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Objective: Postpartum depression (PPD) is a major mental health issue affecting 10%-15% of women globally. This meta-analysis synthesized updated evidence on sub-anesthetic ketamine/esketamine's efficacy in preventing PPD., Methods: Randomized controlled trials (RCTs) comparing ketamine/esketamine to a placebo for PPD prevention were searched without language restriction. Primary outcomes were PPD risk at 1- and 4-6-week postpartum. Secondary outcomes included the difference in depression scores and risk of adverse events. Trial sequential analysis (TSA) was conducted to validate the reliability., Results: A meta-analysis of 22 RCTs (n = 3,463) showed that ketamine/esketamine significantly decreased PPD risk at 1- (risk ratio [RR], 0.41; 95% confidence interval [CI], 0.3-0.57) and 4-6-week (RR, 0.47; 95%CI, 0.35-0.63) follow-ups. Consistently, participants receiving ketamine/esketamine had lower depression-related scores at 1- (standardized mean difference [SMD], -0.94; 95%CI, -1.26 to -0.62) and 4-6-week (SMD, -0.89; 95%CI, -1.25 to -0.53) follow-ups. Despite potential publication bias, TSA confirmed the evidence's reliability. Subgroup analysis showed that ketamine/esketamine's preventive effect on 1-week PPD was consistent, regardless of administration timing, type of agents, or total dosage (<0.5 vs. ≥0.5 mg/kg). For the 4-6-week period, PPD risk was favorably reduced only with postoperative administration or the use of esketamine, with the total dosage having no observed influence. Participants on ketamine/esketamine experienced more frequency of hallucinations (RR, 4.77; 95%CI, 1.39-16.44) and dizziness (RR, 1.36; 95%CI, 1.02-1.81)., Conclusion: Our findings advocate for the postoperative administration of low-dose ketamine/esketamine to avert PPD, which needed additional research for confirmation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and study aims Use of fluoroscopy in gastrointestinal endoscopy is an essential aid in advanced endoscopic interventions. However, it also raises concerns about radiation exposure. This study aimed to develop consensus-based statements for safe and effective use of fluoroscopy in gastrointestinal endoscopy, prioritizing the safety and well-being of healthcare workers and patients. Methods A modified Delphi approach was employed to achieve consensus over three rounds of surveys. Proposed statements were generated in Round 1. In the second round, panelists rated potential statements on a 5-point scale, with consensus defined as ≥80% agreement. Statements were subsequently prioritized in Round 3, using a 1 (lowest priority) to 10 (highest priority) scale. Results Forty-six experts participated, consisting of 34 therapeutic endoscopists and 12 endoscopy nurses from six continents, with an overall 45.6% female representation (n = 21). Forty-three item statements were generated in the first round. Of these, 31 statements achieved consensus after the second round. These statements were categorized into General Considerations (n = 6), Education (n = 10), Pregnancy (n = 4), Family Planning (n = 2), Patient Safety (n = 4), and Staff Safety (n = 5). In the third round, accepted statements received mean priority scores ranging from 7.28 to 9.36, with 87.2% of statements rated as very high priority (mean score ≥ 9). Conclusions This study presents consensus-based statements for safe and effective use of fluoroscopy in gastrointestinal endoscopy, addressing the well-being of healthcare workers and patients. These consensus-based statements aim to mitigate risks associated with radiation exposure while maintaining benefits of fluoroscopy, ultimately promoting a culture of safety in healthcare settings., Competing Interests: Conflict of Interest Tyler Berzin - Consultant for: Medtronic, Boston Scientific, Wision AI, Microtech. Alan N. Barkun - Consultant for Olympus Inc and Medtronic Inc. Cecilia Binda – Lecturer for Steris, Fujifilm, Boston Scientific, Q3 Medical. Alessandro Fugazza – Consultant for Boston Scientific. Rogier P. Voermans - Consultancy and research grant for Boston Scientific, Research grant Prion Medical; Consultancy fee form from Cook Medical. Lecturer Viatris and Zambon. Nauzer Forbes – Speaker for Boston Scientific, Pentax Medical. Consultant for Boston Scientific, Pentax Medical and AstraZeneca. Mariano Villarroel – Consultant for Boston Scientific. Yen-I Chen – Consultant for Boston Scientific. President of Chess Medical. Robert Bechara – Consultant for Olympus, Pentax, Vantage, Medtronic, Pendopharm. Payal Saxena – Consultant for Boston Scientific, Ambu, Erbe. Amrita Sethi – Consultant for Boston Scientific, Interscope, Medtronic, Olympus; Research Support for Boston Scientific, Fujifilm and ERBE. Cesare Hassan: Fujifilm Co. (consultancy); Medtronic Co. (consultancy). Alessandro Repici: Fujifilm Co. (consultancy); Olympus Corp (consultancy); Medtronic Co. (consultancy). Bret Peterson – Consultant for Olympus, Pentax. Investigator for Boston Scientific and Ambu. Silvia Carrara – Consultant for Olympus and Aboca. Jeffrey D. Mosko – Speaker for Boston Scientific, Pendopharm, SCOPE rounds, Vantage, Medtronic. Medical Advisory Board for Pendopharm, Boston Scientific, Janssen, Pentax, Fuji. Grants and Research support from CAG. Christopher W. Teshima – Speaker for Medtronic and Boston Scientific, Consultant for Boston Scientific. Gary R. May – Consultant for Olympus. Speaker for Pentax, Fuji and Medtronic. Samir C Grover –Research grants and personal fees from AbbVie and Ferring Pharmaceuticals, personal fees from Takeda, Sanofi, and BioJAMP, education grants from Janssen, and has equity in Volo Healthcare. All the authors have no relevant financial disclosures or conflicts of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Pre-coordinated lanthanide-containing complexes are used to crosslink polyethyleneimine-modified gelatin to form gelatin hydrogel through imine bond formation.

Background: A significant number of coronavirus disease 2019 (COVID-19) survivors are experiencing long COVID, with symptoms lasting beyond three months. While diverse long COVID symptoms are established, there are gaps in understanding its long-term trends, intensity, and risk factors, requiring further investigation., Aims: This study aimed to investigate the long COVID characteristics and associated factors by following COVID-19 survivors for one year post-infection and comparing them with healthy counterparts., Main Methods: In this longitudinal, correlational study, COVID-19 survivors diagnosed between November 2021 and February 2023 were monitored every three months for a year. Participants aged ≥18 years who had reported a positive COVID-19 test were recruited via social media and healthcare provider referrals., Key Findings: Out of 182 survivors who initially agreed to participate, 176 completed the study. The mean age was 47.56 years (SD = 16.2), and 51.1 % were female. There was a clinically significant decline in cognitive function and health-related quality of life over time, with symptoms like shortness of breath, reduced physical fitness, and increased health concerns. Those with severe acute COVID-19 symptoms experienced greater cognitive and physical declines and more shortness of breath a year later. Lower financial status was linked to poorer health-related quality of life and increased health concerns., Significance: A year post-infection, COVID-19's impact on cognitive function and health-related quality of life remains significant, affecting individuals and communities. Survivors with severe initial symptoms and economic disadvantages need more attention. Future research should identify additional predictors of severe long COVID., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024. Published by Elsevier Inc.)

