Sheba Medical Center

Background The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca²⁺ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear. Results We show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte. Conclusions We discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes.

Antibiotic resistance is a major cause of morbidity and mortality. However, a better understanding of the relationship between bacterial genetic markers, phenotypic resistance, and clinical outcomes is needed. We performed whole-genome sequencing on five medically important pathogens ( Acinetobacter baumannii , Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa ) to investigate how resistance genes impact patient outcomes. A total of 168 isolates from 162 patients with Gram-negative infections admitted to Beilinson Hospital at Rabin Medical Center in Israel were included for final analysis. Genomes were analyzed for resistance determinants and correlated with microbiologic and clinical data. Thirty-day mortality from time of culture was 26.5% (43/162). Twenty-nine patients had carbapenem-resistant isolates (29/168, 17.2%), while 63 patients had multidrug-resistant isolates (63/168, 37.5%). Albumin levels were inversely associated with mortality and length of stay, while arrival from a healthcare facility and cancer chemotherapy predicted having a multidrug-resistant isolate. Sequencing revealed possible patient-to-patient transmission events. bla CTX-M-15 was associated with multidrug-resistance in E. coli (OR = 3.888, P = 0.023) on multivariate analysis. Increased bla OXA-72 copy number was associated with carbapenem-resistance in A. baumannii ( P = 0.003) and meropenem minimum inhibitory concentration ( P = 0.005), yet carbapenem-resistant isolates retained sensitivity to cefiderocol and sulbactam–durlobactam. RJX84154 was associated with multidrug-resistance across all pathogens ( P = 0.0018) and in E. coli ( P = 0.0024). Low albumin levels were associated with mortality and length of stay in this sample population. bla CTX-M-15 was correlated with multidrug-resistance in E. coli , and bla OXA-72 depth predicted meropenem minimum inhibitory concentration in A. baumannii . RJX84154 may play a role in multidrug-resistance. IMPORTANCE While there have been several studies that attempt to find clinical predictors of outcomes in patients hospitalized with bacterial infections, less has been done to combine clinical data with genomic mechanisms of antibiotic resistance. This study focused on a hospitalized patient population in Israel with infections due to medically important bacterial pathogens as a way to build a framework that would unite clinical data with both bacterial antibiotic susceptibility and genomic data. Merging both clinical and genomic data allowed us to find both bacterial and clinical factors that impact certain clinical outcomes. As genome sequencing of bacteria becomes both rapid and commonplace, near real-time monitoring of resistance determinants could help to optimize clinical care and potentially improve outcomes in these patients.

Lay Summary Gastroenterology significantly impacts the environment, contributing to medical waste. Adopting green practices like noninvasive diagnostics, telemedicine, and home monitoring can reduce the carbon footprint while maintaining effective inflammatory bowel disease patient care. Healthcare workers must integrate environmental considerations into their practices.

Background To examine the satisfaction rates and burnout feelings amongst residents physicians in different specialties and to examine associated affecting factors. Method Clalit Health Services (CHS) is the largest health maintenance provider in Israel. A survey was designed by an interdisciplinary team with questions addressing residency and the balance between residency and personal life, as well as the balance between residency and personal life, and was sent to all residents of CHS via personal email from March to May 2022. Results Four hundred sixty seven residents completed the survey. The mean satisfaction rate from the residency was 7.4 (± 1.93, 2–10). The highest satisfaction rate from residency was amongst anesthetics, psychiatrists and ophthalmologists ( 8.6, 8.1 and 8.0, respectively) while the lowest was among general surgeons, oncologists, plastic surgeons and orthopedic surgeons (6.8, 6.8, 6.7, 6.1, respectively). There was no correlation between satisfaction rates and monthly working hours or number of overnight shifts. Seventy four percent feel frequent burnout due to high workload and 68% feel frequent burnout due to high number of administrative tasks. Seventy three percent chose the work environment in their department as most influential of their residency experience, 61% chose relations between attending physicians and residents as most significant, and 60% chose the education during the residency as most influential during their residency training. Conclusions Satisfaction rates from the residency training require improvement, with differences between the residencies. Number of working hours and number of overnight shifts did not correlate with the satisfaction rates. The factor that influences the most between satisfactory rate and less burnout is the relationship with colleagues and good training programs. Major efforts should be done to improve these factors.

