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Rosin derivatives such as dehydroabietic acid and dehydroabietic amine belonging to diterpenoids have similar structure with androgen that inhibited the occurrence and development of prostate cancer. In this study, the effects and possible mechanism of the rosin derivative IDOAMP on prostate cancer were investigated. Our results showed that IDOAMP effectively inhibited cell viabilities of LNCaP, PC3, and DU145 prostate cells. After the treatment with IDOAMP, the levels of cleaved-PARP, LC3BII/I, and HMGB1 were increased, whereas the expression of GPX4 was decreased. Interestingly, cell viability was reversed by the supplements of necrostatin-1 and necrosulfonamide. Meanwhile, the IDOAMP downregulated the expression of human Aurora kinase A that was overexpressed in prostate cancer. In addition, co-IP results showed that IDOAMP inhibited the binding of Aurora kinase A to the receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3. However, the binding of RIPK1 to FADD, RIPK3, or MLKL was significantly promoted. Further studies showed that the phosphorylation levels of RIPK1, RIPK, and MLKL were increased in a concentration-dependent manner. In in vivo model, IDOAMP reduced the tumor volumes and weights. In conclusion, IDOAMP directly inhibited Aurora kinase A and promoted the RIPK1/RIPK3/MLKL necrosome activation to inhibit the prostate cancer.

Behavioral observations suggest a connection between anxiety and predator defense, but the underlying neural mechanisms remain unclear. Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors. By in vivo recordings in male mice, we find that activity of AHN GABAergic (AHNVgat+) neurons shows individually stable increases when animals approach unfamiliar objects in an open field (OF) or when they explore the open-arm of an elevated plus-maze (EPM). Moreover, object-evoked AHN activity overlap with predator cue responses and correlate with the object and open-arm avoidance. Crucially, exploration-triggered optogenetic inhibition of AHNVgat+ neurons reduces object and open-arm avoidance. Furthermore, retrograde viral tracing identifies the ventral subiculum (vSub) of the hippocampal formation as a significant input to AHNVgat+ neurons in driving avoidance behaviors in anxiogenic situations. Thus, convergent activation of AHNVgat+ neurons serves as a shared mechanism between anxiety and predator defense to promote behavioral avoidance.

Nodal peripheral T cell lymphoma (PTCL) confers a dismal prognosis when treated with conventional chemotherapy. Autologous stem cell transplantation (ASCT) seems a reasonable alternative in eligible patients. Nevertheless, a consensus on the role of ASCT as the first-line consolidation therapy for nodal PTCL patients has not been reached so far.A quantitative meta-analysis was performed via a systematic search in PubMed, Web of Science, Embase, and The Cochrane Library. The overall survival (OS), progression-free survival (PFS), hazard ratio (HR), and 95% confidence intervals (CIs) were compared and calculated from database inception to September 2021.Twelve articles were eligible. The results showed that ASCT could improve the survival of patients compared with chemotherapy alone. In terms of subtype analysis, results showed that angioimmunoblastic T cell lymphoma (AITL) patients could benefit more from chemotherapy followed by ASCT. Statistical differences were also confirmed for OS and PFS in different remission status, clinical stage, performance status (PS), chemotherapy regimen, and gender.ASCT could serve as the first-line consolidation treatment strategy for nodal PTCL patients, especially AITL patients. Early clinical stage, good PS status, CR before transplantation, CHOEP regimen, and female patients may indicate a better outcome.

Background Fabry disease (FD) remains poorly recognized, especially in children in China. Considering the diversity and nonspecific clinical manifestations accompanying with life-threatening aspect of this disease, methods to improve effective screening and management of the suspects are needed. This study aims to explore how it can be done effectively from a multidisciplinary perspective for children with FD at a tertiary children’s hospital in China. Methods A multidisciplinary team (MDT) of pediatric FD experts was launched at Children’s Hospital of Fudan University. Children with high-risk characteristics were referred by the MDT screening team using the dried blood spot (DBS) triple-test (α-galactosidase A, globotriaosylsphingosine, GLA gene). For newborns who were undergoing genetic testing in the hospital, the GLA gene was listed as a routine analysis gene. Evaluation, family screening, and genetic counselling were implemented after screening by the MDT management team. Results Before the establishment of the MDT, no case was diagnosed with FD in the hospital. However, twelve months following the MDT program's implementation, thirty-five children with high-risk profiles were referred for screening by DBS triple-test, with a yield of diagnosis of 14.3% (5/35). These 5 diagnosed children were referred due to a high-risk profile of pain accompanied by dermatological angiokeratoma and hypohidrosis (n = 2), pain accompanied by abnormal liver function (n = 1), pain only (n = 1), and unexplained renal tubular dysfunction (n = 1). Two neonates were detected early with GLA mutations in the hospital, with a yield of detection of 0.14% (2/1420). Furthermore, another 3 children diagnosed with FD were referred from other hospitals. Family screening of these 10 diagnosed children indicated that 9 boys inherited it from their mothers and 1 girl inherited it from her father. Four of them started to receive enzyme replacement therapy. Conclusion Screening and management of children with FD is effective based on a defined screening protocol and a multidisciplinary approach. We should pay more attention to the high-risk profiles of pain, angiokeratoma, decreased sweating, and unexplained chronic kidney disease in children.

