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Introduction Mechanical force is attributed to the formation of tumor blood vessels, influences cancer cell invasion and metastasis, and promotes reprogramming of the energy metabolism. Currently, therapy strategies for the tumor microenvironment are being developed progressively. The purpose of this article is to discuss the molecular mechanism, diagnosis, and treatment of mechanical force in urinary tract cancers and outline the medications used in the mechanical microenvironment. Areas covered This review covers the complex mechanical elements in the microenvironment of urinary system malignancies, focusing on mechanical molecular mechanisms for diagnosis and treatment. Expert opinion The classification of various mechanical forces, such as matrix stiffness, shear force, and other forces, is relatively straightforward. However, little is known about the molecular process of mechanical forces in urinary tract malignancies. Because mechanical therapy is still controversial, it is critical to understand the molecular basis of mechanical force before adding mechanical therapy solutions.

Purpose of Review Inhaled environmental exposures cause over 12 million deaths per year worldwide. Despite localized efforts to reduce environmental exposures, tobacco smoking and air pollution remain the urgent public health challenges that are contributing to the growing prevalence of respiratory diseases. The purpose of this review is to describe the mechanisms through which inhaled environmental exposures accelerate lung aging and cause overt lung disease. Recent Findings Environmental exposures related to fossil fuel and tobacco combustion and occupational exposures related to silica and coal mining generate oxidative stress and inflammation in the lungs. Sustained oxidative stress causes DNA damage, epigenetic instability, mitochondrial dysfunction, and cell cycle arrest in key progenitor cells in the lung. As a result, critical repair mechanisms are impaired, leading to premature destruction of the lung parenchyma. Summary Inhaled environmental exposures accelerate lung aging by injuring the lungs and damaging the cells responsible for wound healing. Interventions that minimize exposure to noxious antigens are critical to improve lung health, and novel research is required to expand our knowledge of therapies that may slow or prevent premature lung aging.

Purpose. The finite element analysis method was used to explore the biomechanical stability of a novel locking plate for thoracolumbar burst fracture fusion fixation. Methods. The thoracolumbar CT imaging data from a normal volunteer was imported into finite software to build a normal model and three different simulated surgical models (the traditional double-segment fixation model A, the novel double-segment fixation model B, and the novel single-segment fixation model C). An axial pressure (500 N) and a torque (10 Nm) were exerted on the end plate of T12 to simulate activity of the spine. We recorded the range of motion (ROM) and the maximum stress value of the simulated cages and internal fixations. Results. Model A has a larger ROM in all directions than model B (flexion 5.63%, extension 38.21%, left rotation 46.51%, right rotation 39.76%, left bending 9.45%, and right bending 11.45%). Model C also has a larger ROM in all directions than model B (flexion 555.63%, extension 51.42%, left rotation 56.98%, right rotation 55.42%, left bending 65.67%, and right bending 59.47%). The maximum stress of the cage in model A is smaller than that in model B except for the extension direction (flexion 96.81%, left rotation 175.96%, right rotation 265.73%, left bending 73.73%, and right bending 171.28%). The maximum stress value of the internal fixation in model A is greater than that in model B when models move in flexion (20.23%), extension (117.43%), and left rotation (21.34%). Conclusion. The novel locking plate has a smaller structure and better performance in biomechanical stability, which may be more compatible with minimally invasive spinal tubular technology.

Parental age at time of offspring conception is increasing in developed countries. Advanced male age is associated with decreased reproductive success and increased risk of adverse neurodevelopmental outcomes in offspring. Mechanisms for these male age effects remain unclear, but changes in sperm DNA methylation over time is one potential explanation. We assessed genome-wide methylation of sperm DNA from 47 semen samples collected from male participants of couples seeking infertility treatment. We report that higher male age was associated with lower likelihood of fertilization and live birth, and poor embryo development (p 750 genes enriched in embryonic development, behavior and neurodevelopment among others. High dimensional mediation analyses identified four genes (DEFB126, TPI1P3, PLCH2 and DLGAP2) with age-related sperm differential methylation that accounted for 64% (95% CI 0.42–0.86%; p

The purpose of this study is to investigate the protective effect of gambogenic acid (GA) in acetaminophen (APAP)-induced hepatotoxicity in rat models. GA (10 mg/kg) was administered intraperitoneal (i.p.) to rats for 7 consecutive days followed by APAP (500 mg/kg) single dose (i.p.) on the final day after GA administration. The levels of MDA, GSH, SOD, CAT, GPx, GST, ALP, AST, ALT, proinflammatory cytokines (TNF-α, IL-1β, IL-6), apoptosis markers (caspase-3 and -9, Bax, Bcl-2), 4-hydroxynonenal (4-HNE), and prostaglandin E2 (PGE2) were evaluated. Results exhibited protective effects of GA by inhibiting inflammation, preventing oxidative stress and apoptosis in APAP-induced liver. Histopathological changes caused by APAP were attenuated, protein expressions of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) were upregulated, and nuclear factor–kappa β (NF-kβ) was downregulated by GA. In summary, GA significantly exerted anti-inflammatory and antiapoptotic effects against APAP-induced hepatotoxicity potentially through regulation of PI3K/Akt and NF-kβ signaling pathways.