Purpose The prolonged treatment recommended for nocardiosis does not rely on strong evidence. Consequently, some clinicians opt shorter therapy in certain circumstances. We assessed the effectiveness of shorter therapy. Methods A multi-center retrospective cohort study comprising individuals diagnosed with nocardiosis between 2007 and 2022. We classified all patients who survived 90 days into three groups according to treatment duration: short (≤ 90 days), intermediate (91–180 days), and prolonged (> 180 days). We compared baseline characteristics (comorbidities, immune status) and nocardiosis manifestations across the unadjusted treatment groups, one-year all-cause mortality, disease relapse, and antibiotic-related adverse events to identify patients who may safely receive the short course. Results We detected 176 patients with nocardiosis, their median age was 65 years; 74 (42%) were women. Forty-three (24%) patients died within 90 days. Of the remaining 133, 37 (28%) patients received short therapy, 40 (30%) intermediate, and 56 (42%) prolonged treatment duration. Longer courses were more likely to be administered to patients with immunosuppression, disseminated nocardiosis, and N. farcinica infection. Within a year, 20 (15%) individuals died and 2 (2%) relapsed. Treatment duration was not associated with either mortality (p = 0.945) or relapse (p = 0.509). Nocardiosis was the cause of death in only one patient, receiving a prolonged course. Of 73 patients with solitary pulmonary nocardiosis, 20 (27%) received short duration. None relapsed and 2 (10%) died, both immunocompromised. The rate of AE was similar across the groups. Conclusions With clinically guided case-by-case patient selection nocardiosis can be safely treated for durations significantly shorter than traditionally recommended.

introduction: Placenta accreta spectrum (PAS) is a term used to describe trophoblast invasion into the uterine wall. The condition can be fetal at labor due to a lack of spontaneous separation of the placenta from the uterine wall, leading to severe hemorrhage. In this study we aim to evaluate preoperative risk factors for unplanned immediate hysterectomy in PAS uterine-preserving surgeries. Methods: Preoperative parameters of women who underwent successful uterine-preserving surgery were retrospectively compared to those who underwent an unplanned immediate hysterectomy during these surgeries. A multivariable regression analysis was conducted to identify independent factors associated with unplanned immediate hysterectomy. Results: Overall, 238 were included in the study’s cohort. 86.2% underwent successful uterine-preserving surgery, and 13.8% underwent an unplanned immediate hysterectomy. The number of previous CDs and the proportion of women with grade 3 preoperative PAS was significantly lower among the successful uterine-preserving group. The proportion of preoperative ultrasound lacunae detection, the number of lacunae observed, loss of clear zone detection, the length of clear zone loss, the proportion of retroplacental hypervascularity, bridging vessels detection, and bladder involvement were significantly lower in the successful uterine-preserving group. In a multivariable regression analysis, the presence of lacunae and loss of clear zone were independently associated with unplanned cesarean hysterectomy [adjusted odds ratio (aOR) 95% confidence interval (CI) 3.18(1.11-11.6), p=0.047, and aOR 3.67 (95% CI 1.3-13.2), p=0.025, respectively]. Discussion: Preoperative assessment of the applicability of a uterine-preserving surgery may be performed using the US parameters reported in this study. Keywords: Placenta accrete spectrum, uterine-preserving surgery, hysterectomy, conservative management, Sonographic evaluation.

Purpose To evaluate AI-based chat bots ability to accurately answer common patient’s questions in the field of ophthalmology. Methods An experienced ophthalmologist curated a set of 20 representative questions and responses were sought from two AI generative models: OpenAI’s ChatGPT and Google’s Bard (Gemini Pro). Eight expert ophthalmologists from different sub-specialties assessed each response, blinded to the source, and ranked them by three metrics—accuracy, comprehensiveness, and clarity, on a 1–5 scale. Results For accuracy, ChatGPT scored a median of 4.0, whereas Bard scored a median of 3.0. In terms of comprehensiveness, ChatGPT achieved a median score of 4.5, compared to Bard which scored a median of 3.0. Regarding clarity, ChatGPT maintained a higher score with a median of 5.0, compared to Bard’s median score of 4.0. All comparisons were statistically significant ( p < 0.001). Conclusion AI-based chat bots can provide relatively accurate and clear responses for addressing common ophthalmological inquiries. ChatGPT surpassed Bard in all measured metrics. While these AI models exhibit promise, further research is indicated to improve their performance and allow them to be used as a reliable medical tool.

