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Type 2 diabetes mellitus (T2DM) is a well-established risk factor for cardiovascular diseases. We aimed to identify the biological variation of ten cardiovascular biochemical markers in T2DM patients to aid in their interpretation.Blood samples for evaluating ten biomarkers were collected biweekly from 23 T2DM patients (10 men, 13 women) for three months. The analytical variability and variations of within-subject (CVThe levels of total cholesterol (CHOL), apolipoprotein A (apoA), homocysteine (HCY), high-sensitivity troponin T (hsTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) differed between males and females (P 0.05). The CVThe cardiovascular biochemical markers in T2DM patients showed higher CV

Clinical prostate cancer (PCa) is rare in men aged50 years (early-onset). A well-designed nomogram for prognosis prediction in patients with early-onset PCa has not been studied. Here, we tried to establish nomogram models of overall survival (OS) and cancer-specific survival (CSS) in patients with early-onset PCa.The clinical variables of patients diagnosed with early-onset PCa between 2004 and 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training and validation groups at a ratio of 7:3. Multivariate Cox regression analyses were used to select prognostic factors associated with OS or CSS, followed by the construction and validation of nomograms.We enrolled 8259 patients with early-onset PCa. New nomograms were established and showed good discriminative abilities. Finally, ROC curve analysis demonstrated that these nomograms were superior to the TNM stage and Gleason score in predicting both OS and CSS for patients with early-onset PCa.This is the first study to establish nomograms with effective and high accuracy for prognosis in patients with early-onset PCa.

Although extensive efforts have been paid to identify reliable predictors for renal outcomes of diabetic kidney disease (DKD) patients in type 2 diabetes mellitus (T2DM), there are still only a limited number of predictive factors for DKD progression. Increasing evidence reported the role of the overactivated complement system in the pathogenesis of DKD. Whether renal complement depositions are associated with renal outcomes of DKD in T2DM is of interest.A total of 213 biopsy-proven DKD patients with T2DM were retrospectively recruited. Clinical and pathological data of the patients were analyzed. Kaplan-Meier analysis and Cox regression analysis were performed to explore predictors of end-stage renal disease (ESRD).During a median follow-up of 23.0 (12.0, 39.0) months, 100/213 (46.9%) patients progressed to ESRD. C3c and C1q deposition were observed in 133/213 (62.4%) and 45/213 (21.1%) patients, respectively. Kaplan-Meier analysis revealed patients with C3c or C1q deposition had significantly worse renal outcomes compared with those without C3c or C1q deposition (p = .001 and p .001, respectively). Univariate and multivariate Cox regression analysis demonstrated proteinuria (per 1 g/24 h increase, hazard ratio [HR] 1.134, 95% confidence interval [CI] [1.079, 1.191], p .001), interstitial fibrosis and tubular atrophy score (score 2 and 3 vs. 0 and 1, HR 3.925, 95% CI [1.855, 8.304], p .001), and C3c deposition (per 1+ increase, HR 1.299, 95% CI [1.073, 1.573], p = .007) were independent predictors for ESRD in DKD patients with T2DM.C3c deposition in the kidney was associated with worse renal outcomes and was an independent predictor for ESRD in DKD patients with T2DM.背景: 尽管已经付出了大量努力来确定糖尿病肾病(DKD)合并2型糖尿病(T2DM)患者肾脏结局的可靠预测因子, 但DKD进展的预测因子仍然有限。越来越多的证据表明, 过度激活的补体系统在DKD的发病机制中起着重要作用。T2DM患者肾脏补体沉积是否与DKD的肾脏预后有关值得关注。 方法: 回顾分析213例经手术病理证实的DKD合并T2DM患者的临床资料。对患者的临床和病理资料进行分析。采用Kaplan-Meier分析和Cox回归分析探讨终末期肾病(ESRD)的预测因子。 结果: 中位随访23.0(12.0, 39.0)个月, 100/213(46.9%)患者进展为ESRD。C3c和C1q沉积分别为62.4%(133/213)和21.1%(45/213)。Kaplan-Meier分析显示, C3c或C1q沉积的患者与无C3c或C1q沉积的患者相比, 肾脏结局明显差(分别为p=0.001和p0.001)。单因素和多因素COX回归分析显示, 蛋白尿(每增加1g/24小时, HR 1.134, 95%CI[1.079, 1.191], p0.001), 间质纤维化和肾小管萎缩积分(2和3分 vs. 0和1分, HR 3.925, 95%CI[1.855, 8.304], p0.001)和C3c沉积(每增加1+, HR 1.299, 95%CI[1.073, 1.573], p=0.007)是DKD合并T2DM患者ESRD的独立预测因子。 结论: 肾内C3c沉积与肾脏结局不良相关, 是DKD合并T2DM患者ESRD的独立预测因子。.

This research qualitatively explored user preferences for an app-based mHealth approach to support HIV self-testing and linkage to HIV prevention or care services developed for men who have sex with men (MSM) in China. We conducted 12 online focus group discussions with MSM participants (N = 48) about their preferences for using an app to meet their HIV self-testing and service linkage needs. Data were examined using thematic analysis. Participants specified four domains to align program delivery with their preferences for app-based intervention: (1) expanding HIV prevention/antiretroviral therapy concepts beyond basic knowledge; (2) enhancing the style and presentation of app-based messages; (3) incorporating interactive and dynamic app-engagement features; and (4) creating a “one station” app that covers the continuum of HIV services. Given the changing landscapes of HIV knowledge and community/user preferences for app-based interaction, findings underscore how engagement with end-user participants is essential to optimize mHealth interventions for HIV.

Background Malignancy is a potential comorbidity in patients with systemic lupus erythematosus (SLE). However, risk by malignancy type remains to be fully elucidated. We evaluated the risk of malignancy type in SLE patients in a systematic review and meta-analysis. Methods MEDLINE and EMBASE were searched from inception to July 2018 to identify observational studies that evaluated malignancy risk in adult SLE patients compared with the general population. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Heterogeneity was quantified using the I2 test. Findings Forty-one studies reporting on 40 malignancies (one overall, 39 site-specific) were included in the meta-analysis. The pooled RR for all malignancies from 3694 events across 80 833 patients was 1.18 (95% CI: 1.00-1.38). The risk of 24 site-specific malignancies (62%) was increased in SLE patients. For malignancies with ≥6 studies, non-Hodgkin lymphoma and Hodgkin lymphoma risk was increased >3-fold; myeloma and liver >2-fold; cervical, lung, bladder, and thyroid ≥1.5-fold; stomach and brain >1.3-fold. The risk of four malignancies (breast, uterine, melanoma, prostate) was decreased, whereas risk of 11 other malignancies did not differ between SLE patients and the general population. Heterogeneity ranged between 0% and 96%, and 63% were non-significant. Interpretation The risk of overall and some site-specific malignancies is increased in SLE compared with the general population. However, the risk for some site-specific malignancies is decreased or did not differ. Further examination of risk profiles and SLE patient phenotypes may support guidelines aimed at reducing malignancy risk. Funding AstraZeneca. Systematic review registration PROSPERO number: CRD42018110433.

ObjectiveTo summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH).MethodsA prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults 6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect.ResultsOf 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6–5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth.InterpretationOverall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent.PROSPERO registration numberCRD42019141136.

