Normobaric Hyperoxia Combined With Endovascular Treatment Based on Temporal Gradient: A Dose-Escalation Study.

BACKGROUND: Normobaric hyperoxia (NBO) has neuroprotective effects in acute ischemic stroke. Thus, we aimed to identify the optimal NBO treatment duration combined with endovascular treatment. METHODS: This is a single-center, randomized controlled, open-label, blinded-end point dose-escalation clinical trial. Patients with acute ischemic stroke who had an indication for endovascular treatment at Tianjin Huanhu Hospital were randomly assigned to 4 groups (1:1 ratio) based on NBO therapy duration: (1) control group (1 L/min oxygen for 4 hours); (2) NBO-2h group (10 L/min for 2 hours); (3) NBO-4h group (10 L/min for 4 hours); and (4) NBO-6h group (10 L/min for 6 hours). The primary outcome was cerebral infarction volume at 72 hours after randomization using an intention-to-treat analysis model. The primary safety outcome was the 90-day mortality rate. RESULTS: Between June 2022 and September 2023, 100 patients were randomly assigned to the following groups: control group (n=25), NBO-2h group (n=25), NBO-4h group (n=25), and NBO-6h group (n=25). The 72-hour cerebral infarct volumes were 39.4±34.3 mL, 30.6±30.1 mL, 19.7±15.4 mL, and 22.6±22.4 mL, respectively (P=0.013). The NBO-4h and NBO-6h groups both showed statistically significant differences (adjusted P values: 0.011 and 0.027, respectively) compared with the control group. Compared with the control group, both the NBO-4h and NBO-6h groups showed significant differences (P<0.05) in the National Institutes of Health Stroke Scale scores at 24 hours, 72 hours, and 7 days, as well as in the change of the National Institutes of Health Stroke Scale scores from baseline to 24 hours. Additionally, there were no significant differences among the 4 groups in terms of 90-day mortality rate, symptomatic intracranial hemorrhage, early neurological deterioration, or severe adverse events. CONCLUSIONS: The effectiveness of NBO therapy was associated with oxygen administration duration. Among patients with acute ischemic stroke who underwent endovascular treatment, NBO therapy for 4 and 6 hours was found to be more effective. Larger-scale multicenter studies are needed to validate these findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05404373.

Cold hypersensitivity in the hands and feet is associated with erectile dysfunction in young Taiwanese men.

Cold hypersensitivity in the hands and feet (CHHF) is a protective or predisposing factor for many diseases; however, the relationship between CHHF and erectile dysfunction (ED) remains unclear. We aimed to investigate associations between CHHF and ED among young men of Southeast Asian origin. In this cross-sectional study, sexually active Taiwanese men aged 20-40 years were enrolled via an online questionnaire comprising general demographic information, comorbidities, subjective thermal sensations of their hands and feet in the past 6 months, and their erectile function using the International Index of Erectile Function-5 (IIEF-5). Participants who reported cold sensation of hands and feet were classified to have CHHF; those with IIEF-5 score ≤ 21 were considered to have ED. Total 54.2% and 27.9% of participants had ED and CHHF, respectively. Men with CHHF were significantly younger, had lower body mass index and IIEF-5 scores (p < 0.001), and a lower prevalence of diabetes mellitus (p = 0.033) along with higher prevalence of ED, psychiatric disorders, and insomnia (p < 0.001). After adjusting for predisposing factors of ED, CHHF (odds ratio 1.410, 95% confidence interval 1.159-1.714; p = 0.001) remained an independent predictor of ED. Thus, CHHF is independently associated with ED, affecting more than a quarter of young Taiwanese men. Autonomic dysregulation and subclinical endothelial dysfunction may be common pathophysiologies of CHHF and ED.

Muscularis macrophages controlled by NLRP3 maintain the homeostasis of excitatory neurons.

Peristaltic movements in gut are essential to propel ingested materials through the gastrointestinal tract. Intestinal resident macrophages play an important role in this physiological function through protecting enteric neurons. However, it is incompletely clear how individuals maintain the homeostasis of gut motility. Here we found that NLRP3 is a critical factor in controlling loss of muscularis resident macrophages (MMs), and demonstrate that MMs are involved in the homeostasis of excitatory neurons such as choline acetyltransferase (ChAT)+ and vesicular glutamate transporter 2 (VGLUT2)+ but not inhibitory neuronal nitric oxide synthase (nNOS)+ neurons. NLRP3 knockout (KO) mice had enhanced gut motility and increased neurons, especially excitatory ChAT+ and VGLUT2+ neurons. Single cell analyses showed that there had increased resident macrophages, especially MMs in NLRP3 KO mice. The MM proportion in the resident macrophages was markedly higher than those in wild-type (WT) or caspase 1/11 KO mice. Deletion of the MMs and transplantation of the NLRP3 KO bone marrow cells showed that survival of the gut excitatory ChAT+ and VGLUT2+ neurons was dependent on the MMs. Gut microbiota metabolites ß-hydroxybutyrate (BHB) could promote gut motility through protecting MMs from pyroptosis. Thus, our data suggest that MMs regulated by NLRP3 maintain the homeostasis of excitatory neurons.

