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Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants. Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta‐analysis, only studies with ≥ three ACC cases were included. Meta‐analysis of proportions was employed using a random‐effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria. Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta‐analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35–73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30–57%)) and isolated ACC (32% (95% CI, 18–51%)). Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The authors of the article titled "Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype" respond to comments made by Dr. Finsterer. They clarify that their study did not report on cases of intrauterine fetal death, but rather on cases of termination due to fetal anomalies. They also explain that functional or biochemical testing is not mandatory for determining variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines. The authors provide evidence supporting the pathogenicity of the NDUFAF5 variants they studied and acknowledge the need for further research on one of the variants. They assert that their study contributes to the understanding of prenatal presentations of NDUFAF5-associated disorders and emphasize the challenges of studying prenatal phenotypes. The authors address Dr. Finsterer's mention of other possible abnormalities associated with NDUFAF5 variants and state that the lack of demonstration does not negate their assumption that these variants are causative of the congenital anomalies described in their study. They also clarify that family history and parental carrier status were included in their original manuscript. [Extracted from the article]

Background: Selective bromelain-based enzymatic debridement (BED) has emerged as a valid alternative for the treatment of extensive burns, with Total Body Surface Area (TBSA) > 20%. Autologous skin grafting represents the procedure of choice but the scarcity of donor sites remains the main reconstructive challenge. The modified Meek micro-grafting technique may represent a valid strategy to optimize the final outcome., Methods: A single-cohort retrospective analysis was performed, involving nine burn patients (TBSA > 20%) who underwent both BED and subsequently modified Meek technique. Demographic and clinical data (mechanism of injury, surgical treatment, complications, necessity of re-grafting, further surgery and esthetic outcome) were collected., Results: All patients had large burns of mixed and deep dermal thickness (first, second, and third degree). All burns were enzymatically debrided postadmission and covered by the modified Meek technique. Local infection due to poor general conditions was the main complication for all patients. All but two patients survived. The selectiveness of the enzymatic debridement and dermal preservation seemed to improve the quality of scars resulting from micro-grafting. Evaluations performed at 12 ± 2 months postburn showed superior scar quality compared to areas treated with traditional (sheet/mesh) grafts., Conclusion: Combined BED and Meek techniques may provide an effective synergic combination for the treatment of extensive burns., Competing Interests: All authors declare that they have no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: We aimed to analyse the efficacy and added value of a targeted Israeli expanded carrier screening panel (IL-ECSP), beyond the first-tier test covered by the Israeli Ministry of Health (IMOH) and the second-tier covered by the Health Maintenance Organisations (HMOs)., Methods: A curated variant-based IL-ECSP, tailored to the uniquely diverse Israeli population, was offered at two tertiary hospitals and a major genetics laboratory. The panel includes 1487 variants in 357 autosomal recessive and X-linked genes., Results: We analysed 10 115 Israeli samples during an 18-month period. Of these, 6036 (59.7%) were tested as couples and 4079 (40.3%) were singles. Carriers were most frequently identified with mutations in the following genes: GJB2/GJB6 (1:22 allele frequency), CFTR (1:28), GBA (1:34), TYR (1:39), PAH (1:50), SMN1 (1:52) and HEXA (1:56). Of 3018 couples tested, 753 (25%) had no findings, in 1464 (48.5%) only one partner was a carrier, and in 733 (24.3%) both were carriers of different diseases. We identified 79 (2.6%) at-risk couples, where both partners are carriers of the same autosomal recessive condition, or the female carries an X-linked disease. Importantly, 48.1% of these would not have been detected by ethnically-based screening tests currently provided by the IMOH and HMOs, for example, variants in GBA, TYR, PAH and GJB2/GJB6 ., Conclusion: This is the largest cohort of targeted ECSP testing, tailored to the diverse Israeli population. The IL-ECSP expands the identification of couples at risk and empowers their reproductive choices. We recommend endorsing an expanded targeted panel to the National Genetic Carrier Screening programme., Competing Interests: Competing interests: DMB was involved in the design of the CarrierScan array and is entitled to certain royalties., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Early in the global COVID-19 pandemic, a concern was raised that potentially high volumes of COVID-19 inpatients in general hospitals might compromise the hospitals' capabilities to maintain high-quality care for routine patients and, thereby, to comply with indicators specifying quality of care. The objective of this study is to evaluate the impact of the surges of COVID-19 inpatients into general hospitals in Israel on the compliance rates for selected quality indicators reported by these hospitals within the Israeli National Program for Quality Indicators (NPQI)., Methods: Compliance rate data were collected from the quality indicators reports made to the NPQI by participating hospitals. COVID-19 inpatient volume data were obtained from the Ministry of Health Digital Technologies and Data Division. Both datasets were analyzed on a week-by-week basis and plotted one alongside the other on a time scale. Association of each quality indicator's compliance rate with the number of COVID-19 inpatients was tested by Pearson's correlation analysis. The study included data from July 1, 2019 through June 30, 2022, spanning the duration of the COVID-19 pandemic in Israel. Five quality indicators included in the study were: Surgical repair of femoral neck fracture within 48 h of admission; Assessment of cerebral ischemic event risk for patients with atrial fibrillation; Duplex carotid ultrasound within 72 h of emergency department admission for patients with suspected transient ischemic attack; Antibiotic prophylaxis for caesarean sections; and Percutaneous coronary intervention within 90 min for patients presenting with ST-elevation myocardial infarction., Results: Compliance rates for five quality indicators, representing different aspects of routine health care, remained steady - even at times with high volumes of COVID-19 inpatients in general hospitals. This lack of effect was prominent throughout the analyzed period, i.e., general hospitals maintained similar compliance rates for all quality indicators both during the surges of COVID-19 patients and between these periods. Statistical analysis showed no correlation between the quality indicators' compliance rates and the number of COVID-19 inpatients., Conclusions: Our findings indicate that high volumes of COVID-19 inpatients in general hospitals did not affect the hospitals' capability to comply with routine health care quality indicators. The results of our study imply that general hospitals in Israel were able to withstand the challenges associated with the care of COVID-19 inpatients while preserving high quality of care for routine patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: This study provides an in-depth analysis of the immediate postoperative outcomes and implications or robotic-assisted total knee arthroplasty (RA-TKA) compared with conventional TKA (C-TKA), particularly with regard to mortality, complications, hospital stay and costs, drawing from a comprehensive nationwide data set., Methods: The Nationwide Inpatient Sample (NIS) database, the largest all-payer inpatient healthcare database in the United States, was used to identify all patients who underwent RA-TKA or C-TKA from 2016 to 2019. A total of 527,376 cases, representing 2,638,679 patients who underwent elective TKA were identified, of which 88,415 had RA-TKA. To mitigate potential variations and selection bias in baseline characteristics between the two groups, a propensity score-matched analysis was employed to further balance and refine our data set, resulting in 176,830 patients evenly distributed between the groups. Analysis was performed according to demographics, immediate post-operative complications, and economic data, including payor class, length of stay and total charges., Results: There was a marked shift towards RA-TKA, from an initial 0.70% in 2016 to a notable 7.30% by 2019. Patients who underwent RA-TKA were slightly younger (66.2 ± SD years), compared to the C-TKA group (66.7 ± SD years). Hospital stay was 1.89 days and 2.29 days for RA-TKA and C-TKA, respectively. Charges metrics revealed slightly higher charges for RA-TKA. Less postoperative complications were found in the RA-TKA group, such as blood loss, anaemia, acute kidney injury, venous thromboembolism, pulmonary embolism, pneumonia and surgical wound complication. Even following the propensity score matching, these findings remained consistent and statistically significant., Conclusions: RA-TKA use in the United States has grown substantially in the last few years and has been associated with significantly reduced immediate post-operative complications and length of hospital stay compared to C-TKA, offering safer surgical management for TKA patients. Further studies on the short- and long-term outcomes of RA-TKA would improve the understanding of the full potential of this technology., Levels of Evidence: Level III., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Multimode fiber-based saturable absorbers enable mode-locking in lasers, generating ultrafast pulses and providing an exceptional platform for investigating nonlinear phenomena. Previous analyses in the continuous-wave (CW) limit showed that saturable absorption can be obtained due to nonlinear interactions between transverse modes. We find experimentally that saturable absorption can be achieved, thanks to the interplay of single-mode fiber nonlinearity and the wavelength-dependent linear transmission of the multimode fiber, even with negligible intermodal nonlinearities. We further show that even when intermodal nonlinearities are significant, the CW analysis may not be sufficient for long multimode fibers. Understanding the underlying mechanisms of multimode fiber-based saturable absorbers opens new possibilities for developing programmable devices for ultrafast control.