Emergency medical services (EMS) activation is an integral component in managing individuals with myocardial infarction (MI). EMS play a crucial role in early MI symptom recognition, prompt transport to percutaneous coronary intervention centres and timely administration of management. The objective of this study was to examine sex differences in prehospital EMS care of patients hospitalized with Ml using data from a retrospective population-based cohort study of linked health administrative data for people with a hospital diagnosis of MI in Australia (2001-18).

Aims Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and results Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. Conclusion In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder with an autosomal recessive inherited pattern. It is mainly characterized by deficiencies in lysosome-related organelles, such as melanosomes and platelet-dense granules, and leads to albinism, visual impairment, nystagmus, and bleeding diathesis. A small number of patients will present with granulomatous colitis or fatal pulmonary fibrosis. At present, mutations in ten known genetic loci (HPS1–11) have been identified to be the genetic cause of HPS. In this study, we enrolled a consanguineous family who presented with typical HPS phenotypes, such as albinism, visual impairment, nystagmus, and bleeding diathesis. Whole-exome sequencing and Sanger sequencing were applied to explore the genetic lesions of the patient. A novel homozygous frameshift mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 was identified and cosegregated in the family members. Furthermore, real-time PCR confirmed that the mutation decreased the expression of HPS3, which has been identified as the disease-causing gene of HPS type 3. According to ACMG guidelines, the novel mutation, resulting in a premature stop codon at amino acid 442, is a pathogenic variant. In summary, we identified a novel mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 in a family with HPS. Our study expanded the variant spectrum of the HPS3 gene and contributed to genetic counseling and prenatal genetic diagnosis of the family.

Calcyphosine (CAPS) was initially identified from the canine thyroid. It also exists in many types of tumor, but its expression and function in glioma remain unknown. Here we explored the clinical significance and the functional mechanisms of CAPS in glioma. We found that CAPS was highly expressed in glioma and high expression of CAPS was correlated with poor survival, in glioma patients and public databases. Cox regression analysis showed that CAPS was an independent prognostic factor for glioma patients. Knockdown of CAPS suppressed the proliferation, whereas overexpression of CAPS promoted the proliferation of glioma both in vitro and in vivo. CAPS regulated the G2/M phase transition of the cell cycle, but had no obvious effect on apoptosis. CAPS affected PLK1 phosphorylation through interaction with MYPT1. CAPS knockdown decreased p-MYPT1 at S507 and p-PLK1 at S210. Expression of MYPT1 S507 phosphomimic rescued PLK1 phosphorylation and the phenotype caused by CAPS knockdown. The PLK1 inhibitor volasertib enhanced the therapeutic effect of temozolomide in glioma. Our data suggest that CAPS promotes the proliferation of glioma by regulating the cell cycle and the PLK1 inhibitor volasertib might be a chemosensitizer of glioma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

This study investigated the anti-ascites effect of the total saponins of Phytolaccae Radix(PRTS) and the mechanism.H22 cell suspension was used(ip) to induce ascites in ICR male mice, and the model mice were randomized into model group, positive drug group(furosemide, 6 mg·kg~(-1)), total extract of Phytolaccae Radix(PRTE) group, and PRTS(1.29 g·kg~(-1)).Another 10 male mice were selected as the blank group.Mice in the blank group and model group were given(ig) normal saline containing 0.5% CMC-Na, and those in the positive drug group, PRTE group, and PRTS group received(ig) corresponding doses of drugs, once a day, for 8 consecutive days.The ascites volume, urine volume, and fecal water content in mice with ascites, serum levels of antidiure-tic hormone(ADH), renin in renin-angiotensin-aldosterone system(RAAS), angiotensin Ⅱ(AngⅡ), and aldosterone(ALD), expression of aquaporin(AQP)1-AQP4 in kidney, expression of AQP1, AQP3 in colon, and expression of phosphatidylinositol 3-kinase/protein kinase B(PI3 K/Akt) pathway-related proteins were detected to explore the anti-ascites mechanism of PRTS.The results showed that the PRTS can increase the urine volume and fecal water content and decrease the ascites volume of ascites mice.Moreover, PRTS significantly reduced the expression of AQP1-AQP4 in kidney and AQP1, AQP3 in colon, serum levels of renin, AngⅡ, ALD, and ADH, and the expression of p-PI3 K and p-Akt in the kidney of ascites mice.PRTS exerts anti-ascites effect by promoting urination and defecation.The mechanism is that it inhibits the activities of RAAS and ADH and suppresses the phosphorylation of PI3 K/Akt signaling pathway, thereby restricting the expression of AQPs in the kidney and colon.

BACKGROUND The incidence of primary cardiac lymphoma (PCL) is increasing, but the optimal management approach remains unclear. We assessed the clinical characteristics of a single-centre cohort with the goal of determining the optimal management approach. The treatment outcomes and prognostic factors are reported. MATERIAL AND METHODS All PCL patients were diagnosed via biopsy guided by whole-body imaging (positron emission tomography/computed tomography [PET/CT] and/or contrast-enhanced CT]. Curative therapy involved either surgery or prephase steroids followed by definitive immunochemotherapy, depending on the histological type. The primary outcomes were overall survival (OS) and progression-free survival (PFS); the secondary outcome was the treatment response. RESULTS Twenty-two PCL patients (14 males, 8 females; age: 59.5 ± 14.7 years [mean ± S.D.]) were histologically confirmed to have diffuse large B-cell lymphoma (DLBCL; n = 17 [77.3%]), fibrin-associated DLBCL (FA-DLBCL) (n = 4 [18.2%]) and Burkitt lymphoma (n = 1 [4.5%]). Seven patients underwent cardiotomy (three for biopsy, four with curative intent). The median and longest follow-up periods were 16.3 and 180.0 months, respectively. The 16 patients who received curative therapy (complete response [CR], n = 15 [93.8%]; partial response [PR], n = 1 [6.2%]) showed better survival than those who did not (5-year OS: 83.0 ± 11.3% vs. 0%; hazard ratio [HR]: 0.025[95% confidence interval, CI: 0.003-0.187], p

Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

Background Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC. Methods Patients with advanced NSCLC harboring EGFR mutations who underwent tyrosine kinase inhibitors (TKIs) therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study. All included patients were divided into two groups based on whether they received osimertinib, the osimertinib group (patients treated with osimertinib) and the control group (patients not treated with osimertinib). Propensity score matching (PSM, ratio of 1:1) was used to account for differences in baseline characteristics. The cumulative incidence of LM and the overall survival (OS) were evaluated. Results A total of 304 patients were included in the study population. Among them, 116 patients received osimertinib, and 188 did not. A total of 112 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two cohorts. LM developed in 11 patients (9.82%) in the osimertinib group and 24 patients (21.42%) in the control group (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19–0.79, p = 0.009). Multivariate analysis indicated that osimertinib was an independent, statistically significant predictor for determining the risk for LM, with an HR of 0.33 (p = 0.042). At present, the OS rate data are too immature for statistical analysis. Conclusion Real-world data demonstrate that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring common EGFR mutations. Given this result, osimertinib should be encouraged in clinical practice for specific patient populations.

Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.