Individuals of many species fight with conspecifics to gain access to or defend critical resources essential for survival and reproduction. Such intraspecific fighting is evolutionarily selected for in a species-, sex-, and environment-dependent manner when the value of resources secured exceeds the cost of fighting. One such example is males fighting for chances to mate with females. Recent advances in new tools open up ways to dissect the detailed neural circuit mechanisms that govern intraspecific, particularly inter-male, aggression in the model organism Mus musculus (house mouse). By targeting and functional manipulating genetically defined populations of neurons and their projections, these studies reveal a core neural circuit that controls the display of reactive male-male attacks in mice, from sensory detection to decision making and action selection. Here, we summarize these critical results. We then describe various modulatory inputs that route into the core circuit to afford state-dependent and top-down modulation of inter-male attacks. While reviewing these exciting developments, we note that how the inter-male attack circuit converges or diverges with neural circuits that mediate other forms of social interactions remain not fully understood. Finally, we emphasize the importance of combining circuit, pharmacological, and genetic analysis when studying the neural control of aggression in the future.

STUDY QUESTIONIs the protein l-arginine methyltransferase 3 (PRMT3)/asymmetrical dimethylarginine (ADMA)/nitric oxide (NO) pathway involved in the development of recurrent miscarriage (RM), and what is the potential mechanism?SUMMARY ANSWERElevated levels of PRMT3 and ADMA inhibit NO formation in the decidua, thereby impairing the functions of trophoblast cells at the maternal–foetal interface.WHAT IS KNOWN ALREADYDecreased NO bioavailability is associated with RM. ADMA, an endogenous inhibitor of nitric oxide synthase (NOS), is derived from the methylation of protein arginine residues by PRMTs and serves as a predictor of mortality in critical illness.STUDY DESIGN, SIZE, DURATIONA total of 145 women with RM and 149 healthy women undergoing elective termination of an early normal pregnancy were enrolled. Ninety-six female CBA/J, 24 male DBA/2 and 24 male BALB/c mice were included. CBA/J × DBA/2 matings represent the abortion group, while CBA/J × BALB/c matings represent the normal control group. The CBA/J pregnant mice were then categorised into four groups: (i) normal + vehicle group (n = 28), (ii) abortion + vehicle group (n = 28), (iii) normal + SGC707 (a PRMT3 inhibitor) group (n = 20) and (iv) abortion + SGC707 group (n = 20). All injections were made intraperitoneally on Days 0.5, 3.5 and 6.5 of pregnancy. Decidual tissues were collected on Days 8.5, 9.5 and 10.5 of gestation. The embryo resorption rates were calculated on Day 9.5 and Day 10.5 of gestation.PARTICIPANTS/MATERIALS, SETTING, METHODSNO concentration, ADMA content, NOS activity, expression levels of NOS and PRMTs in decidual tissues were determined using conventional assay kits or western blotting. PRMT3 expression was further analysed in decidual stromal cells, macrophages and natural killer cells. A co-culture system between decidual macrophages (DMs) and HTR-8/SVneo trophoblasts was constructed to study the roles of the PRMT3/ADMA/NO signalling pathway. Trophoblast apoptosis was analysed via Annexin V-fluorescein isothiocyanate/propidium iodide staining. CBA/J × DBA/2 mouse models were used to investigate the effects of SGC707 on embryo resorption rates.MAIN RESULTS AND THE ROLE OF CHANCEOur results show that NO concentration and NOS activity were decreased, but ADMA content and PRMT3 expression were increased in the decidua of RM patients. Moreover, compared with the normal control subjects, PRMT3 expression was significantly up-regulated in the macrophages but not in the natural killer cells or stromal cells of the decidua from RM patients. The inhibition of PRMT3 results in a significant decrease in ADMA accumulation and an increase in NO concentration in macrophages. When co-cultured with DMs, which were treated with SGC707 and ADMA, trophoblast apoptosis was suppressed and induced, respectively. In vivo experiments revealed that the administration of SGC707 reduced the embryo resorption rate of CBA/J × DBA/2 mice.LIMITATIONS, REASONS FOR CAUTIONAll sets of experiments were not performed with the same samples. The main reason is that each tissue needs to be reserved for clinical diagnosis and only a small piece of each tissue can be cut and collected for this study.WIDER IMPLICATIONS OF THE FINDINGSOur results indicate that the PRMT3/ADMA/NO pathway is a potential marker and target for the clinical diagnosis and therapy of RM.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Key Research and Development Program of China (2017YFC1001401), National Natural Science Foundation of China (81730039, 82071653, 81671460, 81971384 and 82171657) and Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015). The authors have declared no conflict of interest.TRIAL REGISTRATION NUMBERN/A.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor without curable therapy. Surgical resection remains the first choice of patients with GBM but tumors relapse rapidly even combined with conventional chemoradiotherapy. The mechanism of GBM rapid recurrence is poorly understood, which is largely due to the lack of an appropriate animal model, thus heavily impedes the improvement of postoperative therapy. Here we established a highly reproducible mouse GBM surgical model by using the syngeneic G422TN-GBM cells, which faithfully recapitulates the features of rapid recurrence of human GBM after surgery. Implanting 2 × 103–5 × 104 of G422TN-GBM cells in mouse cerebral cortex caused death in all animal within 23 days, while surgery was an effective therapy but not curable. After complete removal of visible tumors on day 5–9 of tumor growth, the tumors recurred macroscopically within 5 days accompanied by increasing infiltrative cancer foci. Mechanistically, the rapid recurrence of resected tumors was positively correlated to early Akt activation, which subsequently upregulated PD-L1/Vimentin and promoted proliferation/migration of cancer cells. In addition, environmental astrocytic activation with strong PD-L1 signal was prominent. Taken together, we provided a novel GBM surgical recurrence model for preclinical studies and suggested complicated recurring mechanisms involving in strong oncogenic signaling as well as immune inhibitory signals from both GBM cells and their neighboring astrocytes.

