The Shaare Zedek Medical Center (Hebrew: מרכז רפואי שערי צדק, Merkaz Refu'i Sha'arei Tzedek) (lit. "Gates of Justice") is a major hospital in Jerusalem established in 1902.
In 2024, a comprehensive framework for the screening, diagnosis, and management of metabolic dysfunction–associated steatotic liver disease (MASLD) was incorporated in the EASL-EASD-EASO clinical practice guidelines. However, physicians often face barriers applying these recommendations in routine clinical care, especially in the Southeastern Europe, Middle East, and Africa (SEEMEA) region. As a multidisciplinary group of physicians involved in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) management, our objective is to provide a practice-oriented roadmap including practical and educational considerations beyond the hepatology field that could improve patient care and support implementation of clinical guidance within the SEEMEA region. This work is informed by a narrative review and expert input obtained through structured discussions, to examine the status quo and identify key gaps in the MASLD/MASH management, unravelling the patient journey from screening and diagnosis to treatment and follow-up. Furthermore, we advise on priorities on screening triggers and, considering the limited availability of vibration-controlled transient elastography (VCTE), discuss alternative approaches to achieve accurate and timely diagnosis. Finally, following the approval of resmetirom and semaglutide 2.4 mg for MASH treatment, we review the evolving pharmacotherapy landscape and propose a “blueprint” for a specialised MASLD clinic, suggesting mandatory and optional facilities for optimised care.
BACKGROUND:Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL) but carries a risk of severe neurotoxicity. In a single-arm study, a regimen with methotrexate, procarbazine, vincristine, and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we sought to evaluate the efficacy of R-MPV-A with and without LD-WBRT, as well as determining if such low radiotherapy doses influenced disease control and/or neurotoxicity. METHODS:Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha = 0.15). RESULTS:Ninety-one patients were randomized, with 44 analyzed in the ChemoRT and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated, achieving a complete response rate of 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR = 0.47 (P = .007; 95% CI, 0.26-0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR = 0.71; P = .33). Neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT. CONCLUSIONS:R-MPV-A is a highly efficacious and safe regimen with or without LD-WBRT. LD-WBRT contributes to disease control and increases PFS in PCNSL.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by core behavioral symptoms. We previously showed that nitric oxide (NO) plays a key role in ASD. However, the precise molecular mechanism through which NO acts via its posttranslational modification, S-nitrosylation (SNO), in ASD remains largely unknown. Emerging evidence, including our previous studies, suggests that the mechanistic target of the rapamycin (mTOR) signaling pathway plays a critical role in ASD pathophysiology. Our SNO-proteome systems biology analysis showed the enrichment of the mTOR pathway. In this study, we deciphered a novel mechanism of the cross talk between NO and mTOR pathway using two well-established mouse models as well as clinical samples of children with ASD. To assess changes in the SNO-proteome, we used the SNOTRAP method, revealing increased S-nitrosylation of tuberous sclerosis complex 2 (TSC2) in Shank3Δ4–22 and Cntnap2(-/-) mutant mice. We proved that this modification led to the loss of TSC2 protein via ubiquitination, resulting in dysregulated mTOR signaling in both excitatory and inhibitory neurons. Pharmacological inhibition of neuronal nitric oxide synthase (nNOS) successfully prevented TSC2 S-nitrosylation, mTOR overactivation, and altered protein translation in ASD models, highlighting NO’s role in modulating mTOR function. To further validate the role of TSC2 S-nitrosylation in ASD, we generated a cysteine-to-serine mutation (C203S) in TSC2 to prevent its S-nitrosylation. Intracranial injection of the mutant TSC2 (C203S) in Shank3Δ4–22 mice in the prefrontal cortex prevented ASD-like behaviors, confirming the pathogenic role of NO-mediated TSC2 modification. Critically, analysis of clinical samples from children with ASD, including those with SHANK3 mutations and idiopathic ASD, revealed reduced TSC2 levels and increased mTOR signaling activity, further validating our findings. Collectively, this study uncovers a novel molecular mechanism by which S-nitrosylation disrupts TSC2 function, leading to aberrant mTOR signaling and ASD-like phenotypes. By revealing a unique SNO-TSC2-mTOR axis, our work deciphers the novel nitric oxide-mediated mTOR activation and opens new avenues for targeted therapeutic strategies in ASD, including those carrying SHANK3 mutations.