A randomized controlled study was conducted to investigate the effects of case management on risky sexual behaviors and syphilis in HIV-positive men who have sex with men. Supplemental digital content is available in the text., Background The prevalence of syphilis is very high in human immunodeficiency virus (HIV)–positive men who have sex with men (MSM), and effective interventions are needed to educate HIV-positive individuals about behavioral and biological risk factors. Therefore, we developed a standard case management process and conducted a randomized controlled study to investigate the impact on risky sexual behaviors and syphilis in HIV-positive MSM. Methods Men who have sex with men (n = 220) were enrolled and randomized to the case management intervention group and the control group between May 2016 and January 2017. The control group received routine HIV-related care. In addition to routine HIV-related care, those in the intervention group regularly received extended services from a well-trained case manager. Epidemiological information was collected during the baseline face-to-face interviews by a trained investigator. Serological tests for syphilis and assessments of risky sexual behaviors were performed at baseline and 6 and 12 months after the initiation of treatment. Results The syphilis incidence rates in the intervention and control groups were 11.3 per 100 person-years and 20.6 per 100 person-years, respectively. The multivariable-adjusted hazard ratio (95% confidence inter) for syphilis in case management group was 0.34 (0.14–0.87). The percentages of participants who resumed risky sexual behaviors in both groups were significantly reduced (P < 0.05) but did not significantly differ between the 2 groups. Conclusions A case management intervention reduced the incidence of syphilis in HIV-positive MSM. We should further increase the content of case management on the basis of providing routine HIV-related care to those people.

In nematodes, spermiogenesis is a process of sperm activation in which nonmotile spermatids are transformed into crawling spermatozoa. Sperm motility acquisition during this process is essential for successful fertilization, but the underlying mechanisms remain to be clarified. Herein, we have found that extracellular adenosine-5′-triphosphate (ATP) level regulation by MIG-23, which is a homolog of human ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), was required for major sperm protein (MSP) filament dynamics and sperm motility in the nematode Ascaris suum. During sperm activation, a large amount of ATP was produced in mitochondria and was stored in refringent granules (RGs). Some of the produced ATP was released to the extracellular space through innexin channels. MIG-23 was localized in the sperm plasma membrane and contributed to the ecto-ATPase activity of spermatozoa. Blocking MIG-23 activity resulted in a decrease in the ATP hydrolysis activity of spermatozoa and an increase in the depolymerization rate of MSP filaments in pseudopodia, which eventually affected sperm migration. Overall, our data suggest that MIG-23, which contributes to the ecto-ATPase activity of spermatozoa, regulates sperm migration by modulating extracellular ATP levels.

IntroductionMorphological evaluation is used to select embryos for in vitro fertilisation. However, it does not fully reflect the implantation potential. Preimplantation genetic testing for aneuploidies (PGT-A) can detect embryonic aneuploidy, but biopsy procedure is invasive. Currently, a non-invasive PGT (ni-PGT) approach using spent medium is being evaluated. However, the clinical benefit of ni-PGT has not been clearly demonstrated. A multicentre randomised trial is needed to verify whether ni-PGT can be an new effective tool for evaluating embryos.Methods and analysisOverall, 1148 couples aged 35~42 (women) receiving in vitro fertilization–intracytoplasmic sperm injection are planned to be enrolled. Couples will be digitally randomised to (1) ni-PGT and (2) conventional morphology groups at a 1:1 treatment ratio. The primary outcome will be the ongoing pregnancy rate related to the first transfer cycle within 6 months after oocyte retrieval.Ethics and disseminationThe study protocol is approved by the Ethics Committee of Peking University Third Hospital and the participating hospitals. The results will be disseminated through international conferences and scientific journals.Trial registration numberNCT04339166.

Nuclear factor-E2-related factor 2 (Nrf2) expression in sperm decreases in some oligospermia patients. However, the mechanism of reduced Nrf2 expression in sperm of oligospermia men is not elucidated. In the present study, our clinical trial results showed that Nrf2 and glutathione peroxidase 4 (GPX4) protein expressions in sperm of oligospermia men significantly decreased than those of healthy men. In animal experiments, mice were randomly divided into 3 groups: wild type (WT), Nrf2 knockout (Nrf2

Objective To establish and verify models predictive of thin periodontal phenotype and alveolar fenestration/dehiscence in the anterior teeth of patients with skeletal Class III malocclusion. Material and methods Retrospective data of 669 anterior teeth (305 in maxillae and 364 in mandibles) from 80 patients with skeletal Class III malocclusion before augmented corticotomy were collected. Distribution of thin periodontal phenotype and alveolar fenestration and dehiscence were evaluated and their associations with potential influencing factors were explored using univariate and multivariate analyses. The predictive models were visualized as nomograms, the accuracy of which was tested by receiver operating curve analyses. Results Thin phenotype was associated with Mazza bleeding index, sex, tooth type, probing depth and width of keratinized gingiva (WKG). Labial dehiscence was associated with age, jaw, labial bone thickness, mandibular plane angle, sagittal root position (SRP), sex, tooth type, and WKG. Labial fenestration was associated with sex, tooth type, SRP, and periodontal phenotype. The areas under the curves of nomogram prediction models for periodontal phenotype, alveolar dehiscence, and alveolar fenestration were 0.84, 0.81, and 0.73, respectively. Conclusions Female sex, lateral incisor, and limited WKG may be risk factors for thin periodontal phenotype. Age, canine, male sex, mandible, thin labial bone thickness, and root positioned against the labial plate may be risk factors for labial dehiscence; and female sex, thick phenotype, root positioned against the labial plate, lateral incisor, and canine may be risk factors for labial fenestration. The predictive performance of the models was acceptable.

Background This retrospective study aimed to evaluate the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with stereotactic body radiation therapy (SBRT) and to elucidate potential mechanisms of acquired resistance. Methods Patients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and August 2019. Eligible patients were treated with thoracic SBRT, and TKI was continued after SBRT until it was considered ineffective. The control group was treated with TKIs monotherapy. Propensity score matching (PSM, ratio of 1:2) was used to account for differences in baseline characteristics. Overall survival (OS), progression-free survival (PFS), treatment safety and resistance mechanisms were evaluated. Results Three hundred eight patients were included in the study population. Among them, 262 patients received TKIs alone, and 46 patients received TKIs with SBRT. Baseline characteristics were not significantly different between the two cohorts after PSM. The median PFS was 19.4 months in the TKIs +SBRT group compared to 13.7 months in the TKIs group (p = 0.034). An influence on OS has not yet been shown (p = 0.557). Of the 135 patients evaluated after PSM, 28 and 71 patients in the TKIs and TKIs +SBRT cohorts, respectively, had plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) performed at baseline and disease progression. In the TKIs +SBRT cohort, the NGS results showed that T790M mutations were detected in 64.3% (18/28) of patients. Patients in the TKIs cohort exhibited fewer T790M-positive mutations (40.8%, p = 0.035) compared to patients in the TKIs +SBRT cohort. Conclusion Real world data prove that TKIs plus thoracic SBRT significantly extend PFS with tolerable toxicity. The mutation ratio of T790M was increased in the TKIs +SBRT group compared to the TKIs only group. Further randomized studies are warranted.

