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Cutaneous squamous cell carcinoma (cSCC) is a global malignant tumor with a high degree of malignancy. Once metastasis occurs, it will lead to poor prognosis and even death. This study attempts to find out the central genes closely related to cSCC metastasis, so as to clarify the molecular regulatory mechanism of cSCC metastasis and open up new ideas for clinical treatment.Firstly, cSCC data set GSE98767 was used to establish a tumor metastasis model via clustering analysis. The key module and hub genes associated with cSCC metastasis were analyzed by weighted gene co-expression analysis (WGCNA). Next, the prognostic functions of hub genes were identified by functional and pathway enrichment analysis, pan-cancer analysis, and receiver operating characteristic-area under the curve (ROC-AUC) validation. Finally, the key genes were verified by clinical sample detection and biological in vitro test.A total of 19 hub genes related to cSCC metastasis were identified. They were highly expressed in cSCC metastatic tissues and were mainly enriched in cellular material and energy metabolism pathways. Overall survival (OS) and disease-free survival (DFS) results from pan-cancer analysis showed that eight and six highly expressed genes, respectively, with PAPSS2 and SCG5 had highly reliable ROC-AUC validation values and were poor prognostic factors. Clinical and biological tests also confirmed the upregulation of PAPSS2 and SCG5 in cSCC. Deletion of PAPSS2 and SCG5 resulted in decreased viability, migration, and invasion of A-431 cells.PAPSS2 and SCG5 may be important factors for cSCC metastasis, and they are involved in the regulation of cSCC cell viability, migration, and invasion.

Intravesical instillation (IVI) of Bacillus Calmette-Guerin (BCG) can prevent bladder cancer recurrence, but this agent has been out of stock in recent years. IVI of other agents, like chidamide, a histone deacetylase (HDAC) inhibitor, may have the potential to exert a therapeutic effect against bladder cancer by modifying the gene expression profiles associated with histone modifications that occur during cancer tumorigenesis. Here, we investigated the in vitro therapeutic effect of chidamide and/or mitomycin C in bladder cancer cell lines and screened related molecular pathways using an antibody array. We also quantitatively analyzed the synergistic effect of IVI of chidamide and mitomycin C in vivo in an N-methyl-N-nitrosourea (MNU)-induced rat bladder cancer model. The synergistic cytotoxic effect of chidamide plus mitomycin C was confirmed in both T24 and UMUC3 cells, with significantly greater induction of apoptosis elicited with chidamide plus mitomycin C than with either drug alone. The antibody array identified the Axl signaling pathway as the key target of the synergistic effect. Expression of Axl and its related downstream molecules, including claspin and survivin, was significantly suppressed. In the rat bladder cancer model, IVI of chidamide plus mitomycin C reduced tumor burden (Ki67 index) to a greater extent than either drug alone. Our results suggest that chidamide and mitomycin act synergistically to reduce MNU-induced bladder cancer. These findings provide new insights into a new and potentially effective approach to treating bladder cancer.

Taurine as an essential amino acid in the brain could play an important role in protecting the fetal brain of intrauterine growth restriction (IUGR). The hippocampus with IUGR showed neural metabolic disorder and structure changed that affected memory and learning ability. This study was aimed to identify the effect of taurine supplementation on the metabolism alterations and cellular composition changes of the hippocampus in IUGR immature rats. Metabolite concentrations were determined by magnetic resonance spectroscopy (MRS) in the hippocampus of juvenile rats with IUGR following taurine supplementation with antenatal or postnatal supply. The composition of neural cells in the hippocampus was observed by immunohistochemical staining (IHC) and western blotting (WB). Antenatal taurine supplementation increased the ratios of N-acetylaspartate (NAA) /creatine (Cr) and glutamate (Glu) /Cr of the hippocampus in the IUGR immature rats, but reduced the ratios of choline (Cho) /Cr and myoinositol (mI) /Cr. At the same time, the protein expression of NeuN in the IUGR rats was increased through intrauterine taurine supplementation, and the GFAP expression was reduced. Especially the effect of antenatal taurine was better than postpartum. Furthermore, there existed a positive correlation between the NAA/Cr ratio and the NeuN protein expression (R = 0.496 p 0.001 IHC; R = 0.568 p 0.001 WB), the same results existed in the relationship between the mI/Cr ratio and the GFAP protein expression (R = 0.338 p = 0.019 IHC; R = 0.440 p = 0.002 WB). Prenatal taurine supplementation can better improve hippocampal neuronal metabolism by increasing NAA / Cr ratio related to the number of neurons and reducing Cho / Cr ratio related to the number of glial cells.

As our research on the physiopathology of intervertebral disc degeneration (IVD degeneration, IVDD) has advanced and tissue engineering has rapidly evolved, cell-, biomolecule- and nucleic acid-based hydrogel grafting strategies have been widely investigated for their ability to overcome the harsh microenvironment of IVDD. However, such single delivery systems suffer from excessive external dimensions, difficult performance control, the need for surgical implantation, and difficulty in eliminating degradation products. Stimulus-responsive composite hydrogels have good biocompatibility and controllable mechanical properties and can undergo solution-gel phase transition under certain conditions. Their combination with ready-to-use particles to form a multiscale delivery system may be a breakthrough for regenerative IVD strategies. In this paper, we focus on summarizing the progress of research on the stimulus response mechanisms of regenerative IVD-related biomaterials and their design as macro-, micro- and nanoparticles. Finally, we discuss multi-scale delivery systems as bioinks for bio-3D printing technology for customizing personalized artificial IVDs, which promises to take IVD regenerative strategies to new heights.

Our previous study suggests that upregulated RAB35 is implicated in etiology of Parkinson's disease (PD). We hypothesized that upregulated RAB35 results from single nucleotide polymorphisms (SNPs) in RAB35 gene promoter. We identified SNPs within RAB35 gene promoter by analyzing DNA samples of discovery cohort and validation cohort. SNP rs17525453 within RAB35 gene promoter (T>C at position of -66) was significantly associated with idiopathic PD patients. Compared to normal controls, sporadic PD patients had higher C allele frequency. CC and CT genotype significantly increased risk of PD compared with TT genotype. SNP rs17525453 within RAB35 gene promoter leads to formation of transcription factor TFII-I binding site. Results of EMSA and supershift assay indicated that TFII-I binds to rs17525453 sequence of RAB35 gene promoter. Luciferase reporter assays showed that rs17525453 variant of RAB35 gene promoter possesses an augmented transcriptional activity. Our results suggest that functional variant rs17525453 within RAB35 gene promoter is likely to enhance transcriptional activity and upregulate RAB35 protein, which could lead to increased risk of PD in Taiwanese population.

Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). β-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that β-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.

