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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]

Objective: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.Methods: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs).Results: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs.Conclusions: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 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]

This has been discussed in detail in a recent systematic review by Mellis I et al i .[2], demonstrating that the incremental diagnostic yield of ES over CMA/karyotyping was 15% for non-selected fetal anomalies, 42% for selected anomalies and 17% for CNS anomalies. While patients were offered concurrent chromosomal microarray analysis (CMA) and exome sequencing (ES), most opted for termination of pregnancy even before receiving a genetic test result due to the severity of anomalies and because ES in pregnancy is currently not covered by the Israeli healthcare system. Even if the fetal phenotype may not appear to be severe enough to warrant termination of pregnancy, a genetic test result may point to a severe neurodevelopmental issue that has only mild physical manifestations. [Extracted from the article]

In addition to ventriculomegaly, abnormal corpus callosum and adducted thumbs, fetal MRI has also detected diencephalic and midbrain-hindbrain malformations in most fetuses affected by the L1 syndrome. L1 syndrome includes a spectrum of X-linked disorders caused by pathogenic variants of L1CAM gene, which encodes a cell adhesion molecule involved in the central nervous system (CNS) development. In addition to the evaluation of lateral ventricles, corpus callosum and cortical development, thalami and midbrain-hindbrain were investigated. [Extracted from the article]

OC12.05: Early second trimester diagnosis of fetal midbrain-hindbrain malformations: a transvaginal neurosonographic study To describe the clinical and neurosonographic features of fetal midbrain-hindbrain (MBHB malformation diagnosed at 14-18 weeks. The MBHB abnormalities include; kinking of the brainstem (KBS) (n = 3), Joubert syndrome (JS) (n = 2), aqueductal stenosis (AS) (n = 11), rhombencephalosynapsis (RES) (n = 3), "open" fourth ventricle (OFV) (n = 6), and Mobius syndrome (MS) (n = 1). [Extracted from the article]

Variants of unknown significance (VUS) poses a dilemma in prenatal genetic testing and counselling. Methods Cases were selected from a cohort of 87 patients who underwent TOP for major CNS anomalies and presented VUS either in genetic assessment. [Extracted from the article]

Fetal imaging findings (US, MRI or both) of fetuses with copy number variants (CNVs) or pathogenic/likely pathogenic sequence variants (SVs) were compared to the classical phenotype described by the literature. OC01.02: Genotype-phenotype correlation in fetuses with major brain malformations using whole-exome sequencing When performing fetal ultrasound (US) we are confronted with the difficult task of finding a correlation between imaging findings, diagnosis and prognosis. [Extracted from the article]

OC06.07: Maternal plasma genome-wide cell-free DNA testing can detect fetal aneuploidy in pregnancy loss and can be used to guide further work-up in recurrent losses However, the most common cause of miscarriage, even in RPLs, is random chromosomal aberrations (trisomy, monosomy, triploidy). We suggest that cfDNA-based testing serve to guide management in RPLs: if cfDNA in the 2nd and subsequent RPL demonstrates aneuploidy, no further action is taken; if cfDNA demonstrates an unbalanced rearrangement, parental karyotypes is recommended; and if no abnormality is detected, then the recommended RPL workup is performed. [Extracted from the article]

Investigates the mediation of epigenetic regulation of vernalization (VRN) in arabidopsis by VRN2. Analysis of plant growth conditions, vernalization treatments and flowering time; Administration of genetic and physical mapping; Prediction and identification of genes.

Selective termination is employed in multifetal pregnancies, in the presence of an abnormal fetus, in order to improve the prognosis of the normal fetuses. The term elective reduction is used to describe reduction in twin pregnancies for maternal medical conditions, psychological, or socioeconomic reasons. The purpose of this study was to evaluate the factors that influence outcome in such pregnancies. Eighty-two twin pregnancies underwent selective termination (n = 59) or elective reduction (n = 23) over a 10-year period. Early procedures, performed ≤14 weeks (n = 31), had a pregnancy loss of 9.7% and a mean procedure-to-loss interval of 4.1 ± 2.8 weeks; mean birthweight was 3299 ± 395 g in survivors, with a mean gestational age at delivery of 38.4 ± 2.3 weeks. In comparison, procedures performed >14 weeks (n = 51) had a pregnancy loss of 7.8%, with a procedure-to-loss interval of 1.2 ± 0.6 weeks. Mean birthweight was 2577 ± 999 g, with a mean gestational age at delivery of 35.7 ± 5 weeks. In conclusion, outcomes were more favourable among patients who underwent a first trimester procedure. The slight increase in pregnancy loss may be attributed to a higher than expected rate of spontaneous abortions in the first trimester, as manifested by the higher procedure-to-loss interval after a first trimester procedure. These facts underscore the importance of early detection of fetal abnormalities in twin pregnancies by ultrasonography and chorionic villus sampling. [ABSTRACT FROM PUBLISHER]

