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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]

This article, titled "EP18.14: The fetal brain in RASopathies: Noonan genes revisited," explores the neurodevelopmental variability and brain imaging features of patients with RASopathies. The study focuses on describing the fetal brain and associated features of fetuses with confirmed RASopathies. The researchers conducted a retrospective study that included four patients with variants in RIT1, LZTR1, RRAS-2, and PTPN11. The findings highlight the range of features observed in fetal brain imaging and emphasize the importance of prenatal assessment for accurate diagnosis and counseling. [Extracted from the article]

This article discusses a case study involving a non-consanguineous Jewish couple who terminated a pregnancy due to multiple brain malformations. The couple sought genetic counseling, and trio exome sequencing revealed a heterozygous de-novo likely pathogenic variant in the KIDINS220 gene. This gene encodes a protein that plays a crucial role in embryonic neuronal differentiation and the maturation of axonal/dendritic processes. Heterozygous variants in KIDINS220 have been linked to a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity. The report emphasizes the importance of additional investigations in cases of non-isolated ventriculomegaly and expands the prenatal phenotype associated with KIDINS220 variants. [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]

In breast cancer the human epidermal growth factor receptor 2 (HER2) is an important target for a number of different HER2 inhibitors. Different slide-based assays are available for assessment of treatment eligibility, which include fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods for assessment of the HER2 gene status. Here we report a summary of the validation data on HER2 IQFISH pharmDx™ (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. The assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of 3½ to 4 h from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary covers method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay with a high precision that is at least comparable to the manual HER2 IQFISH pharmDx™ assay and the PathVysion ® HER-2 DNA Probe Kit. [ABSTRACT FROM AUTHOR]

Objectives: To describe the characteristics, secular trends, and outcomes of home parenteral nutrition (HPN) use among children with severe neurological impairment (SNI) and non-primary digestive disorders from 2010 to 2023 and compare outcomes to children with primary digestive disorders on HPN., Methods: A retrospective review of all children with SNI and non-primary digestive disorders, where HPN was initiated between January 2010 and September 2023 at a tertiary care pediatric hospital. The Mann-Kendall trend test was used to assess trends in HPN initiation. We compared acute care service utilization in the year prior and following HPN initiation. Mortality and ability to achieve enteral autonomy outcomes were compared to those of children with HPN and primary digestive disorders., Results: Of the 205 included children with HPN, 18 children had SNI and non-primary digestive disorders, 187 children had primary digestive disorders. There was an increase in HPN initiation among children with SNI and non-primary digestive disorders (p = 0.002) between 2010 and 2020. Among children with SNI and non-primary digestive disorders, HPN-related complications (line-associated infection/thrombus, nephrolithiasis, cholelithiasis) occurred in 72%. There was no change in acute care utilization in the year prior versus year following HPN initiation. Compared with the primary digestive disorders group, children with SNI and non-primary digestive disorders were less likely to achieve enteral autonomy (p < 0.0001); however, no significant differences in mortality were observed (22% vs. 8%, p = 0.09)., Conclusions: HPN is increasingly being used among SNI children with non-primary digestive disorders. Compared to children with primary digestive disorders on HPN, those with SNI are less likely to achieve enteral autonomy., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Finding optimal bipartite matchings-e.g., matching medical students to hospitals for residency, items to buyers in an auction, or papers to reviewers for peer review-is a fundamental combinatorial optimization problem. We found a distributed algorithm for computing matchings by studying the development of the neuromuscular circuit. The neuromuscular circuit can be viewed as a bipartite graph formed between motor neurons and muscle fibers. In newborn animals, neurons and fibers are densely connected, but after development, each fiber is typically matched (i.e., connected) to exactly one neuron. We cast this synaptic pruning process as a distributed matching (or assignment) algorithm, where motor neurons "compete" with each other to "win" muscle fibers. We show that this algorithm is simple to implement, theoretically sound, and effective in practice when evaluated on real-world bipartite matching problems. Thus, insights from the development of neural circuits can inform the design of algorithms for fundamental computational problems., Competing Interests: Competing interests statement:The authors declare no competing interest.