Pterygium belongs to an ocular surface disease with triangular-shaped hyperplastic growth, characterized by conjunctivalization, inflammation, and connective tissue remodeling. We previously demonstrated neoplastic-like properties of pterygium cells. Green tea catechin, (-)-epigallocatechin gallate (EGCG), has been shown to possess antitumorigenic properties; herein, we aimed to determine the effects of green tea catechins on human primary pterygium cell survival and migration and compared to that on patients' conjunctival cells. Both human primary pterygium and conjunctival cells expressed EGCG receptor, the 67 kDa laminin receptor. Seven-day treatment of green tea extract (Theaphenon E; 16.25 μg/mL) and EGCG (25 μM) attenuated pterygium cell proliferation by 16.78% (p < 0.001) and 24.09% (p < 0.001) respectively, without significantly influencing conjunctival cells. Moreover, green tea extract (16.25 μg/mL) and EGCG (25 μM) treatments also hindered pterygium cell migration by 35.22% (p < 0.001) and 25.20% (p = 0.019), respectively, but not conjunctival cells. Yet, green tea extract and EGCG treatments did not significantly induce pterygium cell apoptosis. Furthermore, green tea extract and EGCG treatments significantly increased the phosphorylation of p38 protein but reduced the phosphorylation of p42/p44 protein in pterygium cells. In summary, this study revealed that green tea extract and EGCG attenuated human primary pterygium cell survival and migration in vitro without damaging conjunctival cells, suggesting a novel potential therapeutic approach for primary pterygium treatment.

Background Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. Results In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. Conclusion In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss.

ObjectiveQuality of life (QoL) has been always an important way to evaluate the outcomes of schizophrenia, but there have been few previous longitudinal studies and few in middle-income countries. This study aimed to explore the QoL in Chinese patients with schizophrenia treated in primary mental health care and the risk factors of QoL over time.MethodsPatients with schizophrenia treated in primary mental health care in rural/regional areas in Luoding, Guangdong, PR China, were evaluated with an extended questionnaire including the Chinese version of the World Health Organization Quality of Life (WHOQOL-BREF) at baseline and 2-year follow-up. Bivariate and multivariate analyses were conducted including Generalized Estimated Equation analyses (GEE).ResultsFour hundred and ninety-one patients with schizophrenia in primary care completed the 2-year follow up evaluation. The QoL physical, environmental, and social relationships domains showed improvement after the 2-year period, but the psychological domain did not. GEE results showed that earlier age of onset, older age, being employed, being unmarried, the thicker waist circumference, less use of clozapine or other SGAs, fewer hospitalizations, more frequent insomnia, more severe depressive and negative symptoms as well as worse treatment insight were independently associated with poor QoL in patients with schizophrenia.ConclusionAccording to our results, to improve the quality of life of patients with schizophrenia in primary care, we should pay more attention to the treatment of depression, negative and insomnia symptoms of schizophrenia, the choice and dosage of antipsychotic medication and improvement in the treatment compliance. The combined use of educational and behavioral strategies may improve treatment adherence.

Bus driving is considered a highly stressful and unhealthy occupation, even among sedentary jobs, because of the particular task characteristics. This study used the Nordic Musculoskeletal Questionnaire (NMQ) to interview bus drivers and determine the risk factors for musculoskeletal discomfort. The NMQ was distributed to 152 bus drivers in the Taipei metropolitan area (Taiwan) and the valid data of 145 respondents were analyzed. The survey revealed that the overall prevalence of musculoskeletal disorder symptoms in any body part during the preceding year was 78.3%, and the body parts for which with the prevalence of discomfort was highest were the neck (46.9%), right shoulder (40.0%), lower back (37.2%), and left shoulder (33.8%). Stress and an uncomfortable seat may contribute to neck, shoulder, and lower back discomfort. Stretching between trips may help to reduce neck and shoulder discomfort. When comparing our results with those of similar studies, we discovered that the prevalence of symptoms and detailed risk factors vary by country and region. On this basis, we believe that local investigations emphasizing specific task arrangements and characteristics are needed to address the problem of musculoskeletal disorders in bus drivers.

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin’s lymphoma that occurs in the central nervous system. Although sensitive to chemotherapy, 35–60% of PCNSL patients still relapse within 2 years after the initial treatment. High-dose methotrexate (HD-MTX) rechallenge is generally used in recurrent PCNSL, especially for patients who have achieved a response after initial methotrexate (MTX) treatment. However, the overall remission rate (ORR) of HD-MTX rechallenge is about 70–80%. Additionally, the side effects of HD-MTX treatment endanger the health of patients and affect their quality of life. Methods: This is a retrospective study of patients with first relapse PCNSL at Huashan Hospital, Fudan University between January 2000 and November 2020. By comparing the clinical characteristics and radiological manifestations of first relapsed PCNSL patients with remission and non-remission after receiving HD-MTX rechallenge, we screened out the key factors associated with HD-MTX rechallenge treatment response, to provide some help for the selection of salvage treatment strategies for patients with recurrent PCNSL. Additionally, patients with remission after HD-MTX rechallenge were followed up to identify the factors related to progression-free survival of the second time (PFS2) (time from the first relapse to second relapse/last follow-up). The Kruskal–Wallis and Pearson chi-square tests were performed to examine the univariate association. Further, multivariable logistic regression analysis was used to study the simultaneous effect of different variables. Results: A total of 207 patients were enrolled in the study based on the inclusion criteria, including 114 patients in the remission group (RG) and 81 patients in the non-remission group (nRG), and 12 patients were judged as having a stable disease. In Kruskal–Wallis and Pearson chi-square tests, progression-free survival rates for first time (PFS1) and whether the initial treatment was combined with consolidated whole brain radiotherapy (WBRT) were related to the response to HD-MTX rechallenge treatment, which was further validated in regression analysis. Further, after univariate analysis and regression analysis, KPS was related to PFS2. Conclusions: For PCNSL patients in their first relapse, HD-MTX rechallenge may be an effective salvage treatment. PFS1 and whether initial treatment was combined with consolidation WBRT were associated with HD-MTX rechallenge treatment response. In addition, patients with higher KPS at the time of the first relapse had a longer PFS2 after HD-MTX rechallenge treatment.