The CRISPR/Cas9 system is a highly accurate gene-editing technique, but it can also lead to unintended off-target sites (OTS). Consequently, many high-throughput assays have been developed to measure OTS in a genome-wide manner, and their data was used to train machine-learning models to predict OTS. However, these models are inaccurate when considering OTS with bulges due to limited data compared to OTS without bulges. Recently, CHANGE-seq, a new in vitro technique to detect OTS, was used to produce a dataset of unprecedented scale and quality. In addition, the same study produced in cellula GUIDE-seq experiments, but none of these GUIDE-seq experiments included bulges. Here, we generated the most comprehensive GUIDE-seq dataset with bulges, and trained and evaluated state-of-the-art machine-learning models that consider OTS with bulges. We first reprocessed the publicly available experimental raw data of the CHANGE-seq study to generate 20 new GUIDE-seq experiments, and hundreds of OTS with bulges among the original and new GUIDE-seq experiments. We then trained multiple machine-learning models, and demonstrated their state-of-the-art performance both in vitro and in cellula over all OTS and when focusing on OTS with bulges. Last, we visualized the key features learned by our models on OTS with bulges in a unique representation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Unicompartmental knee arthroplasty (UKA) is increasingly used for knee osteoarthritis due to faster recovery, better range of motion, and lower costs compared to total knee arthroplasty (TKA). While TKA may offer longer-lasting results with lower revision rates, this study compares the relative benefits and limitations of UKA and TKA using the National Inpatient Sample (NIS) database. Methods: This retrospective analysis examined outcomes of elective UKA and TKA procedures from 2016 to 2019, identifying 2,606,925 patients via ICD-10 codes. Propensity score matching based on demographics, hospital characteristics, and comorbidities resulted in a balanced cohort of 136,890 patients. The present study compared in-hospital mortality, length of stay, postoperative complications, and hospitalization costs. Results: The results showed that UKA procedures increased significantly over the study period. Patients undergoing UKA were generally younger with fewer comorbidities. After matching, both groups had low in-hospital mortality (0.015%). UKA patients had shorter hospital stays (1.53 vs. 2.47 days) and lower costs (USD 55,976 vs. USD 61,513) compared to TKA patients. UKA patients had slightly higher rates of intraoperative fracture and pulmonary edema, while TKA patients had higher risks of blood transfusion, anemia, coronary artery disease, pulmonary embolism, pneumonia, and acute kidney injury. Conclusions: UKA appears to be a less-invasive, cost-effective option for younger patients with localized knee osteoarthritis.