Halogenated volatile organic compounds (HVOCs) pose significant bioaccumulative and toxicological risks, necessitating effective strategies for their removal. Here, we show, through a computational study employing density functional theory and coupled cluster methods, the detailed mechanism and kinetic properties of Cl-initiated degradation reactions of 2-chloropropane (2-CP, (CH 3 ) 2 CHCl) and 2-methylpropanoyl halide ((CH 3 ) 2 CHCOX, X = Cl, Br, F). The reaction rate constants of all the channels were calculated by the canonical variational transition state theory (CVT) with the correction of the small curvature tunneling effect (SCT) at 200-1000 K. The subsequent transformation pathways of the major radical products of (CH 3 ) 2 CHCl and (CH 3 ) 2 CHCOCl in the presence of O 2 , NO, and HO 2 radical were investigated. The results elucidate the reaction pathways and rate constants, which are in excellent agreement with the experimental data at 296 K. We further explore the atmospheric implications of these reactions by assessing the atmospheric lifetime (τ) and ozone depletion potential (ODP). Additionally, we delve into the aquatic toxicity and bioaccumulation potential of the reactants and their transformation products. This study not only advances our knowledge of the atmospheric fate of halogenated hydrocarbons but also underscores the importance of considering the environmental and toxicological impacts in the development of HVOC mitigation strategies.

Perovskite light-emitting diodes (PeLEDs) are promising for next-generation high-definition displays. One of the keys to achieving high performance PeLEDs lies in how to fabricate crystalline and dense perovskite films. However, there exist challenges to directly grow well-crystallized CsPbBr 3 nanocrystal thin films on transport layers due to low solubility in solvents and fast precipitation of all-inorganic CsPbBr 3 , and the corresponding bright, efficient, and stable green PeLEDs have rarely been reported. Herein, we report an efficient strategy to prepare well-crystallized and dense CsPbBr 3 nanocubes for ultrabright and efficient green PeLEDs. We introduce sulfobetaine zwitterion as crystallization control agent and strontium fluoride nanocrystals as nucleation seeds to grow high-quality CsPbBr 3 nanocube films. Eventually, the CsPbBr 3 films enable green PeLEDs with a maximum luminance of 162 767 cd m -2 and a champion external quantum efficiency of 21.3% along with a narrow spectral line width of ∼14.7 nm, representing state-of-the-art performances in green PeLEDs.

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM&#95;017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene-environment interactions carefully while developing effective breast cancer prevention and treatment strategies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Deep, second- and third-degree burn injuries may lead to irreversible damage to the traumatized tissue and to coagulation or thrombosis of the microvessels, further compromising wound healing. Engineered, morphologically gradient drug-eluting nanofiber dressings promote wound healing by mimicking tissue structure and providing sustained drug delivery, which is particularly beneficial for wound management., Methods: This study exploited a resorbable, radially aligned nanofiber dressing that provides the sustained gradient release of metformin at the wound site using a pin-ring electrospinning technique and a differential membrane-thickness approach., Results: The experimental results suggested that the electrospun nanofibrous dressings exhibited uniform and radially oriented fiber distributions. In vitro, these dressings offered an extended release of metformin for 30 d. The incorporation of water-soluble metformin significantly enhanced the hydrophilicity of the nanofiber membranes. Moreover, the in vivo burn-wound-healing model of rats showed that the radially aligned gradient metformin-eluting poly(lactic-co-glycolic acid) (PLGA) nanofibers exhibited significantly superior healing capability compared to the pristine PLGA, metformin-eluting, and control dressings. Histological images showed that the mesh/nanofibers produced no adverse effects., Conclusion: The findings in this study emphasize the potential of resorbable, radially aligned nanofiber dressings as advanced wound care solutions, offering broad applicability and meaningful clinical impact., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (© 2024 Chen et al.)

Purpose: An association between pituitary gland disorders and breast cancer remains controversial. We examined the prevalence and risk of breast cancer over a 15-year follow-up period or until diagnosed as breast cancer among premenopausal women (12-49 years old) with pituitary gland disorders in Taiwan., Methods: This retrospective matched-cohort study included 52,265 individuals each in the study group (women with pituitary gland disorders) and the matched control group from 2000 to 2004 identified using Taiwan's National Health Insurance Research Database. We compared sociodemographic characteristics and medical disorders between the two groups and examined the differences in clinicopathological characteristics of breast cancer. We also estimated the risk of breast cancer over 15 years of follow-up (median follow-up time = 11.2 years)., Results: Overall, 924 (1.8%) and 734 (1.4%) patients in the study and control groups, respectively, were diagnosed as having breast cancer (p < 0.001). Over the 15-year follow-up period, the study group had a 1.16-fold (95% confidence interval [CI] = 1.04-1.29, p < 0.05) increased risk of breast cancer compared with the control group. This risk was particularly pronounced in the 20-29 and 30-39 age groups (adjusted hazard ratio = 1.46 and 1.25, respectively; 95% CI = 1.15-1.86 and 1.07-1.44, p value < 0.01, respectively)., Conclusion: Our findings reveal a relationship between pituitary gland disorders and breast cancer among premenopausal women in an Asian country. Physicians should check for signs of breast cancer in premenopausal women with pituitary gland disorders for early detection and treatment. Future studies should confirm our findings and clarify the causal relationship., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Advancing lithium-sulfur battery technology requires addressing both extrinsic cell-fabrication and intrinsic material challenges to improve efficiency, cyclability, and environmental sustainability. A key challenge is the low conductivity of sulfur cathodes, which is typically managed by incorporating conductive carbon materials. These materials enhance the performance of sulfur cathodes by facilitating high sulfur loading and improving polysulfide retention. In line with green chemistry principles and circular economy concepts, this study explores the use of recycled materials-specifically recycled quartz and board-as substrates for graphene coatings in lithium-sulfur cells. Recycled quartz bricks and blocks, predominantly SiO 2 , and recycled shelf boards, rich in Al 2 O 3 , are successfully coated with graphene, which significantly improves polysulfide adsorption and overall battery performance. The graphene-coated quartz exhibits high sulfur loading (8 mg cm -2 ), exceptional charge-storage capacity (1,114 mA h g -1 ), and long cycle stability (200 cycles) with an energy density of 19 mW h cm -2 . This approach enhances the electrochemical performance of the lithium-sulfur cells and also aligns with sustainability goals by repurposing waste materials and minimizing environmental impact. This novel methodology demonstrates that integrating recycled materials can effectively address key challenges in lithium-sulfur battery technology, advancing both performance and environmental sustainability., (© 2024 Wiley-VCH GmbH.)

Background: Stent misdeployment (SMD) is a feared technical challenge of EUS-guided choledochoduodenostomy using a lumen apposing stent (EUS-CDS) that has been poorly characterized. We aim to ascertain the rate of SMD in EUS-CDS for malignant distal biliary obstruction (MDBO) and describe its outcomes while identifying variables associated with its occurrence. In addition, we aim to propose a de novo SMD classification., Method: A post hoc analysis of two RCTs comparing EUS-CDS vs. endoscopic retrograde cholangiopancreatography in MDBO. The main endpoint was the rate of SMD classified as misdeployment of the distal flange (type I), proximal flange (type II), contralateral bile duct wall injury (type III), or double mucosal puncture (type IV). A multivariable analysis was performed to identify variables associated with the odds of SMD and/or technical failure and clinical failure or stent dysfunction., Results: 152 patients were included with a technical success of 93.4%. SMDs occurred in 11 (7.2%) patients (95% CI, 3.1%-11.4%): 8 type I, 1 type II, and 2 type III. Endoscopic salvage was successful in 81.8%. SMDs led to an adverse event (AE) in 4 cases (2 mild and 2 moderate) with an overall AE rate of 2.6% (95% CI, 0.7%-6.6%). On multivariable analysis, an extrahepatic bile duct diameter of ≤ 15 mm was associated with increase odds of SMD and/or technical failure., Conclusion: SMD is relatively common in EUS-CDS and is associated with an extra-hepatic bile duct diameter measuring ≤ 15 mm. The majority of SMDs can be rescued endoscopically with low risk for AE., Competing Interests: Yen-I Chen is a consultant for Boston Scientific, has received research funding from Boston Scientific and is the co-founder of Chess Medical Inc. Anand Sahai is a consultant Boston Scientific and Pentax. Bertrand Napoleon has received honorarium for proctoring endoscopy training from Maunea Kea, Boston Scientific, Olympus, and Taewoong Medical. Rastislav Kunda is a consultant for Boston Scientific, Olympus, M.I.Tech, Omega Medical Imaging, Q3 Medical-AMG International and EndoGastricSolutions. Nauzer Forbes is a consultant and speaker for Boston Scientific and Pentax Medical, a speaker for AstraZeneca, and has received research funding from Pentax Medical. Anthony Yuen Bun Teoh is a consultant for Boston Scientific, Cook, Taewoong, Microtech, and MI Tech Medical Corporations. All other authors have no relevant conflict of interest., (Thieme. All rights reserved.)