Fracture nonunion can result in considerable physical harm and limitation of quality of life in patients, exerting an extensive economic burden to the society. Nonunion largely results from unresolved inflammation and impaired osteogenesis. Despite advancements in surgical techniques, the indispensable treatment for nonunion is robust anti-inflammation therapy and the promotion of osteogenic differentiation. Herein, we report that plasma exosomes derived from infected fracture nonunion patients (Non-Exos) delayed fracture repair in mice by inhibiting the osteogenic differentiation of bone marrow stromal cells in vivo and in vitro. Unique molecular identifier microRNA-sequencing (UID miRNA-seq) suggested that microRNA-708-5p (miR-708-5p) was overexpressed in Non-Exos. Mechanistically, miR-708-5p targeted structure-specific recognition protein 1, thereby suppressing the Wnt/β-catenin signaling pathway, which, in turn, impaired osteogenic differentiation. AntagomicroRNA-708-5p (antagomiR-708-5p) could partly reverse the above process. A bacteria-sensitive natural polymer hyaluronic-acid-based hydrogel (HA hydrogel) loaded with antagomiR-708-5p exhibited promising effects in an in vivo study through antibacterial and pro-osteogenic differentiation functions in infected fractures. Overall, the effectiveness and reliability of an injectable bacteria-sensitive hydrogel with sustained release of agents represent a promising approach for infected fractures.

ObjectiveTo evaluate the microstructural changes of the orbital optic nerve in thyroid-associated ophthalmopathy (TAO) patients with or without dysthyroid optic neuropathy (DON) using diffusion tensor imaging (DTI) and investigate whether DTI can be used to detect DON.Materials and Methods59 bilateral TAO patients with (n= 23) and without DON (non-DON, n= 36) who underwent pretreatment DTI were included and 118 orbits were analyzed. The clinical features of all patients were collected. DTI parameters, including mean, axial, and radial diffusivity (MD, AD, and RD, respectively) and fractional anisotropy (FA) of the intra-orbital optic nerve for each orbit were calculated and compared between the DON and non-DON groups. ROC curves were generated to evaluate the diagnostic performance of single or combined DTI parameters. Correlations between DTI parameters and ophthalmological characteristics were analyzed using correlation analysis.ResultsCompared with non-DON, the DON group showed decreased FA and increased MD, RD, and AD (P < 0.01). In the differentiation of DON from non-DON, the MD was optimal individually, and the combination of the four parameters had the best diagnostic performance. There were significant correlations between the optic nerve’s four DTI metrics and the visual acuity and clinical active score (P < 0.05). In addition, optic nerve FA was significantly associated with the amplitude of visual evoked potentials (P = 0.022).ConclusionsDTI is a promising technique in assessing microstructural changes of optic nerve in patients with DON, and it facilitates differentiation of DON from non-DON eyes in patients with TAO.

Objectives To delineate the disease-causing mutations of the Stargardt disease-related genes in Chinese patients diagnosed with Stargardt disease or retinitis pigmentosa (RP) by whole exome sequencing analysis. Methods A total of 123 sporadic RP or Stargardt disease patients and 2 Stargardt disease families were recruited. All sporadic patients and the probands of the families were subjected to whole exome sequencing analysis. The candidate mutations were verified by direct sequencing based on the cosegregation pattern and in 200 control subjects and by the bioinformatics analyses. Results A total of three reported ABCA4 mutations were identified in the probands of the two Stargardt disease families. The probands and the affected family members with either homozygous or compound heterozygous mutations showed typical Stargardt disease features, which was absent in their unaffected family members. The cosegregation pattern confirmed the mode of recessive inheritance. Moreover, two sporadic Stargardt disease patients were identified to carry two novel ABCA4 and one PROM1 mutations. In addition, 13 novel variants were found in 119 sporadic RP patients in 7 Stargardt disease-related genes, and 8 novel missense variants were conserved across different species and predicted to be damaging to the protein. All 15 novel variants were absent in our 200 control subjects. Conclusions This study revealed 22.4% study subjects carrying Stargardt disease-related gene mutations with total 15 novel variants in seven Stargardt disease-related genes, assuring that targeted next-generation sequencing analysis is a high throughput strategy to facilitate the clinical diagnosis from suspicious patients and recommended as a routine examination for inherited retinal dystrophies.

Human immunodeficiency virus (HIV) attacks human immune system and causes life-threatening acquired immune deficiency syndrome (AIDS). Treatment with combination antiretroviral therapy (cART) could inhibit virus growth and slow progression of the disease, however, at the same time posing various adverse effects. Host ubiquitin-proteasome pathway (UPP) plays important roles in host immunity against pathogens including viruses by inducing degradation of viral proteins. Previously a series of methods for retargeting substrates for ubiquitin-proteasome degradation have been successfully established. In this study, we attempted to design and construct artificial chimeric ubiquitin ligases (E3s) based on known human E3s in order to manually target HIV-1 integrase for ubiquitin proteasome pathway-mediated degradation. Herein, a series of prototypical chimeric E3s have been designed and constructed, and original substrate-binding domains of these E3s were replaced with host protein domains which interacted with viral proteins. After functional assessment screening, 146LI was identified as a functional chimeric E3 for HIV-1 NL4-3 integrase. 146LI was then further optimized to generate 146LIS (146LI short) which has been shown to induce Lys48-specific polyubiquitination and reduce protein level of HIV-1 NL4-3 integrase more effectively in cells. Lymphocyte cells with 146LIS knock-in generated by CRISPR/Cas-mediated homology-directed repair (HDR) showed remarkably decreased integration of HIV-1 NL4-3 viral DNAs and reduced viral replication without obvious cell cytotoxicity. Our study successfully obtained an artificial chimeric E3 which can induce Lys48-specific polyubiquitination and proteasome-mediated degradation of HIV-1 NL4-3 integrase, thus effectively inhibiting viral DNA integration and viral replication upon virus infection.

Objective: Patient safety is a worldwide problem and a focus of academic research. Human factors and ergonomics (HFE) is an approach to improving healthcare work systems and processes. From the perspective of the cognitive ergonomics of HFE, the aim of this study is to improve the flow level, communication skills, and safety attitudes of surgeons through focused-attention meditation (FAM) training, thus helping to reduce adverse clinical events. Methods: In total, 140 surgeons were recruited from three hospitals in China and randomly divided into two groups (FAM group and control group). The FAM group received 8 weeks of FAM training, while the control group was on the waiting list and did not receive any interventions. Three scales (WOLF, LCSAS, and SAQ-C) were used to measure the data of three variables (flow, communication skills, and safety attitude), respectively, at two times, before and after the intervention (pre-test and post-test). The incidence of adverse events during the intervention was also collected for both groups. Results: The ANOVA results showed that all three variables had a significant main effect of time and significant interactions between time and group. The independent-sample T-test results showed that the incidence of adverse events during the intervention was significantly lower in the FAM group than in the control group. Conclusions: The intervention of FAM could significantly improve surgeons’ flow levels, communication skills, and safety attitudes, potentially helping to reduce adverse clinical events.

