Comparison of the Mortality of Non-COVID Hospitalized Patients during the COVID Pandemic: A Retrospective Cohort Study in a Tertiary Medical Center in Israel.

BACKGROUND: At the beginning of 2020, the coronavirus disease 2019 (COVID-19) pandemic presented a new burden on healthcare systems. OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on the outcome of non-COVID patients in Israel. METHODS: We conducted a retrospective observational cohort study at a tertiary medical center in Israel. From December 2018 until June 2022, 6796 patients were hospitalized in the internal medicine wards. Patients were grouped based on their admission date: admitted during COVID waves (waves group), admitted between waves (interim group), and admitted during the same months in the previous year (former-year group). RESULTS: Mortality during hospitalization and 30-day mortality were higher in the waves group compared to the interim and former-year groups (41.4% vs. 30.5% and 24%, 19.4% vs. 17.9% and 12.9%, P < 0.001). In addition, 1-year mortality was higher in the interim group than in the waves and former-year group (39.1 % vs. 32.5% and 33.4%, P = 0.002). There were significant differences in the readmissions, both at 1 year and total number. The waves group had higher rates of mechanical ventilation and noradrenaline administration during hospitalization. Moreover, the waves group exhibited higher troponin levels, lower hemoglobin levels, and more abnormalities in liver and kidney function. CONCLUSIONS: Hospitalized non-COVID patients experienced worse outcomes during the peaks of the pandemic compared to the nadirs and the preceding year, perhaps due to the limited availability of resources. These results underscore the importance of preparing for large-scale threats and implementing effective resource allocation policies.

[ETHICAL CHALLENGES IN TREATING CRITICAL CORONAVIRUS PATIENTS: EXPERIENCE FROM THE SHEBA MEDICAL CENTER ON THE FIRST COVID-19 PANDEMIC OUTBREAK].

INTRODUCTION: As the coronavirus pandemic emerged in late 2019, a task force was founded in the Sheba Medical Center and began preparing for the arrival of the pandemic to Israel. Several wards were put in charge of isolated COVID-19 patients. A new intensive care unit was formed for the most critical COVID-19 patients, requiring mechanical ventilation and multi-organ treatment. The Corona ICU began operating in March 2020, with a multi-disciplinary team, gathered from ICU units, an internal medicine ward, an anesthesiology department, social workers and psychologists. Simultaneously, the routine medical center functions in non-corona sections were maintained, as much as possible. The coronavirus pandemic entails challenges of many aspects: an unfamiliar pathogen causing an unknown illness, a necessity for social distancing, ambiguity regarding the risk factors for contamination and illness severity, and medical crews put at risk. Consequently, the pandemic involves ethical, social, economic and moral aspects, affecting the medical crew members and system, the patients and their families, and our society as a whole. In this article we review our joint experience in the Sheba Medical Center Corona ICU, of the medical, ethical and moral dilemmas that emerged from the first COVID-19 wave.

Acute response to the October 7th hostage release: rapid development and evaluation of the novel ReSPOND protocol implementation within a children's hospital.

BACKGROUND: The decision to allocate hospitals for the initial reception of hostages abducted on the October 7th Hamas attack introduced an array of unprecedented challenges. These challenges stemmed from a paucity of existing literature and protocols, lack of information regarding captivity conditions, and variability in hostage characteristics and circumstances. OBJECTIVE: To describe the rapid development, implementation and evaluation of the Hostage-ReSPOND protocol, a comprehensive trauma-informed procedure for the care of hostages, including young children, their caregivers and families, immediately following their release from prolonged captivity. METHODS: A multidisciplinary expert focus group conducted a comprehensive literature review to develop the ReSPOND protocol, consisting of: Readiness of teams via multifaceted trainings, utilizing live simulations and video debriefings; Specialized professional teams experienced in providing holistic trauma-informed care; Personalized care tailored to individualized and developmentally-informed needs; Optimal safety rooted in creating a secure environment and trauma-informed response to young children, adolescents, caregivers and families; and Navigating Discharge, through coordination with community-based care systems. RESULTS: A designated facility at the Children's hospital was carefully prepared for receiving 29 hostages, aged 3.9-80 years, 28% under the age of 18. Implementation of the ReSPOND protocol, which prioritized holistic psychosocial interventions above urgent medical care, proved feasible and effective in managing the diverse and complex needs of returnees as per provider report. Finally, systemic assessment of returnee's immediate and long-term mental health needs proved highly challenging. CONCLUSIONS: There is currently no literature addressing the response to released hostages, especially those involving infants, young children and families within a children's hospital facility. This study has the potential to fill a crucial gap in knowledge by introducing a novel protocol which could offer valuable insights for public health organizations tasked with providing acute care to diverse individuals and families experiencing extreme, multi-layered mass traumatization.

