) patients, monitored weekly for CMV DNAemia. CMV reactivation was defined as any detectable DNAemia or as clinically-significant reactivation (high-level, ≥ 10,000 copies/mL DNAemia, and/or CMV disease). Results Overall, 30.6% of ICU patients experienced CMV reactivation, with 10% exhibiting clinically-significant reactivation. COVID-19 ICU patients had significantly higher rates of any CMV reactivation (41% vs. 20.7%, p = 0.006), high-level DNAemia (15.3% vs. 1.2%, p = 0.001), and CMV disease (8.9% vs. 1.2%, p = 0.029) compared to concomitant non-COVID-19 patients. Risk factors associated with clinically-significant CMV reactivation in ICU patients included septic shock, lower absolute lymphocyte count, high-dose steroid use, multiple blood transfusions, and COVID-19. CMV reactivation correlated with prolonged ventilation and ICU stay, and increased in-hospital mortality. Conclusion The high rates of clinically-significant CMV reactivation in both COVID-19 and non-COVID-19 ICU patients and the identified risk factors, along with the worse clinical outcomes linked to CMV reactivation, highlight the need for vigilant monitoring of CMV reactivation and for consideration of early antiviral treatment in ICU patients at risk, and support future interventional trials.

Abstract Background: IDH-wildtype glioblastoma (GBM) is an aggressive, heterogeneous brain tumor with limited treatment options. This study tries to improve our understanding of GBM by applying DNA methylation-based deconvolution to define its cellular composition and its association with patient outcomes. Methods: We generated oligodendroglial precursor cells at various developmental stages from enriched human neural progenitor cultures and used their DNA methylation signatures, along with published signatures of cells types relevant to brain tumors and the tumor microenvironment, to deconvolve 263 adult GBMs (Heidelberg cohort). Tumor purity was estimated using RF_Purify. An independent cohort of 199 GBMs from TCGA and GEO, all treated with standard-of-care therapy, was similarly deconvolved, followed by Kaplan–Meier survival analysis to assess the prognostic value of the proportions of the neoplastic components. Results: Deconvolution uncovered distinct cellular compositions that differed between the neoplastic and non-neoplastic components of GBM. Tumor purity analysis showed that the neoplastic fractions averaged 70% of the tumor bulk: they were predominantly oligodendrocyte-like (43%), along with oligodendrocyte precursor-like (27%), astrocyte-like (19%), and mesenchymal stem cell-like (11%) populations. The non-neoplastic fractions were enriched for macrophages, vascular cells, and immune cell populations. A higher oligodendrocyte-like signature was linked to poorer survival (median survival 14.3 vs. 15.3 months; p = 0.017), while a higher astrocyte-like signature correlated with improved survival (15.3 vs. 13.4 months; p = 0.044). The astrocyte-to-oligodendrocyte ratio emerged as a strong prognostic marker, with a higher ratio predicting significantly longer survival (15.8 vs. 11.9 months; p < 0.00011). Conclusions: The methylation-based deconvolution data provided insight into GBM heterogeneity, highlighting the prognostic relevance of the astrocyte-to-oligodendrocyte ratio and its potential to guide personalized treatment strategies.

Medical schools rely on tests for the applicants' academic and nonacademic attributes to select students. The former is based on evidence that students with top past academic achievements outperform other students during the clerkship rotations. Testing for nonacademic attributes responds to the expectation that those selected will perform better as physicians than those chosen by academic standards alone. However, even if nonacademic attributes do contribute to identifying applicants with improved later performance, I believe that their use should be re-examined for two reasons. First, applicants rejected because of poor past academic achievements would understand why they were not admitted. Not so those who "fail" nonacademic tests: their rejection may affect their self-esteem. I am concerned that my profession, guided by the principle of "do no harm," does not consider the harm of admission processes that purport to select virtuous applicants. Second, society needs not only clinicians but also physicians with other subspecialties that require different qualities: compassion is important for people-oriented professions, but less so for technology-oriented professions. Therefore, the selection of medical students that is solely based on their past academic performance would be not only less expensive, but also more responsive to societal needs, and more consistent with the ethical requirement to not harm.

This study aims to assess the impact of war-related psychological stress on multiple sclerosis (MS) activity using magnetic resonance imaging (MRI) scans and clinical follow-up.

Background: Most newly developed anticancer treatments trigger tumor cell death through apoptosis, for which involvement of caspases activity is essential. However, numerous mutations in apoptotic pathways that lead to cancer and favor resistance to apoptosis are known; most are related to caspase-dependent apoptosis pathways and thus have low efficacy. To overcome these limitations, we constructed a novel chimeric protein, GnRH-AIF, using a gonadotropin-releasing hormone (GnRH) analog as a targeting moiety and the apoptosis-inducing factor (AIF) in its cleaved form as a killing moiety, fused at the cDNA level. AIF has a crucial role in the caspase-independent apoptotic pathway. A wide variety of solid tumors overexpress GnRH-receptors (GnRH-R) that are targeted by the new GnRH-AIF chimeric protein. Methods and Results: In this study, we constructed, expressed, and highly purified GnRH-AIF chimeric proteins. We demonstrated the ability of the chimera to enter and specifically and very efficiently kill solid cancer cell lines overexpressing GnRH-R. Most importantly, upon its entry, GnRH-AIFs translocate to the nucleus where it causes DNA fragmentation leading to a direct caspase-independent apoptotic death. As AIFs lack nuclease activity, our findings also emphasize that cell death induced by GnRH-AIF is dependent on the presence of the ENDOG and PPIA proteins, known to participate in the formation of a DNA-degradosome complex. Finally, we demonstrated the high anti-tumor efficacy of the GnRH-AIF ex vivo, in a human, colon cancer organoid model. Conclusions: Our study shows the potential of using a GnRH-AIF chimeric protein as a novel approach to treat solid cancers that overexpress GnRH-R, via a caspase-independent apoptotic pathway.