Aims Monocyte-lymphocyte ratio (MLR) or neutrophil-lymphocyte ratio (NLR) are useful for diagnosing periprosthetic joint infection (PJI), but their diagnostic values are unclear for screening fixation-related infection (FRI) in patients for whom conversion total hip arthroplasty (THA) is planned after failed internal fixation for femoral neck fracture. Methods We retrospectively included 340 patients who underwent conversion THA after internal fixation for femoral neck fracture from January 2008 to September 2020. Those patients constituted two groups: noninfected patients and patients diagnosed with FRI according to the 2013 International Consensus Meeting Criteria. Receiver operating characteristic (ROC) curves were used to determine maximum sensitivity and specificity of these two preoperative ratios. The diagnostic performance of the two ratios combined with preoperative CRP or ESR was also evaluated. Results The numbers of patients with and without FRI were 19 (5.6%) and 321 (94.4%), respectively. Areas under the ROC curve for diagnosing FRI were 0.763 for MLR, 0.686 for NLR, 0.905 for CRP, and 0.769 for ESR. Based on the Youden index, the optimal predictive cutoffs were 0.25 for MLR and 2.38 for NLR. Sensitivity and specificity were 78.9% and 71.0% for MLR, and 78.9% and 56.4% for NLR, respectively. The combination of CRP with MLR showed a sensitivity of 84.2% and specificity of 94.6%, while the corresponding values for the combination of CRP with NLR were 89.5% and 91.5%, respectively. Conclusion The presence of preoperative FRI among patients undergoing conversion THA after internal fixation for femoral neck fracture should be determined. The combination of preoperative CRP with NLR is sensitive tool for screening FRI in those patients. Cite this article: Bone Joint J 2021;103-B(9):1534–1540.

Background Postoperative moderate and severe anemia (PMSA) has been a serious perioperative complication in primary total knee arthroplasty (TKA). However, the ideal cutoff values to predict PMSA is still undetermined. The aim of this study was (1) to identify the risk factors associated with PMSA and (2) to establish the cutoff values of preoperative hemoglobin (HB) associated with increased PMSA in primary TKA. Methods We identified 474 patients undergoing primary TKA and separated those in which PMSA (HB was less than 110 g/L on postoperative day 1 and 3) was developed from those without PMSA. Multivariate logistic regression model was used to identify independent risk factors for PMSA. Area under the receiver-operator curve (AUC) was used to determine the best-supported preoperative HB cutoff across all the patients. Results The PMSA rate in primary TKA was 53.2%. Significant risk factors were lower preoperative HB (OR [odds ratio] = 1.138, 95% CI [confidence interval] = 1.107–1.170, p p A preoperative HB cutoff value that maximized the AUC was 138.5 g/L for men (sensitivity: 79.4%, specificity: 75.0%) and 131.5 g/L for women (sensitivity: 74.7%, specificity: 80.5%), respectively. Conclusion We should recognize and consider the related risk factors to establish specific, personalized risk assessment for PMSA, including preoperative HB and intraoperative blood loss. Of these, preoperative HB was a referable tool to predict PMSA in primary TKA.