Physiologists have long regarded sweating as an effective and safe means of detoxification, and heavy metals are excreted through sweat to reduce the levels of such metals in the body. However, the body can sweat through many means. To elucidate the difference in the excretion of heavy metals among sweating methods, 12 healthy young university students were recruited as participants (6 men and 6 women). Sweat samples were collected from the participants while they were either running on a treadmill or sitting in a sauna cabinet. After they experienced continuous sweating for 20 min, a minimum of 7 mL of sweat was collected from each participant, and the concentrations of nickel (Ni), lead (Pb), copper (Cu), arsenic (As), and mercury (Hg) were analyzed. The results demonstrated that the sweating method affected the excretion of heavy metals in sweat, with the concentrations of Ni, Pb, Cu, and As being significantly higher during dynamic exercise than during sitting in the sauna (all p < 0.05). However, the concentrations of Hg were unaffected by the sweating method. This study suggests that the removal of heavy metals from the body through dynamic exercise may be more effective than removal through static exposure to a hot environment.

BackgroundAs genetic genetic factors are important in SLE, so screening causative genes is of great significance for the prediction and early prevention in people who may develop SLE. At present, it is very difficult to screen causative genes through pedigrees. The analytical method described herein can be used to screen causative genes for SLE and other complex diseases through pedigrees.MethodsFor the first time, 24 lupus pedigrees were analyzed by combining whole exon sequencing and a variety of biological information tools including common-specific analysis, pVAAST (pedigree variant annotation, analysis and search tool), Exomiser (Combining phenotype and PPI associated analysis), and FARVAT (family based gene burden), and the causative genes of these families with lupus identified. Selected causative genes in peripheral-blood mononuclear cells (PBMCs) were evaluated by quantitative polymerase chain reaction (qPCR).ResultsCell division cycle 27 (CDC27) was screened out by common-specific analysis and Exomiser causative gene screening. FARVAT analysis on these families detected only CDC27 at the extremely significant level (false discovery rate PPPPPConclusionThe CDC27 gene, as found through WES combined with multiple analytical method may be a causative gene of lupus. CDC27 may serve as a marker for the diagnosis of SLE and is closely related to the lupus activity. We hope that the analytical method in this study will be used to screen causative genes for other diseases through small pedigrees, especially among non-close relatives.

Prior investigations have been primarily conducted in a laboratory to examine the effects of the smartphone use on the neck and head positions, whether these results are applicable to actual conditions is still unknown. This field survey thus analyzed the neck flexion (NF), head flexion (HF), gaze angle (GA), and viewing distance (VD) of smartphone users in public areas in Taipei, Taiwan. Six hundred smartphone users (300 men and 300 women) were photographed sagittally in standing, supported sitting, or unsupported sitting postures while using a smartphone. Results showed that women had significantly less NF and HF and shorter VDs than male users. Regardless of gender, higher NF was observed for standing than for sitting. Women had similar NF and HF while sitting supported and unsupported, but both were significantly lower than those while standing. By contrast, male users had higher NF and HF during unsupported sitting than during supported sitting. The NF (45°–50°) was much greater than the recommended maximum safe NF of 15°. Women may be at higher risk of visual strain because of shorter VD.

Objective: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia.Design: An open treatment trial with pre- and posttreatment evaluations.Subjects: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization.Methods: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared.Results: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks.Conclusion: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative. LAY ABSTRACTDetrusor botulinum toxin type A (BoNT-A) injection has become the standard of care for bladder overactivity associated with neurological pathology in recent years. However, increased post-void residual and even acute urinary retention make it difficult for patients to accept this treatment. Our study demonstrates that a combination of detrusor and urethra sphincter BoNT-A injections may relieve detrusor and urethral pressures without increasing intermittent catheterization (IC) frequency. Life quality associated with voiding is also improved after combined injections. Physicians should take into account the patient’s expectation and ability to manage his bladder when planning BoNT-A injection in treatment of neurogenic lower urinary tract dysfunction (NLUTD) in spinal cord injury (SCI) patients. For male SCI patients with NLUTD who are unwilling or inconvenient to increase IC frequency and want to preserve spontaneous voiding, this treatment may provide optional alternative.

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation., Tibetan adaptation to the high-altitude environment represents a case of natural selection during recent human evolution. Here the authors investigated the chromatin and transcriptional landscape of umbilical endothelial cells from Tibetan and Han Chinese donors and provide genome-wide characterization of the hypoxia regulatory network associated high-altitude adaptation.

Rates of incident treatment were quantified in this study for diabetes mellitus, hypertension, and venous thromboembolism (VTE) associated with oral glucocorticoid exposure in children aged 1–18 years. The retrospective cohort included more than 930,000 children diagnosed with autoimmune diseases (namely, inflammatory bowel disease, juvenile idiopathic arthritis, or psoriasis) or a nonimmune comparator condition (attention-deficit/hyperactivity disorder) identified using US Medicaid claims (2000–2010). Associations of glucocorticoid dose per age- and sex-imputed weight with incident treated diabetes, hypertension, and VTE were estimated using Cox regression models. Crude rates were lowest for VTE (unexposed: 0.5/million person-days (95% confidence interval (CI): 0.4, 0.6); currently exposed: 15.6/million person-days (95% CI: 11.8, 20.1)) and highest for hypertension (unexposed: 6.7/million person-days (95% CI: 6.5, 7.0); currently exposed: 74.4/million person-days (95% CI: 65.7, 83.9)). Absolute rates for all outcomes were higher in unexposed and exposed children with autoimmune diseases compared with those with attention-deficit/hyperactivity disorder. Strong dose-dependent relationships were found between current glucocorticoid exposure and all outcomes (adjusted hazard ratios for high-dose glucocorticoids: for diabetes mellitus, 5.93 (95% CI: 3.94, 8.91); for hypertension, 19.13 (95% CI: 15.43, 23.73); for VTE, 16.16 (95% CI: 8.94, 29.22)). These results suggest strong relative risks, but low absolute risks, of newly treated VTE, diabetes, and especially hypertension in children taking high-dose oral glucocorticoids.

Objective To observe the rates of repeated computed tomographic scans (CTs) in a cohort of patients with coronavirus disease-2019 (COVID-19) and to assess the validity of repeat CTs. Methods Each CT was recorded, and the validity of the repeated CTs was assessed. Results The 394 patients underwent a total of 1493 CTs. Of the 394 patients, 260 received at least one non-value-added CT. Both the total number of CTs (median, 4; interquartile range (IQR), 3–5) and non-value-added CTs (median, 1; IQR, 0–1) per patient were strongly related to the disease duration (R2 = 0.566 for total CTs, R2 = 0.432 for non-value-added CTs, p 35%). Conclusions There was a high rate of repeat CTs for the COVID-19 patients, and the proportion of non-value-added CTs increased with disease duration. Follow-up CT should be avoided without clinical decline. Advances in Knowledge As COVID-19 is impacting healthcare systems across the globe, we believe in our findings that serial chest CT imaging has limited clinical utility in basically stable COVID-19 patients, will help relieve some of this burden.