Background: The role of preoperative breast MRI to evaluate the extent of disease in breast cancer patients is considered controversial. We aimed at assessing the effect of breast MRI on the management of newly diagnosed breast cancer., Materials: A retrospective review of 202 consecutively seen patients who were newly diagnosed with breast cancer and who underwent preoperative breast MRIs at Assuta Ashdod between June 1, 2017, and June 1, 2020. Data included discovering suspicious lesions by conventional imaging, MRI findings, and surgical pathology results. This was analyzed to determine whether the MRI changed the management and whether it had a justified or unjustified effect on the treatment., Results: The mean age was 54.51 (standard deviation, 11.34 years). Breast MRI revealed additional findings in 56 % of patients and modified therapeutic management in 32 % of the cases evaluated, having a justified effect in 87.6 %. Patients with changed management had a statistically significantly higher mastectomy rate (36 %) than those who did not (14 %). No statistically significant association was found between independent variables such as breast density, tumor location on the breast, type of tumor, patient's demographic information, etc. And whether MRI findings changed the initial treatment plan., Conclusions: MRI played an essential role in the preoperative staging of breast cancer in our study, modifying therapeutic planning in approximately one-third of the cases and having a justified effect on most of them. We, therefore, support preoperative breast MRI in newly diagnosed breast cancer patients., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: This study compares postoperative outcomes of robotic-assisted total knee arthroplasty (RA-TKA) versus navigation-guided total knee arthroplasty (NG-TKA). Using Nationwide Inpatient Sample (NIS) data, it provides an analysis of postoperative complications, mortality, hospital costs and duration of stay., Methods: The study analysed 217,715 patients (81,830 RA-TKA; 135,885 NG-TKA) using NIS data from 2016 to 2019. Elective TKA patients were identified through the International Classification of Diseases, 10th Revision codes. Statistical analyses, including logistic regression modelling, were performed using Statistical Package for the Social Sciences and MATLAB., Results: RA-TKA patients were younger (66.1 vs. 67.1 years, p < 0.0001) and had similar mortality rates (0.024% vs. 0.018%, p = 0.342) but shorter length of stay (LOS) (1.89 vs. 2.1 days, p < 0.0001). Mean total charges were comparable between RA-TKA ($66,180) and NG-TKA ($66,251, p = 0.669). RA-TKA demonstrated lower incidences of blood-related complications (11.67% vs. 14.19%, p < 0.0001), pulmonary oedema (0.0306% vs. 0.066%, p < 0.0001), deep vein thrombosis (0.196% vs. 0.254%, p = 0.006) and acute kidney injury (AKI) (1.356% vs. 1.483%, p = 0.016)., Conclusion: RA-TKA reduces postoperative complications and LOS without increasing costs, highlighting the relevance of this technology in patient care., Level of Evidence: Level III., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Super-enhancers are unique gene expression regulators widely involved in cancer development. Spread over large DNA segments, they tend to be found next to oncogenes. The super-enhancer c-MYC locus forms long-range chromatin looping with nearby genes, which brings the enhancer and the genes into proximity, to promote gene activation. The colon cancer-associated transcript 1 (CCAT1) gene, which is part of the MYC locus, transcribes a lncRNA that is overexpressed in colon cancer cells through activation by MYC. Comparing different types of cancer cell lines using RNA fluorescence in situ hybridization (RNA FISH), we detected very prominent CCAT1 expression in HeLa cells, observed as several large CCAT1 nuclear foci. We found that dozens of CCAT1 transcripts accumulate on the gene locus, in addition to active transcription occurring from the gene. The accumulating transcripts are released from the chromatin during cell division. Examination of CCAT1 lncRNA expression patterns on the single-RNA level showed that unspliced CCAT1 transcripts are released from the gene into the nucleoplasm. Most of these unspliced transcripts were observed in proximity to the active gene but were not associated with nuclear speckles in which unspliced RNAs usually accumulate. At larger distances from the gene, the CCAT1 transcripts appeared spliced, implying that most CCAT1 transcripts undergo post-transcriptional splicing in the zone of the active gene. Finally, we show that unspliced CCAT1 transcripts can be detected in the cytoplasm during splicing inhibition, which suggests that there are several CCAT1 variants, spliced and unspliced, that the cell can recognize as suitable for export., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes., Methods: We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events., Results: We included 318 patients (69% males, average age 58.3 ± 11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in GLP1-RAs users compared with 134 of 1000 in controls (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.27-0.78). GLP1-RAs similarly reduced the risk of MACE-PVD (HR 0.53; 95% CI, 0.33-0.88) and the risk of all-cause mortality (HR 0.39; 95% CI, 0.18-0.84). Biliopancreatic adverse events occurred less in GLP1-RA users., Conclusions: Transplant recipients with diabetes who used GLP1-RAs had lower risks for MACE and all-cause mortality. These results may profoundly implicate the daily management of posttransplant recipients with diabetes, a population with a high prevalence of cardiometabolic risk factors and cardiovascular death. Transplant patients are usually excluded from randomized controlled trials and, hence might be undertreated with disease-modifying drugs. Larger prospective studies are needed in this unique population., Competing Interests: I.D. has received fees from AstraZeneca, Novonordisk, Abbott, Boeringham Ingleheimer, Elli Lilly, and Sanofi for educational lectures and participated in advisory boards of Novonordisk, Boeringham Ingleheimer, Sanofi, and Novartis that are outside the scope of this work. I.D. reports a grant from AstraZeneca that is outside the scope of the submitted work. T.D.C. has received fees from AstraZeneca for educational lectures that are outside the scope of this work. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Congenital diarrheas and enteropathies (CODE) are a group of rare, heterogenous, monogenic disorders that lead to chronic diarrhea in infancy. Definitive treatment is rarely available, and supportive treatment is the mainstay. Nutritional management in the form of either specialized formulas, restrictive diet, or parenteral nutrition support in CODE with poor enteral tolerance is the cornerstone of CODE treatment and long-term growth. The evidence to support the use of specific diet regimens and nutritional approaches in most CODE disorders is limited due to the rarity of these diseases and the scant published clinical experience. The goal of this review was to create a comprehensive guide for nutritional management in CODE, based on the currently available literature, disease mechanism, and the PediCODE group experience. Enteral diet management in CODE can be divided into 3 distinct conceptual frameworks: nutrient elimination, nutrient supplementation, and generalized nutrient restriction. Response to nutrient elimination or supplementation can lead to resolution or significant improvement in the chronic diarrhea of CODE and resumption of normal growth. This pattern can be seen in CODE due to carbohydrate malabsorption, defects in fat absorption, and occasionally in electrolyte transport defects. In contrast, general diet restriction is mainly supportive. However, occasionally it allows parenteral nutrition weaning or reduction over time, mainly in enteroendocrine defects and rarely in epithelial trafficking and polarity defects. Further research is required to better elucidate the role of diet in the treatment of CODE and the appropriate diet management for each disease., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B + natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B + NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aims: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF)., Methods and Results: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper., Conclusions: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The role of immunosenescence, particularly the natural process of thymic involution during aging, is increasingly acknowledged as a factor contributing to the development of autoimmune diseases and cancer. Recently, a concern has been raised about deleterious consequences of the surgical removal of thymic tissue, including for patients who undergo thymectomy for myasthenia gravis (MG) or resection of a thymoma. This review adopts a multidisciplinary approach to scrutinize the evidence concerning the long-term risks of cancer and autoimmunity postthymectomy. We conclude that for patients with acetylcholine receptor antibody-positive MG and those diagnosed with thymoma, the removal of the thymus offers prominent benefits that well outweigh the potential risks. However, incidental removal of thymic tissue during other thoracic surgeries should be minimized whenever feasible.