Mechanisms of silicosis, caused by the inhalation of silica are still unclear, and the effect of sex on silicosis has rarely been reported. The purpose of this study was to investigate whether sex affects the silicotic lesions and the progressive fibrotic responses in silicosis. Our study showed that sex had no significant effect on the area of silicon nodules and the collagen deposition after a one-time bronchial perfusion of silica. Immunohistochemical staining showed that CD68 and the transforming growth factor-β1 (TGF-β1) were positive in male and female silicotic mice. In addition, the western blot results showed that the fibrosis-related factors type I collagen (COL I), α-smooth muscle actin (α-SMA), vimentin, TGF-β1, p-SMAD2/3, inflammatory-related factors interleukin 6 (IL 6), interleukin 1β (IL 1β), and senescence-related factors p16 and p21 were up-regulated in silicotic mice and there was no difference between female or male mice exposed to silica. The expression of TGF-β1, p-SMAD2/3, p16, and p21 were downregulated in the early stage of female silicotic mice, compared to the males. Thus, despite differences in the expression of certain factors, there was no overall difference in the progressive fibrosis between female and male mice in silicosis. These results thus provide a new perspective for studying the pathological development of silicosis.

Object: The correct use of nutrition labels for prepackaged food helps university students develop healthy eating habits and prevent the occurrence of chronic non-communicable diseases. This study evaluates the understanding and use of nutrition labels of prepackaged food by university students in four different fields of study in Chongqing, China. Methods: This cross-sectional study used an online survey platform conducted in July 2022 in colleges and universities in Chongqing, China. The convenience sampling method was used to select students in four different fields of study, including medicine, humanities, science and technology, and arts and sports. Ten questions were used to assess participants’ understanding of nutrition labels. A score of six or above (60%) indicates that the respondent has a basic understanding of the nutritional labels of prepackaged food. Descriptive statistics and generalized linear models (GLMs) were used to assess participants’ understanding and use of nutrition labels for prepackaged foods and their influencing factors. Results: A total of 1262 valid questionnaires was collected. The average age of the participants was 21.8 years (SD: 2.43), 50.1% were male, 80.8% were ethnic Han, and 50.9% were from rural areas. Only 21.3% of the university students in Chongqing had a good understanding of the nutrition labels of prepackaged food, where medical students were the highest (39.9%) and science and engineering students were the lowest (15.6%). Gender, ethnicity, grade, major, and whether received courses related to nutrition were influential factors in the understanding and use of nutrition labels of prepackaged food. Medical students also had more positive attitudes toward nutritional labels of prepackaged food. Conclusions: Understanding and use of nutrition labels for prepackaged food by university students in Chongqing are unsatisfactory. Student’s major was a significant influencing factor in nutrition label comprehension, with medical students having the greatest understanding. Based on these results, we suggest that nutrition and health courses should be popularized among non-medical students to narrow the differences between different fields of study. For university students in all fields of study, education and publicity of nutrition labels of prepackaged food are needed, not only in the classroom but also in daily life.

This study aimed to develop and validate a bedside risk analysis system for predicting the clinical severity and prognosis of patients with coronavirus disease 2019 (COVID-19). In total, 444 COVID-19 patients were included and randomly assigned in a 2:1 ratio to 2 groups: derivation group and validation group. The new scoring system comprised of the following 8 variables: history of malignant diseases, history of diabetes mellitus, dyspnea, respiratory rate >24 breaths/min, C-reactive protein level >14 mg/L, white blood cell count >8×109/L, platelets count

It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2O2) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2O2 in LUAD cells and that the AQP3‐dependent transport of H2O2 accelerated cell growth and inhibited rapamycin‐induced autophagy. Mechanistically, AQP3‐mediated H2O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3‐induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD., Aquaporin 3 (AQP3) is a lung adenocarcinoma (LUAD) oncogene with the capacity to transport exogenous hydrogen peroxide (H2O2) and increase intracellular ROS levels. The devitalized oxidation of PTEN by AQP3‐transported H2O2 induces the hyperactivation of the PI3K/AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells.