This study investigated the prevalence of and risk factors for alveolar fenestration and dehiscence in the anterior teeth of Chinese patients with skeletal Class III malocclusion.This study included clinical and radiographic examinations and intraoperative observations of 460 anterior teeth from 54 patients who underwent corticotomy and periodontal regenerative surgery before orthodontic treatment. Fenestration and dehiscence were detected and recorded during open-flap surgery. Univariate and multivariate analyses were performed to assess relationships between fenestration and dehiscence and age, sex, history of previous orthodontic treatment, mandibular plane angle, dentition, tooth position, sagittal root position, periodontal biotype, gingival recession, width of keratinized gingiva, and width of the basal bone.The prevalence of buccal alveolar bone defects was 16.1% (fenestration) and 20.7% (dehiscence) at the tooth level. Multivariate logistic regressions showed that fenestration was significantly associated with tooth position (canine vs central incisor, odds ratio [OR] = 3.324; P = 0.006; lateral incisor vs central incisor, OR = 5.588; P 0.001), and sagittal root position (buccally positioned vs centrally positioned, OR = 5.865; P = 0.025). Dehiscence was significantly associated with dentition (mandible vs maxilla, OR = 11.685; P 0.001), tooth position (canine vs central incisor, OR = 3.863; P = 0.007), age (OR = 1.227; P = 0.010), sex (male vs female, OR = 5.530; P = 0.026), and history of orthodontic treatment (yes vs no, OR = 4.773; P = 0.028).Buccally positioned teeth in the osseous housing, lateral incisors, and canines were more likely to exhibit alveolar fenestration. Mandibular teeth and canines, patients who were older, were male, and had a history of orthodontic treatment, were more likely to exhibit alveolar dehiscence.

Background: The findings of associations between prenatal air pollution exposure and hypospadias risk in offspring are inconsistent. No systematic review or meta-analysis has yet summarized the present knowledge on the aforementioned topic. Methods: Relevant manuscripts were identified by searching PubMed and Web of Science databases through January 31, 2020. Summary odds ratios (ORs) with 95% confidence intervals (CIs) in meta-analyses were estimated based on a random effects model. Publication bias was evaluated by funnel plots, Begg’s test, and Egger’s test. Results: The search identified 3,032 relevant studies. Sixteen studies cumulatively involving 21,701 hypospadias cases and 1,465,364 participants were included. All of these studies were classified as having a low risk of bias. We classified pollutants as nitrogen oxides, particulate matter (PM), ozone, and other exposures. The exposure window to pollutants varied from three months before conception to seven days after delivery. In the meta-analyses, only PM2.5 exposure in the first trimester was related to increased risk of hypospadias (per 10 μg/m3 OR = 1.34; 95% CI: 1.06–1.68). Conclusion: We found evidence for an effect of PM2.5 exposure on hypospadias risk. Improvements in the areas of study design, exposure assessment, and specific exposure window are needed to advance this field.

Background: This study evaluates the feasibility, safety, and clinical results of the self-pulling and latter transected delta-shaped anastomosis (Delta SPLT) in totally laparoscopic distal gastrec...

Background Mounting evidence suggests that cesarean delivery may have a long-lasting effect on infant health. But the underlying mechanisms remain unclear. This study aims to examine whether cesarean delivery on maternal request without any medical indications (CDMR) impacts DNA methylation status in the umbilical cord blood of the infant. Methods A cross-sectional study was conducted in Shanghai, China. A total of 70 CDMR and 70 vaginal deliveries (VD) were recruited in 2012. The cord blood DNA methylation status was measured in 30 CDMR and 30 VD newborns using Illumina Infinium Human Methylation 450 K BeadChip. To validate the results, the cord blood DNA methylation status was measured in another 40 CDMR and 40 VD newborns using targeted bisulfite sequencing assay. A total of 497 CpG sites from 40 genes were included in the analysis. Results A total of 165 differentially methylated positions (DMPs) exhibited differences in DNA methylation by 10% or more between the CDMR and VD groups, many of which were related to the development of the immune system. Based on the targeted bisulfite sequencing assay, 16 genes (16/22, 72.7%) had higher methylation level in the CDMR group than the VD group. Among them, 5 genes were related to the immune system. After considering the estimation of cell type proportions, there was few significant differences in DNA methylation between CDMR and VD groups. Conclusions The DMPs identified between CDMR and VD groups might be largely explained by the cell type proportions. Further studies are needed to examine DNA methylation in each cell type separately.

Summary Background Wuhan was the epicentre of the COVID-19 outbreak in China. We aimed to determine the seroprevalence and kinetics of anti-SARS-CoV-2 antibodies at population level in Wuhan to inform the development of vaccination strategies. Methods In this longitudinal cross-sectional study, we used a multistage, population-stratified, cluster random sampling method to systematically select 100 communities from the 13 districts of Wuhan. Households were systematically selected from each community and all family members were invited to community health-care centres to participate. Eligible individuals were those who had lived in Wuhan for at least 14 days since Dec 1, 2019. All eligible participants who consented to participate completed a standardised electronic questionnaire of demographic and clinical questions and self-reported any symptoms associated with COVID-19 or previous diagnosis of COVID-19. A venous blood sample was taken for immunological testing on April 14–15, 2020. Blood samples were tested for the presence of pan-immunoglobulins, IgM, IgA, and IgG antibodies against SARS-CoV-2 nucleocapsid protein and neutralising antibodies were assessed. We did two successive follow-ups between June 11 and June 13, and between Oct 9 and Dec 5, 2020, at which blood samples were taken. Findings Of 4600 households randomly selected, 3599 families (78·2%) with 9702 individuals attended the baseline visit. 9542 individuals from 3556 families had sufficient samples for analyses. 532 (5·6%) of 9542 participants were positive for pan-immunoglobulins against SARS-CoV-2, with a baseline adjusted seroprevalence of 6·92% (95% CI 6·41–7·43) in the population. 437 (82·1%) of 532 participants who were positive for pan-immunoglobulins were asymptomatic. 69 (13·0%) of 532 individuals were positive for IgM antibodies, 84 (15·8%) were positive for IgA antibodies, 532 (100%) were positive for IgG antibodies, and 212 (39·8%) were positive for neutralising antibodies at baseline. The proportion of individuals who were positive for pan-immunoglobulins who had neutralising antibodies in April remained stable for the two follow-up visits (162 [44·6%] of 363 in June, 2020, and 187 [41·2%] of 454 in October–December, 2020). On the basis of data from 335 individuals who attended all three follow-up visits and who were positive for pan-immunoglobulins, neutralising antibody levels did not significantly decrease over the study period (median 1/5·6 [IQR 1/2·0 to 1/14·0] at baseline vs 1/5·6 [1/4·0 to 1/11·2] at first follow-up [p=1·0] and 1/6·3 [1/2·0 to 1/12·6] at second follow-up [p=0·29]). However, neutralising antibody titres were lower in asymptomatic individuals than in confirmed cases and symptomatic individuals. Although titres of IgG decreased over time, the proportion of individuals who had IgG antibodies did not decrease substantially (from 30 [100%] of 30 at baseline to 26 [89·7%] of 29 at second follow-up among confirmed cases, 65 [100%] of 65 at baseline to 58 [92·1%] of 63 at second follow-up among symptomatic individuals, and 437 [100%] of 437 at baseline to 329 [90·9%] of 362 at second follow-up among asymptomatic individuals). Interpretation 6·92% of a cross-sectional sample of the population of Wuhan developed antibodies against SARS-CoV-2, with 39·8% of this population seroconverting to have neutralising antibodies. Our durability data on humoral responses indicate that mass vaccination is needed to effect herd protection to prevent the resurgence of the epidemic. Funding Chinese Academy of Medical Sciences & Peking Union Medical College, National Natural Science Foundation, and Chinese Ministry of Science and Technology. Translation For the Chinese translation of the abstract see Supplementary Materials section.