Tuning cellular metabolism for cancer virotherapy.

Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.

(±)-hypermonanones A-G, seven pairs of monoterpenoid polyprenylated acylphloroglucinol enantiomers from Hypericum monanthemum.

Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.

Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) constitute the primary forms of chronic liver disease, and their incidence is progressively increasing with changes in lifestyle habits. Earlier studies have documented a correlation between the occurrence and development of prevalent mental disorders and fatty liver. AIM: To investigate the correlation between fatty liver and mental disorders, thus necessitating the implementation of a mendelian randomization (MR) study to elucidate this association. METHODS: Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog, while information on mental disorders, including Alzheimer's disease, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia was acquired from the psychiatric genomics consortium. A two-sample MR method was applied to investigate mediators in significant associations. RESULTS: After excluding weak instrumental variables, a causal relationship was identified between fatty liver disease and the occurrence and development of some psychiatric disorders. Specifically, the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD (OR: 5.81, 95%CI: 5.59-6.03, P < 0.01), bipolar disorder (OR: 5.73, 95%CI: 5.42-6.05, P = 0.03), OCD (OR: 6.42, 95%CI: 5.60-7.36, P < 0.01), and PTSD (OR: 5.66, 95%CI: 5.33-6.01, P < 0.01). Meanwhile, NAFLD significantly increased the risk of developing bipolar disorder (OR: 55.08, 95%CI: 3.59-845.51, P < 0.01), OCD (OR: 61.50, 95%CI: 6.69-565.45, P < 0.01), and PTSD (OR: 52.09, 95%CI: 4.24-639.32, P < 0.01). CONCLUSION: Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders, namely bipolar disorder, OCD, and PTSD, highlighting the significance of preventive measures against psychiatric disorders in patients with fatty liver disease.

Building a workforce of diverse women leaders: Understanding intersectional identities.

BACKGROUND: Women have made significant advancements in the dentist workforce, growing from 20% of dentists in 2005 to 34.5% in 2020. Women have also made inroads in academic dentistry. While much scholarship has documented a growing feminization in dentistry and efforts to promote gender equity in the profession, there has been less exploration of the intersectional identities of these women. This manuscript explores how academic dentistry can support diverse women's leadership focusing on intersectional identities. METHODS: Applying the theoretical framework of intersectionality, we assess publicly available data to explore the percentages of faculty and deans who are women of color. Drawing upon best practices in higher education and our personal experiences, we explore opportunities to increase participation and support the advancement of women of color in academia. RESULTS: In the academic year 2018-2019, of the 5066 full-time faculty members, 40.5% were women. Minoritized women comprised 13.4% of full-time faculty members, compared to White women who were 20.6% of full-time faculty. Minoritized women comprised 7.3% of dental school deans, compared to White women who were 17.6% of deans. CONCLUSION: Intersectionality allows for a deeper examination of women in academic dentistry. Women of color are often erased in discussions about women in academic dentistry, even as the profession celebrates the progress made by women. Embracing the intersectional identities of women and by extension, people who identify as gender non-confirming may help dental schools to become humanistic environments where faculty and leadership represent the growing diversity in the profession and in the world.

Platelet-derived major histocompatibility complex class I coating on Treponema pallidum attenuates natural killer cell lethality.

The evasive tactics of Treponema pallidum pose a major challenge in combating and eradicating syphilis. Natural killer (NK) cells mediate important effector functions in the control of pathogenic infection, preferentially eliminating targets with low or no expression of major histocompatibility complex (MHC) class I. To clarify T. pallidum's mechanisms in evading NK-mediated immunosurveillance, experiments were performed to explore the cross-talk relations among T. pallidum, NK cells, and platelets. T. pallidum adhered to, activated, and promoted particle secretion of platelets. After preincubation with T. pallidum, platelets expressed and secreted high levels of MHC class I, subsequently transferring them to the surface of T. pallidum, potentially inducing an immune phenotype characterized by the "pseudo-expression" of MHC class I on the surface of T. pallidum (hereafter referred to a "pseudo-expression" of MHC class I). The polA mRNA assay showed that platelet-preincubated T. pallidum group exhibited a significantly higher copy number of polA transcript than the T. pallidum group. The survival rate of T. pallidum mirrored that of polA mRNA, indicating that preincubation of T. pallidum with platelets attenuated NK cell lethality. Platelets pseudo-expressed the MHC class I ligand on the T. pallidum surface, facilitating binding to killer cell immunoglobulin-like receptors with two immunoglobulin domains and long cytoplasmic tail 3 (KIR2DL3) on NK cells and initiating dephosphorylation of Vav1 and phosphorylation of Crk, ultimately attenuating NK cell lethality. Our findings elucidate the mechanism by which platelets transfer MHC class I to the T. pallidum surface to evade NK cell immune clearance.