Background:Frailty is regarded as a key predictor of adverse surgical outcomes. The 5-item modified frailty index (mFI-5) offers a simplified version of the validated 11-item risk stratification tool. Despite its use across surgical fields, its utility in plastic and reconstructive surgery remains underexplored. The purpose of this study was to evaluate and quantify the predictive value of frailty, as measured by the mFI-5 on postoperative outcomes in adult patients undergoing plastic and reconstructive surgery. Methods:PubMed, Embase, Web of Science, and Cochrane Library were systematically queried for studies comparing adverse events in frail (mFI-5 ≥ 2) versus nonfrail patients undergoing plastic and reconstructive surgery. Two independent reviewers performed study selection, data extraction, and risk of bias assessment using the risk of bias in non-randomized studies-of interventions tool, with evidence quality evaluated using the grading of recommendations, assessment, development and evaluation approach. Outcomes included surgical, medical, and any complications, readmission, reoperation, and mortality. Subgroup analyses were conducted by subject of study, database source, and study sample size. Results:Twenty-nine studies encompassing 302,641 patients were included. Frailty was significantly associated with increased odds of complications, readmission, reoperation, and mortality. Subgroup analyses by procedure type, database, and sample size consistently confirmed elevated risk across all outcomes, with varying degrees of statistical significance. Conclusions:Frailty, as measured by the mFI-5, is associated with an increased risk of postoperative complications, hospital readmission, reoperation, and mortality in plastic and reconstructive surgery patients. These findings support the integration of the index in clinical practice and preoperative patient evaluation and decision-making.
BACKGROUND:Over the past decade, lung cancer management has been reshaped by advances in early detection, treatment, and prevention. Prevention now extends beyond tobacco control to include recognition of non-tobacco risk factors, screening, and incidental nodule programs. Yet progress in primary prevention remains uneven, with marked regional disparities. Smoking prevalence continues to decline and measures to reduce particulate matter exposure are expanding, but the overall global impact remains inconsistent. PATIENTS AND METHODS:This article draws upon the discussions and expert recommendations presented at the New York Lung Cancer Foundation Summit 2025, integrating perspectives on prevention, screening, therapeutic innovation, and health system challenges across diverse health care settings. RESULTS:Screening programs, now active in >40 countries, achieve lower false-positive rates and earlier-stage diagnoses, although lung cancer incidence is rising among individuals who never used any tobacco products in some regions. Therapeutic innovations-including perioperative immunotherapy, targeted treatments for oncogene-driven non-small-cell lung cancer, and antibody-drug conjugates (ADCs)-have markedly improved survival outcomes. Persistent challenges include refining patient selection, sequencing multimodal therapies, managing toxicity, and understanding mechanisms of resistance. Systemic barriers such as unequal progress in tobacco and vaping prevention, limited screening uptake, delayed molecular testing, and restricted access to multidisciplinary care continue to blunt these gains. Ongoing research on novel immunotherapies, ADCs, and bispecific antibodies aims to overcome therapeutic resistance. In small-cell lung cancer, consolidation immunotherapy and delta-like ligand 3-targeted approaches have improved outcomes and are redefining treatment paradigms. Persistent disparities in access and trial participation underscore the need for more equitable study designs, stronger international collaboration, and clearer communication with the public. CONCLUSIONS:This article summarizes current advances and strategic priorities in lung cancer research and care, reflecting the discussions and recommendations of the New York Lung Cancer Foundation Summit 2025.