Summary Background Pregnancy is associated with deteriorations in maternal bone strength and heightened susceptibility to bone fractures. We aimed to investigate whether ambient particulate matter (PM)2·5 concentrations were associated with bone strength during pregnancy. Methods In this longitudinal cohort study, we analysed longitudinal data from women participating in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City, Mexico. Eligible women were aged 18 years or older, at less than 20 weeks' gestation at the time of recruitment, planning to stay in Mexico City for the next 3 years, without heart or kidney disease, did not use steroids or anti-epileptic drugs, were not daily consumers of alcohol, and had access to a telephone. Daily ambient PM2·5 concentrations were estimated from a spatio-temporal model that was based on the individual's address. Trabecular bone strength was measured using quantitative ultrasound from the radius of the middle finger and cortical bone strength from the proximal phalanx of the middle finger, during the second trimester, third trimester, and 1 and 6 months post partum. Bone strength T scores were modelled with PM2·5 concentrations using linear mixed models and distributed lag models. Findings Adjusting for multiple exposure windows, each 10 ug/m3 increase in PM2·5 exposure concentrations in the first trimester was associated with a 0·18 SD decrease (95% CI −0·35 to −0·01; p=0·033) in ultrasound speed-of-sound (SOS) T score of trabecular bone strength from the second trimester until 6 months post partum. Similarly, each 10 μg/m3 increase in third trimester PM2·5 exposure was associated with a 0·18 SD decrease (–0·36 to −0·01; p=0·044) in the SOS T score of trabecular bone strength from the third trimester until 6 months post partum. PM2·5 exposure in the first month post partum was associated with a 0·20 SD decline (–0·39 to −0·01; p=0·043) in cortical bone strength until 6 months post partum. Interpretation Ambient PM2·5 exposure during and after pregnancy was associated with diminished trabecular and cortical bone strength. Early pregnancy PM2·5 exposure was associated with a greater decline in bone strength later during pregnancy. Late pregnancy and early post-partum exposures adversely affected the post-partum bone strength recovery. Technological and policy solutions to reduce PM2·5 pollution could improve public health by reducing bone fracture risk. Funding US National Institute of Environmental Health Sciences.

Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1–BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women. Various mechanisms are involved in the initiation and progression of breast cancer. Metabolic dysregulation has been associated with increasing breast cancer incidence and mortality. However, little is known about how metabolic disease regulates the development and progression of breast cancer at the molecular level. Here, using a hybridization capture-based panel including 124 cancer-associated genes, we performed targeted next-generation sequencing of tumor tissues and matched blood samples from 20 postmenopausal patients with primary breast cancer, in which 6 cases suffered from preexisting metabolic disorders including hypertension, type 2 diabetes, and coronary heart disease. We took only the protein-altering variants and identified 170 somatic mutations of 59 genes. Among these, 40 mutated genes were found in the metabolic disease group, and 33 mutated genes were found in the non–metabolic disease group. Importantly, nonsynonymous mutations of 26 genes (MSH3, BRAF, MLH3, MTOR, DDR2, ALK, etc.) were uniquely present in the metabolic disease group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to investigate biological functions and key pathways of somatic mutations. TP53, PIK3CA, and PTEN were the top three commonly mutated genes at a higher frequency compared with the Cancer Genome Atlas (TCGA) data, and several novel but infrequent mutations in other genes were also found. Although further studies are required to validate these variants, our results are the first to suggest a specific molecular profile of breast cancer with preexisting metabolic disease.

Population aging is a looming global health challenge. New biological aging metrics based on DNA methylation levels have been developed in addition to traditional aging biomarkers. The prospective relationships of aging biomarkers with mitochondrial changes are still not well understood. Here, we examined the prospective associations of mitochondrial copy number (mtDNAcn) with several aging biomarkers - DNAm-Age, DNAm-PhenoAge, DNAm-GrimAge, and leukocyte telomere length. We analyzed 812 individuals from Veteran Affairs Normative Aging Study (NAS) with available blood samples from 1999-2013. Whole blood mtDNAcn and relative leukocyte telomere length were measured via qPCR. DNA methylation was assessed and used to calculate DNAm-Age, DNAm-GrimAge, and DNAm-PhenoAge. Linear mixed models were used to quantify the associations of mtDNAcn with DNAm-Age, DNAm-GrimAge, DNAm-PhenoAge, and leukocyte telomere length. In multivariable cross-sectional analyses, mtDNAcn is negatively associated with DNAm-Age PhenoAge and DNAm-PhenoAge. In contrast, mtDNAcn is associated with prospective measures of higher DNAm-PhenoAge and shorter leukocyte telomere length. Our study shows that higher mtDNAcn is associated with prospective measures of greater DNAm-PhenoAge and shorter leukocyte telomere length independent of chronological age. This indicates a role for mitochondrial in aging-related disease and mortality, but not the departure of biological age from chronological age.

Background/Aim Adiposity trajectories reflect dynamic process of growth and may predict later life health better than individual measures. Prenatal phthalate exposures may program later childhood adiposity, but findings from studies examining these associations are conflicting. We investigated associations between phthalate biomarker concentrations during pregnancy with child adiposity trajectories. Methods We followed 514 mother-child pairs from the Mexico City PROGRESS cohort from pregnancy through twelve years. We measured concentrations of nine phthalate biomarkers in 2nd and 3rd trimester maternal urine samples to create a pregnancy average using the geometric mean. We measured child BMI z-score, fat mass index (FMI), and waist-to-height ratio (WHtR) at three study visits between four and 12 years of age. We identified adiposity trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We estimated associations of phthalates biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the potential effect of the total phthalate mixture and assessed effect modification by sex. Results We identified three trajectories of child adiposity, a “low-stable”, a “low-high”, and a “high-high” group. A doubling of the sum of di (2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with 1.53 (1.08, 2.19) greater odds of being in the “high-high” trajectory in comparison to the “low-stable” group, whereas a doubling in di-isononyl phthalate metabolites (ΣDiNP) was associated with 1.43 (1.02, 2.02) greater odds of being in the “low-high” trajectory and mono (carboxy-isononyl) phthalate (MCNP) was associated with 0.66 (0.45, 97) lower odds of being in the “low-high” trajectory. No sex-specific associations or mixture associations were observed. Conclusions Prenatal concentrations of urinary DEHP metabolites, DiNP metabolites, and MCNP, a di-isodecyl phthalate metabolite, were associated with trajectories of child adiposity. The total phthalate mixture was not associated with early life child adiposity.