Hip fractures in the elderly account for more than half of osteoporotic fractures and represent a substantial economic and social burden. Novel coronavirus pneumonia (COVID-19), which began to spread in December 2019, has created challenges in the management of elderly hip fracture patients, not only by influencing the choice of operation and postoperative rehabilitation methods, but also by generating new risks for the medical staff. During this period, our infection and orthopedic treatment unit in the center of the epidemic area effectively treated 82 elderly patients with hip fracture, and no cross-infection occurred. Therefore, our experience in prevention and treatment is worth recommending to frontline anti-epidemic personnel.

Background Enhancing angiogenesis is critical for accelerating wound healing. Application of different types of exosomes (Exos) to promote angiogenesis represents a novel strategy for enhanced wound repair. Saliva is known to accelerate wound healing, but the underlying mechanisms remain unclear. Results Our results have demonstrated that saliva-derived exosomes (saliva-Exos) induce human umbilical vein endothelial cells (HUVEC) proliferation, migration, and angiogenesis in vitro, and promote cutaneous wound healing in vivo. Further experiments documented that Ubiquitin-conjugating enzyme E2O (UBE2O) is one of the main mRNAs of saliva-Exos, and activation of UBE2O has effects similar to those of saliva-Exos, both in vitro and in vivo. Mechanistically, UBE2O decreases the level of SMAD family member 6 (SMAD6), thereby activating bone morphogenetic protein 2 (BMP2), which, in turn, induces angiogenesis. Conclusions The present work suggests that administration of saliva-Exos and UBE2O represents a promising strategy for enhancing wound healing through promotion of angiogenesis.

Diabetic foot ulcers are a common complication of diabetes, and are usually incurable in the clinic. Exosomes (carriers that transfer endogenous molecules) from diabetic patients' blood have been demonstrated to suppress diabetic wound repair. In this study, we investigated the effects of circulating exosomal microRNA-15a-3p (miR-15a-3p) on diabetic wound repair. Exosomes were extracted from diabetic patients' blood, and were found to inhibit diabetic wound repair in vitro and in vivo. miR-15a-3p was upregulated in diabetic exosomes, and impaired wound healing. When miR-15a-3p was knocked down in diabetic exosomes, their negative effects were partially reversed both in vitro and in vivo. NADPH oxidase 5 (NOX5) was identified as a potential target of miR-15a-3p, and the inhibition of NOX5 reduced the release of reactive oxygen species, thereby impairing the functionality of human umbilical vein endothelial cells. In summary, inhibition of circulating exosomal miR-15a-3p accelerated diabetic wound repair by activating NOX5, providing a novel therapeutic target for diabetic foot ulcer therapy.

Objective To establish nomogram based on inflammatory indices for differentiating intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC). Methods A cohort of 422 patients with HCC or ICC hospitalized at Xiangya Hospital between January 2014 and December 2018 was included in the study. Univariate and multivariate analysis was performed to identify the independent differential factors. Through combining these independent differential factors, a nomogram was established for differential diagnosis between ICC and HCC. The accuracy of nomogram was evaluated by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). The results were validated using a prospective study on 98 consecutive patients operated on from January 2019 to November 2019 at the same institution. Results Sex (OR = 9.001, 95% CI: 3.268‐24.792, P, Nomogram based on inflammatory indices was established for the differential diagnosis between ICC and HCC preoperatively, and better therapeutic choice would be made if it was applied in clinical practice.

Objective Despite strong recommendations for routine measurement of rheumatoid arthritis (RA) disease activity and associated treatment changes to attain remission/low disease activity, the measurement tools that clinicians use to evaluate RA patients' disease activity and frequency of treatment change have not been well characterized. Therefore, we evaluated different measurement tools that physicians used to assess RA disease activity and associated RA treatment changes. Methods Using data from the Rheumatology Informatics System for Effectiveness (RISE) registry from January 2016 through June 2017, and using the following criteria: age ≥18 years, diagnosis of RA (International Classification of Diseases, Ninth and Tenth Revision, codes), ≥2 RISE visits, and ≥1 RA disease activity measure scored in 2016, we classified eligible patients' drug use at the index visit as monotherapy or combination therapy with conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (bDMARDs). Outcomes include change in treatment over 12 months. Mixed models identified factors associated with treatment change. Results Among 50,996 eligible patients, 27,274 had longitudinal data. The most commonly used measures were RAPID3 (78.9%) and the Clinical Disease Activity Index (CDAI) (34.2%). The frequency of treatment change during follow-up was relatively low (35.6-54.6%), even for patients with moderate/high disease activity according to RAPID3 or CDAI scores. Older patients (age ≥75 years; adjusted odds ratio [ORadj ] 0.63 [95% confidence interval (95% CI) 0.50-0.78]) and those already receiving combination therapy with csDMARDs (ORadj 0.45 [95% CI 0.33-0.61]) or combination therapy with bDMARDs (ORadj 0.30 [95% CI 0.24-0.38]) were less likely to change RA treatment even after multivariable adjustment. Conclusion Using the American College of Rheumatology's national RISE registry, one- to two-thirds of RA patients failed to change their treatment, even when experiencing moderate/high disease activity. Multimodal interventions directed at both patients and providers are needed to encourage shared decision-making, goal-directed care, and to overcome barriers to treatment escalation.

This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.

The development of mathematical skills in early childhood relies on number sense, the foundational ability to discriminate among quantities. Number sense in early childhood is predictive of academic and professional success, and deficits in number sense are thought to underlie lifelong impairments in mathematical abilities. Despite its importance, the brain circuit mechanisms that support number sense learning remain poorly understood. Here, we designed a theoretically motivated training program to determine brain circuit mechanisms underlying foundational number sense learning in female and male elementary school-age children (7–10 years). Our 4 week integrative number sense training program gradually strengthened the understanding of the relations between symbolic (Arabic numerals) and nonsymbolic (sets of items) representations of quantity. We found that our number sense training program improved symbolic quantity discrimination ability in children across a wide range of math abilities including children with learning difficulties. Crucially, the strength of pretraining functional connectivity between the hippocampus and intraparietal sulcus, brain regions implicated in associative learning and quantity discrimination, respectively, predicted individual differences in number sense learning across typically developing children and children with learning difficulties. Reverse meta-analysis of interregional coactivations across 14,371 fMRI studies and 89 cognitive functions confirmed a reliable role for hippocampal–intraparietal sulcus circuits in learning. Our study identifies a canonical hippocampal–parietal circuit for learning that plays a foundational role in children's cognitive skill acquisition. Findings provide important insights into neurobiological circuit markers of individual differences in children's learning and delineate a robust target for effective cognitive interventions.SIGNIFICANCE STATEMENTMathematical skill development relies on number sense, the ability to discriminate among quantities. Here, we develop a theoretically motivated training program and investigate brain circuits that predict number sense learning in children during a period important for acquisition of foundational cognitive skills. Our integrated number sense training program was effective in children across a wide a range of math abilities, including children with learning difficulties. We identify hippocampal–parietal circuits that predict individual differences in learning gains. Our study identifies a brain circuit critical for the acquisition of foundational cognitive skills, which will be useful for developing effective interventions to remediate learning disabilities.