Background: The pathophysiology of Takotsubo syndrome (TTS) remains incompletely understood. While coronary microvascular dysfunction (CMD) is a potential pathophysiologic mechanism, evidence is limited., Objectives: We sought to evaluate CMD in patients with TTS., Methods: Consecutive patients diagnosed with TTS were included and underwent coronary angiography with invasive microvascular function evaluation, including fractional flow reserve, Coronary Flow Reserve (CFR), Index of Microcirculatory Resistance (IMR), and Resistive Reserve Ratio (RRR). Patients had an echocardiography evaluation during their index admission and at approximately 6 weeks., Results: Thirty patients were included (mean age 74 ±9, 90 % female). Twenty-five patients (83 %) had at least one abnormal coronary microvascular function parameter. Abnormal parameters included CFR<2.5 in 20 patients (67 %), IMR>25 in 18 patients (60 %), and RRR<3.5 in 25 (83 %). Longer time from symptoms to angiography correlated with a higher CFR (r = 0.51, P<0.01), and had an area under the receiver operating characteristic curve of 0.793 (95 % CI 0.60-0.98) for pathologic CFR. Patients with emotional trigger had a lower rate of pathologic IMR compared with non-emotional trigger (36 % vs 81 %, p = 0.01). Follow up echocardiography performed at a median of 1.5 months (IQR 1.15-6) showed an improvement in left ventricular ejection fraction for all patients (from mean of 40 % to 57 %)., Conclusion: CMD was present in most patients with TTS. The role of microvascular function in TTS may vary according to the clinical presentation and RRR may be more sensitive for the diagnosis of CMD in TTS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Very few studies evaluated the global prevalence of pruritus., Objective: To assess its prevalence according to age, gender, ethnicity, and geographic regions., Methods: An international cross-sectional study was conducted in 20 countries from January to April 2023. Participants were asked to complete a questionnaire on sociodemographics, confirm the presence or absence of a skin disease in the last 12 months and the presence or absence of pruritus in the last 7 days., Results: The studied sample included 50552 individuals. The worldwide prevalence of pruritus was 39.8%. The age group ≥65 had the highest prevalence (43.3%). The prevalence was 40.7% among women and 38.9% among men (p<0.001). There was no significant difference between ethnicities (p=0.14). Compared to North America (41.6%), the prevalence of pruritus was significantly lower in Europe (35.9%, p<0.001), Australia (38.4%, p=0.017), East Asia (40.2%, p=0.04), and Latin America (36.5%, p<0.001), and higher in Africa (45,7%, p=0.007). No significant difference was found with the Middle East (40.2%, p=0.36). The prevalence was 40.3% in developed countries and 38.7% in BRICS countries 40.7% (p<10-3)., Limitations: No information about the severity or type (acute, chronic) of pruritus., Conclusion: Global prevalence of pruritus revealed age, gender, and geographic region differences, with no ethnic differences., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

The concept of free will has challenged physicists, biologists, philosophers, and other professionals for decades. The constrained disorder principle (CDP) is a fundamental law that defines systems according to their inherent variability. It provides mechanisms for adapting to dynamic environments. This work examines the CDP's perspective of free will concerning various free will theories. Per the CDP, systems lack intentions, and the "freedom" to select and act is built into their design. The "freedom" is embedded within the response range determined by the boundaries of the systems' variability. This built-in and self-generating mechanism enables systems to cope with perturbations. According to the CDP, neither dualism nor an unknown metaphysical apparatus dictates choices. Brain variability facilitates cognitive adaptation to complex, unpredictable situations across various environments. Human behaviors and decisions reflect an underlying physical variability in the brain and other organs for dealing with unpredictable noises. Choices are not predetermined but reflect the ongoing adaptation processes to dynamic prssu½res. Malfunctions and disease states are characterized by inappropriate variability, reflecting an inability to respond adequately to perturbations. Incorporating CDP-based interventions can overcome malfunctions and disease states and improve decision processes. CDP-based second-generation artificial intelligence platforms improve interventions and are being evaluated to augment personal development, wellness, and health., (© 2024. The Author(s).)