The pathogenesis of androgenetic alopecia (AGA) is related to the level of androgen and its metabolic pathways. The binding of androgen and androgen receptor (AR) depends on the assistance of heat shock protein 27 (HSP27). HSP27 combined with microRNAs (miR)-1 can regulate AR levels. However, it is not clear whether HSP27 and miR-1 jointly participate in the pathogenesis of AGA. This study aims to investigate the role of AR up-regulation in the pathogenesis of AGA and underlying mechanisms.A total of 46 male AGA patients (AGA group), who admitted to the First Affiliated Hospital of Guangzhou Medical University from September 2019 to February 2020, and 52 healthy controls admitted to the same period were enrolled in this study. Serum levels of dihydrotestosterone (DHT) and HSP27 in patients and healthy controls were measured by ELISA. Western blotting was used to detect the protein expression of HSP27 and AR in scalp tissues of patients and the healthy controls. The levels ofThe levels of DHT and HSP27 in the AGA group were (361.4±187.7) pg/mL and (89.4±21.8) ng/mL, respectively, which were higher than those in the control group [(281.8±176.6) pg/mL and (41.2±13.7) ng/mL, bothHSP27 could combine with miR-1 to up-regulate AR levels, which is closely related to the development of AGA.

To investigate how asymptomatic bacterial imbalance affects the clinical pregnancy rate after artificial insemination with the husband's semen (AIH).This study included married heterosexual couples who underwent AIH. According to the follow-up results, participants were divided into the pregnancy and non-pregnancy groups. Based on the first 10 pair participants in each group with vaginal flora bacterial 16S rRNA sequencing results, six semen samples received bacterial-sperm mixed test. Moreover, 34 cytokines were detected in the peripheral blood sera of the first three pairs by high-throughput Luminex, which were verified in vaginal secretions, cervical mucus, and blood sera from the first 200 pairs by ELISA.The results of the 16S sequencing of vaginal secretions showed that compared with the pregnant group, the non-pregnant group had a significantly increased bacterial species diversity, which was mainly manifested by a decrease in Lactobacillus crispatus and an increase in Prevotella bivia. When Prevotella bivia or Lactobacillus crispatus were mixed with sperms, the sperm motility was decreased (p .05). The vaginal posterior fornix secretions, cervical mucus, and peripheral blood sera of the non-pregnant group showed decreased levels of MIP-1α and increased levels of IL-17A (p .05).The imbalance of vaginal flora leading to the increase of Prevotella bivia and the decrease of Lactobacillus crispatus may cause an imbalance of immune regulation. Low expression of MIP-1α and high expression of IL-17A were associated with reduced clinical pregnancy rate in AIH.

To examine whether pre-hospital emergency medical service care differs for women and men subsequently admitted to hospital with stroke.Population-based cohort study; analysis of linked Admitted Patient Data Collection and NSW Ambulance data for people admitted to New South Wales hospitals with a principal diagnosis of stroke at separation, 1 July 2005 - 31 December 2018.Emergency medical service assessments, protocols, and management for patients subsequently diagnosed with stroke, by sex.Of 202 231 people hospitalised with stroke (mean age, 73 [SD, 14] years; 98 599 women [51.0%]), 101 357 were conveyed to hospital by ambulance (50.1%). A larger proportion of women than men travelled by ambulance (52.4% v 47.9%; odds ratio [OR], 1.09; 95% CI, 1.07-1.11), but time between the emergency call and emergency department admission was similar for both sexes. The likelihood of being assessed as having a stroke (adjusted OR [aOR], 0.97; 95% CI, 0.93-1.01) or subarachnoid haemorrhage (aOR, 1.22; 95% CI, 0.73-2.03) was similar for women and men, but women under 70 years of age were less likely than men to be assessed as having a stroke (aOR, 0.89; 95% CI, 0.82-0.97). Women were more likely than men to be assessed by paramedics as having migraine, other headache, anxiety, unconsciousness, hypertension, or nausea. Women were less likely than men to be managed according to the NSW Ambulance pre-hospital stroke care protocol (aOR, 0.95; 95% CI, 0.92-0.97), but the likelihood of basic pre-hospital care was similar for both sexes (aOR, 1.01; 95% CI, 0.99-1.04).Our large population-based study identified sex differences in pre-hospital management by emergency medical services of women and men admitted to hospital with stroke. Paramedics should receive training that improves the recognition of stroke symptoms in women.

Raised blood pressure (BP) is the leading cause of death and disability worldwide, and its particular strong association with stroke is well established. Although systolic BP increases with age in both sexes, raised BP is more prevalent in males in early adulthood, overtaken by females at middle age, consistently across all ethnicities/races. However, there are clear regional differences on when females overtake males. Higher BP among males is observed until the seventh decade of life in high-income countries, compared with almost 3 decades earlier in low- and middle-income countries. Females and males tend to have different cardiovascular disease risk profiles, and many lifestyles also influence BP and cardiovascular disease in a sex-specific manner. Although no hypertension guidelines distinguish between sexes in BP thresholds to define or treat hypertension, observational evidence suggests that in terms of stroke risk, females would benefit from lower BP thresholds to the magnitude of 10 to 20 mm Hg. More randomized evidence is needed to determine if females have greater cardiovascular benefits from lowering BP and whether optimal BP is lower in females. Since 1990, the number of people with hypertension worldwide has doubled, with most of the increase occurring in low- and-middle-income countries where the greatest population growth was also seen. Sub-Saharan Africa, Oceania, and South Asia have the lowest detection, treatment, and control rates. High BP has a more significant effect on the burden of stroke among Black and Asian individuals than Whites, possibly attributable to differences in lifestyle, socioeconomic status, and health system resources. Although pharmacological therapy is recommended differently in local guidelines, recommendations on lifestyle modification are often very similar (salt restriction, increased potassium intake, reducing weight and alcohol, smoking cessation). This overall enhanced understanding of the sex- and ethnic/racial-specific attributes to BP motivates further scientific discovery to develop more effective prevention and treatment strategies to prevent stroke in high-risk populations.

Background and objective The involvement of eyelids occurs in only 5-6% of patients with discoid lupus erythematosus (DLE), commonly with mucocutaneous lesions elsewhere. DLE solely involving the eyelids is relatively rare. This study aimed to describe the clinical features and treatments of all the reported cases of DLE with eyelid involvement as the only symptom. Methods A systematic review was done of all the related literature published both in English and Chinese from May 1, 1984, to March 1, 2020. Only those cases of DLE solely involving eyelids were selected and summarized in two tables. Results (i) DLE solely involving the eyelids is five times more likely to affect females than males. (ii) The majority of cases were presenting with unilateral eyelid involvement. Lower lids, especially both lower lids, were the most commonly affected locations. (iii) An erythematous plaque with scales is the most frequent manifestation. (iv) Approximately 22.9% of the cases had a positive antinuclear antibody (ANA) titer, and the speckled pattern was the most seen. For direct immunofluorescence (DIF), 94.4% of the performed cases showed positive results. (v) More than 85% of these cases showed an excellent response to treatment with oral antimalarials. Conclusion Awareness of this atypical presentation is important to avoid underdiagnosis of DLE solely involving the eyelids. A biopsy for both routine histology and DIF is critical for establishing the diagnosis.