Panniculectomy for a Rare End-Stage Complication of Severe Obesity and Increasing Surgical Phenomenon.

Panniculus morbidus (PM) is a presentation of severe chronic abdominal lymphoedema associated with obesity resulting in oedema and chronic fibrosis. It is a multifaceted condition with significant clinical and psychosocial implications. A 29-year-old female weighing 260 kg with a body mass index of 95 kg/m2 had recurrent infections and sepsis associated with an abdominal pannus extending to her knees and an area of ulceration. The pannus was indurated with extensive fibrosis that significantly affected her quality of life (QOL) requiring assistance for all activities of daily living (ADLs). A panniculectomy was performed with a negative pressure skin dressing over the skin wound. She was discharged after two days. Two months postoperatively, she reported significant improvement in QOL and can now mobilise and perform ADLs independently with no recurrent admissions. The global prevalence of obesity is reaching pandemic proportions and so will its complications. It can be functionally debilitating and worsen obesity. Surgical resection is indicated to restore mobility and function, prevent recurrent infections, improve QOL, and reduce economic burden. Patients report high satisfaction rates following surgery. Panniculectomy is an effective treatment to alleviate morbidity in severe obesity and should be considered in patients with recurrent infections and a significant impact on QOL.

Development and evaluation of a usable blastocyst predictive model using the biomechanical properties of human oocytes.

PURPOSE: The purposes of this study were to determine whether biomechanical properties of mature oocytes could predict usable blastocyst formation better than morphological information or maternal factors, and to demonstrate the safety of the aspiration measurement procedure used to determine the biomechanical properties of oocytes. METHODS: A prospective split cohort study was conducted with patients from two IVF clinics who underwent in vitro fertilization. Each patient's oocytes were randomly divided into a measurement group and a control group. The aspiration depth into a micropipette was measured, and the biomechanical properties were derived. Oocyte fertilization, day 3 morphology, and blastocyst development were observed and compared between measured and unmeasured cohorts. A predictive classifier was trained to predict usable blastocyst formation and compared to the predictions of four experienced embryologists. RESULTS: 68 patients and their corresponding 1252 oocytes were included in the study. In the safety analyses, there was no significant difference between the cohorts for fertilization, while the day 3 and 5 embryo development were not negatively affected. Four embryologists predicted usable blastocyst development based on oocyte morphology with an average accuracy of 44% while the predictive classifier achieved an accuracy of 71%. Retaining the variables necessary for normal fertilization, only data from successfully fertilized oocytes were used, resulting in a classifier an accuracy of 81%. CONCLUSIONS: To date, there is no standard guideline or technique to aid in the selection of oocytes that have a higher likelihood of developing into usable blastocysts, which are chosen for transfer or vitrification. This study provides a comprehensive workflow of extracting biomechanical properties and building a predictive classifier using these properties to predict mature oocytes' developmental potential. The classifier has greater accuracy in predicting the formation of usable blastocysts than the predictions provided by morphological information or maternal factors. The measurement procedure did not negatively affect embryo culture outcomes. While further analysis is necessary, this study shows the potential of using biomechanical properties of oocytes to predict embryo developmental outcomes.

The cementless taper wedge vs. fit-and-fill stem in primary total hip arthroplasty: risk of stem-related complication differs across Dorr types.

INTRODUCTION: The choice between a cementless taper wedge stem and a fit-and-fill stem in total Hip arthroplasty (THA) for various proximal femoral morphological types has not been thoroughly evaluated. This study aimed to compare the risk of stem-related complications between these two stem types in Dorr type A, B, and C femurs. MATERIALS AND METHODS: From January 2015 through April 2021, we retrospectively reviewed 1995 cementless THA procedures. We stratified all procedures into three groups: Dorr type A (N = 360, 18.0%), B (N = 1489, 74.7%) and C (N = 146, 7.3%). The primary outcome domain was stem-related complications, including stem subsidence ≥ 3 mm, intraoperative fracture, periprosthetic fracture and aseptic stem loosening. We performed multivariate regression analysis to compare the risk of stem-related complication between the two stem types. Other factors included age, sex, body mass index, diagnosis, age-adjusted Charlson comorbidity index, stem alignment and canal fill ratio. RESULTS: The incidence of stem-related complications in the taper wedge and fit-and-fill stem groups was 4.4% (N = 15) and 6.5% (N = 107), respectively. Fit-and-fill stems showed an increased risk of stem-related complications (aOR: 9.903, 95% CI: 1.567-62.597) only in Dorr type C femurs. No significant difference in risk was observed in Dorr type A and B femurs. Furthermore, the canal fill ratio at the lesser trochanter, 2 cm and 7 cm below the lesser trochanter, did not exhibit an association with stem-related complications in any Dorr type. CONCLUSIONS: Concerning the risk of stem-related complications, the taper wedge stem was a better choice in Dorr type C femurs. However, there was no difference in risk between the taper wedge stem and fit-and-fill stem in Dorr type A and B femurs.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity.