The maintenance of corneal transparency and normal vision is dependent on preservation of epithelial and endothelial cell layer homeostases. Different types of corneal injury can induce swelling and losses in transparency. Fuchs endothelial corneal dystrophy (FECD) is one type of injury that is commonly treated with rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors. While their clinical benefit is apparent, certain aspects of their mechanism of action require clarification. Specifically, although topical eye drops containing ROCK inhibitors have been employed to treat corneal endothelial dysfunction-associated corneal edema, it remains unclear whether interactions between both corneal epithelial and endothelial cell contribute to mitigating clinical signs that compromise normal vision. To address this question, we first review the intricate ROCK signaling pathways and their role in modulating a variety of functions that are related to the maintenance of corneal transparency and normal vision. We also review the results of ongoing clinical trials employing current FDA-approved ROCK inhibitors, highlighting the prominent role of Y-27632 in the treatment of a variety of ocular conditions, particularly FECD, and its promising results in reversing losses in normal vision through facilitating cell proliferation and suppressing apoptosis. This review shows that the ROCK inhibitor clinical benefit is affected by their interactions between the epithelium and the endothelium. This realization makes it likely that ROCK inhibitors will be approved for use in a clinical setting to treat FECD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Lieh-Yu Yi et al.)

Importance: The association between nonarteritic anterior ischemic optic neuropathy (NAION) and an increased risk of stroke has been a subject of debate. However, multinational studies on this topic are scarce., Objective: To evaluate the short-term and long-term stroke risk after NAION compared with a matched control group., Design, Setting, and Participants: This global, retrospective, population-based cohort study used aggregated electronic health records from January 1, 2004, through March 19, 2024, sourced from the Global Collaborative Network of TriNetX, which includes data from over 152 million patients across 17 countries. Patients in the study were followed up for a maximum duration of 10 years. Patients with NAION and age-related cataract were included in the analysis. Those with stroke before the diagnosis of NAION and age-related cataract were excluded. Propensity score matching was applied to balance age, sex, race, ethnicity, comorbidities, and medication use., Exposure: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code for NAION or age-related cataract., Main Outcomes and Measures: The primary outcome was the relative risk (RR) of stroke (ICD-10 code I60-63) in the NAION cohort vs the matched controls. Multivariable logistic regression analyses were applied to identify potential clinical factors associated with stroke within the NAION cohort., Results: A total of 89 811 patients were identified in both the NAION (mean [SD] age, 57.2 [18.5] years; 38 678 men [43.1%]) and control (mean [SD] age, 57.0 [17.9] years; 40 014 men [44.6%]) cohorts after matching. The NAION cohort demonstrated a significantly higher all-stroke risk at all time points: 1 month (RR, 5.04; 95% CI, 4.41-5.78), 3 months (RR, 3.79; 95% CI, 3.40-4.21), 1 year (RR, 2.50; 95% CI, 2.32-2.70), 5 years (RR, 1.54; 95% CI, 1.45-1.63), and 10 years (RR, 1.33; 95% CI, 1.23-1.43). Sensitivity analysis in patients without comorbidities similarly revealed a significantly increased all-stroke risk across all intervals: 1 month (RR, 7.55; 95% CI, 4.74-12.03), 3 months (RR, 6.70; 95% CI, 4.48-10.04), 1 year (RR, 3.96; 95% CI, 2.94-5.34), 5 years (RR, 2.85; 95% CI, 2.18-3.72), and 10 years (RR, 1.68; 95% CI, 1.25-2.26). Among all the clinical factors of interest, only hypertension was consistently associated with all subtypes of stroke following NAION., Conclusions and Relevance: This cohort study of patients with NAION found a significantly elevated risk of stroke compared with matched controls, independently of comorbidities. These findings underscore the importance of regular stroke workups following the onset of NAION.