Background: Hip fracture repair surgery carries a certain mortality risk, yet evidence suggests that orthopedic surgeons often refrain from discussing this issue with patients prior to surgery., Aim: This study aims to examine whether orthopedic surgeons raise the issue of one-year post-surgery mortality before hip fracture repair surgery and to explore factors influencing this decision., Method: The study employs a cross-sectional design, administering validated digital questionnaires to 150 orthopedic surgeons., Results: A minority of orthopedic surgeons reported always informing patients about the risk of mortality in the year following hip fracture surgery. The main reasons for not discussing this risk were a desire to avoid frightening patients, time constraints, and concerns about undermining patient hope. Orthopedic surgeons reported a medium-high level of perceived self-efficacy, with higher self-efficacy associated with a reduced likelihood of discussing one-year mortality risk. Conversely, older age and holding a specialist status in orthopedic surgery were associated with an increased likelihood of discussing this risk with patients., Conclusions: These findings suggest a need for interventions to address communication barriers and ensure consistent provision of essential information to patients undergoing hip fracture surgery. Additionally, they highlight the importance of considering individual factors such as self-efficacy, age, and expertise in designing strategies to improve patient-provider communication in orthopedic care settings., Trial Registration: The study doesn`t report the results of a health care intervention., (© 2024. The Author(s).)

In recent decades, a growing number of discoveries in mathematics have been assisted by computer algorithms, primarily for exploring large parameter spaces. As computers become more powerful, an intriguing possibility arises-the interplay between human intuition and computer algorithms can lead to discoveries of mathematical structures that would otherwise remain elusive. Here, we demonstrate computer-assisted discovery of a previously unknown mathematical structure, the conservative matrix field. In the spirit of the Ramanujan Machine project, we developed a massively parallel computer algorithm that found a large number of formulas, in the form of continued fractions, for numerous mathematical constants. The patterns arising from those formulas enabled the construction of the first conservative matrix fields and revealed their overarching properties. Conservative matrix fields unveil unexpected relations between different mathematical constants, such as π and ln(2), or e and the Gompertz constant. The importance of these matrix fields is further realized by their ability to connect formulas that do not have any apparent relation, thus unifying hundreds of existing formulas and generating infinitely many new formulas. We exemplify these implications on values of the Riemann zeta function ζ (n), studied for centuries across mathematics and physics. Matrix fields also enable new mathematical proofs of irrationality. For example, we use them to generalize the celebrated proof by Apéry of the irrationality of ζ (3). Utilizing thousands of personal computers worldwide, our research strategy demonstrates the power of large-scale computational approaches to tackle longstanding open problems and discover unexpected connections across diverse fields of science., Competing Interests: Competing interests statement:The authors declare no competing interest.

Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity., Competing Interests: LF, MN, AZ, AK, NS, AR, AG, AG, LB, TG, AA, AB No competing interests declared, DR This paper was funded by Gilboa Therapeutics where Diana Rasoulouniriana is a shareholder, PR This paper was funded by Gilboa Therapeutics where Peleg Rider is a shareholder, YC This paper was funded by Gilboa Therapeutics where Yaron Carmi is a shareholder, (© 2023, Farhat-Younis et al.)

Connectomics provides essential nanometer-resolution, synapse-level maps of neural circuits to understand brain activity and behavior. However, few researchers have access to the high-throughput electron microscopes necessary to generate enough data for whole circuit or brain reconstruction. To date, machine-learning methods have been used after the collection of images by electron microscopy (EM) to accelerate and improve neuronal segmentation, synapse reconstruction and other data analysis. With the computational improvements in processing EM images, acquiring EM images has now become the rate-limiting step. Here, in order to speed up EM imaging, we integrate machine-learning into real-time image acquisition in a singlebeam scanning electron microscope. This SmartEM approach allows an electron microscope to perform intelligent, data-aware imaging of specimens. SmartEM allocates the proper imaging time for each region of interest - scanning all pixels equally rapidly, then re-scanning small subareas more slowly where a higher quality signal is required to achieve accurate segmentability, in significantly less time. We demonstrate that this pipeline achieves a 7-fold acceleration of image acquisition time for connectomics using a commercial single-beam SEM. We apply SmartEM to reconstruct a portion of mouse cortex with the same accuracy as traditional microscopy but in less time., Competing Interests: Declaration of Interests P.P., M.P. and R.S. are employees of Thermo Fisher Scientific.

Background: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described., Methods: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up., Results: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC., Conclusions: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC., Competing Interests: Potential conflicts of interest . A. F. reports grants from the University of Calgary Eyes High Postdoctoral Fellowship and Canadian Institutes of Health Research Banting Postdoctoral Fellowship, and support for meetings and/or travel from a Trainee Travel Grant (Pediatric Academic Societies and Trainee travel grant), Alberta Children's Hospital Association, University of Calgary. L. A. reports grants from Pfizer. M. W. reports support for meetings and/or travel from US Acute Care Solutions (USACS), stock and a board of directors position for EM Device Lab. N. K. reports a leadership or fiduciary role for the Pediatric Emergency Care Applied Research, Pediatric Emergency Research Network; research funding from the National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and Patient-Centered Outcomes Research Institute (PCORI). R. M. reports royalties or licenses for Affinivax; consulting fees from GSK, Affinivax, and Merck; payment for lectures and support for meetings and/or travel from GSK; patents planned, issued, or pending for Boston Children's Hospital; being a member of the Affinivax board of directors; and stock options for Affinivax and Corner Therapeutics. S. M. M. reports grants from Sanofi, Merck, Pfizer National Minority Quality Forum (US); support for meetings and/or travel from Sanofi, Merck, GSK, Pfizer, CSL, Biosciences Association of Manitoba (BAM), and the National Minority Quality Forum (US); and participation on a Data and Safety Monitoring Board or Advisory board for Sanofi. T. A. F. reports grants from the National Heart, Lung, and Blood Institute (NHLBI) and leadership or fiduciary roles for the Society of Pediatric Research and the Pediatric Academic Societies. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ~280,000 human non-coding RNA genes, identified algorithmically from ~690,000 RNAcentral transcripts. This expands by ~tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains ~120,000 long non-coding RNAs (LncRNAs, >200 bases long), including ~100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1547 genes associated with 1 to 50 diseases. About 15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of lncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 lncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for ~110,000 lncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further lncRNA research in disease decipherment.