BACKGROUND AND AIM: Previous research have suggested the link between air pollution and epigenetic changes such as microRNA expression. In this study, we examined whether short- and long-term expos...

BACKGROUND AND AIM: Perfluoroalkyl substances (PFAS), the “forever chemicals”, accumulate mainly in the liver and have various adverse health effects. Little is known about the mechanistic pathways...

BACKGROUND AND AIM: The gut microbiome is important in modulating health in childhood. Metal exposures affect multiple health outcomes, but their ability to modify bacterial communities in children...

Esophageal cancer related gene-4 (ECRG4) has been shown to be a candidate tumor suppressor in many tumors, but its role in glioma remains poorly understood. This study aimed to explore whether extracellular vesicles (EVs) derived from brain endothelial cells which overexpressed ECRG4 have anti-tumor effect on gliomas in vivo and in vitro, as well as the possible mechanism. A constructed lentivirus expressing the ECRG4 gene was transfected into the hCMEC/D3 cell line. The EVs were isolated from the cells and characterized by Western blot with exosome markers of CD9, CD63, CD81, Alix. RT-PCR and Western blot were performed to verify ECRG4 expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clone formation assays were applied to detect the proliferation of glioma cells incubated with EVs expressing the ECRG4 (ECRG4-exo). The level of inflammatory cytokines and angiogenesis related factors, including nuclear factor kappa-B (NF-κB), interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) levels were detected by ELISA. The T98G cell xenograft mouse model was established and treated with ECRG4-EV. The tumor volume and weight were recorded. p38-MAPK, p-p38-MAPK proteins were determined by Western blot in tumor tissues. As a result, EVs can be internalized into U87MG and T98G cells. ECRG4-EV inhibited U87MG and T98G cell proliferation. ECRG4-EV also inhibited the expression of factors involved in inflammation and angiogenesis. In addition, ECRG4-EVs suppressed tumor growth and decreased the production of inflammatory cytokines through inactivation of p38-MAPK signal pathway. In conclusion, ECRG4-EVsuppresses glioma proliferation through modulating the inflammation and angiogenesis. This article is protected by copyright. All rights reserved.

Haotian Wu,1,2 Song Liu,1,2 Chunxia Li,3 Zhaohui Song1,2 1Department of Orthopaedic Surgery, The 3rd Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, People’s Republic of China; 2Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, 050051, Hebei, People’s Republic of China; 3Department of Imaging Medicine, General Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia 010017, People’s Republic of ChinaCorrespondence: Haotian WuDepartment of Orthopaedic Surgery, The 3rd Hospital, Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, 050051, People’s Republic of China, Tel +86-311-88603682Fax +86-311-87023626Email liu18633031986@163.comAim: This study aims to present a modified Laboratory Risk Indicator for Necrotizing Fasciitis (m-LRINEC) scoring system and to evaluate its ability in discriminating necrotizing fasciitis (NF) from other severe soft-tissue infections.Methods: Patients with NF diagnosed by surgical findings in our institution between January 2014 and December 2020 were included as the case group, matched by controls with severe soft-tissue infections other than NF in a ratio of 2:1, based on demographics, calendar time and immunosuppressant status. Patients’ demographics, comorbidities and laboratory test results were extracted from medical records. Logistic regression analyses were used to determine the association with NF after adjustment for confounders, whereby m-LRINEC was developed. Receiver operating characteristics (ROC) curves and the area under the curve (AUC) were used to evaluate its discriminating ability.Results: There were 177 patients included, 59 in the NF group and 118 in the non-NF group. We added comorbid diabetes and kidney disease to the original LRINEC scoring system, used high-sensitivity C-reactive protein (HCRP) to replace the CRP and redefined the cut-off values for the other four variables, to develop the m-LRINEC system. The cut-off value for m-LRINEC was 17 points, with corresponding sensitivity of 93.2% and specificity of 86.9%, and the AUC was 0.935 (95% CI 0.892 to 0.977; p< 0.001).Conclusion: The m-LRINEC scoring system shows a high sensitivity and specificity in discriminating NF from other severe soft-tissue infections. Patients with an m-LRINEC score of > 17 points should have a high index of suspicion for the presence of NF. The validity of the m-LRINEC needs to be confirmed in studies with larger samples and better design.Keywords: necrotizing fasciitis, factors, biomarkers, scoring system, m-LRINEC

Supplemental Digital Content is available in the text., Background: Previous studies suggest a negative association between prenatal polybrominated diphenyl ethers (PBDEs) exposure and child cognitive and psychomotor development. However, the timing of the relationship between PBDE exposure and neurodevelopment is still unclear. We examined the association between PBDE concentration at two different prenatal times (early and late pregnancy) and cognitive function in children 6–8 years of age. Methods: Eight hundred pregnant women were recruited between 2007 and 2009 from Sherbrooke, Canada. Four PBDE congeners (BDE-47, -99, -100, and -153) were measured in maternal plasma samples collected during early pregnancy (12 weeks of gestation) and at delivery. At 6–8 years of age, 355 children completed a series of subtests spanning multiple neuropsychologic domains: verbal and memory skills were measured using the Wechsler Intelligence Scale for Children, Fourth Edition; visuospatial processing using both Wechsler Intelligence Scale for Children, Fourth Edition and Neuropsychological Assessment second edition; and attention was assessed through the Test of Everyday Attention for Children. Additionally, parents completed subtests from the Developmental Coordination Disorder Questionnaire to measure child motor control. We used linear regression and quantile g-computation models to estimate associations of PBDE congener concentrations and psychologic test scores. Results: In our models, no significant associations were detected between PBDE mixture and any of the child psychologic scores. BDE-99 concentration at delivery was nominally associated with higher scores on short-term and working memory while a decrease in spatial perception and reasoning was nominally associated with higher BDE-100 concentration at delivery. Conclusion: Overall, our results did not show a significant association between PBDEs and child cognitive and motor development.