Objective. Hidradenitis suppurativa (HS) is a rare autosomal dominant condition characterized by inflamed nodules, cysts, deep abscesses, draining sinuses in the axillae, inguinal, and anogenital regions. Mutations in the NCSTN gene have been perceived to be responsible for the major underlying changes in the disorder. The purpose of this study is to identify a novel gene mutation in a Chinese family with HS. Methods. A Chinese family with HS present was investigated. The proband had manifested with multiple draining sinuses on the posterior neck, chest, bilateral axillae, and perineal regions. DNA was isolated from the peripheral blood of the family members. The encoding exons with introns of the NCSTN gene were analyzed by polymerase chain reactions (PCR) and direct DNA sequencing. Sanger sequencing was performed to confirm the next-generation sequencing results and to analyze each mutation’s familial segregation. Furthermore, the identified mutation was localized onto a 3D structure model using the DeepView Swiss-PdbViewer 4.1 software. Results. In this family comprising 10 HS patients, one novel mutation of the NCSTN gene was identified, involving a deletion mutation (c.447delC(p.N150Ifs ∗ 52)) in the NCSTN gene resulting in a frameshift and the new formation of a hydrogen bond. Conclusion. Our study reports the identification of a novel mutation that causes familial HS and could expand the spectrum of mutations in the γ-secretase genes underlying HS.

Background Cleaning workers experience severe musculoskeletal symptoms. Objective The objective of this paper was to examine musculoskeletal symptoms in cleaners of different heights to evaluate the effects of height on working postures in the work environment (schools). Methods We used a three-stage method including using the Nordic Musculoskeletal Questionnaire (NMQ) to evaluate musculoskeletal symptoms, a task analysis to confirm typical cleaning tasks, and the OVAKO Working Posture Assessment System (OWAS) for posture analysis. Multinomial logistic regression was performed to evaluate the adjusted effects of individual characteristics on painful body regions, using individuals without any pain as the reference category. Results This study found that the prevalence of musculoskeletal symptoms is very high for cleaners, especially in the shoulders, elbows, and lower back. Odds ratios for the accumulation of two or more risk factors were higher among men and were inversely associated with national economic indicators. The relatively high prevalence of musculoskeletal symptoms may stem from the multiple operations involved in cleaning tasks, such as trash collecting, floor mopping, toilet cleaning, and mirror polishing. Workers of different heights had differential work loadings for different tasks. Conclusions This paper proposes recommendations for job adaptations and occupational safety training. Cleaners of different heights execute the typical tasks via different postures, and awkward postures often result in musculoskeletal symptoms. Cleaners should be provided with specific tools and training regarding working postures on the basis of height. These findings can be used as a reference for related operation designs and task improvements to ensure correct tool usage and safer working postures during cleaning.

In breast conserving surgery (BCS), specimen mammography is one of the most widely used intraoperative methods of assessing margin status. We performed a meta-analysis to evaluate the diagnostic accuracy of specimen mammography. Literature databases including PubMed, Cochrane Library, Web of Science, and EMBASE were searched prior to Jun 2022. A total of 1967 patients were included from 20 studies. A pooled analysis, heterogeneity testing, threshold effect testing, publication bias analysis, and subgroup analyses were performed from extracted data. The pooled weighted values were a sensitivity of 0.55 (95% confidence interval [CI], 0.47–0.63), a specificity of 0.85 (95% CI, 0.78–0.90), a diagnostic odds ratio of 7 (95% CI, 4–12), and a pooled positive likelihood ratio of 3.7 (95% CI 2.6–5.5). The area under the receiver operator characteristic curve was 0.75 (95% CI 0.71–0.78). In the subgroup analysis, the pooled specificity in the positive margin defined as tumor at margin subgroup was lower than the other positive margin definition subgroup (0.82 [95% CI: 0.71, 0.92] vs. 0.87 [95% CI: 0.80, 0.94], p = 0.01). Our findings indicated that specimen mammography was an accurate intraoperative imaging technique for margin assessment in BCS.

The treatment of diabetic wounds remains a major challenge in clinical practice, with chronic wounds characterized by multiple drug-resistant bacterial infections, angiopathy, and oxidative damage to the microenvironment. Herein, a novel in situ injectable HA@MnO2 /FGF-2/Exos hydrogel is introduced for improving diabetic wound healing. Through a simple local injection, this hydrogel is able to form a protective barrier covering the wound, providing rapid hemostasis and long-term antibacterial protection. The MnO2 /e-PL nanosheet is able to catalyze the excess H2 O2 produced in the wound, converting it to O2 , thus not only eliminating the harmful effects of H2 O2 but also providing O2 for wound healing. Moreover, the release of M2-derived Exosomes (M2 Exos) and FGF-2 growth factor stimulates angiogenesis and epithelization, respectively. These in vivo and in vitro results demonstrate accelerated healing of diabetic wounds with the use of the HA@MnO2 /FGF-2/Exos hydrogel, presenting a viable strategy for chronic diabetic wound repair.

Frailty has been related with the risk of postoperative complication in patients with colorectal cancer (CRC). However, the association between frailty and long-term survival in patients with CRC has not been comprehensively evaluated. We performed a meta-analysis to systematically evaluate the relationship between frailty and long-term survival of these patients.Relevant cohort studies with follow-up duration ≥ 1 year were identified from Medline, Embase, and Web of Science. A random-effect model after incorporation of the between-study heterogeneity was selected to pool the results.Ten cohort studies with 35,546 patients were included, and 4100 (11.5%) of them had frailty. Pooled results showed that patients with frailty had worse overall survival compared to those without frailty at baseline (relative risk [RR]: 2.21, 95% confidence interval [CI] 1.43-3.41, P 0.001; IFrailty at admission is associated with worse survival of patients with colorectal cancer.