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. Establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA drives X transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing molecule CBL137 inhibits X transcription and HBV infection in hepatocytes. Our results shed light on a long-standing paradox and represent a potential new therapeutic avenue for the treatment of chronic HBV infection., Competing Interests: Declaration of interests R.E.S. is on the scientific advisory boards of Miromatrix Inc. and Lime Therapeutics and is a speaker and consultant for Alnylam Inc. All other authors declare that they have no competing interests.

Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage., (© 2024. The Author(s).)

The presence of gunshot residue (GSR) in a sample can provide valuable information in forensic investigations by associating a suspect with a shooting incident. However, in order to have confidence in the integrity of the results' interpretation, the possibility of contamination by secondary transfer of GSR occurring during the transportation of a person under custody in a police vehicle should be evaluated. In order to investigate police vehicles as a source for secondary transfer of GSR particles, a total of 51 samples were collected from the rear seats of random police vehicles and used to transport arrested individuals. Results indicated that the type of upholstery of the seats plays a main role in determining the potential for secondary GSR contamination. The potential chance of coming into contact with GSR particles in police vehicles is low. GSR contamination from police vehicles is, maybe, not of a major concern but should be taken into consideration mainly when very few characteristic GSR particles are found on an analyzed sample., (© 2024 American Academy of Forensic Sciences.)

The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels in C. elegans and in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases., Competing Interests: Competing interests: The authors have declared that no competing interests exist.

Background/Objectives: Gaucher Disease type 1 (GD1) is a recessively inherited lysosomal storage disorder caused by a deficiency in the enzyme β-glucocerebrosidase. Enzyme replacement therapy (ERT) has become the standard of care for patients with GD. However, over 10% of patients experience an incomplete response or partial loss of response to ERT, necessitating the exploration of alternative approaches to enhance treatment outcomes. The present feasibility study aimed to determine the feasibility of using a second-generation artificial intelligence (AI) system that introduces variability into dosing regimens for ERT to improve the response to treatment and potentially overcome the partial loss of response to the enzyme. Methods: This was an open-label, prospective, single-center proof-of-concept study. Five patients with GD1 who received ERT were enrolled. The study used the Altus Care™ cellular-phone-based application, which incorporated an algorithm-based approach to offer random dosing regimens within a pre-defined range set by the physician. The app enabled personalized therapeutic regimens with variations in dosages and administration times. Results: The second-generation AI-based personalized regimen was associated with stable responses to ERT in patients with GD1. The SF-36 quality of life scores improved in one patient, and the sense of change in health improved in two; platelet levels increased in two patients, and hemoglobin remained stable. The system demonstrated a high engagement rate among patients and caregivers, showing compliance with the treatment regimen. Conclusions: This feasibility study highlights the potential of using variability-based regimens to enhance ERT effectiveness in GD and calls for further and longer trials to validate these findings.

Background: The inclusion of nurse practitioners (NPs) specializing in orthopedics shows potential for improving the quality of care for orthopedic patients. A critical aspect of assessing the feasibility and acceptance of introducing NPs into orthopedic settings involves understanding patients' perspectives on this role. This study aims to explore the receptiveness of orthopedic patients to treatment by orthopedic Nurse Practitioners (NPs). Additionally, it investigates potential associations between patients' willingness to engage with NPs, their familiarity with the NPs role, perceptions of nursing, and satisfaction with orthopedic nursing care., Methods: This cross-sectional study involved patients admitted to an orthopedic department in a central Israeli hospital between January and February 2023. Data was collected using a questionnaire consisting of five sections, validated by content experts. Statistical analyses, performed using SPSS, included descriptive statistics, independent samples t-tests, Pearson correlations, and linear regression., Results: Orthopedic patient participants demonstrated a moderate willingness to undergo treatment by orthopedic NPs, with over two-thirds expressing strong openness. Patients displayed a high willingness for NPs to engage in various clinical tasks, albeit showing lesser enthusiasm for medication management and preoperative evaluation. Positive attitudes towards nurses and familiarity with the NP's role emerged as significant predictors of patient receptiveness to NPs' treatment., Conclusion: Patient acceptance of orthopedic NPs varies across different aspects of care. While there is overall willingness to receive care from NPs, these nuanced preferences should be considered when implementing NPs in orthopedic settings. Awareness and positive perceptions play crucial roles in shaping patients' willingness to receive care from these NPs., Trial Registration: The research doesn't report the results of a health care intervention., (© 2024. The Author(s).)