Introduction: A common tool used to measure cognitive reserve is the Cognitive Reserve Index questionnaire (CRIq). In the present study, we aimed to adapt and determine the psychometric properties (validity and intra-rater test-retest reliability) of the Hebrew version of the CRIq in a cohort of people with multiple sclerosis (pwMS). Methods: Fifty pwMS (30 women aged 48.3 (SD=10.2)) completed the CRIq and the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), which were used for validation. Secondary outcome measures included the evaluation of depression, anxiety, and perceived fatigue. Twenty-five (of the 50) pwMS were randomly selected and participated in the CRIq intra-rater test-retest reproducibility study based on a 7-12-day interval between tests. Results: The mean CRIq total was 101.8 (S.D.=13.04), which is considered at the medium level. The CRIq section scores were at a similar medium level. According to Pearson's Rho correlation analysis, the CRIq total score and sections of education, work, and leisure were significantly correlated at a medium level (Rho ranging between 0.282 to 0.415) with the SDMT score, a measurement of cognitive information processing speed. The intraclass correlation coefficient (ICC) values of the CRIq total and CRIq sections ranged between 0.942 to 0.998, indicating a strong correlation. Conclusions: The Hebrew version of the CRIq is a reliable and valid tool for assessing cognitive reserve in pwMS, hence enabling clinicians and researchers to effectively monitor cognitive reserve in this population.

This study investigates distal 2q13 microdeletion, presenting the largest cohort to date, including prenatal cases, alongside a comprehensive literature review. A retrospective analysis was conducted on distal 2q13 microdeletions from clinical charts and laboratory reports. The cohort was divided into “clinically indicated” and “not‐clinically indicated” groups based on the reason for chromosomal microarray testing. Clinical cases from medical literature were reviewed and compared with our cohort. The study included 25 cases: 17 index patients and 8 family members, with 47% males and 53% females. Of these, 2 were postnatal and 15 were prenatal. In the “clinically indicated” group, 35% had abnormalities on prenatal ultrasound, while 65% in the “not‐clinically indicated” group had no major anomalies. Inheritance was 50% paternal in the “clinically indicated” group, and in the “not‐clinically indicated” group, 44% paternal, 22% maternal, and 33% de novo . Symptoms varied from asymptomatic to severe developmental issues. Literature review identified 51 postnatal cases, with intellectual disability, and dysmorphism being common features. Familial cases showed 20% de novo , 20% maternal, 21.5% paternal, and 40% unknown inheritance. Distal 2q13 microdeletion is linked to cognitive impairment risk and should be reported in test results based on parental preferences, requiring special considerations for clinical classification and reporting.

Introduction Hemophilia A (HA) therapy poses a significant healthcare burden. In recent years, emicizumab has been approved for prophylaxis. The current study explores the impact of transitioning to emicizumab on emergency department (ED) visits and hospitalizations in pediatric and adult HA patients. Methods Data of HA patients transitioned to emicizumab at the Israeli National Hemophilia Center was retrospectively analyzed. Demographic information, inhibitor status, treatment duration, number, and reasons of ED visits and hospitalizations were assessed. Results Overall, transitioning to emicizumab significantly reduced ED visits and hospitalizations. While children experienced a significant reduction in both ED visits and hospitalizations, adults showed no statistically significant change. Post‐emicizumab initiation, main reasons for ED visits among children shifted from prophylactic treatment and central line‐associated complications to injury‐related incidents. Conclusions This real‐world analysis demonstrates a substantial decrease in ED visits and hospitalizations, following emicizumab prophylaxis in HA patients. However, this improvement was age dependent as it was observed only among children. Further prospective studies evaluating this aspect may shed light on these findings.

Purpose Cytomegalovirus (CMV) is associated with significant morbidity and mortality among solid organ transplant (SOT) recipients. Strategies for CMV prevention include universal prophylaxis or preemptive approach. We aimed to evaluate the optimal approach. Methods We performed a systematic review and meta-analysis of randomized controlled trials comparing prophylaxis versus preemptive therapy for CMV in SOT. The primary outcome was CMV disease. Subgroup analysis of outcomes in D+ R− patients was performed. Results Nine trials have met inclusion criteria, five of them included kidney transplant recipients, all compared val/ganciclovir universal prophylaxis versus preemptive approach. Universal prophylaxis resulted in lower probability of CMV infection (relative risk [RR] 0.44, 95% confidence interval [CI] 0.33–0.58), yet the impact on CMV disease was insignificant (RR 0.54, 95% CI 0.24–1.23), in neither SOT recipients in general nor among D+R− subgroup (RR 0.93, 95% CI 0.37–2.32). Late-onset CMV disease rates were lower with preemptive approach. Sensitivity analysis according to allocation concealment and blinding showed similar results for CMV disease. No significant differences were demonstrated for the outcomes of mortality, bacterial or fungal infection or graft related outcomes. Acute kidney injury was significantly more common with prophylaxis (RR 1.79, 95% CI 1.12–2.89). Conclusion Preemptive approach is a reasonable approach for CMV prevention in SOT recipients, if feasible. Strategies for combining the preemptive with prophylaxis strategies, as well as immune monitoring, should be investigated.