Biological oscillators can specify time- and dose-dependent functions via dedicated control of their oscillatory dynamics. However, how biological oscillators, which recurrently activate noisy biochemical processes, achieve robust oscillations remains unclear. Here, we characterize the long-term oscillations of p53 and its negative feedback regulator Mdm2 in single cells after DNA damage. Whereas p53 oscillates regularly, Mdm2 from a single MDM2 allele exhibits random unresponsiveness to ∼9% of p53 pulses. Using allelic-specific imaging of MDM2 activity, we show that MDM2 alleles buffer each other to maintain p53 pulse amplitude. Removal of MDM2 allelic buffering cripples the robustness of p53 amplitude, thereby elevating p21 levels and cell-cycle arrest. In silico simulations support that allelic buffering enhances the robustness of biological oscillators and broadens their plausible biochemical space. Our findings show how allelic buffering ensures robust p53 oscillations, highlighting the potential importance of allelic buffering for the emergence of robust biological oscillators during evolution. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We investigated whether shock wave (SW)-pretreated autologous adipocyte-derived mesenchymal stem cells (ADMSCs) seeded in the cell-sheet scaffold (CSS) could inhibit left ventricular (LV) remodeling and improve LV ejection fraction (LVEF) in old myocardial infarction (MI)., Methods: Mini-pigs (n=20) were divided into group 1 (sham-operated control), group 2 (old MI), group 3 (old MI + autologous ADMSCs/1.0×107 in CSS on LV myocardium), and group 4 [old MI + SW (0.12 mJ/mm2 for total 140 shots)-pretreated ADMSCs in CSS on LV myocardium]. Treatments started on day 28 after MI induction. In vivo and in vitro studies were conducted., Results: Cell viability/relative mitochondria DNA expression/mitochondrial cytochrome C/adenosine triphosphate concentration in ADMCSs and protein expressions of angiogenesis factors (vascular endothelial growth factor [VEGF]/stromal cell-derived factor-1 [SDF-1])/mitochondrial respiratory chain complexes I-IV/oxygen consumption rate were higher in group 4 than in group 3 (P<0.001). By day 180, LVEF and small vessel numbers in the peri-infarct or infarct area were highest in group 1, lowest in group 2, and significantly lower in group 3 than in group 4. In contrast, the LV dimension was opposite to the pattern of change in LVEF in all groups (P<0.0001). The basal/middle/apical infarct and fibrotic areas were inversely related to LVEF in all groups (all P<0.0001). Protein levels of angiogenetic markers (SDF-1α/C-X-C chemokine receptor type 4/VEGF/angiopoietin-1) were significantly and persistently increased from groups 1 to 4. In contrast, protein levels of endothelial-cell markers (von Willebrand factor or endothelial nitric oxide synthase) showed an identical pattern to LVEF in all groups (all P<0.0001)., Conclusion: SW pretreatment of ADMSCs seeded in CSS offered significant benefits in preserving LV performance and ameliorating LV remodeling in mini-pigs with old MI., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Adolescent and young adult (AYA) patients with breast cancer generally have poor prognoses and a higher risk of secondary cancers compared to those at the same cancer stage. Notably, AYA patients in Asia exhibit a higher incidence rate of breast cancer, with Luminal A as the predominant molecular subtype, which contrasts with the trends observed in Western countries. This study aims to compare the efficacy of Taxane/Anthracycline combination-based regimens (TACB) versus Anthracycline-based regimens (AB) in AYA patients with stage I-II breast cancer, focusing on different molecular subtypes., Methods: This study utilized data from the Taiwan National Health Insurance Research Database (NHIRD) and the Taiwan Cancer Registry (TCR) from 2011 to 2019. The study cohort included patients aged 15 to 39 years who were diagnosed with stage I-II breast cancer and received either TACB or AB regimens. Propensity score matching and Cox proportional hazards regression models were used to calculate the hazard ratios (HR) for recurrence., Results: The results showed that TACB regimens significantly reduced the risk of recurrence compared to AB regimens across all patients (aHR 0.73, 95% CI 0.55-0.97). Specifically, for low/middle-recurrence risk groups, the aHR was 0.68 (95% CI 0.49-0.96), and for high-recurrence risk groups, it was 0.43 (95% CI 0.21-0.87). The analysis further indicated no significant differences in recurrence risk between AYA and non-AYA patients using TACB regimens., Conclusion: The TACB regimens showed a more favorable prognosis than AB regimens across all molecular subtypes. Furthermore, TACB regimens not only outperformed AB treatments but also closed the gap in prognostic outcomes between AYA and non-AYA patients. We believe the findings of this study are highly reliable and can provide valuable guidance for physicians in choosing the most appropriate treatment strategies for AYA patients with stage I-II breast cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Clinically significant post-endoscopic retrograde cholangiopancreatography (ERCP) bleeding (CSPEB) is common. Contemporary estimates of risk are lacking. We aimed to identify risk factors of and outcomes after CSPEB., Methods: We analyzed multicenter prospective ERCP data between 2018 and 2024 with 30-day follow-up. The primary outcome was CSPEB, defined as hematemesis, melena, or hematochezia resulting in (i) hemoglobin drop ≥ 20 g/L or transfusion and/or (ii) endoscopy to evaluate suspected bleeding and/or (iii) unplanned healthcare visitation and/or prolongation of existing admission. Firth logistic regression was used. P values <0.05 were significant, with odds ratios (ORs) and 95% confidence intervals reported., Results: CSPEB occurred after 129 (1.5%) of 8,517 ERCPs (mean onset 3.2 days), with 110 of 4,849 events (2.3%) occurring after higher risk interventions (sphincterotomy, sphincteroplasty, precut sphincterotomy, and/or needle-knife access). Patients with CSPEB required endoscopy and transfusion in 86.0% and 53.5% of cases, respectively, with 3 cases (2.3%) being fatal. P2Y 12 inhibitors were held for a median of 4 days (interquartile range 4) before higher risk ERCP. After higher risk interventions, P2Y 12 inhibitors (OR 3.33, 1.26-7.74), warfarin (OR 8.54, 3.32-19.81), dabigatran (OR 13.40, 2.06-59.96), rivaroxaban (OR 7.42, 3.43-15.24), and apixaban (OR 4.16, 1.99-8.20) were associated with CSPEB. Significant intraprocedural bleeding after sphincterotomy (OR 2.32, 1.06-4.60), but not after sphincteroplasty, was also associated. Concomitant cardiorespiratory events occurred more frequently within 30 days after CSPEB (OR 12.71, 4.75-32.54)., Discussion: Risks of antiplatelet-related CSPEB may be underestimated by endoscopists based on observations of suboptimal holding before higher risk ERCP. Appropriate periprocedural antithrombotic management is essential and could represent novel quality initiative targets., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: Individuals living with obesity are differentially susceptible to cardiometabolic diseases. We hypothesized that an integrative multi-omics approach might improve identification of subgroups of individuals with obesity who have distinct cardiometabolic disease patterns., Methods: We performed machine learning-based, integrative unsupervised clustering to identify proteomics- and metabolomics-defined subpopulations of individuals living with obesity (BMI ≥ 30 kg/m 2 ), leveraging data from 243 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Omics that contributed to the observed clusters were functionally characterized. We performed multivariate regression to assess whether the individuals in each cluster demonstrated differential patterns of cardiometabolic traits., Results: We identified two distinct clusters (iCluster1 and 2). iCluster2 had significantly higher average BMI values, fasting blood glucose, and inflammation. iCluster1 was associated with higher levels of total cholesterol and high-density lipoprotein cholesterol. Pathways mediating cell growth, lipogenesis, and energy expenditures were positively associated with iCluster1. Inflammatory response and insulin resistance pathways were positively associated with iCluster2., Conclusions: Although the two identified clusters may represent progressive obesity-related pathologic processes measured at different stages, other mechanisms in combination could also underpin the identified clusters given no significant age difference between the comparative groups. For instance, clusters may reflect differences in dietary/behavioral patterns or differential rates of metabolic damage., (© 2024 The Obesity Society.)

Cell shape reflects the spatial configuration resulting from the equilibrium of cellular and environmental signals and is considered a highly relevant indicator of its function and biological properties. For cancer cells, various physiological and environmental challenges, including chemotherapy, cause a cell state transition, which is accompanied by a continuous morphological alteration that is often extremely difficult to recognize even by direct microscopic inspection. To determine whether deep learning-based image analysis enables the detection of cell shape reflecting a crucial cell state alteration, we used the oral cancer cell line resistant to chemotherapy but having cell morphology nearly indiscernible from its non-resistant parental cells. We then implemented the automatic approach via deep learning methods based on EfficienNet-B3 models, along with over- and down-sampling techniques to determine whether image analysis of the Convolutional Neural Network (CNN) can accomplish three-class classification of non-cancer cells vs. cancer cells with and without chemoresistance. We also examine the capability of CNN-based image analysis to approximate the composition of chemoresistant cancer cells within a population. We show that the classification model achieves at least 98.33% accuracy by the CNN model trained with over- and down-sampling techniques. For heterogeneous populations, the best model can approximate the true proportions of non-chemoresistant and chemoresistant cancer cells with Root Mean Square Error (RMSE) reduced to 0.16 by Ensemble Learning (EL). In conclusion, our study demonstrates the potential of CNN models to identify altered cell shapes that are visually challenging to recognize, thus supporting future applications with this automatic approach to image analysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hsieh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A two-step procedure, combining a SmI 2 -mediated transannular pinacol coupling reaction with an acid-catalyzed pinacol rearrangement process, was employed to prepare a diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones from cyclobutanedione derivatives. To underscore the significance of these bicyclic ketones in drug synthesis, an sp 3 -rich analog of nitazoxanide, a well-known antiparasitic and antiviral agent, was synthesized.

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.