Having a profound influence on marine and coastal environments worldwide, jellyfish hold significant scientific, economic, and public interest. 1 , 2 , 3 , 4 , 5 The predictability of outbreaks and dispersion of jellyfish is limited by a fundamental gap in our understanding of their movement. Although there is evidence that jellyfish may actively affect their position, 6 , 7 , 8 , 9 , 10 the role of active swimming in controlling jellyfish movement, and the characteristics of jellyfish swimming behavior, are not well understood. Consequently, jellyfish are often regarded as passively drifting or randomly moving organisms, both conceptually 2 , 11 and in process studies. 12 , 13 , 14 Here we show that the movement of jellyfish is modulated by distinctly directional swimming patterns that are oriented away from the coast and against the direction of surface gravity waves. Taking a Lagrangian viewpoint from drone videos that allows the tracking of multiple adjacent jellyfish, and focusing on the scyphozoan jellyfish Rhopilema nomadica as a model organism, we show that the behavior of individual jellyfish translates into a synchronized directional swimming of the aggregation as a whole. Numerical simulations show that this counter-wave swimming behavior results in biased correlated random-walk movement patterns that reduce the risk of stranding, thus providing jellyfish with an adaptive advantage critical to their survival. Our results emphasize the importance of active swimming in regulating jellyfish movement and open the way for a more accurate representation in model studies, thus improving the predictability of jellyfish outbreaks and their dispersion and contributing to our ability to mitigate their possible impact on coastal infrastructure and populations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression., (© 2024. The Author(s).)

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 p a O2 /FiO 2 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 p a O2 /FiO 2 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 p a O2 /FiO 2 ratios. No significant differences were found regarding postoperative pulmonary complications and overall outcomes., Trial Registration: NCT04807413., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Caustic ingestions are relatively uncommon, but remain a significant source of morbidity. Patients with caustic injury often undergo an urgent EGD, although it is not clear if an EGD is routinely needed in an asymptomatic patient. The study has two primary objectives; 1) to determine the utility of routine EGD in asymptomatic suicidal caustic ingestions; 2) to determine if asymptomatic unintentional acidic ingestions can be managed with observation alone, similar to basic ingestions., Methods: This retrospective study, which took place at 14 hospitals in three countries evaluated all patients who presented with a caustic ingestion between 2014-2020. The presence of symptoms and esophageal injury, demographic information, pH of ingested substance, reason for the ingestion, and outcome were recorded., Results: 409 patients were identified; 203 (46.9%) were male. The median (IQR) age was 18 (4-31) years; overall range 10 months to 78 years. Suicidal ingestions accounted for 155 (37.9%) of cases. Dysphagia or dysphonia were more likely in those with significant esophageal injury compared to those without (59.3% vs. 12.6% respectively; OR 10.1; 95% CI 4.43-23.1). Among 27 patients with significant esophageal injury, 48% were found in suicidal patients, compared with 51.9% in non-suicidal patients (p = NS). On multivariate regression, there was no difference in the rate of significant esophageal injury among suicidal vs. non suicidal patients (aOR 1.55; p = 0.45, 95% CI 0.45-5.33). Most ingestions involved basic substances (332/409; 81.2%). Unknown or mixed ingestions accounted for 25 (6.11%) of the ingestions. Significant esophageal burns were found in 6/52 (11.5%) of acid ingestions, compared with 21/332 (6.3%) of basic ingestions. Of the 42 cases of acidic ingestions without dysphagia or odynophagia, 2 (4.8%; 0.58-16.1%) had significant esophageal burns, compared with 9 (3.2%; 95% CI 1.4-5.9%) of the 284 basic ingestions; p = 0.64). On multivariate logistic regression, patients with acidic ingestions were not more likely to experience a significant burn (aOR 1.7; p = 0.11, 95% CI 0.9-3.1) compared to those with basic ingestions. No patient with significant esophageal burns was asymptomatic., Conclusion: In this study, there was no statistical differences in the rates of significant burns between acidic and basic caustic ingestions. There were no significant esophageal injuries noted among asymptomatic patients., (© 2024. American College of Medical Toxicology.)

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.)