PURPOSE The activity of osimertinib is not fully characterized in non–small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor ( EGFR ) mutations. Therefore, we conducted a systematic review and meta-analysis to assess the safety and efficacy of osimertinib in patients with NSCLC harboring uncommon somatic EGFR mutations. METHODS PubMed, Embase, and the Cochrane Library were searched for eligible studies reporting the efficacy and safety of osimertinib in NSCLC with uncommon EGFR mutations defined as any mutations other than exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Then, we performed a meta-analysis to pool survival outcomes and antitumoral activity, including intracranial (ic) response and adverse events. RESULTS Fifteen studies comprising 594 patients were included. The most frequently observed uncommon solitary mutations were G719X in 25% (81/327) of patients and L861Q in 21% (69/327). The most common compound mutations were G719X with T790M in 12% (23/192) of patients and G719X with S768I in 11% (22/192). Pooled analysis showed an objective response rate (ORR) of 51.30% (95% CI, 45.80 to 56.81), a disease control rate (DCR) of 90.11% (95% CI, 86.27 to 92.96), a median progression-free survival of 9.71 months (95% CI, 7.96 to 11.86), and a median overall survival of 16.79 months (95% CI, 9.93 to 28.39). icORR was 45.96% (95% CI, 30.18 to 62.17), and icDCR was 95.76% (95% CI, 69.84 to 100). Osimertinib was well tolerated with a frequency of grade 3 or more adverse events of 21.77% (95% CI, 6.24 to 43.33). CONCLUSION Osimertinib demonstrated robust response in NSCLC harboring uncommon EGFR mutations, without unanticipated safety concerns.

Chimeric Antigen Receptor (CAR) T cells targeting CD19 induce durable remissions in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), but many patients experience treatmentrelated toxicity. Cytokine release syndrome and immune effector cell-associated neurologic syndrome are extensively characterized. However, limited data exist on the burden, predictors, and implications of acute kidney injury (AKI) after CAR T cell therapy. On initial screening of the FDA adverse event reporting system, we identified a disproportionately high rate of renal adverse events among nearly 6,000 CAR T adverse event reports, suggesting it is clinically important in this patient population. In a subsequent single-center analysis of 399 NHL patients treated with CD19 CAR T cells, we found a substantial burden of AKI after CAR T infusion (10% and 5% of any grade and grade ≥2 AKI) with pre-renal causes being predominant (72%). Evolution to chronic kidney disease was rare, however, 3 patients required hemodialysis. Importantly, patients experiencing cytokine release syndrome and/or neurotoxicity as well as those with low serum albumin and high inflammatory cytokines, including IL-6 and TNF-alpha, were more likely to develop AKI. While pre-CAR T renal dysfunction was not associated with adverse outcomes, patients developing post-CAR T AKI had lower overall survival compared to their counterparts. Our findings indicate that renal dysfunction is a common toxicity of CAR T cell therapy with meaningful prognostic impact. Notably, the link between systemic inflammation and renal dysfunction, suggests that readily available biomarkers may inform on renal injury risk after CAR T cell therapy.

