Citations

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Abstract Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Abstract Objective: Global concern exists for workplace violence against healthcare workers (HCWs), especially in low and middle-income nations. This violence includes physical, verbal, or sexual abuse and has a significant impact despite initiatives like Occupational Safety and Health Administration (OSHA) guidelines. We conducted a study in Kenya to address this issue. Methods: We did a cross-sectional survey that collected responses during June 6th to August 9th, 2022, focused on healthcare professionals in Kenya within the global ViSHWaS study. Violence against healthcare professionals in multiple Kenyan counties was analysed, The study reached participants through social media, emails, and other channels using a snowball sampling technique. Results: The survey included 1,458 HCWs, primarily females (66.5%), aged 36-45 (42.4%), and of African race, representing 40 counties, with the majority from Nairobi (28.9%) and working in government academic (35.5%) and private academic institutions (20.6%). Most had over 11 years of healthcare experience (64.4%), and registered nurses were the most common cadre (27.8%). Approximately half (49.9%) reported experiencing violence, with verbal violence (80.6%) and emotional abuse (78.6%) being common. Online harassment was reported by only 3.5%, mainly on Facebook (63.2%), involving hate speech (92.1%). Patients or their relatives were the most common aggressors (44.7%), while supervisors accounted for 12.5%. The frequency of violence varied, and 80.2% noted an increase after the COVID-19 pandemic. Only 41.2% of incidents were reported. Most were familiar with safety guidelines (93.6%). Self-violence was associated with familiarity with guidelines, concern about violence, preparedness, and night shifts, while colleague violence was associated with age, gender, race, work experience, training, preparedness, and night shifts. Conclusion: Our Kenya-based cross-sectional sub-analysis highlights that a significant number of HCWs experienced violence, especially during the COVID-19 pandemic, which negatively affected job satisfaction. Although most HCWs were familiar with OSHA guidelines, there were difficulties in their practical implementation.

Abstract During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block‐face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase‐quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3 , Chchd6 , and Mitofilin . We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age‐related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age‐related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue‐dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.

Background The presence of an outer shell has been recently described as a common feature of acute ischemic stroke (AIS) thrombi. We performed a systematic review of the current literature on shell genesis, structure, and clinical significance. Methods Following PRISMA guidelines, we searched Ovid Cochrane Central Register of Controlled Trials, Embase, Medline, Scopus, and Web of Science for studies reporting the composition and structure of AIS thrombi and clot analogs. Identified studies were added to Covidence software for primary screening. Two reviewers independently screened titles and abstracts followed by full-text screening. Results From 1290 identified studies, 10 were included in this review. Studies using histology/immunohistochemistry/immunofluorescence described fibrin, platelets, von Willebrand factor, and neutrophil extracellular traps as the main components of the shell. Scanning electron microscopy demonstrated a dense, compact fibrin/platelet-rich shell, and a core rich in polyhedrocytes. Microfluidics studies identified highly activated P-selectin-positive platelets and fibrin forming the core while secondary agonists adenosine diphosphate and thromboxane, along with loosely packed P-selectin-negative platelets constituted the shell. Conclusions The composition, compaction, and integrity of the shell may impact thrombolysis and revascularization outcomes. The preponderance of studies supported this conclusion.

Abstract Background Impella is an advanced ventricular assist device frequently used as a bridge to heart transplantation. The association of Impella with increased rates of gout flares has not been studied. Our primary aim is to determine the rates of gout flares in patients on Impella support. Methodology A retrospective study was conducted between January 2017 and September 2022 involving all patients who underwent heart transplantation. The cohort was divided into groups based on Impella support for statistical analysis. In patients receiving Impella support, outcome measures were compared based on the development of gout flares. Results 213 patients were analyzed, with 19.71% supported by Impella. Impella and non-Impella groups had similar age, race, and BMI, but more males were in the Impella group. Gout and chronic kidney disease were more prevalent in Impella-supported patients, while coronary artery disease was less common. The incidence of gout flare was significantly higher in Impella patients (31% vs. 5.3%). The Impella group had an adjusted odds ratio for in-hospital gout flare of 8.069 (95% CI = 2.13–35.08, P = 0.003). Impella-supported patients with gout flares had longer intensive care unit and hospital stays but no difference in mortality or other outcomes. Conclusion Our study is the first to identify the potential association between Impella support and increased rates of gout flares in hospitalized patients. Future studies are required to confirm this association and further elucidate the biological pathways. It is imperative to consider introducing appropriate measures to prevent and promptly manage gout flares in Impella-supported patients.

Background The North Africa and Middle East (NAME) region has one of the highest burdens of ischemic heart disease (IHD) worldwide. This study reports the contemporary epidemiology of IHD in NAME. Methods and Results We estimated the incidence, prevalence, deaths, years of life lost, years lived with disability, disability‐adjusted life years (DALYs), and premature mortality of IHD, and its attributable risk factors in NAME from 1990 to 2019 using the results of the GBD (Global Burden of Disease study 2019). In 2019, 0.8 million lives and 18.0 million DALYs were lost due to IHD in NAME. From 1990 to 2019, the age‐standardized DALY rate of IHD significantly decreased by 33.3%, mostly due to the reduction of years of life lost rather than years lived with disability. In 2019, the proportion of premature death attributable to IHD was higher in NAME compared with global measures: 26.8% versus 16.9% for women and 18.4% versus 14.8% for men, respectively. The age‐standardized DALY rate of IHD attributed to metabolic risks, behavioral risks, and environmental/occupational risks significantly decreased by 28.7%, 37.8%, and 36.4%, respectively. Dietary risk factors, high systolic blood pressure, and high low‐density lipoprotein cholesterol were the top 3 risks contributing to the IHD burden in most countries of NAME in 2019. Conclusions In 2019, IHD was the leading cause of death and lost DALYs in NAME, where premature death due to IHD was greater than the global average. Despite the great reduction in the age‐standardized DALYs of IHD in NAME from 1990 to 2019, this region still had the second‐highest burden of IHD in 2019 globally.