Background: While mammalian target of rapamycin inhibitors have revolutionized the management of angiofibroma in tuberous sclerosis complex (TS), physical modalities such as laser are still indicated for recalcitrant lesions., Objective: The authors performed a systematic review of the efficacy and safety of laser treatment for TS-related facial angiofibroma., Methods: The electronic databases such as MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to October 10, 2023, for eligible records., Results: Forty-seven articles met the inclusion criteria, representing a total of 217 patients with TS-related facial angiofibroma who received laser treatment. Several lasers have been trialed in patients including carbon dioxide ( n = 95, 43.7%), pulsed dye ( n = 21, 9.7%), argon ( n = 16, 7.4%), neodymium-doped: yttrium aluminum garnet ( n = 12, 5.5%), copper vapor ( n = 9, 4.1%), potassium titanyl phosphate ( n = 7, 3.2%), erbium: yttrium aluminum garnet ( n = 2, 0.9%), lasers and various combination therapies ( n = 55, 25.3%)., Conclusion: Potassium titanyl phosphate, pulsed dye, and neodymium-dopsed:yttrium aluminum garnet lasers are better suited to manage the vascular components of angiofibroma while ablative lasers such as erbium: yttrium aluminum garnet and carbon dioxide lasers may present better options for lesions with a prominent fibrous component. While several lasers have been trialed with broadly favorable results, the low level of evidence precludes definitive conclusions, and no single laser appears superior., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society for Dermatologic Surgery, Inc.)

Background: Esophageal cancer is the eighth most common cause of cancer-related deaths worldwide. There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma. Among the factors associated with the development of esophageal cancer, estrogen receptor beta (ERβ) has been found to have a clinical significance., Aim: To investigate the relationship between ERβ expression and esophageal cancer., Methods: English Medical literature searches were conducted for ERβ expression in patients with esophageal cancer versus healthy controls. Searches were performed up to August 31, 2023, using MEDLINE, PubMed, Embase and Google Scholar. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 4, Biostat Inc., Englewood, NJ, USA). Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated. Heterogeneity was evaluated using Cochrane Q-test, and it was considered present if the Q-test P value was less than 0.10. I 2 statistic was used to measure the proportion of inconsistency in individual studies, with I 2 > 50% representing heterogeneity. We also calculated a potential publication bias., Results: Ten studies representing 11 substudies were selected according to the inclusion criteria. The odds ratio of ERβ expression in fixed effect analysis was 0.448, 95% CI: 0.237 to 0.846, 55.2% lower in esophageal cancer than in normal mucosa. Heterogeneity and inconsistency were low, and no publication bias was demonstrated., Conclusion: This meta-analysis showed that ERβ expression is lower in esophageal cancer biopsy specimens than in healthy controls, this finding may have a significant effect on survival and can lead to new therapeutic avenues.

Introduction: Despite diagnostic and therapeutic advances, infective endocarditis (IE) is still associated with high mortality rates. Currently, there are no good prognostic tools for the risk assessment of patients with IE. The CHA 2 DS 2 -VASc score, used to estimate the risk of ischemic stroke in patients with non-valvular atrial fibrillation (AF), has been shown to be a powerful predictor of stroke and death in patients without known AF associated with other cardiovascular conditions. Objective: We aimed to evaluate the usefulness of the CHA 2 DS 2 -VASc score as a prognostic tool in a population of patients with IE. Methods: The Rabin Medical Center Endocarditis Team (RMCET) registry is a retrospective cohort of all patients evaluated at our center due to acute or sub-acute bacterial endocarditis. The CHA 2 DS 2 -VASc score was extracted for all patients. All-cause mortality was depicted for all patients. Results: The cohort included 330 patients with a mean age of 65.2 ± 14.7 years (70% men). During a median follow-up of 24 months [IQR 4.7-48.6], 121 (36.7%) patients died. The median CHA 2 DS 2 -VASc score was 3, and any score above 2 was associated with increased overall mortality (50.8% vs. 19.9%, p < 0.001). A multivariate model incorporating important confounders not included in the CHA 2 DS 2 -VASc model showed consistent results with a risk increase of 121% for the higher CHA 2 DS 2 -VASc score groups (HR 2.21 [CI 1.12-4.39], p = 0.023). Conclusions: IE currently has no good risk stratification models for clinical practice. The CHA 2 DS 2 -VASc score might serve as a simple and available tool to stratify risk among patients with IE.