Therapy for relapsed or refractory (R/R) aggressive B‐cell non‐Hodgkin lymphoma (aB‐NHL) post autologous stem cell transplantation (ASCT) or in elderly patients can be challenging. In this single‐center, single‐arm, phase II clinical study, we investigated the efficacy of ibrutinib (560 mg once daily) in combination with bendamustine and rituximab (IBR) given for six 28‐day cycles in their standard dose, to patients with R/R aB‐NHL who were either transplant ineligible in first or second relapse or post‐ASCT for second relapse. The primary endpoint was overall response rate (ORR). Fifty‐six patients (54% male, median age 69.7 years) were included. ORR was 49.1% among 55 patients treated with ≥ 1 cycle of IBR and 69.4% among 36 patients treated with ≥ 3 cycles. Patients with relapsed disease had significantly higher ORR compared to those with refractory disease (72.3% vs. 37.8%, p = 0.024). Median overall survival (OS) was 11.6 months (95% CI, 7.1–22.3) and median progression‐free survival was 5.3 months (95% CI, 2.5–7.4). Patients with complete and partial responses had significantly longer median OS compared to those with stable and progressive disease (28.1 vs. 5.2 months, p < 0.0001). Adverse events included thrombocytopenia (19.6%), anemia (16.1%), neutropenia (7.1%), fatigue (35.7%), diarrhea (28.6%) and nausea (28.6%). At the first efficacy evaluation 8 patients were referred to transplantation, and 3 more were referred during follow‐up. These data indicate that the IBR regimen is a safe and effective treatment option that can also be used for bridging to transplantation in patients with R/R aB‐NHL. Trial Registration: ClinicalTrials.gov : NCT02747732

Objectives The study aims to evaluate the safety and efficacy of the BeBack™ crossing catheter for percutaneous recanalization of lower limb chronic total occlusions (CTO) via tibial artery access in patients with chronic limb-threatening ischemia (CLTI). Methods This single-center, retrospective study included 21 patients who underwent 22 limb recanalization procedures between May 2021 and April 2024. The BeBack™ catheter was utilized after traditional methods of recanalization failed. Patients aged 18 years or older with peripheral artery disease (PAD) and treated exclusively through the tibialis anterior artery were included. Data on demographics, occlusion characteristics, procedural details, and outcomes were collected from hospital records. Procedural success was defined as achieving less than 30% residual stenosis and an improvement in the ankle-brachial index (ABI) by at least 0.2 within 24 h. Results The median patient age was 77 years (IQR 73–81.5), with the majority being male (71%). Technical success was achieved in 95% of cases (21/22), and procedural success was achieved in 91% (20/22) cases. The device was primarily used for re-entry (77%), with a minority of cases (23%) where it was used as a crossing device. The most frequently treated artery was the superficial femoral artery (95%). One procedural failure was noted due to an inability to traverse a heavily calcified occlusion. Complications included one case of intra-procedural acute thrombosis, which was resolved, and one instance of post-procedural pulmonary edema, treated with diuretics. No reinterventions or amputations were required during the 30-day follow-up, although there were three mortalities (14%). Conclusions The BeBack™ crossing catheter demonstrated high technical success and a low complication rate for recanalizing lower limb CTOs via a single tibial artery access. These findings suggest that the BeBack™ catheter could be an effective and safe option for managing complex CTOs, particularly when traditional approaches are not feasible. Further prospective studies are needed to validate these results and compare them with other crossing and re-entry devices.

Background: Self-rated health (SRH) has been shown to predict mortality across a lifespan. However, its predictive value might differ between populations. We compared the association between SRH and mortality in Israeli Jewish and Arab older adults (65+). Methods: A prospective cohort study was conducted among Jewish (n = 1463) and Arab (n = 298) participants in the first National Health and Nutrition Survey of Older Adults (2005–2006). SRH was measured on a four-point scale. Mortality data were available from baseline (2005–2006) through 2019. A survival analysis was performed using Cox models. Results: Mean baseline age (SD) was 75 (6) years among Jewish participants (54% women) and 72 (5) years among Arab participants (50% women). Jewish participants were more likely to rate their health as not good (35% vs. 29%) or poor (11% vs. 8%) than Arab participants (p = 0.01). During a median follow-up of 13.3 years, 896 deaths occurred; 744 in the Jewish group (mean age [SD] 77.8 [6.6] years) and 152 in the Arab group (mean age [SD] 74.0 [5.2] years). The age- and sex-adjusted hazard ratio (HR) for mortality in the Arab vs. Jewish participants was 1.33 (95% CI: 1.12–1.60). Mortality risk increased with declining SRH, with multivariable-adjusted HRs in the lowest vs. most-favorable SRH categories of 2.46 (95% CI: 1.66–3.63) in the Jewish sample and 2.60 (95% CI: 0.98–6.93) in the Arab sample. Conclusions: Although Jewish participants reported poorer SRH, their survival rate was better than Arab participants. Lower SRH was consistently and strongly associated with higher mortality in both groups in a dose–response manner.