BACKGROUND: Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. METHODS: Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. RESULTS: Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. CONCLUSIONS: Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

Neurocognition and its predictors in a linguistically and culturally diverse cohort of people with HIV.

Objective: HIV/AIDS disproportionately affects Black and Latino people in the United States, yet there is a lack of research on predictors of neurocognitive outcomes in these groups. We examined neurocognitive performance and its key predictors across White, Black, and Latino people with HIV (PWH). Method: Participants included 586 PWH of White, Black, and Latino (English- and Spanish-speaking) background. Neurocognition was assessed via demographically-adjusted Fluid Cognition Composite T-scores from the NIH-Toolbox cognition battery, and individual tests comprising this composite. Predictors examined included sociodemographic and HIV disease characteristics, and medical, psychiatric and substance comorbidities. Results: Compared to White PWH, English-speaking Latino PWH had lower T-scores on the Fluid Cognition Composite, as well as Flanker Inhibition and Picture Sequence Memory tests. While there were no other significant group differences on Fluid Cognition, both Latino PWH language groups performed worse than Black PWH on Flanker Inhibition, and Black PWH performed worse than White PWH on List Sorting. Separate multivariable linear regression models by ethnic/racial/language group showed that significant correlates of worse Fluid Cognition included depressive symptoms among White PWH; hepatitis C co-infection among Black PWH; hypertension among English-speaking Latino PWH; and higher estimated duration of HIV disease and depressive symptoms in Spanish-speaking Latino PWH. Conclusions: Findings suggest worse neurocognition among English-speaking Latino PWH compared to Whites. Predictors of neurocognitive function among PWH differ across ethnic/racial and language groups. Consideration of these HIV disease characteristics and comorbidities may be valuable in developing targeted culturally-relevant interventions aimed at ameliorating neurocognitive dysfunction among diverse PWH.

Efficient Lead Removal by Assembly of Bio-Derived Ellagate Framework, Which Enables Electrocatalytic Reduction of CO2 to Formate.

Lead (Pb) poisoning and CO2-induced global warming represent two exemplary environmental and energy issues threatening humanity. Various biomass-derived materials are reported to take up Pb and convert CO2 electrochemically into low-valent carbon species, but these works address the problems separately rather than settle the issues simultaneously. In this work, cheap, natural ellagic acid (EA) extracted from common plants is adopted to assemble a stable metal-organic framework (MOF), EA-Pb, by effective capture of Pb2+ ions in an aqueous medium (removal rate close to 99%). EA-Pb represents the first structurally well-defined Pb-based MOF showing selective electrocatalytic CO2-to-HCOO- conversion with Faradaic efficiency (FE) of 95.37% at -1.08 V versus RHE. The catalytic mechanism is studied by 13CO2 labeling, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and theoretical calculation. The use of EA-Pb as an electrocatalyst for CO2 reduction represents a 2-in-1 solution of converting detrimental wastes (Pb2+) as well as natural resources (EA) into wealth (electrocatalytic EA-Pb) for addressing the global warming issue.

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.

Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.

New infundibulopelvic angle measurement method can predict stone-free rates following retrograde intrarenal surgery.

To enhance the accuracy of predicting stone-free rates after retrograde intrarenal surgery, we devised a novel approach to assess the renal infundibulopelvic angle. We conducted a retrospective review of patient records for those who underwent retrograde intrarenal surgery for renal stones between April 2018 and August 2019. Patient demographics, stone characteristics, and perioperative data were recorded. Subsequently, we introduced a modified angle measurement called the pelvic stone angle and evaluated its predictive performance for stone-free rates by comparing it with the traditional method in scoring systems. A total of 43 individuals were included in this study. Notable differences in stone burden and Hounsfield unit measurements were found between stone-free and non-stone-free patients. The pelvic stone angle demonstrated a good model fit when used in scoring systems, performing equally well as the conventional approach. The area under the receiver operating characteristic curve for the R.I.R.S. scoring system using the pelvic stone angle and the conventional approach did not show a significant difference. In conclusion, the predictive ability of the pelvic stone angle for stone-free rates was comparable to the old measurement method. Moreover, scoring systems using the pelvic stone angle exhibited a better model fit than those using the conventional approach.