BACKGROUND Low-dose glucocorticoids are commonly used in the treatment of rheumatoid arthritis (RA). Observational studies have found an increased risk of serious infection associated with low-dose glucocorticoids, but concerns about residual confounding remain. METHODS We identified adults with RA on stable immunomodulatory therapy for >6 months receiving no glucocorticoids or ≤5 mg/day using Medicare data from 2006 to 2015. We used provider preference for glucocorticoids as an instrumental variable (IV) to assess associations between low-dose glucocorticoid use and the risk of infection requiring hospitalization using a cause-specific proportional hazards model. RESULTS We identified 163,603 qualifying treatment episodes among 120,656 patients. Glucocorticoids ≤5 mg/day were used by 25,373/81,802 (31.0%) of patients seen by a rheumatologist with low provider preference for glucocorticoids and by 36,087/81,801 (44.1%) of patients seen by a rheumatologist with high provider preference for glucocorticoids (adjusted odds ratio 1.81, 95% confidence interval 1.77, 1.84 for association between provider preference and glucocorticoids). Chronic obstructive pulmonary disease, opioids, antibiotics, previous emergency department visits, hospitalizations, and infections requiring hospitalization infections were unbalanced with regard to exposure but not to the IV. The incidence of infection requiring hospitalization was 8.0/100 person-years among patients unexposed to glucocorticoids versus 11.7/100 person-years among those exposed. The association between glucocorticoids and infection requiring hospitalization from IV analysis (hazard ratio 1.26 [1.02-1.56]) was similar to results from a standard multivariable model (hazard ratio 1.24 [1.21-1.28]). CONCLUSIONS Among patients with RA on stable immunomodulatory therapy, IV analysis based on provider preference demonstrated an increased risk of infection requiring hospitalization associated with low-dose glucocorticoids, similar to a traditional analysis.

This preliminary study examined the effects of a stretching intervention after training and its duration (15 vs. 30 min) on participants’ shank circumference (SC) reduction and subjective discomfort score. Ten male volleyball players underwent a routine 3 h training. A two-way analysis of variance revealed that the stretching intervention had significant effects on SC reduction (p &lt, 0.01) and subjective discomfort scores (p &lt, 0.001). Stretching after training could help eliminate shank strain, and a slighter discomfort in shanks when stretching was also seen (score, 20.1/100). An independent-samples t test revealed a significantly higher SC reduction (p &lt, 0.01) with 30 min of stretching (5.6 mm) than with 15 min of stretching (2.7 mm), both stretching durations reduced SC significantly more than the no-stretching condition did. The findings of this study can serve as a reference for volleyball players to alleviate shank strain after daily routine training.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in the world. Sorafenib is the first-line drug for patients with advanced HCC. However, long-term treatment with sorafenib often results in reduced sensitivity of tumor cells to the drug, leading to acquired resistance. Identifying biomarkers which can predict the response to sorafenib treatment may represent a clinical challenge in the personalized treatment era. Niemann-Pick type C2 (NPC2), a secretory glycoprotein, plays an important role in regulating intracellular free cholesterol homeostasis. In HCC patients, downregulation of hepatic NPC2 is correlated with poor clinical pathological features through regulating mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation. This study aimed to investigate the roles of secretory NPC2-mediated free cholesterol levels as biomarkers when undergoing sorafenib treatment and evaluate its impact on acquired sorafenib resistance in HCC cells. Herein, we showed that NPC2 downregulation and free cholesterol accumulation weakened sorafenib’s efficacy through enhancing MAPK/AKT signaling in HCC cells. Meanwhile, NPC2 overexpression slightly enhanced the sorafenib-induced cytotoxic effect. Compared to normal diet feeding, mice fed a high-cholesterol diet had much higher tumor growth rates, whereas treatment with the free cholesterol-lowering agent, hydroxypropyl-β-cyclodextrin, enhanced sorafenib’s tumor-inhibiting ability. In addition, sorafenib treatment induced higher NPC2 secretion, which was mediated by inhibition of the Ras/Raf/MAPK kinase (MEK)/ERK signaling pathway in HCC cells. In both acquired sorafenib-resistant cell and xenograft models, NPC2 and free cholesterol secretion were increased in culture supernatant and serum samples. In conclusion, NPC2-mediated free cholesterol secretion may represent a candidate biomarker for the likelihood of HCC cells developing resistance to sorafenib.

The purpose of this study was to evaluate the pathological involvement of erythropoietin (EPO) in experimental choroidal neovascularization (CNV) and its association with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in the Chinese population.Treatment effect of recombinant EPO protein were assessed by human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, and ex vivo choroid-sprouting ability. The effect of intravitreal injection of Epo siRNA against neovascularization was evaluated in the laser-induced CNV mouse model. In addition, the association of EPO variants with neovascular AMD and PCV was determined.Exogenous supplementation of EPO significantly enhanced the migration and tube formation of HUVECs and promoted ex vivo choroid sprouting in mouse retinal pigment epithelium (RPE)-choroid-sclera complex culture. In the experimental CNV mouse model, Epo expression was found to be significantly upregulated by 3.5-folds in RPE-choroid-sclera complex at day 10 after laser induction as compared to the baseline. Immunofluorescence analysis showed that Epo was mainly expressed around the vascular endothelial cells in the RPE-choroid-sclera complex. Intravitreal injection of siRNA targeting Epo reduced 40% Epo expression and 40% CNV lesion areas as compared to the scramble control. However, EPO variants were not associated with neovascular AMD nor PCV in the Chinese population.This study revealed the promotion of human endothelial cell tube formation in vitro and choroid sprouting ex vivo by EPO, and the reduction of laser-induced CNV in vivo by Epo RNA interference.Targeting EPO could be a potential additional treatment for CNV-related diseases.

International audience; Mathematical knowledge is constructed hierarchically during development from a basic understanding of addition and subtraction, two foundational and inter-related, but semantically distinct, numerical operations. Early in development, children show remarkable variability in their numerical problem-solving skills and difficulties in solving even simple addition and subtraction problems are a hallmark of math learning difficulties. Here, we use novel quantitative analyses to investigate whether less distinct representations are associated with poor problem-solving abilities in children during the early stages of math-skill acquisition. Crucially, we leverage dimensional and categorical analyses to identify linear and nonlinear neurobehavioral profiles of individual differences in math skills. Behaviorally, performance on the two different numerical operations was less differentiated in children with low math abilities, and lower problem-solving efficiency stemmed from weak evidence-accumulation during problem-solving. Children with low numerical abilities also showed less differentiated neural representations between addition and subtraction operations in multiple cortical areas, including the fusiform gyrus, intraparietal sulcus, anterior temporal cortex and insula. Furthermore, analysis of multi-regional neural representation patterns revealed significantly higher network similarity and aberrant integration of representations within a fusiform gyrus-intraparietal sulcus pathway important for manipulation of numerical quantity. These findings identify the lack of distinct neural representations as a novel neurobiological feature of individual differences in children's numerical problem-solving abilities, and an early developmental biomarker of low math skills. More generally, our approach combining dimensional and categorical analyses overcomes pitfalls associated with the use of arbitrary cutoffs for probing neurobehavioral profiles of individual differences in math abilities.

Importance Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, setting, and participants A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main outcomes and measures Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and relevance These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.