Background. Wnt/β-catenin signaling has been reported to exert cytoprotective effects in a cellular model of Parkinson’s disease (PD). Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of PD, and excitatory amino acid transporters (EAATs) play a predominant role in clearing excessive glutamate. EAAT2 is mainly expressed in astrocytes, which are an important source of Wnt signaling in the brain. Methods. Wnt1-overexpressing U251 astrocytes were indirectly cocultured with dopaminergic SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA). Cell toxicity was determined by cell viability and flow cytometric detection. Glutamate level in the culture medium was determined by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the expression of Wnt1, β-catenin, and EAAT2. Immunofluorescence was used to display the expression and translocation of NF-κB p65. Results. 6-OHDA treatment significantly decreased cell viability in both U251 cells and SH-SY5Y cells, inhibited the expression of Wnt1, β-catenin, and EAAT2 in U251 cells, and increased the glutamate level in the culture medium. Coculture with Wnt1-overexpressing U251 cells attenuated 6-OHDA-induced apoptosis in SH-SY5Y cells. Overexpression of Wnt1 decreased the glutamate level in the culture media, upregulated β-catenin, EAAT2, and NF-κB levels, and promoted the translocation of NF-κB from the cytoplasm to the nucleus in U251 cells. Conclusion. Wnt1 promoted EAAT2 expression and mediated the cytoprotective effects of astrocytes on dopaminergic cells. NF-κB might be involved in the regulation of EAAT2 by Wnt1.

Renal cell carcinoma is a highly heterogeneous cancer group, and the complex microenvironment of the tumor provides appropriate immune evasion opportunities. The molecular mechanism of immune escape in renal cell carcinoma is currently a hot issue, focusing primarily on the major complex of histocompatibility, immunosuppressive cells, their secreted immunosuppressive cytokines, and apoptosis molecule signal transduction. Immunotherapy is the best treatment option for patients with metastatic or advanced renal cell carcinoma and combination immunotherapy based on a variety of principles has shown promising prospects. Comprehensive and in-depth knowledge of the molecular mechanism of immune escape in renal cell carcinoma is of vital importance for the clinical implementation of effective therapies. The goal of this review is to address research into the mechanisms of immune escape in renal cell carcinoma and the use of the latest immunotherapy. In addition, we are all looking forward to the latest frontiers of experimental combination immunotherapy.

Background This study was done to observe the incidence of Osteo-line on the femur neck and to explore the clinical application of Osteo-line in osteotomy. Methods Eighty-nine adult femur specimens were selected to observe the incidence of Osteo-line on the femur neck. From August 2015 to January 2019, a total of 278 patients who completed unilateral hip arthroplasty at the Third Hospital of Hebei Medical University were retrospectively included. Patients who accepted osteotomy via Osteo-line on the femur neck were defined as the experimental group (n = 139), and patients who accepted osteotomy via traditional method (The femoral distance 1.5 cm above the trochanter was retained for osteotomy by visual inspection.) were defined as the control group (n = 139). According to the postoperative pelvic X-ray, Photoshop was used to evaluate the leg length discrepancy (LLD) by the CFR-T-LT method. Results Among the 89 specimens, the incidence of anterior Osteo-line was 75.28%, and the incidence of posterior Osteo-line was 100%. According to the clinical application results, the incidence of anterior Osteo-line on the femur neck was 80%, and the incidence of posterior Osteo-line was 100%. The Osteo-line was clearer than those on the femoral specimens. Twenty-six cases had LLD greater than 1 cm (9.29%), including 2 cases in the experimental group and 24 cases in the control group. The average postoperative LLD in the experimental group (0.19 ± 0.38 mm) was significantly shorter than in the control group (0.54 ± 0.51 mm)(P = 0.005). Conclusion The incidence of Osteo-line on the femur neck was high, and patients who accepted osteotomy via Osteo-line on the femur neck can achieve shorter postoperative LLD than the control group.

Autophagy is a treatment target for many disorders, including cancer, and its specific role is becoming increasingly well known. In tumors, researchers pay attention to microribonucleic acids (miRNAs) with regulatory effects to develop more effective therapeutic drugs for autophagy and find new therapeutic targets. Various studies have shown that autophagy-related miRNAs play an irreplaceable role in different tumors, such as miR-495, miR-30, and miR-101. These miRNAs are associated with autophagy resistance in gastric cancer, non-small cell lung cancer, and cervical cancer. In recent years, autophagy-related miRNAs have also been reported to play a role in autophagy in urinary system tumors. This article reviews the regulatory effects of autophagy-related miRNAs in kidney, bladder, and prostate cancer and provides new ideas for targeted therapy of the three major tumors of the urinary system.

Studies have reported associations between phthalates, a family of ubiquitous environmental contaminants, and metabolic complications of pregnancy, but no study has considered these outcomes beyond...