Objective: We sought to examine the effects of acute seizures and respiratory derangement on the cardiac electrical properties reflected on the electrocardiogram (ECG); and to analyze their potential interactions with a diagnosis of epilepsy in children., Methods: Emergency center (EC) visits with seizure or epilepsy diagnostic codes from 1/2011-12/2013 were included if they had ECG within 24 h of EC visit. Patients were excluded if they had pre-existing cardiac conditions, ion channelopathy, or were taking specific cardiac medications. Control subjects were 1:1 age and gender matched. Abnormal ECG was defined as changes in rhythm, PR, QRS, or corrected QT intervals; QRS axis or morphology; ST segment; or T wave morphology from normal standards. We identified independent associations between clinical factors and abnormal ECG findings using multivariable logistic regression modeling., Results: Ninety-five children with epilepsy presented to the EC with seizures, respiratory distress, and other concerns. Three hundred children without epilepsy presented with seizures. There was an increased prevalence of minor ECG abnormalities in children with epilepsy (49 %) compared to the control subjects (29 %) and those without epilepsy (36 %). Epilepsy (OR: 1.61, 95 %CI: 1.01-2.6), need for supplemental oxygen (OR 3.06, 95 % CI: 1.45-6.44) or mechanical ventilation (OR: 2.5, 95 % CI: 1.03-6.05) were independently associated with minor ECG abnormalities. Secondary analyses further demonstrated an independent association between level of respiratory support and ECG abnormalities only in the epilepsy group., Significance: Independent association of increased respiratory support with minor ECG abnormalities suggests a potential respiratory influence on the hearts of children with epilepsy., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. We confirm that we have read journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The Baylor College of Medicine Institutional Review Board approved the study with waiver of consent (H-34453)., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: EMR and endoscopic submucosal dissection (ESD) are minimally invasive endoscopic techniques, developed for the removal of benign and early malignant lesions throughout the GI tract. Submucosal injection of a marking agent can help to identify lesions during surgery. Endoscopic resection frequently involves "lifting" of the lesions by injection of a substance within the submucosal space to create a cushion for safe resection. This review summarizes the current techniques and agents available for endoscopic marking and lifting of GI tract lesions., Methods: The MEDLINE database was searched through April 2023 for relevant articles related to the lifting and marking aspect of EMR by using key words such as "endoscopy" or "endoscopic" combined with "marking," "tattoo," and "lifting." The report was drafted, reviewed, and edited by the American Society for Gastrointestinal Endoscopy Technology Committee and approved by the Governing Board of the American Society for Gastrointestinal Endoscopy., Results: This technology review describes the techniques for endoscopic tattoo placement and submucosal lifting, along with currently available agents, safety, and costs., Conclusions: Endoscopists performing EMR and ESD have several choices in submucosal injection materials for lifting and marking agents for tattoos. These may be commercially prepared agents or off-the-shelf materials with or without additives to facilitate visualization. A thorough understanding of the indications, techniques, properties of various agents, costs, and adverse events is necessary in choosing the appropriate materials and technique to optimize lesion resection in EMR and ESD., Competing Interests: Disclosure The following authors disclosed financial relationships: A. Bhatt: Consultant for Medtronic, Inc, US Endoscopy, Olympus Corporation, and Intuitive Surgical Inc; patent-holder for a commercial device licensed to Medtronic, Inc. V. S. Akshintala: Board member for Origin Endoscopy Inc; consultant for Dragonfly Endoscopy Inc; research support from Abbvie, Boston Scientific Corporation, and Medtronic. Y. Chen: President of Chess Medical; consultant for Boston Scientific Corporation. K. K. Das: Consultant for Olympus Medical Systems Corporation; patent-holder with Interpace Biosciences. A. Kahn: Consultant for MiMedx. K. Krishnan: Consultant for Boston Scientific Corporation and Olympus Corporation of the Americas. G. Leung: Consultant for Boston Scientific Corporation, Steris Corporation, AI Medical Service, and Mirai Medical. D. R. Lichtenstein: Consultant for Olympus Corporation of the Americas and Boston Scientific Corporation; speaker for Olympus Corporation of the Americas and Boston Scientific Corporation; Clinical Events Committee for Boston Scientific Corporation (chair) and SafeHeal; advisory board and research committee for Iterative Health; GI boards committee for the American Board of Internal Medicine. G. Mishra: Consultant for Pentax of America, Inc and Cook Medical LLC. V. Raman Muthusamy: Consultant for Medtronic and Boston Scientific Corporation; research support from Boston Scientific Corporation; stock options/equity in Capsovision; advisory board for Endogastric Solutions and Motus GI. J. V. Obando: Shareholder with Surgenly LLC. S. Pawa, T. Rustagi, G. Trikudanathan: Consultant for Boston Scientific Corporation. M. Saumoy: Consultant for Becton, Dickinson and Company and Intuitive Surgical, Inc. A. J. Trindade: Consultant for Pentax of America, Inc, Boston Scientific Corporation, Lucid Diagnostics, and Exact Science. J. Yang: Consultant for Cook Medical, Interscope, and Steris. R. Law: Consultant for Conmed Corporation, Boston Scientific Corporation, Olympus America Inc, and Medtronic USA Inc; royalties from UpToDate. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Postpartum depression is a major psychiatric disorder associated with maternal suicide and child developmental disturbances. In this study, we aimed to investigate whether general anesthesia for cesarean delivery is associated with a higher rate of new-onset depression after delivery than neuraxial anesthesia., Methods: This is a nationwide retrospective cohort study using data retrieved from the National Health Insurance Research Database between 2014 and 2018. Women who had cesarean delivery under general or neuraxial anesthesia were enrolled. After 1:4 propensity score matching, there were 4544 and 18,176 women under the general and neuraxial anesthesia groups, respectively. The primary outcome was new-onset depression diagnosed after delivery in a time-to-event analysis setting., Results: After propensity-score matching, the rate of new-onset depression diagnosed within 1 year was 1.10 % (50/4488) and 0.86 % (157/18176) after cesarean delivery under general and neuraxial anesthesia, respectively. For depression diagnosed within 90 days of delivery, significant difference between the two groups was noted (0.51 % vs. 0.30 %, P = 0.031). In the time-to-event analysis with Cox regression model, women who delivered under general anesthesia were associated with significantly higher risk of postpartum depression within 90 days (Hazard ratio [HR], 1.71; 95 % CI, 1.05-2.79) compared with those under neuraxial anesthesia., Limitations: The observational design only allows asserting association, rather than establishing causality between exposure and outcomes., Conclusions: Women who underwent cesarean delivery under general anesthesia had a higher risk of subsequent depression within 90 days than those under neuraxial anesthesia. Early screening for depressive disorders might facilitate timely management., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding., (© 2024 Wiley Periodicals LLC.)