Background Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. Results We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. Conclusions PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing. Graphic abstract

The cortical organization of the semantic network has been examined extensively in neuropsychological and neuroimaging studies; however, after decades of research, several issues remain controversial. A comprehensive and systematic investigation is needed to characterize the consistent patterns of category-specific activations as well as to examine factors that contribute to the varying findings across numerous neuroimaging studies. In this study, we reviewed 113 published papers that reported category-specific activations for living or nonliving concepts from the past two decades. Using the Activation Likelihood Estimate (ALE) method, we characterized the brain regions associated with living and nonliving concepts and revealed how the observed patterns were heavily influenced by methodological factors including imaging mode, task demand, and stimuli modality. Our findings provided the most comprehensive summary of category-specific activations for living and nonliving concepts and critically revealed that these activation patterns are highly contextually dependent. This work advanced our knowledge about the organization of the cortical semantic network and provided important insights into theoretical accounts and future research directions.

Myopia is the most prevalent ocular disorder in the world, and corneal parameters have been regarded as key ocular biometric parameters determining the refractive status. Here, we aimed to determine the association of genome-wide association study-identified corneal curvature (CC)-related gene variants with different severity of myopia and ocular biometric parameters in Chinese population.Total 2,101 unrelated Han Chinese subjects were recruited, including 1,649 myopia and 452 control subjects. Five previously reported CC-associated gene variants (Joint additive effect analysis showed thatThis study revealed that male high myopia subjects are more prone to carry CC-relatedACD: anterior chamber depth; AL: axial length; AL/CR: axial length/corneal radius ratio; ANOVA: analysis of variance; CC: corneal curvature; CCT: central corneal thickness; C.I.: confidence interval; CMPK1: cytidine/uridine monophosphate kinase 1; CR: corneal radius; D: diopter; GWAS: genome-wide association studies; HWE: Hardy-Weinberg equilibrium; LT: lens thickness; MIPEP: mitochondrial intermediate peptidase; MTOR: mechanistic target of rapamycin kinase; OR: odds ratio; PDGFRA: platelet-derived growth factor receptor-α; RBP3: retinol-binding protein 3; SD: standard deviation; SE: spherical equivalence; SNTB1: syntrophin beta 1; VCD: vitreous chamber depth; VIPR2: vasoactive intestinal peptide receptor 2; WNT7B: wingless/integrated family member 7B.

This study examined the variation in individuals' static maximum forward pushing and backward pulling (FPBP) strength for handleless cartons under different task conditions. Thirty young Taiwanese men were recruited as participants and were requested to perform maximum FPBP exertion tests under four exertion heights (50, 80, 110, and 140 cm), two types of hand contact (bare hands and gloves), and two carton widths (40 and 60 cm). The results of this study indicated that the pushing strength for handleless cartons was almost twice the pulling strength for all exertion heights. This finding is different from those of previous relevant studies. The pulling force generated when gloves were worn was 38% higher than that generated under barehanded pulling. Moreover, the pulling force generated with a 40-cm-wide carton was 13% higher than that generated with a 60-cm-wide carton. Pushing strength was affected by only the exertion height.

Background Tennis elbow or lateral epicondylitis is a common source of pain among craftsmen. Although it cannot be completely resolved, extracorporeal shock wave therapy (ESWT) and ultrasonics (US) have been found to be effective for tennis elbow as highlighted in previously published randomized controlled trials (RCTs) and reviews. However, the efficacy of these two therapies in treating tennis elbow is unknown. This meta-analysis compares the effectiveness of ESWT and US in relieving pain and restoring the functions of tennis elbow following tendinopathy. Methods RCTs published in the PubMed, Embase, Cochrane Library, and SpringerLink databases comparing ESWT and US in treating tennis elbow were identified by a software and manual search. The risk of bias and clinical relevance of the included studies were assessed. Publication bias was explored using funnel plot and statistical tests (Egger’s test and Begg’s test). The major outcomes of the studies were analyzed using the Review Manager 5.3. Results Five RCTs comprising five patients were included in the present meta-analysis. The results revealed a significantly lower VAS score of pain in the ESWT group (1 month: MD = 4.47, p = 0.0001; 3 months: MD = 20.32, p

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. Hepatitis B virus (HBV) is one of the leading causes of HCC, but the precise mechanisms by which this infection promotes cancer development are not fully understood. Recently, miR-340-5p, a microRNA (miRNA) that has been identified as a cancer suppressor gene, was found to inhibit the migration and invasion of liver cancer cells. However, the effect of miR-340-5p on cell proliferation and apoptosis in HBV-associated HCC remains unknown. In our study, we show that miR-340-5p plays an important role during HBV infection and hepatocellular carcinoma development. Specifically, this miRNA directly binds to the mRNA encoding activating transcription factor 7 (ATF7), a protein that both promotes cell proliferation and suppresses apoptosis through its interaction with heat shock protein A member 1B (HSPA1B). We further found that miR-340-5p is downregulated by HBV, which enhances ATF7 expression, leading to enhanced cell proliferation and inhibition of apoptosis. Notably, ATF7 is upregulated in HCC tissue, suggesting that HBV may target miR-340-5p in vivo to promote ATF7/HSPA1B-mediated proliferation and apoptosis and regulate liver cancer progression. This work helps to elucidate the complex interactions between HBV and host miRNAs and further suggests that miR-340-5p may represent a promising candidate for the development of improved therapeutic strategies for HCC.

Background: Shock-wave (SW) therapy has been widely promoted and proven to be effective in ameliorating symptoms of lateral epicondylitis (LE) during recent years. Corticosteroid (CS) injection is another common treatment of LE, and several researches have documented its significant effect in the treatment of LE. Despite this, few studies have focused on comparing the use of SW and CS in the treatment of LE. The aim of this meta-analysis is to assess whether SW is superior to CS in managing LE, both in terms of ameliorating pain and improving functionality. Methods: A systematic search of the literature was conducted to identify relevant articles that were published in Pubmed, Medline, Embase, the Cochrane Library, SpringerLink, Clinical Trials.gov and OVID from the databases' inception to December 2018. All studies comparing the efficacy of SW and CS in terms of pain levels and functionality improvement were included. Data on the two primary outcomes were collected and analyzed using the Review Manager 5.3. Results: Four studies were included in the current meta-analysis. A significant difference in VAS score (SMD = 1.13, Cl 0.72-1.55 P < 0.00001, I2 = 0) was noted between the SW group and the CS group. Furthermore, Significant difference was also seen in the term of grip strength (including HGS and GSS scoring system) (SMD = -1.42, Cl -1.85--0.98 P < 0.00001, I2 = 0). Conclusions: In light of the better improvement in the terms of VAS and grip strength with follow-up more than 12 weeks, we assume that SW may be a superior alternative for the treatment of LE.