Background: Long-term outcomes of congenital diarrheas and enteropathies (CODE) are poorly described. We evaluated the morbidity and mortality of children with CODE followed by an intestinal rehabilitation program (IRP) compared to children with short bowel syndrome (SBS)., Methods: Matched case-control study of children with intestinal failure (IF) due to CODE (diagnosed between 2006 and 2020; N = 15) and SBS (N = 42), matched 1:3, based on age at diagnosis and duration of parenteral nutrition (PN). Nutritional status, growth, and IF-related complications were compared. Survival and enteral autonomy were compared to a nonmatched SBS cohort (N = 177)., Results: Fifteen CODE patients (five males, median age 3.2 years) were followed for a median of 2.9 years. Eleven children were alive at the end of the follow-up, and two achieved enteral autonomy. The CODE group had higher median PN fluid and calorie requirements than their matched SBS controls at the end of the follow-up (83 vs. 45 mL/kg/day, p = 0.01; 54 vs. 30.5 kcal/kg/day, p < 0.01), but had similar rates of growth parameters, intestinal failure associated liver disease (IFALD), central venous catheter (CVC) complications and nephrocalcinosis. Kaplan-Meier (KM) analyses of 10-year survival and enteral autonomy were significantly lower in CODE patients compared to the nonmatched SBS population (60% vs. 89% and 30% vs. 87%, respectively; log-rank p < 0.008)., Conclusions: Despite higher PN needs in CODE, rates of IF complications were similar to matched children with SBS. Enteral autonomy and survival rates were lower in CODE patients. Treatment by IRP can mitigate IF-related complications and improve CODE patient's outcome., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

A new hydrothermal hot isostatic pressing (HHIP) approach, involving hydrothermal water conditions and no usage of inert gas, was hypothesized and tested on 3D-printed Al-10%Si-0.3%Mg (%Wt) parts. The aluminum-based metal was practically inert at the applied HHIPing conditions of 300-350 MPa and 250-350 °C, which enabled the employment of a long (6-24 h) HHIP treatment with hardly any loss of material (the overall loss due to corrosion was mostly <0.5% w / w ). Applying the new approach on the above-mentioned samples resulted in an 85.7% reduction in the AM micro-pores, along with a 90.8% reduction in the pores' surface area at a temperature of 350 °C, which is much lower than the 500-520 °C applied in common argon-based aluminum HIPing treatments, while practically maintaining the as-recieved microstructure. These results show that better mechanical properties can be expected when using the suggested treatment without affecting the material fatigue resistance due to grain growth. The proof of concept presented in this work can pave the way to applying the new HHIPing approach to other AM metal parts.

Background: Coronary microvascular disease (CMD) is common in patients with and without obstructive coronary artery disease, and is associated with adverse clinical outcomes. Respiratory-related variables are associated with pulmonary and systemic microvascular dysfunction, while evidence about their relationship with CMD is limited. We aim to evaluate respiratory-related variables as risk factors of CMD., Methods: This is an observational, single-center study enrolling consecutive patients undergoing invasive evaluation of coronary microvascular function in the catheterization laboratory. Patients with evidence of obstructive coronary artery disease or with missing data were excluded. Associations between respiratory-related variables and indices of CMD were assessed using univariate and multivariate regression models., Results: Overall, 266 patients (mean age 67 ± 11 years, 59% females) were included in the current analysis. Of those, 155 (58%) had evidence of CMD. Among the respiratory variables, independent predictors of CMD were current smoking (adjusted odds ratio [AOR] 2.5; 95% confidence interval [CI], 1.2-5; P = .01) and obstructive sleep apnea (AOR 5.7; 95% CI, 1.2-26; P = .03), while chronic obstructive pulmonary disease was not. Among ever-smokers, higher smoking pack-years was an independent risk factor for CMD (median 35 vs 25 pack-years, AOR 1.09; 95% CI, 1.04-1.13; P < .01), and was associated with higher rates of pathologic index of microcirculatory resistance and resistive reserve ratio., Conclusion: In patients undergoing invasive coronary microvascular evaluation, current smoking and obstructive sleep apnea are independently associated with CMD. Among smokers, higher pack-years is a strong predictor for CMD. Our findings should raise awareness for prevention and possible treatment options., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: The HLA-B*15:02 allele has been associated with an increased risk of carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in specific Asian populations (including Han Chinese, Malaysian, Thai, and Vietnamese individuals). While HLA-B*15:02 genotype testing in Asian populations is recommended by several international prescribing guidelines, it is not subsidized by the Medicare Benefits Schedule in Australia., Objective: To evaluate the cost-effectiveness of HLA-B*15:02 genotyping in Asian Australian patients with epilepsy., Design, Setting, and Participants: A model with components of decision analysis and Markov simulation was developed to simulate clinical trajectories of adult Asian Australian patients with newly diagnosed epilepsy being considered for carbamazepine treatment. Cost-effectiveness and cost-utility analyses over a lifetime time horizon were conducted from the perspective of the Australian health care sector. The study was conducted in May 2023 and data analysis was performed from August 2023 to November 2023., Intervention: No HLA-B*15:02 genotyping and the empirical initiation of treatment with carbamazepine vs HLA-B*15:02 genotyping and the initiation of treatment with valproate in allele carriers., Main Outcomes and Measures: Life-years (LYs), quality-adjusted life-years (QALYs), and costs in 2023 Australian dollars (A$); incremental cost-effectiveness ratios., Results: HLA-B*15:02 screening was associated with an additional mean cost of A$114 (95% CI, -A$83 to A$374; US$76; 95% CI, -US$55 to US$248) and a reduction in 0.0152 LYs (95% CI, 0.0045 to 0.0287 LYs) but improvement by 0.00722 QALYs (95% CI, -0.0247 to -0.01210) compared with no screening, resulting in an incremental cost-effectiveness ratio of A$15 839 per QALY gained (US$10 523 per QALY). Therefore, universal genotyping for Asian Australian individuals was cost-effective compared with current standards of practice at the A$50 000 per QALY willingness-to-pay threshold. Sensitivity analyses demonstrated that the intervention remained cost-effective across a range of costs, utilities, transition probabilities, and willingness-to-pay thresholds. At the A$50 000 per QALY willingness-to-pay threshold, universal screening was the preferred strategy in 88.60% of simulations., Conclusions and Relevance: The results of this economic evaluation suggest that HLA-B*15:02 screening represents a cost-effective choice for Asian Australian patients with epilepsy who are being considered for treatment with carbamazepine.