TWIST1 is an important basic helix‐loop‐helix protein linked to multiple physiological and pathological processes. Although TWIST1 is believed to be involved in vascular pathogenesis, its effects on homeostasis of smooth muscle cells (SMCs) remain poorly understood. Here, we show that TWIST1 protein levels were significantly elevated during SMC phenotypic switching in vivo and in vitro. TWIST1 overexpression promoted phenotypic switching of SMCs, while siRNA targeting of TWIST1 prevented cell transition. Mechanistically, TWIST1 decreased the level of microRNA‐143/145, which governs smooth muscle marker gene transcription. In addition, TWIST1 repressed p68 mRNA and protein expression, a crucial modulator of SMC behavior and microRNA biogenesis. Our co‐immunoprecipitation assay demonstrated a previously unrecognized molecular interaction between TWIST1 and p68 protein. Finally, we found that TWIST1 triggered SMC phenotypic switching and suppressed microRNA‐143/145 expression by promoting the proteasomal degradation of p68. These data suggest a novel role of TWIST1 in the regulation of SMC homeostasis by modulating p68/microRNA‐143/145 axis., Increased TWIST1 expression leads to the suppression of the DDX5/microRNA‐143/145 pathway in VSMC, which induces phenotypic switching of VSMC and promotes the progression of vascular remodeling. Therefore, TWIST1 might be a attractive therapeutic target for inhibiting phenotype‐related vascular disorders.

Summary Infection-associated hemophagocytic syndrome (IAHS), a severe complication of various infections, is potentially fatal. This study aims to determine whether IAHS occurs in critically ill patients with coronavirus disease 2019 (COVID-19). We conducted a retrospective observational study on 268 critically ill patients with COVID-19 between February 1st, 2020 and February 26th, 2020. Demographics, clinical characteristics, laboratory results, information on concurrent treatments and outcomes were collected. A diagnosis of secondary hemophagocytic lymphohistiocytosis (sHLH) was made when the patients had an HScore greater than 169. Histopathological examinations were performed to confirm the presence of hemophagocytosis. Of 268 critically ill patients with confirmed SARS-CoV-2 infection, 17 (6.3%) patients had an HScore greater than 169. All the 17 patients with sHLH died. The interval from the onset of symptom of COVID-19 to the time of a diagnosis of sHLH made was 19 days and the interval from the diagnosis of sHLH to death was 4 days. Ten (59%) patients were infected with only SARS-CoV-2. Hemophagocytosis in the spleen and the liver, as well as lymphocyte infiltration in the liver on histopathological examinations, was found in 3 sHLH autopsy patients. Mortality in sHLH patients with COVID-19 is high. And SARS-CoV-2 is a potential trigger for sHLH. Prompt recognition of IAHS in critically ill patients with COVID-19 could be beneficial for improving clinical outcomes.

Our aim was to detect type 2 innate lymphoid cells (ILC2s)-related cytokines of infants with bronchiolitis by using Elisa, Liquidchip technology and RT-PCR and investigated its correlation with bronchiolitis. We recruited 26 infants with bronchiolitis and 20 healthy infants as control from Xiangya Hospital. Compared to the control group, the serum levels of interleukin-5 (IL-5) [41.99 (21.11) vs 25.70 (19.64)], IL-9 [27.04 (37.51) vs 8.30 (0.54)], IL-13 [184.05 (132.81) vs 121.75 (176.13)], IL-33 [83.70 (46.69) vs 11.23 (55.31)] and thymic stromal lymphopoietin (TSLP) [31.42 (5.41) vs 28.76 (2.56)] were significantly increased in infants with bronchiolitis (P P > 0.05]. The mRNA expression of IL-17RB (9.83 ± 0.35 vs 9.19 ± 0.58), TSLP (16.98 ± 2.12 vs 15.07 ± 2.25), retinoid acid receptor related orphan receptor α (7.18 ± 0.71 vs 5.46 ± 1.09) and trans-acting T-cell-specific transcription factor 3 (4.86 ± 0.66 vs 4.19 ± 0.90) were significantly increased in infants with bronchiolitis versus the control group (P P > 0.05). Our findings suggested that ILC2s possibly play a specific role in immunopathology of bronchiolitis.

Objective Use of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA. Methods We used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren–Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW. Results Of 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = −0.042, 95% CI −0.08, −0.0004). No other associations were observed. Conclusions In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.

Coronavirus disease-2019 (COVID-19) has become a pandemic disease globally. The First Affiliated Hospital of Chengdu Medical College has adopted telestroke to make stroke care accessible in remote areas. During the period January 2020 to March 2020, there was no COVID-19 case reported in our stroke center. A significant reduction of stroke admission was observed between the ischemic stroke group (235 vs. 588 cases) and the intracerebral hemorrhage group (136 vs. 150 cases) when compared with the same period last year (p < 0.001). The mean door-to-needle time (DNT) and door-to-puncture time (DPT) was 62 and 124 min, respectively. Compared to the same period last year, a significant change was observed in DNT (62 ± 12 vs. 47 ± 8 min, p = 0.019) but not in DPT (124 ± 58 vs. 135 ± 23 min, p = 0.682). A total of 46 telestroke consultations were received from network hospitals. Telestroke management in the central hospital was performed on 17 patients. Of them, 3 (17.6%) patients had brain hernia and died in hospital and 8 (47.1%) patients were able to ambulation at discharge and had a modified Rankin Scale of 0–2 at 3 months. The COVID-19 pandemic impacted stroke care significantly in our hospital, including prehospital and in-hospital settings, resulting in a significant drop in acute ischemic stroke admissions and a delay in DNT. The construction of a telestroke network enabled us to extend health-care resources and make stroke care accessible in remote areas. Stroke education and public awareness should be reinforced during the COVID-19 pandemic.

We aimed to assess the effect of childhood parental rearing on post-traumatic stress disorder (PTSD) among young HIV-positive men who have sex with men (MSM), as well as the mediation effect of social support on this association. A convenient sampling method and questionnaire-based survey were used to recruit eligible participants from the Wuhan Medical Treatment Center from 20 December 2018 to 28 February 2019. Bivariate analyses were used to investigate the correlations between PTSD and childhood parental rearing, the number of sexual partners and social support. Mediation analyses were used to investigate the mediation of social support. Totally, 142 eligible MSM participated in our study, with prevalence of PTSD being 33.10%. It was found that maternal warmth (M1) and maternal favoring (M5) were positively correlated with social support. Paternal rejection (F5) was positively correlated with PTSD. The effects of M1 and M5 on PTSD were completely mediated by social support. The effects of paternal favoring (F4) and M5 on PTSD were completely mediated by subjective social support, and the effects of F5 and M1 were completely mediated by social support utility. Social support was an important mediator between parental rearing and PTSD.

The depressant-like effects of albiflorin (AF) were studied on stressed chronic restraint stress (CRS) rats. Experimental rats were subjected to immobilization stress for a daily 6 h-restraining in a plastic restrainer for continuous 21 d and were treated with 30 or 15 mg·kg-1 of AF for 21 d. Control rats were maintained in completely non stressed conditions. Behavioral tests and biochemical analysis were applied to investigating a regulatory mechanism of anti-stress of AF. Treatment with AF significantly restored the depressant-like behaviors. Besides, AF increased the levels of 5-hydroxytryptophan (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NE) and dopamine (DA) in the hippocampus and increased the level of brain-derived neurotrophic factor (BDNF) in serum and protein expression in hippocampus. In addition, AF decreased the levels of hypothalamo-pituitary-adrenal (HPA) cascade, reduced the level of NO and cGMP in serum and inhibited the overexpression of 5-HT2AR mRNA and protein expression. Taken together, AF can modulate the NO-mediated network pathway in the hippocampus against stress-induced depressive-like behaviors. These physiological and behavioral changes allow rats to avoid potential deleterious effects of stress that may result from chronically elevated levels of glucocorticosteroids over days.