Background Prenatal phthalate exposures may affect processes that underlie offspring cardiometabolic health, but findings from studies examining these associations are conflicting. We examined associations between biomarkers of phthalate exposures during pregnancy with child lipid and adipokine levels. Methods Data were from 463 mother-child pairs in the PROGRESS cohort of Mexico City. We quantified 15 phthalate metabolites in 2nd and 3rd trimester maternal urine samples and created an average pregnancy measure using the geometric mean. We evaluated the 15 metabolites as nine biomarkers, including four metabolite molar sums. We measured fasting serum triglycerides, non-HDL cholesterol, leptin, and adiponectin in children at the six-year follow-up visit (mean = 6.8 years). We estimated associations using linear regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) and assessed effect modification by sex. Results In BKMR and WQS models, higher concentrations of the total mixture of phthalate biomarkers were associated with lower triglycerides (β = −3.7% [-6.5, −0.78] per 1 unit increase in WQS biomarker index) and non-HDL cholesterol (β = −2.0 [-3.7, −0.25] ng/ml per increase in WQS biomarker index). Associations between individual biomarkers and child outcomes were largely null. We observed some evidence of effect modification by child sex for mono-3-carboxypropyl phthalate (β = 19.4% [1.26, 40.7] per doubling of phthalate) and monobenzyl phthalate (β = −7.6% [-14.4, -0.23]) in girls for adiponectin. Conclusions Individual prenatal phthalate biomarkers were not associated with child lipid or adipokine levels. Contrary to our hypothesis, the total phthalate mixture was associated with lower child triglycerides and non-HDL cholesterol.

Importance Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight. Objective To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity. Design, Setting, and Participants This prospective birth cohort study from the Centre Hospitalier Universite de Sherbrooke in Sherbrooke, Quebec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020. Exposures Acetaminophen levels measured in meconium. Main Outcomes and Measures Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity. Results Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%). Conclusions and Relevance Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.

Extracellular vesicles (EVs) are nano-sized membrane bound complexes that have been identified as a mean for intercellular communication between cells and tissues both in physiological and pathological conditions. These vesicles contain numerous molecules involved in signal transduction including microRNAs, mRNAs, DNA, proteins, lipids, and cytokines and can affect the behavior of recipient cells. Female reproduction is dependent on extremely fine-tuned endocrine regulation, and EVs may represent an added layer that contributes to this regulation. This narrative review article provides an update on the research of the role of EVs in female reproduction including folliculogenesis, fertilization, embryo quality, and implantation. We also highlight potential pitfalls in typical EV studies and discuss gaps in the current literature.

Background: Distal tibia shaft fractures have a high risk of mal-alignment when treated with intramedullary nailing (IMN). Permanent blocking screws (BSs) and temporary blocking pins (BPs) are often used as supplements to help IMN get good alignment. The purpose of this study was to compare the clinical and radiographic outcomes of temporary BPs and permanent BSs for distal tibia shaft fractures.Methods: From March 2014 to May 2019, a total of 89 patients with distal tibia shaft fractures were included in this retrospective study and divided into two groups. All fractures were located below the isthmus but 4 cm above the tibial plafond. The differences in operating time, intraoperative bleeding, fibula plate fixation, number of BP/BS, initial and final alignment, loss of reduction, fracture healing time, and postoperative complications were analyzed. Functional outcomes of the ankle were assessed with the American Orthopedic Foot and Ankle Society (AOFAS) score.Results: All patients underwent a minimum follow-up of 13 months. The operating time was (73.9±6.1) min and (80.2±8.6) min in the BP group and BS group, respectively (P < 0.05); intraoperative bleeding was (88.2±18.0) mL and (92.9±26.6) mL, respectively (P > 0.05); initial reduction deformity in coronal plane was (0.5±2.3) degrees and (0.9±2.3) degrees, respectively (P > 0.05); final alignment deformity in coronal plane was (1.2±2.7) degrees and (1.3±2.4) degrees, respectively (P > 0.05); initial reduction deformity in sagittal plane was (0.6±2.2) degrees and (0.6±2.4) degrees, respectively (P > 0.05); final alignment deformity in sagittal plane was (0.9±2.3) degrees and (1.0±2.2) degrees, respectively (P > 0.05); As for the loss of reduction, there was no significant difference in sagittal plane between the two groups(P > 0.05). Although the loss of reduction in the coronal plane of the BP group (0.8±0.7 degrees) is statistically higher than that of the BS group (0.5±0.5 degrees), the small difference was not clinically important (P < 0.05). No significant differences were found between the two groups in fracture healing time, AOFAS score and complications (P > 0.05).Conclusion: Both temporary BP and permanent BS can help achieve equivalent overall alignment. However, BP technique is simpler and takes less time.

BACKGROUND: Parabens, which are used as a preservative in foods and personal care products, are detected in nearly 100% of human urine samples. Exposure to parabens is associated with DNA damage, male infertility, and endocrine disruption in adults, but the effects of prenatal exposure are unclear. In part, this is due to inadequate assessment of exposure in maternal urine, which may only reflect maternal rather than fetal exposure. To address this gap, we examined the association of prenatal methylparaben measured in meconium with preterm birth, gestational age, birthweight, maternal thyroid hormones, and child Attention-Deficit Hyperactivity Disorder (ADHD) at 6-7 years. DESIGN: Data come from the GESTation and the Environment (GESTE) prospective observational pregnancy cohort in Sherbrooke, Quebec, Canada. Participants were 345 children with data on ADHD among 394 eligible pregnancies in women age ≥18 years with no known thyroid disease before pregnancy and meconium collected at delivery. Methylparaben was measured in meconium. Birthweight, gestational age, and maternal thyroid hormones at