Background: Owing to the heterogeneity of underlying primary tumors, noncolorectal, nonneuroendocrine metastases to the liver (NCNNMLs), although relatively rare, pose major challenges to treatment and long-term management. Despite being considered the gold standard for colorectal cancer liver metastases, the role of surgical resection for NCNNML remains controversial. Furthermore, advancements in locoregional treatment modalities, such as ablation and various chemotherapeutic modalities, have contributed to the treatment of patients with NCNNML., Methods: This was a comprehensive review of literature that used Medline/PubMed, Google Scholar, the Cochrane Library, and the Web of Science, which were accessed between 2014 and 2024., Results: NCNNMLs are rare tumor entities with varied presentation and outcomes. A multidisciplinary approach, which includes chemotherapy, surgery, and interventional radiologic techniques, can be implemented with good results., Conclusion: Given the complex nature of NCNNML, its management should be highly individualized and multidisciplinary. Locoregional treatments, such as surgical resection and/or ablation, may be more appropriate for select patients and should be offered as a viable therapeutic option for a subset of individuals., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Multifocal papillary thyroid carcinomas (PTCs) are common and the majority of the tumors harbor mutual BRAF p.V600E mutation. This study aimed to investigate a contemporary series of multifocal PTCs with discordant molecular drivers. Consecutive thyroidectomies diagnosed with multifocal PTCs ≥0.5 cm between 2019 and 2023 were reviewed. Immunohistochemistry (IHC) for BRAF VE1 was performed for all tumors. Cases with discordant BRAF IHC results or morphologic discrepancy were identified, and BRAF IHC-negative tumors were subjected to RAS Q61R IHC and/or targeted RNA next-generation sequencing. A total of 770 patients with a main PTC ≥0.5 cm were identified; 255 (33.1%) had multifocal disease, and 142 (18.4%) had at least another PTC ≥0.5 cm. Among them, 13 cases (9.2%, 13/142) had discordant molecular drivers. Twelve cases had one or more BRAF -positive PTCs accompanied by a BRAF -negative PTC (3 with CCDC6::RET fusion, 1 with NCOA4::RET fusion, 1 with ACBD5::RET fusion, 2 with ETV6::NTRK3 fusion, 1 with TG::FGFR1 fusion, 1 with LMTK2::BRAF fusion, 1 with AGK::BRAF fusion and RAS p.Q61R mutation, 1 with RAS p.Q61R mutation, and 1 without detectable molecular drivers). The last case had tumors with discordant fusion drivers ( VIM::NTRK3 and TNS1::BRAF ). Most cases showed tumors that were morphologically distinct (92.3%, 12/13) and occurred in the contralateral lobes (76.9%, 10/13). Notably, we identified 4 cases (30.8%) that presented as collision tumors and 6 cases (46.2%) that showed lymph node metastases, including 2 with simultaneous involvement by tumors with discordant molecular drivers, as novel findings. In summary, a subset (9.2%) of multifocal PTCs had discordant molecular drivers and 84.6% of them were a combination of BRAF -positive and kinase gene fusion-associated PTCs, most with distinct morphologies. Almost half of the cases had nodal metastasis and a third of them showed simultaneous involvement by tumors with discordant molecular drivers. The results highlight the clinical importance of identifying such cases, given the potentially different treatments., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Evaluate the relationship between first and second-line medication dosing and progression to refractory status epilepticus (RSE) in children., Methods: This is a retrospective analysis of prospectively collected data from September 2014 to February 2020 of children with status epilepticus (SE) who received at least two antiseizure medications (ASMs). We evaluated the risk of developing RSE after receiving a low total benzodiazepine dose (lower than 100 % of the minimum recommended dose for each benzodiazepine dose administered within 10 min) and a low first non-benzodiazepine ASM dose (lower than 100 % of the minimum recommended dose of non-benzodiazepine ASM given as the first single-dose) using a logistic regression model, adjusting for confounders such as time to ASMs. The proportion of patients receiving low first non-benzodiazepine ASM doses was calculated and a logistic regression model was used to evaluate risk factors for low dosing of the first non-benzodiazepine ASM., Results: Among 320 children, 170 (53.1 %) developed RSE, and 150 (46.9 %) responded to the first non-benzodiazepine ASM dose (non-RSE). One hundred thirty-seven (42.8 %) received a low total benzodiazepine dose, and 128 (40 %) received a low first non-benzodiazepine ASM dose. The odds of developing RSE were not higher after a low total benzodiazepine dose (OR=0.76, 95 %CI 0.47-1.23, p = 0.27) or low first non-benzodiazepine ASM dose (OR=0.85, 95 %CI 0.42-1.71, p = 0.65). Receiving a low first non-benzodiazepine ASM dose was independently associated with having received a low total benzodiazepine dose (OR=1.65, 95 %CI 1.01-2.70, p = 0.04)., Conclusion: For most patients, dosing variability in first and second-line medications for SE was not the sole clinical feature predicting progression to RSE in this cohort of benzodiazepine-resistant patients. Identification of additional modifiable clinical biomarkers that predict progression to RSE is needed. Though lower ASM doses did not predict RSE in this model, the administration of ASMs at doses likely to prevent RSE remains crucial in SE treatment., Competing Interests: Declaration of competig interest TL is part of pending patent applications to detect and predict seizures and to diagnose epilepsy. He receives research support from the NIH, the Epilepsy Research Fund, and Epitel. He received research grants from Sage, Lundbeck, Eisai, Upsher-Smith, Mallinckrodt, Pfizer, and MIKU in the past. He served as a consultant for Engage and Upsher Smith, in the past., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: The authors report no conflicts of interest in this communication.

The most common mutation in southern Chinese individuals with late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD; a fatty acid metabolism disorder) is c.250G > A (p.Ala84Thr) in the electron transfer flavoprotein dehydrogenase gene (ETFDH). Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. Given that axonal degeneration and neuronal apoptosis may be regulated by B-cell lymphoma (BCL)-2 family proteins and mitochondrial outer membrane permeabilization through the activation of proapoptotic molecules, we measured the expression levels of proapoptotic BCL-2 family proteins (e.g., BCL-2-associated X protein and p53-upregulated modulator of apoptosis), cytochrome c, caspase-3, and caspase-9 in NSC-34 cells carrying the most common ETFDH mutation. The levels of these proteins were higher in the mutant cells than in the wide-type cells. Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. These results suggest that the activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway promotes apoptosis in cellular models of MADD and that coenzyme Q10 can reverse this effect. Our findings aid the development of novel therapeutic strategies for reducing axonal degeneration and neuronal apoptosis in MADD., (© 2024. The Author(s).)

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication., (© 2024. The Author(s).)

Photoperiod/thermo-sensitive genic male sterility (P/TGMS) is critical for rice two-line hybrid system. Previous studies showed that slow development of pollen is a general mechanism for sterility-to-fertility conversion of TGMS in Arabidopsis. However, whether this mechanism still exists in rice is unknown. Here, we identified a novel rice TGMS line, ostms16, which exhibits abnormal pollen exine under high temperature and fertility restoration under low temperature. In mutant, a single base mutation of OsTMS16, a fatty acyl-CoA reductase (FAR), reduced its enzyme activity, leading to defective pollen wall. Under high temperature, the mOsTMS16 M549I couldn't provide sufficient protection for the microspores. Under low temperature, the enzyme activity of mOsTMS16 M549I is closer to that of OsTMS16, so that the imperfect exine could still protect microspore development. These results indicated whether the residual enzyme activity in mutant could meet the requirement in different temperature is a determinant factor for fertility conversion of P/TGMS lines. Additionally, we previously found that res2, the mutant of a polygalacturonase for tetrad pectin wall degradation, restored multiple TGMS lines in Arabidopsis. In this study, we proved that the osres2 in rice restored the fertility of ostms16, indicating the slow development is also suitable for the fertility restoration in rice., (© 2024 John Wiley & Sons Ltd.)