Severe pneumonia caused by COVID-19 has resulted in many deaths worldwide. Here, we analyzed the clinical characteristics of the first 17 reported cases of death due to COVID-19 pneumonia in Wuhan, China. Demographics, initial symptoms, complications, chest computerized tomography (CT) images, treatments, and prognoses were collected and analyzed from the National Health Committee of China data. The first 17 reported deaths from COVID-19 were predominately in older men; 82.35% of patients were older than 65 years, and 76.47% were males. The most common initial symptoms were fever or fatigue (14 cases, 82.35%), respiratory symptoms, such as cough (12 cases, 70.59%), and neurological symptoms, such as headache (3 cases, 17.65%). The most common finding of chest CT was viral pneumonia (5 cases, 29.41%). Anti-infectives (11 cases, 64.71%) and mechanical ventilation (9 cases, 52.94%) were commonly used for treatment. Most of the patients (16 cases, 94.12%) died of acute respiratory distress syndrome (ARDS). Our findings show that advanced age and male gender are effective predictors of COVID-19 mortality, and suggest that early interventions to reduce the incidence of ARDS may improve prognosis of COVID-19 pneumonia patients.

Limited data exist on the optimum level of SBP in thrombolyzed patients with acute ischemic stroke (AIS). We aimed to determine the effects of intensive blood pressure (BP) lowering, specifically in patients with severe AIS who participated in the international, Enhanced Control of Hypertension and Thrombolysis Stroke Study.Prespecificed subgroup analyzes of the BP arm of Enhanced Control of Hypertension and Thrombolysis Stroke Study, a multicenter, partial-factorial, open, blinded outcome assessed trial, in which 2227 thrombolysis-eligible and treated AIS patients with elevated SBP (150 mmHg) were randomized to intensive (target 130-140 mmHg) or guideline-recommended (180 mmHg) BP management. Severe stroke was defined by computed tomography or magnetic resonance angiogram confirmation of large-vessel occlusion, receipt of endovascular therapy, final diagnosis of large artery atheromatous disease, or high (10) baseline neurological scores on the National Institutes of Health Stroke Scale. The primary efficacy outcome was death or any disability (modified Rankin scale scores 2-6). The key safety outcome was intracranial hemorrhage (ICH). Treatment effects estimated in logistic regression models are reported as odds ratios (ORs) with 95% confidence intervals (CIs).There were 1311 patients [mean age 67 years; 37% female; median baseline National Institutes of Health Stroke Scale of 11 (range 6.0-15.0)] with severe AIS. Overall, there was no significant difference in the primary outcome of death or disability. However, intensive BP lowering significantly increased mortality (OR 1.52, 95% CI 1.09-2.13; P = 0.014) compared with guideline BP lowering, despite significantly lowering clinician-reported ICH (OR 0.63, 95% CI 0.43-0.92; P = 0.016).Intensive BP lowering is associated with increased mortality in patients with severe AIS despite lowering the risk of ICH. Further randomized trials are required to provide reliable evidence over the optimum SBP target in the most serious type of AIS.ClinicalTrials.gov Identifier: NCT01422616.

More and more premature infants were born worldwide that are suffering from various complications, vaccination for whom is often delayed in China. We aim to describe current vaccination recommendations in practice, immunization status, and vaccination safety for premature infants in Zhejiang.The demographic information, medical records of treatments, and adverse events following immunization (AEFI) history were collected from infants' parents by questionnaire in the Vaccination Consultation Clinic(VCC). Vaccination data were retrieved from Zhejiang Provincial Immunization Information System. The information of AEFI was collected from the Chinese National Adverse Event Following Immunization Information System.A total of 1515 premature infants visiting the VCC were included in the study. The majority (65.94%) of them were under 7 months. 47.59% of premature infants were advised to receive normal vaccinations, while 45.94% were advised to defer a specific vaccination and 6.47% were advised to defer all vaccinations. A total of 807 infants received 7187 vaccine doses were administered and only seven cases experienced mild and self-limiting adverse reactions (9.74/10,000). No uncommon or serious side effects were reported.Most premature infants visiting the VCC did not receive vaccines on time. The majority of them can be safely vaccinated according to the national-recommended schedule.

Gastric cancer (GC) is one of the most common cancers around the world. We demonstrate that SPIN1 is upregulated and associated with poor prognosis in GC. SPIN1 sustains GC cell proliferation via activation of MDM2‐p21‐E2F1 signaling pathway by binding to H3K4me3 of the MDM2 promoter. E2F1 could directly bind to the SPIN1 promoter and activate its transcription, forming a positive feedback loop., Gastric cancer (GC) is one of the most common cancers around the world. Searching for specific gene expression changes during the development of GC could help identify potential therapy targets. We previously showed that the histone code reader SPIN1 may act as an oncogene in breast cancer. At present, the biological function and regulation of SPIN1 in GC remain unclear. Here, we demonstrate that SPIN1 is upregulated in GC tissues, compared with nontumorous gastric tissues. Increased expression of SPIN1 is closely associated with poor prognosis for patients with GC. Increased SPIN1 expression enhances GC cell proliferation, migration, and invasion and promotes cell cycle progression. Mechanically, SPIN1 sustains GC cell proliferation via activation of the MDM2‐p21‐E2F1 signaling pathway by binding to H3K4me3 of the MDM2 promoter region. Interestingly, E2F1 could directly bind to the SPIN1 promoter and activate its transcription, thus forming a positive feedback loop. Our data suggest that SPIN1 plays an important role in the development of GC and could be used as a promising prognostic biomarker and therapeutic target for GC.

Objective: The transcription factor forkhead box protein O1 (FOXO1) is critical for regulating cytokine and chemokine secretion. However, its function in the tumor microenvironment (TME) remains largely unexplored. In this study, we characterized the prognostic value of FOXO1 and the interaction between tumor-derived FOXO1 and M2 macrophages in esophageal squamous cell carcinoma (ESCC). Methods: FOXO1 expression and macrophage infiltration in clinical samples and mouse models were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry staining. Western blotting, qRT-PCR, and enzyme-linked immunosorbent assay were used to evaluate chemokine ligand 20 (CCL20) and colony stimulating factor 1 (CSF-1) expression in FOXO1(+) and FOXO1(-) tumor cells. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and RNA sequencing. Transcriptional activity was measured using chromatin immunoprecipitation (ChIP)-qPCR. Tumor viability was investigated using XTT proliferation and foci formation assays. Results: FOXO1 upregulation in tumor tissues was found to drive the polarization of M0 macrophages and infiltration of M2 macrophages into the TME, resulting in worse prognosis in ESCC patients. CSF-1, a vital factor inducing M0-to-M2 polarization, was upregulated via a FOXO1-mediated mechanism. RNA sequencing results corroborated that the FOXO1-induced macrophages exhibited similar molecular signatures to the IL4-stimulated M2 macrophages. The transwell assays showed that FOXO1 promoted the migration of M2 macrophages via CCL20 secretion, which could be inhibited using an anti-CCL20 antibody. FOXO1(+) tumor-induced M2 macrophages promoted tumor proliferation via the FAK-PI3K-AKT pathway and the PI3K inhibitor could effectively impede the oncogenical process. Conclusions: FOXO1 facilitated M0-to-M2 polarization and the recruitment of M2 macrophages in the TME via the transcriptional modulation of CCL20 and CSF-1. Our data deciphered the FOXO1-dependent mechanism in M2 macrophage infiltration in the TME of ESCC, which has implications for the development of novel prognostic and therapeutic targets to optimize the current treatment against ESCC.