Burns are serious injuries associated with significant morbidity and mortality. In Israel, burn patients are often transferred between facilities. However, unstructured and non-standardized transfer processes can compromise the quality of patient care and outcomes. In this retrospective study, we assessed the impact of implementing a transfer form for burn management, comparing two populations: those transferred before and after the transfer form implementation. This study included 47 adult patients; 21 were transferred before and 26 after implementing the transfer form. We observed a statistically significant improvement in reporting rates of crucial information obtained by Emergency Room clinicians and inpatient management indicators. Introducing a standardized transfer form for burn patients resulted in improved communication and enhanced primary management, transfer processes, and emergency room preparation. The burns transfer form facilitated accurate and comprehensive information exchange between clinicians, potentially improving patient outcomes. These findings highlight the importance of structured transfer processes in burn patient care and emphasize the benefits of implementing a transfer form to streamline communication and optimize burn management during transfers to specialized burn centers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: Efficacy of transfer form implementation for adult burn patients between institutions to the Israeli National Burn Center., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiac surgery involving cardiopulmonary bypass induces a significant systemic inflammatory response, contributing to various postoperative complications, including pulmonary dysfunction, myocardial and kidney injuries., Objective: To investigate the effect of Nitric Oxide delivery via the cardiopulmonary bypass circuit on various postoperative outcomes., Design: A prospective, single-centre, double-blinded, randomised controlled trial., Setting: Rabin Medical Centre, Beilinson Hospital, Israel., Patients: Adult patients scheduled for elective cardiac surgery were randomly allocated to one of the study groups., Interventions: For the treatment group, 40 ppm of nitric oxide was delivered via the cardiopulmonary bypass circuit. For the control group, nitric oxide was not delivered., Outcome Measures: The primary outcome was the incidence of hypoxaemia, defined as a paO2/FiO2 ratio less than 300 within 24 h postoperatively. The secondary outcomes were the incidences of low cardiac output syndrome and acute kidney injury within 72 h postoperatively., Results: Ninety-eight patients were included in the final analysis, with 47 patients allocated to the control group and 51 to the Nitric Oxide group. The Nitric Oxide group exhibited significantly lower hypoxaemia rates at admission to the cardiothoracic intensive care unit (47.1 vs. 68.1%), P = 0.043. This effect, however, varied in patients with or without baseline hypoxaemia. Patients with baseline hypoxaemia who received nitric oxide exhibited significantly lower hypoxaemia rates (61.1 vs. 93.8%), P = 0.042, and higher paO2/FiO2 ratios at all time points, F (1,30) = 6.08, P = 0.019. Conversely, this benefit was not observed in patients without baseline hypoxaemia. No significant differences were observed in the incidence of low cardiac output syndrome or acute kidney injury. No substantial safety concerns were noted, and toxic methaemoglobin levels were not observed., Conclusions: Patients with baseline hypoxaemia undergoing cardiac surgery and receiving nitric oxide exhibited lower hypoxaemia rates and higher paO2/FiO2 ratios. No significant differences were found regarding postoperative pulmonary complications and overall outcomes., Trial Registration: This trial was registered at ClinicalTrials.gov (NCT04807413)., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Despite effectiveness of the implantable cardioverter-defibrillator (ICD) in saving patients with life-threatening ventricular arrhythmias (VAs), the temporal occurrence of VA after ICD implantation is unpredictable., Objective: The study aimed to apply machine learning (ML) to intracardiac electrograms (IEGMs) recorded by ICDs as a unique biomarker for predicting impending VAs., Methods: The study included 13,516 patients who received Biotronik ICDs and enrolled in the CERTITUDE registry between January 1, 2010, and December 31, 2020. Database extraction included IEGMs from standard quarterly transmissions and VA event episodes. The processed IEGM data were pulled from device transmissions stored in a centralized Home Monitoring Service Center and reformatted into an analyzable format. Long-range (baseline or first scheduled remote recording), mid-range (scheduled remote recording every 90 days), or short-range predictions (IEGM within 5 seconds before the VA onset) were used to determine whether ML-processed IEGMs predicted impending VA events. Convolutional neural network classifiers using ResNet architecture were employed., Results: Of 13,516 patients (male, 72%; age, 67.5 ± 11.9 years), 301,647 IEGM recordings were collected; 27,845 episodes of sustained ventricular tachycardia or ventricular fibrillation were observed in 4467 patients (33.0%). Neural networks based on convolutional neural networks using ResNet-like architectures on far-field IEGMs yielded an area under the curve of 0.83 with a 95% confidence interval of 0.79-0.87 in the short term, whereas the long-range and mid-range analyses had minimal predictive value for VA events., Conclusion: In this study, applying ML to ICD-acquired IEGMs predicted impending ventricular tachycardia or ventricular fibrillation events seconds before they occurred, whereas midterm to long-term predictions were not successful. This could have important implications for future device therapies., Competing Interests: Disclosures A.L. receives consulting fees from SHL Telemedicine. A number of AI ECG algorithms have been licensed by Mayo Clinic to Anumana, Eko Health, and AliveCor; Mayo Clinic, P.A.F., I.Z.A., and S.J.A. may benefit financially from their commercialization. G.A.U. receives consulting and speaking fees from Biotronik, St Jude Medical, Medtronic, Boston Scientific, Philips BioTel, and Zoll Medical. S.J.A. receives honoraria and consulting and speaking fees from Biotronik, St Jude Medical, Medtronic, Boston Scientific, BioSig Technologies, and MediLynx. All other authors have no relevant relationships to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)