In this investigation, we explored the molecular dynamics guiding the progression of castration-resistant prostate cancer (CRPC) influenced by Helicobacter pylori (H. pylori)-mediated M2 polarization of macrophages through the IL-17RA/CTSK/EMT axis. An 830-patient clinical trial categorized subjects into hormone-sensitive prostate cancer (HSPC) and CRPC groups. H. pylori infection, evaluated by ELISA, exhibited a higher incidence in CRPC patients, impacting overall survival (OS) and progression-free survival. In-depth in vitro and in vivo experiments, including 16S rDNA sequencing, immunohistochemical tests, and transcriptome analysis, unveiled that H. pylori promotes CRPC growth and metastasis by upregulating IL-17RA and CTSK, leading to enhanced EMT. Notably, M2 macrophages emerged as pivotal immune cells influencing CRPC progression. This study uncovers a novel pathway wherein H. pylori enrichment exacerbates CRPC by inducing macrophage M2 polarization, IL-17RA/CTSK expression, and EMT activation, shedding light on a previously unrecognized mechanism contributing to the growth and metastasis of CRPC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Metabolic syndrome (MetS) includes cardiovascular risk factors like obesity, dyslipidemia, hypertension, and glucose intolerance, which increase the risk of overactive bladder (OAB), characterized by urgency, frequency, urge incontinence, and nocturia. Both MetS and ovarian hormone deficiency (OHD) are linked to bladder overactivity. Nitric oxide (NO) is known to reduce inflammation and promote healing but its effect on bladder overactivity in MetS and OHD is unclear. This study aimed to investigate NO's impact on detrusor muscle hyperactivity in rats with MetS and OHD. Female Sprague-Dawley rats were divided into seven groups based on diet and treatments involving L-arginine (NO precursor) and L-NAME (NOS inhibitor). After 12 months on a high-fat, high-sugar diet with or without OVX, a cystometrogram and tracing analysis of voiding behavior were used to identify the symptoms of detrusor hyperactivity. The MetS with or without OHD group had a worse bladder contractile response while L-arginine ameliorated bladder contractile function. In summary, MetS with or without OHD decreased NO production, reduced angiogenesis, and enhanced oxidative stress to cause bladder overactivity, mediated through the NF-kB signaling pathway, whereas L-arginine ameliorated the symptoms of detrusor overactivity and lessened oxidative damage via the NRF2/HIF-1α signaling pathway in MetS with or without OHD-induced OAB.

Background: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS., Methods: Prp-TDP-43 A315T mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43 A315T mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43 A315T mice with or without SLCP were determined., Results: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43 A315T mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43 A315T mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes., Conclusions: Our results showed that Prp-TDP-43 A315T mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD., 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. Published by Elsevier Inc.)

New-onset refractory status epilepticus (NORSE) is a devastating clinical condition that often leads to severe disability. Intrathecal dexamethasone (IT-DEX) has been reported to improve refractory status epilepticus. We present an 11-year-old female with anti-GAD 65 encephalitis presenting as NORSE who had minimal response to standard anti-seizure medications and first-line immunotherapies. The patient received 6 doses of IT-DEX in conjunction with rituximab which correlated with subsequent decreased neuroinflammation, reduced seizure burden and aided in weaning anesthetic infusions. Our case with literature review suggests IT-DEX may be utilized as an early intervention in those with refractory status epilepticus from various etiologies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abnormal differentiation of cells is a hallmark of malignancy. Induction of cancer-cell differentiation is emerging as a novel therapeutic strategy with low toxicity in hematological malignances, but whether such treatment can be used in solid tumors is not known. Here, we uncovered a novel function of acetyl coenzyme A acetyltransferase (ACAT1) in regulating the differentiation of glioblastoma (GBM) cells. Inhibition of ACAT1 promoted the differentiation of GBM cells into astrocytes but also delayed tumor growth. Mechanistically, suppression of ACAT1 restored mitochondrial function and led to metabolic "reprogramming" in GBM cells: reduction of fatty-acid oxidation and acetyl-CoA, but an increase in free fatty acids. Importantly, ACAT1 negatively regulated the choline metabolic pathway, which is crucial for the differentiation of GBM cells. Finally, we demonstrated that a naturally available substance, chlorogenic acid (CHA), could inhibit phosphorylation of ACAT1 and so delay GBM progression, CHA is a promising candidate to treat GBM because it could induce the differentiation of cancer cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy., Methods: Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling., Results: Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities., Significance: CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD., Competing Interests: Declaration of competing interest All the authors declare that there are no conflicts of interest., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Laminated (NbTaMoW)N x films were prepared via co-sputtering. The sputtering variables were a substrate holder rotation speed of 2 and 10 rpm and a nitrogen flow ratio ( f N2 = N 2 /(Ar + N 2 )) of 0.1, 0.2, and 0.4. The (NbTaMoW)N x films fabricated at 30 rpm displayed columnar structures. The phase structures of the laminated (NbTaMoW)N x films varied from multiple body-centered cubic phases to a nanocrystalline and a face-centered cubic phase as the f N2 increased from 0.1 to 0.2 and 0.4. The mechanical and tribological properties of the laminated (NbTaMoW)N x films were evaluated. The laminated (NbTaMoW)N x films deposited at an f N2 of 0.4 had hardnesses of 25.2 and 26.1 GPa when prepared at 2 and 10 rpm, respectively, lower than the value of 29.9 GPa for the columnar (NbTaMoW)N x film prepared at an f N2 of 0.4 and 30 rpm. In contrast, the wear resistances of the laminated (NbTaMoW)N x films were superior to those of the columnar (NbTaMoW)N x films.

Competing Interests: Disclosure The following authors disclosed financial relationships: K. K. Das: Patent with Interpace Biosciences; food and beverage compensation from Medtronic, Inc. D. Chen: Food and beverage compensation from Ambu Inc. V. S. Akshintala: Board member for Origin Endoscopy Inc; consultant for Dragonfly Endoscopy Inc; research support from Abbvie, Boston Scientific Corporation, and Medtronic; travel compensation from Mauna Kea Technologies, Inc; food and beverage compensation from Mauna Kea Technologies, Inc, Boston Scientific Corporation, and AbbVie Inc. Y.-I. Chen: President of Chess Medical; consultant for Boston Scientific Corporation. A. Kahn: Consultant for MiMedx. G. Mishra: Consultant for Pentax of America, Inc and Cook Medical LLC; travel compensation from Pentax of America, Inc; food and beverage compensation from Pentax of America, Inc, Cook Medical LLC, Ambu Inc, Boston Scientific Corporation, and Wilson Cook Medical Incorporated. V. Raman Muthusamy: Consultant for Medtronic and Boston Scientific Corporation; research support from Boston Scientific Corporation; stock options and equity in Capsovision; advisory board for Endogastric Solutions and Motus GI; travel compensation from Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation, Steris Corporation, Medtronic, Inc, Apollo Endosurgery US Inc, Endogastric Solutions, Inc, Cook Medical LLC, Pentax of America, Inc, and Olympus America Inc. J. V. Obando: Shareholder with Surgenly LLC. F. U. Onyibma: Food and beverage compensation from Endogastric Solutions, Inc and Medtronic, Inc. S. Pawa: Consultant for Boston Scientific Corporation. T. Rustagi: Consultant for Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation and Merit Medical Systems Inc. S. Sakaria: Food and beverage compensation from AbbVie Inc. G. Trikudanathan: Consultant for Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation. R. Law: Consultant for ConMed Corporation, Boston Scientific Corporation, Medtronic USA Inc, and Olympus America Inc; royalties from UpToDate; food and beverage compensation from Olympus America Inc, Boston Scientific Corporation, and Ethicon Inc. All other authors disclosed no financial relationships.