Fertilization requires sperm migration toward oocytes and subsequent fusion. Sperm chemotaxis, a process in which motile sperm are attracted by factors released from oocytes or associated structures, plays a key role in sperm migration to oocytes. Here, we studied sperm chemotaxis in the nematode

This study aims to analyze the difference in clinical features and prognosis of severe adenovirus pneumonia (SAP) in children of different ages and analyze the risk factors for poor prognosis in children with SAP. A retrospective observational study was performed to describe the clinical features and analyze the risk factors for death and postinfectious bronchiolitis obliterans (PIBO) in 303 children hospitalized with SAP from January 2015 through to January 2020. The participants were divided into four age groups:6 months (n = 25, 8.3%); 6-12 months (n = 98, 32.3%); 12-36 months (n = 118, 38.9%); and36 months (n = 62, 20.5%). Fever rate, peak, and duration were the lowest in the6 months group, while no significant difference was found among other age groups. Serum levels of lactate dehydrogenase and a load of adenovirus were the lowest in the6 months group, and the highest in the 6-12 and 12-36 months groups, respectively. A total of 80.9% of patients recovered, 3.3% of patients died, and 15.8% of patients were diagnosed with PIBO. The mortality rate showed no significance between age groups. The36 months group had the highest recovery rate and the lowest incidence of PIBO, while the 6-12 months group had the lowest recovery rate and the highest incidence of PIBO. Independent risk factors for PIBO among all participants from the four groups were invasive mechanical ventilation, administration of intravenous steroids, duration of fever, and male gender. Independent risk factors for death among all participants from the four groups were hypercapnia, low albumin levels, and invasive mechanical ventilation. Risk factor analysis of different ages was not possible due to the limited sample size. The morbidity, clinical features, and prognosis of SAP are affected by children's ages. Pediatric patients with a longer duration of fever, hypercapnia, low serum albumin levels, invasive mechanical ventilation, and intravenous steroids use are more likely to develop a poor prognosis in SAP, especially if the patient is male.

Several studies demonstrate that para-phenylenediamine (PPD) is often added to permanent oxidative hair dyes. Sub-chronic topical exposure to PPD in male rats damages their testicular function; however, little is known about the effects of PPD exposure on the female reproductive system, especially on oocyte quality. In this study, we found that PPD can affect the meiotic capacity of oocytes and their fertilization potential. In particular, PPD can damage the spindle/chromosome structure and prevent oocytes from developing and maturing normally. Furthermore, PPD exposure compromised the dynamics of cortical granules and their component, ovastacin. In addition to the protein level of Juno, the sperm receptors on the egg membrane, were substantially impaired in PPD-administered oocytes, thus leading to fertilization failure. Finally, we found that PPD exposure resulted in abnormal mitochondrial function, which led to oocyte degeneration, apoptosis, and increased ROS levels. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation are the major causes of the poor quality of oocytes exposed to PPD.

The brown planthopper (BPH), Nilaparvata lugens (Stål), is one of the most destructive pests in rice-growing regions of Asia. Extensive studies have suggested that SWI/SNF chromatin remodeling ATPase Brahma (BRM) plays multiple roles in the insect model Drosophila. Yet much less is known about the physiological properties for NlBRM. In the present study, the cloned full-length cDNA of NlBRM was 5637 bp and contained an ORF of 5292 bp encoding a 194.53 kD protein. The spatiotemporal dynamics of NlBRM was investigated by qPCR, which showed that it was abundantly expressed in the egg and ovary. Then significant downregulation of NlBRM by dsRNA injection had a relatively greater impact on female survival than male. Moreover, the number of oviposition marks of the NlBRM-RNAi females were declined by 61.11% - 73.33% compared with the controls during the subsequent 5 days after dsRNA injection. Meanwhile, the number of newly hatched BPH nymphs also decreased correspondingly by 93.56% - 100%. Phenotypic analysis revealed that none of normally banana-shaped eggs were discernable in the ovaries of NlBRM-deficient females, where mRNA expression of N. lugens vitellogenin gene was also reduced. Our results demonstrated that NlBRM played a crucial role in ovarian development and fecundity of BPH, likely by regulating the vitellogenin gene in vivo, which could be as a promising target for parental RNAi-based control of this serious rice pest.

Purpose The oxygen-induced retinal neovascularization mouse model closely approximates pathological changes associated with human retinal neovascularization-associated diseases, including retinopathies. We used this model and human retinal endothelial cells (HRECs) under hypoxia to explore the relationship between taurine upregulated gene-1 (TUG1), vascular endothelial growth factor (VEGF), and miR-299-3p on retinopathy of prematurity (ROP). Methods An oxygen-induced retinopathy (OIR) mouse model was established; the mice were divided into a normal control group, OIR group, TUG1 control group (lentivirus control), and TUG1-knockdown group. The apoptosis of retinal cells was evaluated using a TUNEL assay. Angiogenic, apoptotic, and inflammatory factors were detected by Western blot, immunohistochemistry, and immunofluorescence analyses. HRECs were cultured under hypoxia and assessed for VEGF expression, apoptosis, tubule formation, and migration ability. The relationship between TUG1, VEGF, and miR-299-3p was detected via a dual luciferase reporter gene assay. Results Intravitreal injection of TUG1 lentivirus reduced the inflammatory response in the mouse retinal tissue and markedly reduced pathological changes in the retina. Overexpression of miR-299 in HRECs reduced the apoptosis rate, tube formation, and migration ability of hypoxia-treated cells, thereby inhibiting the formation of new blood vessels. The dual luciferase reporter gene assay suggested that miR-299 has binding sites for TUG1 and VEGF. Conclusions TUG1 reduces the expression of VEGFA by competitively adsorbing miR-299-3p and facilitates the regulation of retinal neovascularization, suggesting that it may serve as a new therapeutic target for retinal neovascular diseases.

To investigate the effeicacy of Yishen Huoxue decoction (YSHX) on renal fibrosis induced by unilateral ureteric obstruction (UUO), and on reactive oxygen species (ROS) homeostasis in human umbilical vein endothelial cells (HUVECs).Forty male mice were randomly divided into six groups, sham group, UUO group, UUO+ resveratrol (RSV) (15 mg/kg) group, UUO + YSHX 20 mg/kg group (UUO + YSHX-L), UUO + YSHX 40 mg/kg group (UUO + YSHX-M), UUO + YSHX 80 mg/kg group (UUO + YSHX-H). Western blotting was used to measure protein expression levels. Reverse transcription-quantitative polymerase chain reaction was used to measure the mRNA expression. Immunohistochemistry was used to examine the histopathological changes of kidney tissue sample. Cell apoptosis was measured by Annexin V/PI staining. Cell viability was measured using CCK-8/WST-8 assay.YSHX treatment reduced α-SMA and Col-4 expressions, and increased CD31 and VE-cadherin expressions in UUO model mice. In vitro, YSHX increased cell viability and decreased apoptosis of HUVECs under hypoxic conditions. YSHX inhibited ROS generation by activating adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor coactivator-1α (PGC-1α)/silent mating-type information regulation 2 homolog 3 (Sirt3) signaling.YSHX treatment reduced 109KJ UUO-induced renal injury and fibrosis. Furthermore, YSHX treatment attenuated hypoxia-induced oxidative stress by regulating AMPK/PGC-1α/Sirt3 signaling.