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are inflammatory demyelinating diseases of the central nervous system. Exosomal microRNAs (miRNAs) are emerging biomarkers for demyelinating diseases. In this study, 52 aquaporin-4 antibody serum-positive NMOSD patients, 18 relapsing-remitting multiple sclerosis (RRMS) patients and 17 healthy controls (HCs) were included for the next-generation sequencing (NGS). To validate the NGS results, the valuable miRNAs were selected for validation by real-time quantitative polymerase chain reaction in another cohort of patients, comprising 31 NMOSD patients and 14 HCs. In addition, these miRNAs were also validated in a longitudinal study. NGS data revealed the exosomal miRNAs profile in NMOSD patients was different from HCs. Among those potential exosomal miRNAs which can distinguish NMOSD status, hsa-miR-122-3p and hsa-miR-200a-5p were the most abundant miRNAs. In addition, hsa-miR-122-3p and hsa-miR-200a-5p were significantly upregulated in the serum exosome of relapsing NMOSD compared with that in remitting NMOSD. Hsa-miR-122-3p and hsa-miR-200a-5p had positive correlations with disease severity in NMOSD patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the MAPK, Wnt and Ras signaling pathways were enriched. Further biological function analysis demonstrated that these two miRNAs might be involved in the immunoregulation of NMOSD pathogenesis. Our results indicated that miRNAs delivered by exosomes could be applied as potential biomarkers for NMOSD.

Phthalates are associated with several adverse health outcomes, but few studies have evaluated phthalate exposures in Mexican populations, particularly pregnant women. Between 2007 and 2011, 948 pregnant women from Mexico City were recruited as part of the PROGRESS cohort. We quantified 17 metabolites of phthalates and phthalate alternatives in urine samples collected during the second and third trimesters and examined temporal trends of metabolite concentrations, within-person reproducibility, and relations of individual metabolites with sociodemographic, lifestyle, and occupational factors. Concentrations of mono-2-ethyl-5-carboxypentyl terephthalate, a metabolite of the alternative phthalate di-2-ethylhexyl terephthalate, increased monotonically from 2007 to 2010 (31% per year; 95% confidence interval = 23 and 39%). We observed moderate to high correlations among metabolites collected at the same visit, but there was high variability between second and third trimester phthalate metabolite concentrations (intraclass correlation coefficients = 0.17-0.35). In general, higher socioeconomic status was associated with higher phthalate concentrations. Some metabolites were associated with maternal age and education, but no consistent patterns were observed. Women working in the home and those who worked in administration had higher concentrations of several phthalate metabolites relative to students, professionals, and those in customer service. Biomonitoring efforts are warranted to investigate present and future exposure trends and patterns.

Perinatal exposures to polybrominated diphenyl ethers permanently reprogram liver metabolism and induce a nonalcoholic fatty liver disease-like phenotype and insulin resistance in rodents. Aim: To test if these changes are associated with altered liver epigenome. Materials & methods: Expression of small RNA and changes in DNA methylation in livers of adult rats were analyzed following perinatal exposure to 2,2′,4,4′-tetrabromodiphenyl ether, the polybrominated diphenyl ether congener most prevalent in human tissues. Results: We identified 33 differentially methylated DNA regions and 15 differentially expressed miRNAs. These changes were enriched for terms related to lipid and carbohydrate metabolism, insulin signaling, Type-2 diabetes and nonalcoholic fatty liver disease. Conclusion: Changes in the liver epigenome are a likely candidate mechanism of long-term maintenance of an aberrant metabolic phenotype.

Background and Purpose— The relationship between infarct dimensions and neurological progression in patients with acute pontine infarctions remains unclear. This study aimed to investigate the morphometric predictive value of magnetic resonance imaging for early neurological deterioration (END) in acute pontine infarction. Methods— We included all patients admitted to our department having an acute ischemic stroke in the pons. The ventrodorsal length multiplied by thickness was measured as parameters of infarct size. END was defined as an incremental increase in the National Institutes of Health Stroke Scale score by ≥1 point in motor power, or ≥2 points in the total score within the first week after admission. Results— We enrolled 407 patients, and 114 (28.0%) patients were diagnosed with END. Adjusted logistic regression analyses showed the maximum length multiplied by thickness was independently associated with END (odds ratio, 4.580 [95% CI, 2.909–7.210]). The sensitivity, specificity, and area under the curve were 77.2%, 79.2%, and 0.843, respectively, in the receiver operating characteristic curve analysis of maximum length multiplied by thickness for predicting END. Conclusions— These results suggest that the maximum length multiplied by thickness may be a possible predictor in the evaluation of progression with isolated acute pontine infarction. The extent of the pontine infarction along the conduction tract may contribute to deterioration.

Background Phthalates, a chemical class of plasticizers, are ubiquitous environmental contaminants that have been associated with oxidative stress. Mitochondria DNA copy number (mtDNAcn) and DNA deletions (mtDNAdel) are emerging biomarkers for cellular oxidative stress and environment exposures. Objectives To examine associations of urinary phthalate metabolite and isoprostane concentrations on sperm mtDNAcn and mtDNAdel in male partners undergoing assisted reproductive technologies (ART). Methods Ninety-nine sperm samples were collected from male partners undergoing ART at Baystate Medical Center in Springfield, MA as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen urinary phthalate metabolite concentrations were analyzed by the Centers for Disease Control using tandem mass spectrometry. Urinary 15-F2t-isoprostane concentrations, a biomarker of lipid peroxidation, were measured using a competitive enzyme-linked immunosorbent assay. A triplex qPCR method was used to determine the relative quantification of mtDNAcn and mtDNAdel. Results Sperm mtDNAcn and mtDNAdel were positively correlated (Spearman rho = 0.31; p = .002). Adjusting for age, BMI, current smoking, race, and measurement batch, urinary monocarboxy-isononyl phthalate (MCNP) concentrations were positively associated with mtDNAcn (β = 1.63, 95% CI: 0.14, 3.11). Other urinary phthalate metabolite and isoprostane concentrations were not associated with sperm mtDNAcn or mtDNAdel. Conclusions Among this cohort of male ART participants, those with higher MCNP had higher mtDNAcn; other phthalate metabolites and isoprostane were not associated with mtDNAcn and mtDNAdel. Given our relatively small sample size, our results should be interpreted with caution. Future research is needed to replicate the findings in larger studies and among sperm samples obtained from the general population.