There are numerous studies concerning pregnancy rates in oocyte donation, yet only a handful report the obstetric outcome in such pregnancies. The purpose of this study was to assess factors that influence pregnancy rates, to determine the incidence of complications, and to evaluate obstetric outcome in pregnancies resulting from oocyte donation. This study included 423 oocyte recipients who underwent 1001 oocyte donation cycles at the Oocyte Donation Programme, In-Vitro Fertilization (IVF)-Embryo Transfer Unit, Herzlia Medical Center, Israel. Donors were all healthy women lt;34 years old who underwent IVF themselves. In 873 cycles, fertilization occurred and embryo transfer was performed, resulting in 194 clinical pregnancies. Pregnancy rates (PR) significantly declined with the increase in number of previous attempts, and with increasing age of recipient (36.8%/embryo transfer in patients 30 compared to 17.8% in patients >40 years old). A significant increment in PR was noted with the increasing number of embryos transferred. The overall PR was 22.2%/embryo transfer. However, in young amenorrhoeic patients with normal karyotypes undergoing their first cycle, PR was 52.2%; the 'take home baby' rate was 38.3% per patient undergoing embryo transfer and 17.8% per embryo transfer cycle. A significant increase in the incidence of pregnancy-induced hypertension and a higher proportion of abortions were noted in older patients. A significantly higher incidence of prematurity and low birthweight was observed in multiple pregnancies. [ABSTRACT FROM PUBLISHER]

There has been growing concern about the number of multiple gestations resulting from assisted reproductive technologies. For in-vitro fertilization (IVF), there are guidelines concerning the number of embryos to be transferred. In oocyte donation, however, there is a paucity of studies addressing this issue and common practice is extrapolated from standard IVF procedures. This may not be correct since endometrial receptivity has been shown to be altered in oocyte donation. Thus the purpose of this study was to assess the optimal number of embryos to be transferred in oocyte donation. The study population included 254 patients with ovarian failure who underwent a total of 601 embryo transfers in a single shared oocyte donation programme. Pregnancy rates (PRs), multiple pregnancies, triplet pregnancy rates, and implantation rates were evaluated according to the number of embryos transferred. A significant linear increase in PRs was noted with the increasing number of embryos transferred up to five (11.1% for one embryo, 36.7% for five embryos). Multiple pregnancies increased significantly from 15.8% for two embryos transferred, to 44.4% for five embryos. The rate of triplet pregnancies also increased from 2.7% for three embryos transferred, to 8.3% for five embryos. Optimization of the number of embryos to be transferred is discussed. [ABSTRACT FROM PUBLISHER]

Multifetal pregnancy reduction (MFPR) appears to be an efficacious method for improving the perinatal outcome of ‘high order’ multifetal gestations. The present study was undertaken to evaluate pregnancy outcomes after MFPR to twins in comparison with spontaneously conceived twins. In all, 10 patients with quadruplet gestations (group 1) and 30 patients with triplet gestations (group 2), who underwent MFPR to twins, were prospectively enrolled. Pregnancy complications, gestational age at delivery, mode of delivery and birthweights were compared with 30 consecutive spon-taneous twin gestations (group 3) matched by maternal age and parity. Mean gestational age at delivery and mean birthweights were significantly lower in group 1, compared with groups 2 and 3 (33.2, 35.9, 36.9 weeks, and 1843, 2209, 2361 g respectively). The incidence of pregnancy complications was significantly higher in group 1 compared with group 3. There was also a clear trend of increased incidence of specific pregnancy complications in group 1 compared with groups 2 and 3, especially premature contractions (PMC; 50, 27 and 13% respectively), and pregnancy-induced hypertension (PIH; 40, 23 and 7% respectively). In conclusion, the initial number of fetuses before reduction was inversely correlated with gestational age at delivery and birthweight, and positively correlated with pregnancy complications. Contrary to previous studies, we found a higher incidence of pregnancy complications after MFPR compared with spontaneous twins, especially PMC and PIH. [ABSTRACT FROM PUBLISHER]

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.)

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.

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.)

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).)

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.)

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.

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).)

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).)

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.