Objective: The management of visual field damage in patients with macroprolactinomas is a major therapeutic challenge. We aimed to study the visual morbidity associated with macroprolactinoma and its outcomes following medical and surgical treatment. We aimed to identify predictors of visual recovery., Methods: We retrospectively reviewed patient's data including clinical presentation, serial pituitary magnetic resonance imaging, laboratory tests, visual symptoms and neuro-ophthalmologic examination, visual field tests and optical coherence tomography tests. The main outcome was complete visual field recovery. Descriptive analyses were conducted. Predictors of visual recovery were investigated., Patients: The study cohort included 150 patients with macroprolactinoma [median follow-up, 6.0 years (interquartile range (IQR) 2.9-10.6)]., Results: At diagnosis, visual field defects were evident in 40 patients (26.7%). At the end of follow-up, 24 out of 39 available visual field tests (61.5%) exhibited complete recovery. Patients that achieved complete visual recovery had smaller macroadenomas at diagnosis [30.5 mm (15.0-80.0) vs. 42.0 mm (30.0-85.0), p < .01], lower baseline serum prolactin levels [1414 mcg/L (489-3586) vs. 4119 mcg/L (2715-6315), p < .01], lower rates of central hypogonadism (78.3% vs. 93.3%, p = .05) and central hypothyroidism (20.8% vs. 53.3%, p = .04), lower rates of compressive optic neuropathy (35.3% vs. 87.5%, p = .02) and a better visual acuity (better than 6/8 in both eyes, 93.7% vs. 28.6%, p < .01)., Conclusions: In our cohort of 150 patients with macroprolactinoma, 40 patients (26.7%) presented with visual field defects, of which 61.5% achieved complete visual recovery with treatment. Patients that achieved complete visual recovery presented with smaller macroadenomas, lower serum prolactin levels, lower rates of central hypogonadism and central hypothyroidism, lower rates of compressive optic neuropathy and better visual acuity., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Millicharged particles appear in several extensions of the standard model, but have not yet been detected. These hypothetical particles could be produced by an intense proton beam striking a fixed target. We use data collected in 2020 by the SENSEI experiment in the MINOS cavern at the Fermi National Accelerator Laboratory to search for ultrarelativistic millicharged particles produced in collisions of protons in the NuMI beam with a fixed graphite target. The absence of any ionization events with 3 to 6 electrons in the SENSEI data allow us to place world-leading constraints on millicharged particles for masses between 30 to 380 MeV. This work also demonstrates the potential of utilizing low-threshold detectors to investigate new particles in beam-dump experiments, and motivates a future experiment designed specifically for this purpose.

This study describes the neurodevelopmental outcome of children with urea cycle disorders (UCD) and organic acidemias (OA) preliver transplant (LT), 1-year, and 3-years post-LT. We performed a retrospective chart review of children with OA or UCD transplanted between January 2014 and December 2021. Standardized motor and cognitive assessment scores were collected from children who had ≥1 motor/cognitive assessment at any timepoint. Pre-LT brain magnetic resonance imaging (MRI) was graded. Associations between demographic/medical variables and neurodevelopmental outcomes were explored. Twenty-six children (64% male) underwent LT at a median age of 1.4 (interquartile range 0.71, 3.84) years. Fifteen (58%) had a UCD diagnosis, 14 (54%) required dialysis for hyperammonemia, and 10 (42%) had seizures typically around diagnosis. The proportion of children with gross motor scores >1 standard deviation (SD) below the mean increased across timepoints, and ≥50% demonstrated general intellect scores >2 SD below the mean at each timepoint. The following significant associations were noted: UCD diagnoses with lower general intellect scores (p = 0.019); arginosuccinate lyase deficiency diagnosis with lower visual motor scores at 3-years post-LT (p = 0.035); a history of seizures pre-LT with lower general intellect (>2SD below the mean) at 3-years post-LT (p = 0.020); dialysis pre-LT with lower motor scores (>1 SD below the mean) at 1-year post-LT (p = 0.039); pre-emptive LT with higher general intellect scores at 3-years post-LT (p = 0.001). MRI gradings were not associated with developmental scores. In our single centre study, children with UCD or OA had a higher prevalence of developmental impairment post-LT compared to population norms. Earlier screening, pre-emptive transplant, and rehabilitation may optimize long-term outcomes., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Mapping neuronal networks is a central focus in neuroscience. While volume electron microscopy (vEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide molecular information to identify cell types or functions. We developed an approach that uses fluorescent single-chain variable fragments (scFvs) to perform multiplexed detergent-free immunolabeling and volumetric-correlated-light-and-electron-microscopy on the same sample. We generated eight fluorescent scFvs targeting brain markers. Six fluorescent probes were imaged in the cerebellum of a female mouse, using confocal microscopy with spectral unmixing, followed by vEM of the same sample. The results provide excellent ultrastructure superimposed with multiple fluorescence channels. Using this approach, we documented a poorly described cell type, two types of mossy fiber terminals, and the subcellular localization of one type of ion channel. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable molecular overlays for connectomic studies., (© 2024. The Author(s).)