Autoimmune Neutropenia Associated With HHV-6 Virus Infection: A Case Report.

Background: Autoimmune neutropenia (AIN) is divided into primary and secondary forms. The former is more prevalent in children and is usually a self-limiting disease. Secondary AIN is more common in adults and often occurs in the setting of another autoimmune disorder or secondary to infections, malignancies or medications. Several viral and bacterial pathogens were described to trigger AIN. Here we report a case of AIN in an adult woman associated with human herpesvirus-6 (HHV-6) infection. Case Presentation: We report a case of AIN in an adult woman associated with HHV-6 infection. The patient presented to the emergency department with fever and painful genital ulcers. Upon arrival, her laboratory workup demonstrated severe neutropenia and elevated inflammatory markers. She was hospitalized and underwent a thorough infectious, hematological, autoimmune and inflammatory workup. Malignancy was also excluded using an advanced whole body radiological scan. Serological tests confirmed the presence of both acute and chronic types of HHV-6 antibodies, at very high titers. Polymerase chain reaction demonstrated a numerous copies of the virus in the patient's blood. Specific immunofluorescence test confirmed the diagnosis of autoimmune neutropenia. Conclusion: Secondary AIN is a rare disease that may affect all range of ages. The adult type is a challenging disorder that has different etiologies and may be triggered by a variable infectious pathogen. The finding of HHV-6 as a possible culprit pathogen may warrant physicians into widening the evaluation and include HHV-6 in the analysis.

Prevalence and clinical implication of thrombocytopenia and heparin-induced thrombocytopenia in patients who are critically ill with COVID-19.

As the COVID-19 pandemic continues to evolve, different clinical manifestations are better understood and studied. These include various haematologic disorders that have been shown to be associated with increased morbidity and mortality. We studied the prevalence of one unusual manifestation, heparin-induced thrombocytopenia (HIT) and its clinical implications in patients who are severely ill with COVID-19 in a single tertiary centre in Israel. The presence of thrombocytopenia, disseminated intravascular coagulation (DIC) and HIT, and their association with clinical course and outcomes were studied. One-hundred and seven patients with COVID-19 were included. Fifty-seven (53.2%) patients developed thrombocytopenia, which was associated with the worst outcomes (ventilation, DIC and increased mortality). Sixteen (28.0%) patients with thrombocytopenia were positive for HIT, all of which were supported by extracorporeal devices. HIT was independently associated with ventilation days, blood product transfusions, longer hospitalisation and mortality.Platelet abnormalities and HIT are common in patients who are critically ill with COVID-19 and are associated with the worst clinical outcomes. The mechanisms underlying HIT in COVID-19 are yet to be studied; HIT may contribute to the dysregulated immunologic response associated with COVID-19 critical illness and may play a significant part in the coagulopathy seen in these patients. As many patients with COVID-19 require aggressive thromboprophylaxis, further understanding of HIT and the implementation of appropriate protocols are important.

Utilization of machine-learning models to accurately predict the risk for critical COVID-19.

Among patients with Coronavirus disease (COVID-19), the ability to identify patients at risk for deterioration during their hospital stay is essential for effective patient allocation and management. To predict patient risk for critical COVID-19 based on status at admission using machine-learning models. Retrospective study based on a database of tertiary medical center with designated departments for patients with COVID-19. Patients with severe COVID-19 at admission, based on low oxygen saturation, low partial arterial oxygen pressure, were excluded. The primary outcome was risk for critical disease, defined as mechanical ventilation, multi-organ failure, admission to the ICU, and/or death. Three different machine-learning models were used to predict patient deterioration and compared to currently suggested predictors and to the APACHEII risk-prediction score. Among 6995 patients evaluated, 162 were hospitalized with non-severe COVID-19, of them, 25 (15.4%) patients deteriorated to critical COVID-19. Machine-learning models outperformed the all other parameters, including the APACHE II score (ROC AUC of 0.92 vs. 0.79, respectively), reaching 88.0% sensitivity, 92.7% specificity and 92.0% accuracy in predicting critical COVID-19. The most contributory variables to the models were APACHE II score, white blood cell count, time from symptoms to admission, oxygen saturation and blood lymphocytes count. Machine-learning models demonstrated high efficacy in predicting critical COVID-19 compared to the most efficacious tools available. Hence, artificial intelligence may be applied for accurate risk prediction of patients with COVID-19, to optimize patients triage and in-hospital allocation, better prioritization of medical resources and improved overall management of the COVID-19 pandemic.

The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators.

Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.