Background and Objective: Low serum levels of bilirubin and albumin are associated with multiple autoimmune diseases, but their role in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. Methods: Serum bilirubin and albumin levels were evaluated in 60 patients with anti-NMDAR encephalitis, 50 cryptococcal encephalitis, and 145 healthy controls (CTLs). Of the 60 anti-NMDAR encephalitis patients, 30 had a follow-up evaluation at 3 months after admission. Results: Serum bilirubin and albumin levels were both significantly lower in anti-NMDAR encephalitis than in CTLs, and serum bilirubin levels were significantly lower in anti-NMDAR encephalitis than in cryptococcal encephalitis. Serum bilirubin levels were significantly lower in patients with psychiatric symptoms, with severe impairment, and with limited responses to treatment than those without psychiatric symptoms, with mild impairment, and with favorable responses to treatment, respectively. A follow-up evaluation of 30 patients revealed that the modified Rankin Scale scores were significantly decreased after treatment. Serum bilirubin significantly associated with serum albumin, and plasma hemoglobin. Conclusions: Our results revealed for the first time an association between the serum levels of bilirubin in the anti-NMDAR encephalitis. Further studies investigating the role of bilirubin and albumin in anti-NMDAR encephalitis are required.

Background Pregnancy induces numerous cardiovascular and metabolic changes. Alterations in these sensitive processes may precipitate long-term post-delivery health consequences. Studies have reported associations between phthalates and metabolic complications of pregnancy, but no study has investigated metabolic outcomes beyond pregnancy. Objectives To examine associations of exposure to phthalates during pregnancy with post-delivery metabolic health. Design We quantified 15 urinary phthalate biomarker concentrations during the second and third trimesters among 618 pregnant women from Mexico City. Maternal metabolic health biomarkers included fasting blood measures of glycemia [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], % hemoglobin A1c (HbA1c%)] and lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides), at 4–5 and 6–8 years post-delivery. To estimate the influence of the phthalates mixture, we used Bayesian weighted quantile sum regression and Bayesian kernel machine regression; for individual biomarkers, we used linear mixed models. Results As a mixture, higher urinary phthalate biomarker concentrations during pregnancy were associated with post-delivery concentrations of plasma glucose (interquartile range [IQR] difference: 0.13 SD, 95%CrI: 0.05, 0.20), plasma insulin (IQR difference: 0.06 SD, 95%CrI: −0.02, 0.14), HOMA-IR (IQR difference: 0.08 SD, 95% CrI: 0.01, 0.16), and HbA1c% (IQR difference: 0.15 SD, 95%CrI: 0.05, 0.24). Associations were primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and the sum of dibutyl phthalate biomarkers (∑DBP). The phthalates mixture was associated with lower HDL (IQR difference: −0.08 SD, 95%CrI: −0.16, −0.01), driven by ∑DBP and monoethyl phthalate (MEP), and higher triglyceride levels (IQR difference: 0.15 SD, 95%CrI: 0.08, 0.22), driven by MECPTP and MEP. The overall mixture was not associated with total cholesterol and LDL. However, ∑DBP and MEP were associated with lower and higher total cholesterol, respectively, and MECPTP and ∑DBP were associated with lower LDL. Conclusions Phthalate exposure during pregnancy is associated with adverse long-term changes in maternal metabolic health. A better understanding of timing of the exact biological changes and their implications on metabolic disease risk is needed.

Study question Are preconception phthalate and phthalate replacements associated with sperm differentially methylated regions (DMRs) among men undergoing IVF? Summary answer Ten phthalate metabolites were associated with 131 sperm DMRs that were enriched in genes related to growth and development, cell movement and cytoskeleton structure. What is known already Several phthalate compounds and their metabolites are known endocrine disrupting compounds and are pervasive environmental contaminants. Rodent studies report that prenatal phthalate exposures induce sperm DMRs, but the influence of preconception phthalate exposure on sperm DNA methylation in humans is unknown. Study design, size, duration An exploratory cross-sectional study with 48 male participants from the Sperm Environmental Epigenetics and Development Study (SEEDS). Participants/materials, setting, methods The first 48 couples provided a spot urine sample on the same day as semen sample procurement. Sperm DNA methylation was assessed with the HumanMethylation 450 K array. Seventeen urinary phthalate and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH) metabolite concentrations were measured from spot urine samples. The A-clust algorithm was employed to identify co-regulated regions. DMRs associated with urinary metabolite concentrations were identified via linear models, corrected for false discovery rate (FDR). Main results and role of chance Adjusting for age, BMI, and current smoking, 131 DMRs were associated with at least one urinary metabolite. Most sperm DMRs were associated with anti-androgenic metabolites, including mono(2-ethylhexyl) phthalate (MEHP, n = 83), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, n = 16), mono-n-butyl phthalate (MBP, n = 22) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl (MCOCH, n = 7). The DMRs were enriched in lincRNAs as well as in regions near coding regions. Functional analyses of DMRs revealed enrichment of genes related to growth and development as well as cellular function and maintenance. Finally, 13% of sperm DMRs were inversely associated with high quality blastocyst-stage embryos after IVF. Limitations, reasons for caution Our modest sample size only included 48 males and additional larger studies are necessary to confirm our observed results. Non-differential misclassification of exposure is also a concern given the single spot urine collection. Wider implications of the findings To our knowledge, this is the first study to report that preconception urinary phthalate metabolite concentrations are associated with sperm DNA methylation in humans. These results suggest that paternal adult environmental conditions may influence epigenetic reprogramming during spermatogenesis, and in turn, influence early-life development. Study funding/competing interest(s) This work was supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.