Objective: Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls., Design: A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel., Methods: Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event., Results: A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9-20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44-2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies., Conclusion: Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population., Competing Interests: Conflict of Interest: Yaron Rudman, Laura Dery, Hiba Masr-Iraqi, Liat Sasson, Tzipora Shochat, and Shiri Kushnir do not have any financial or personal relationships with other people or organizations to disclose. Amit Akirov has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm. Maria Fleseriu has been a PI with research funding from the university and has received occasional scientific fee for scientific consulting and advisory boards from Crinetics, Recordati, Sparrow, and Xeris. Ilan Shimon has been an investigator for Xeris Biopharma and has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. 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.)

Background: This study investigates the rising trend of total hip arthroplasty (THA) in patients under 55 years old, commonly referred to as "younger" THA patients. Traditionally a procedure for older adults with osteoarthritis, THA is increasingly performed on younger patients. Methods: Using data from the Nationwide Inpatient Sample (NIS) from 2016 to 2019, we analyze the factors driving this trend, including the causes of hip issues, patient characteristics, and coexisting medical conditions. The study examines in-hospital mortality, length of stay, post-surgical complications, and hospitalization costs for 231,630 THA patients aged 18-54.9, identified using ICD-10 codes. Results: Statistical analysis revealed that younger patients (aged 18-34.9) had higher rates of chronic anemia, inflammatory bowel disease, sickle cell disorders, connective tissue disorders, and coagulation defects compared to patients aged 35-44.9 and 45-54.9. They also experienced the longest hospital stays (2.08 days) and highest costs ($70,540). Significant odds ratios were found for sickle cell disorders (36.078), coagulation defects (1.566), inflammatory bowel disease (2.582), connective tissue disorders (11.727), hip dislocation (3.447), and blood transfusion (1.488) in younger patients compared to other THA patients. Conclusions: Comprehensive analysis of these unique needs is crucial for optimizing care, tailoring treatment, managing co-existing conditions, and personalizing recovery strategies to improve outcomes and quality of life for younger THA patients.

Motivation: CRISPR/Cas9 technology has been revolutionizing the field of gene editing. Guide RNAs (gRNAs) enable Cas9 proteins to target specific genomic loci for editing. However, editing efficiency varies between gRNAs and so computational methods were developed to predict editing efficiency for any gRNA of interest. High-throughput datasets of Cas9 editing efficiencies were produced to train machine-learning models to predict editing efficiency. However, these high-throughput datasets have a low correlation with functional and endogenous datasets, which are too small to train accurate machine-learning models on., Results: We developed DeepCRISTL, a deep-learning model to predict the editing efficiency in a specific cellular context. DeepCRISTL takes advantage of high-throughput datasets to learn general patterns of gRNA editing efficiency and then fine-tunes the model on functional or endogenous data to fit a specific cellular context. We tested two state-of-the-art models trained on high-throughput datasets for editing efficiency prediction, our newly improved DeepHF and CRISPRon, combined with various transfer-learning approaches. The combination of CRISPRon and fine-tuning all model weights was the overall best performer. DeepCRISTL outperformed state-of-the-art methods in predicting editing efficiency in a specific cellular context on functional and endogenous datasets. Using saliency maps, we identified and compared the important features learned by DeepCRISTL across cellular contexts. We believe DeepCRISTL will improve prediction performance in many other CRISPR/Cas9 editing contexts by leveraging transfer learning to utilize both high-throughput datasets and smaller and more biologically relevant datasets., Availability and Implementation: DeepCRISTL is available via https://github.com/OrensteinLab/DeepCRISTL., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate., Methods: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response., Results: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received., Conclusion: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Purpose: The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status., Methods: This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter., Results: The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85 years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70 g/dL vs. 13.12 g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20 g/dL and 40.08% in patients with CD and aCS vs. 13.20 g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001)., Conclusion: Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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, central venous catheter complications and nephrocalcinosis. Kaplan-Meier 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.)