Background and Aims: Difficult biliary cannulation (DBC) is a known risk factor for developing post-ERCP pancreatitis (PEP). To better understand how DBC increases PEP risk, we examined the interplay between technical aspects of DBC and known PEP risk factors., Methods: This was a secondary analysis of a multicenter, randomized controlled trial comparing rectal indomethacin alone with the combination of rectal indomethacin and prophylactic pancreatic duct (PD) stent placement for PEP prophylaxis in high-risk patients. Participants were categorized into 3 groups: DBC with high preprocedure risk for PEP, DBC without high preprocedure risk for PEP, and non-DBC at high preprocedure risk for PEP., Results: In all, 1601 participants (84.1%) experienced DBC, which required a mean of 12 cannulation attempts (standard deviation, 10) and mean duration of 14.7 minutes (standard deviation, 14.9). PEP rate was highest (20.7%) in DBC with a high preprocedure risk, followed by non-DBC with a high preprocedure risk (13.5%), and then DBC without a high preprocedure risk (8.8%). Increasing number of PD wire passages (adjusted odds ratio [aOR], 1.97; 95% confidence interval [CI], 1.25-3.1) was associated with PEP in DBC, but PD injection, pancreatic sphincterotomy, and number of cannulation attempts were not associated with PEP. Combining indomethacin with PD stent placement lowered the risk of PEP (aOR, .61; 95% CI, .44-.84) in DBCs. This protective effect was evident in up to at least 4 PD wire passages., Conclusions: DBC confers higher PEP risk in an additive fashion to preprocedural risk factors. PD wire passages appear to add the greatest PEP risk in DBCs, but combining indomethacin with PD stent placement reduces this risk, even with increasing PD wire passages., Competing Interests: Disclosure Dr. Andrew Y. Wang discloses owning publicly traded stock in Pfizer and GE HealthCare Technologies. Dr. Mouen Khashab is a consultant for Boston Scientific and Olympus and he receives royalties from Elsevier and UpToDate. Dr. Andy Ross is a consultant for Boston Scientific and Olympus. Dr. Samuel Han is a consultant for Boston Scientific. Dr. Ji Young Bang is a consultant for Boston Scientific and Olympus. Dr. Shyam Varadarajulu is a consultant for Boston Scientific and Olympus. Dr. Field F. Willingham is a consultant for Boston Scientific and Cook Medical. Dr. Somashekar G. Krishna receives honoraria and grant support from Taewoong. Dr. Rajesh Keswani is a consultant for Boston Scientific. Dr. Steven A. Edmundowivcz is a consultant for Olympus and receives honoraria from Boston Scientific. Dr. Raj J. Shah is a consultant for Boston Scientific and Cook Medical. Dr. Nauzer Forbes is a consultant for Boston Scientific and Pentax. Dr. Yen-I Chen is a consultant for Boston Scientific. Dr. Alan Barkun is a Research support, consultation, Advisory board in Medtronic; Research support in Cook; Consultant, Payment or honoraria for lectures and trave in Takeda Canada Inc.; Consultant, Payment or honoraria for lectures and travel fees in Olympus Inc.; Payment or honoraria for lectures and travel fees in AstraZeneca Inc.; Advisory board in Pendopharm Canada Inc. The other authors disclosed no financial relationships. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award number: U01DK104833. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk., (© 2024. The Author(s).)

In a recent study, spectroscopic observations of modified cholesterol in both lipid-coated nanoparticles and liposomes provided evidence for a disorder-to-order orientational transition with increasing temperature. Below a critical temperature, in a membrane composed of modified cholesterol, saturated (DPPC) lipid, and anionic (DOPS) lipid, a roughly equal population of head-out and head-in conformations was observed. Surprisingly, as temperature was increased the modified cholesterol presented an abrupt transition to a population of all head-in orientations. Additionally, when saturated DPPC lipids were replaced by unsaturated DOPC the disorder-to-order transition was eliminated. To gain insight into this curious transition, we use all-atom molecular dynamics simulations to characterize the structure and fluctuations of lipid bilayers composed of saturated and unsaturated lipids, in the presence of normal and modified cholesterol. Free energy differences between head-out and head-in conformations are computed as a function of varying lipid membrane composition for normal and modified cholesterol. In bilayers primarily composed of DPPC, the orientation of modified cholesterol is observed to depend sensitively on the orientation of the surrounding normal or modified cholesterol molecules, suggesting cooperative Ising-like interactions favoring an ordered state. In bilayers primarily composed of DOPC, spontaneous flip-flop of modified cholesterol is observed, consistent with the measured small free energy barrier separating the head-in and head-out orientations. This combined experimental and computational study effectively characterizes the orientational dimorphism and provides novel insight into the fundamental nature of cholesterol interactions in membrane.

Background: Despite improvements in intraoperative and postoperative outcomes of laparoscopic cholecystectomy (LC), spilled gallstones (SGs) after LC remain a significant yet often overlooked complication, occurring in 1% to 40% of cases. This review discusses the most recent updates regarding the risk factors, presentations, complications, diagnosis, management, and prognosis of SGs after LC., Methods: A comprehensive systematic review was conducted using MEDLINE/PubMed, Google Scholar, Cochrane Library, and the Web of Science databases, with the range of search dates being between January 2015 and July 2024, regarding SG incidence, management, and complications., Results: Risk factors for SGs after LC include intraoperative gallbladder perforation because of poor operational environment, quantity, size, and type of stone (pigment, cholesterol rich, or mixed); presence of adhesions or anatomic variations; and insufficient surgical training. Of note, 60% of SG complications are abscesses from bacterial infections, which can progress to peritonitis, fistulas, lung/liver abscesses, and choledocholithiasis. SGs were associated with delayed presentation of unexpected clinical problems, with even diagnosis. Although treatment depends on the severity of the complication, when SGs are identified through imaging, often ultrasound and computed tomography, minimally invasive approaches and antibiotic courses are viable first-line approaches., Conclusion: Although LC-associated spillage of gallstones is rare, the complications can be a serious cause of morbidity. Therefore, proper notification of operative complications, a high index of suspicion for patients with a previous history of LC, and awareness of appropriate diagnostic modalities are key variables for the early diagnosis and prevention of SG-related complications., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare vertebroplasty (VP) and kyphoplasty (KP) with a titanium implantable vertebral augmentation device (TIVAD) in symptomatic subsequent vertebral compression fracture (SVCF) incidence among osteoporotic vertebral compression fracture (OVCF) patients stratified by age and sex., Methods: This retrospective cohort study involved OVCF patients aged ≥ 50, who underwent KP with TIVAD or VP in our hospital from 2014 to 2019. Subgroup analysis was conducted to evaluate the efficacy of KP with TIVAD and VP in patients stratified by age and sex., Results: The study included 472 patients (VP group: 303; TIVAD group: 169). SVCF incidence rates were 15.2% for VP group and 14.8% for TIVAD group (P = 0.87). In subgroup analysis, TIVAD group showed significantly lower SVCF incidence than VP group in women aged 50-70 (2.1% vs 14.3%; P = 0.03) and had significantly higher SVCF incidence than VP group in women aged > 70 (24.2% vs 13.1%; P = 0.02). In men, adjacent SVCF incidence was significantly lower in TIVAD group than VP group (0% vs 14.1%; P = 0.03)., Conclusion: Compared to VP, TIVAD is associated with lower symptomatic SVCF rate in men and younger women aged 50-70 but not in older women aged > 70. Age and gender may influence SVCF incidence., Level of Evidence: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats., Methods: A total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology., Results: In comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role., Conclusion: This study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits., (© 2024. The Author(s).)

Illustrating molecular mechanisms of human embryonic development has always been one of the most significant challenges in biology. The scarcity of human embryo samples, the difficulty in dissecting embryo samples, and the complex structures of human organs are the major obstacles in studying human embryogenesis. In recent years, with the rapid advancement of single-cell technology, humans can systematically analyze the dynamic changes in differentiation at various stages of the central dogma and achieve observation and research with spatial information. This has accelerated the progress in constructing a human developmental cell atlas, ultimately allowing us to depict the cell ontology, fate trajectories, and three-dimensional dynamic changes of human development. In this review, we first introduce the single-cell technologies used to construct the atlas, then summarize the latest progress in human developmental cell atlas, followed by identifying the main problems and challenges in this field so far. Finally, we discuss how to utilize the human developmental cell atlas to address key biological and medical issues. This review provides guidance for the optimal use of single-cell omics technology in constructing and applying a human developmental cell atlas.