Background Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. Methods To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55–59, 60–64, 65–69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2’ deoxycytidine [5-mdC] to 2’-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2’-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. Results Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6–1.3), 0.88 (95% CI, 0.6–1.3), and 0.84 (95% CI, 0.6–1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. Discussion These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease.

Since 1965, polybrominated diphenyl ethers (PBDEs) have been used internationally as flame-retardant additives. PBDEs were recently withdrawn from commerce in North America and Europe due to their environmental persistence, bioaccumulative properties and endocrine-disrupting effects. Generations exposed perinatally to the highest environmental doses of PBDE account for one-fifth of the total United States population. While, toxicity of PBDE for the male reproductive system has been demonstrated in several human and animal studies, the long-lasting effects of perinatal exposures on male reproduction are still poorly understood. In this study, pregnant Wistar rats were exposed to 0.2 mg/kg 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. Male reproductive outcomes were analyzed on postnatal day 120 in offspring. Exposed animals had significantly smaller testes, displayed decreased sperm production per testis weight, had significantly increased percentage of morphologically abnormal spermatozoa, and showed an increase in spermatozoa head size. Perinatal BDE-47 exposure led to significant changes in testes transcriptome, including suppression of genes essential for spermatogenesis and activation of immune response genes. In particular, we observed a 4-fold average decrease in expression of protamine and transition protein genes in testes, suggesting that histone-protamine exchange may be dysregulated during spermatogenesis, resulting in an aberrant sperm epigenome. The possibility of long-lasting effects of developmental PBDE exposures calls for additional studies to build a foundation for the development of preventive and protective interventions against the environmentally-induced decline in fertility.

Background: Th9 cells are a newly discovered CD4+ T helper cell subtype, characterized by high interleukin (IL)-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of multiple sclerosis (MS). Mast cells are multifunctional innate immune cells, which are perhaps best known for their role as dominant effector cells in allergies and asthma. Several lines of evidence point to an important role for mast cells in MS and its animal models. Simultaneously, there is dynamic "cross-talk" between Th9 and mast cells. The aim of the present study was to examine the IL-9-mast cell axis in experimental autoimmune encephalomyelitis (EAE) and determine its interaction after neutralizing anti-IL-9 antibody treatment. Methods: Female C57BL/6 mice were randomly divided into three groups (n = 5 in each group): mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE (EAE group), EAE mice treated with anti-IL-9 antibody (anti-IL-9 Abs group), and EAE mice treated with IgG isotype control (IgG group). EAE clinical score was evaluated. Mast cells from central nervous system (CNS) were detected by flow cytometry. The production of chemokine recruiting mast cells in the CNS was explored by reverse transcription-polymerase chain reaction (RT-PCR). In mice with MOG-induced EAE, the expression of IL-9 receptor (IL-9R) complexes in CNS and spleen mast cells was also explored by RT-PCR, and then was repeating validated by immunocytochemistry. In vitro, spleen cells from EAE mice were cultured with anti-IL-9 antibody, and quantity of mast cells was counted by flow cytometry after co-culture. Results: Compared with IgG group, IL-9 blockade delayed clinical disease onset and ameliorated EAE severity (t = −2.217, P = 0.031), accompany with mast cells infiltration decreases (day 5: t = −8.005, P < 0.001; day 15: t = −11.857, P < 0.001; day 20: t = −5.243, P = 0.001) in anti-IL-9 Abs group. The messenger RNA expressions of C-C motif chemokine ligand 5 (t = −5.932, P = 0.003) and vascular cell adhesion molecule-1 (t = −4.029, P = 0.004) were significantly decreased after IL-9 neutralization in anti-IL-9 Abs group, compared with IgG group. In MOG-induced EAE, the IL-9R complexes were expressed in CNS and spleen mast cells. In vitro, splenocytes cultured with anti-IL-9 antibody showed significantly lower levels of mast cells in a dose-dependent manner, compared with splenocytes cultured with anti-mouse IgG (5 μg/ml: t = −0.894, P = 0.397; 10 μg/ml: t = −3.348, P = 0.019; 20 μg/ml: t = −7.639, P < 0.001). Conclusions: This study revealed that IL-9 neutralization reduced mast cell infiltration in CNS and ameliorated EAE, which might be relate to the interaction between IL-9 and mast cells. Key words: Experimental Autoimmune Encephalomyelitis; Interleukin-9; Mast Cell; Multiple Sclerosis; Th9

This study aimed to evaluate the functional outcomes and mortality following hip fracture surgery in elderly patients, and to identify the associated risk factors. Between January 2016 and December 2017, 480 consecutive patients were finally included for data analyses. The Harris score and Barthel index were used to evaluate the hip function and ability to perform activities of daily living (ADL). Univariate and multivariate logistics regression analyses were performed to determine the independent risk factors for mortality, poor hip function or poor ability to perform ADL. The mortality rate was 15.6% (75/480). In the survivors, poor outcome developed in 133 (32.8%) patients and poor ADL was in 72 (17.8%) patients. The independent factors that influenced mortality were advanced age (p = 0.033), male gender (0.031), living in rural area (p 7 days (p = 0.020), postoperative drainage use (p = 0.034), WBC > 10 × 109/L (p = 0.005), reduced RBC (p = 0.011), PLT 200 U/L (p = 0.003). The independent factors that influenced the hip function were male gender (p = 0.009), WBC > 10 × 109/L (p 7 days (p = 0.027), postoperative drainage use (p = 0.010), elevated WBC (p = 0.020), lower HGB (p