Weeds are the primary biotic constraint affecting sesame growth and production. Here, we applied EMS mutagenesis to an elite sesame cultivar and discovered a novel point mutation in the sesame SiALS gene conferring resistance to imidazolinone, a group of acetolactate-synthase (ALS)-inhibitors. The mutant line exhibited high resistance to imazamox, an ALS-inhibitor, with hybrid plants displaying an intermediate response. Field-based validation confirmed the mutant line's substantial resistance, leading to a significantly higher yield under imazamox treatment. Under pre-emergence application of imazapic, the mutant plants sustained growth, whereas wild-type and weed were effectively controlled. Field trials using s-metolachlor and imazapic combined resulted in weed-free plots compared to untreated controls. Consequently, this treatment showed a significantly greater yield (2280 vs. 880 Kg ha -1 ) than the commercial practice (s-metolachlor). Overall, our study unveils the potential of utilizing this point mutation in sesame breeding programs, offering new opportunities for integrated weed management strategies for sesame cultivation. Developing herbicide-resistant crop plants holds promise for supporting sustainable production and addressing the challenges of weed infestations in sesame farming., 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 B.V. All rights reserved.)

Suicide is the second leading cause of death among youth aged 15-24 years. Identifying modifiable risk factors relevant to adolescents is crucial for suicide prevention. Sleep patterns have been linked to suicidality in adults, but lack sufficient study in youth. This ecological momentary assessment (EMA) study aimed to explore the relationship between objectively and subjectively measured sleep characteristics and next-day suicidal ideation in high-risk youth. We included 29 adolescents (12-18 years old) admitted to the inpatient psychiatric ward post-suicide attempt or due to suicidal intent within the previous month. We conducted objective (actigraphy) and subjective (sleep diary) sleep pattern assessments over ten consecutive days. Daily suicidal ideation was evaluated using a questionnaire based on the validated C-SSRS interview. A significant positive association was observed between sleep onset latency (SOL) and expressing a "death wish" the following day (OR = 1.06, 95% CI [1-1.11], p = .04), with each minute of longer SOL increased the risk for a death wish the following day by 6%. In addition, a marginally significant negative association was observed between total sleep time (TST) and expressing a "death wish" the following day (OR = 0.57, 95% CI [0.3-1.11], p = 0.1), with each one-hour decrease in objectively measured TST increasing the odds of a death wish by 43%. Our study highlights the interplay between sleep patterns and suicidal ideation, with SOL and TST playing a significant role that may function as proximal risk factors for suicidality and as a target for intervention while treating suicidal youth., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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.)

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.)

Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability., Methods: A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib-an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence., Results: At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded., Summary: The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach., Competing Interests: YI is the founder of Oberon Sciences, SA is a consultant for Oberon Sciences, and MB is a consultant for Area9. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sigawi, Gelman, Maimon, Yossef, Hemed, Agus, Berg, Ilan and Popovtzer.)

Purpose: This study investigates the seasonal patterns of hip fracture occurrence and mortality rates in the elderly population of Israel., Methods: In this retrospective study, we examined a random sample of 400 patients who underwent a hip fracture repair surgery at a 495-bed hospital in northern-central Israel during the years 2021-2022., Results: Our findings reveal a heightened incidence of hip fractures during the spring (30.8%) in contrast to relatively consistent rates during other seasons (22-24.2%). Patients experiencing hip fractures in the spring were notably younger and had shorter hospital stays compared to those in other seasons. Furthermore, we identified seasonal variations in hip fracture incidence concerning gender, culture, and nationality. Over the 2-year follow-up period, 20% of patients had succumbed to mortality. The highest survival rate was associated with hip fractures sustained in the spring, while the lowest rates were observed in the autumn and winter., Conclusion: While our study highlights significant seasonal variations in hip fracture occurrence and mortality rates among the elderly population in Israel, caution is warranted in interpreting the implications for post-fracture care and resource allocation. The observed heightened incidence of hip fractures during the spring, particularly among younger patients with shorter hospital stays, suggests the need for further investigation into potential risk factors and preventive measures specific to this season. Additionally, our identification of seasonal variations in hip fracture incidence across demographic factors underscores the importance of tailored interventions to address the diverse needs of different populations., (© 2024. The Author(s).)