Background The role of transvaginal sonography (TVS) in screening endometrial cancer and hyperplasia is significant in postmenopausal women. The objective of this study is to determine the endometrium thickness (ET) cut-off to distinguish premalignancy and malignancy in asymptomatic postmenopausal women. Methods We retrospectively evaluated data of 968 eligible patients among 2537 asymptomatic postmenopausal women with ET ≥ 5 mm examined by TVS who were subjected to hysteroscopy and endometrial biopsy between January 1, 2017, and June 30, 2020 in an urban tertiary specialized hospital in China. The patients were divided into two groups according to the pathology outcomes: benign, and atypical hyperplasia (AH) and endometrial carcinoma (EC). The risk factors and the optimal cut-off of ET for detecting AH and EC were determined by logistic regression analysis and receiver operating characteristic curve. Results 2537 patients were offered hysteroscopy during a 42-month period. Finally, 968 patients were included for further analysis. Of these, 8 (0.8%) women were diagnosed with EC and 5 (0.5%) women with AH. The mean ET of AH and EC group was substantially higher than that in benign group (10.4 mm vs. 7.7 mm, P P P Conclusion An ET cut-off of ≥ 8 mm shows a reasonable performance to detect AH and EC in asymptomatic postmenopausal women, thereby avoiding more invasive endometrial biopsy.

To investigate the clinical characteristics and treatment of pneumocystis carinii pneumonia (PCP) in children with acute lymphoblastic leukemia (ALL), in order to improve the early diagnosis and effective treatment.Clinical data of five children with ALL developing PCP in the post-chemotherapy granulocyte deficiency phase were analyzed retrospectively. The clinical manifestations, laboratory tests, imaging findings, treatment methods and effect were summarized.The male-to-female ratio of the five children was 1∶4, and the median age was 5.5 (2.9-8) years old. All patients developed PCP during granulocyte deficiency phase after induction remission chemotherapy. The clinical manifestations were generally non-specific, including high fever, tachypnea, dyspnea, non-severe cough, and rare rales in two lungs (wet rales in two patients). Laboratory tests showed elevated C-reactive protein (CRP), serum procalcitonin (PCT), (1,3)-β-D-glucan (BDG), lactate dehydrogenase (LDH) and inflammatory factors including IL-2R, IL-6 and IL-8. Chest CT showed diffuse bilateral infiltrates with patchy hyperdense shadows. Pneumocystis carinii(PC) was detected in bronchoalveolar lavage fluid (BALF) or induced sputum by high-throughput sequencing in all patients. When PCP was suspected, chemotherapy was discontinued immediately, treatment of trimethoprim-sulfame thoxazole (TMP-SMX) combined with caspofungin against PC was started, and adjunctive methylprednisolone was used. Meanwhile, granulocyte-stimulating factor and gammaglobulin were given as the supportive treatment. All patients were transferred to PICU receiving mechanical ventilation due to respiratory distress during treatment. Four children were cured and one died.PCP should be highly suspected in ALL children with high fever, dyspnea, increased LDH and BDG, and diffuse patchy hyperdense shadow or solid changes in lung CT. The pathogen detection of respiratory specimens should be improved as soon as possible. TMP/SMZ is the first-line drug against PCP, and the combination of Caspofungin and TMP/SMZ treatment for NH-PCP may have a better efficacy. Patients with moderate and severe NH-PCP may benefit from glucocorticoid.儿童急性淋巴细胞白血病合并卡氏肺孢子虫肺炎的临床特点和诊治分析.探讨儿童急性淋巴细胞白血病（ALL）化疗后骨髓抑制期并发卡氏肺孢子虫肺炎(PCP)的临床特点和治疗对策，为临床医生进行早期诊断和有效治疗提供参考.回顾性分析5例儿童ALL化疗后粒细胞缺乏期发生PCP的临床表现、实验室检查、影像学结果以及治疗和转归.5例患儿男女比例为1∶4，中位年龄5.5（2.9-8）岁。5例患儿均为诱导缓解化疗后粒细胞缺乏期间出现PCP，临床表现缺乏特异性，主要表现为高热、气促、呼吸费力，咳嗽不剧烈，2例出现肺部湿啰音，3例双肺无啰音。实验室检查结果提示，C反应蛋白（CRP）、血清降钙素原（PCT）、（1，3）-β-D-葡聚糖(BDG)、乳酸脱氢酶(LDH)以及炎症因子IL-2R、IL-6、IL-8均升高；胸部CT表现为双肺弥漫多发斑片状密度增高影；均通过高通量测序技术在肺泡灌洗液或深部痰中检出卡氏肺孢子虫。所有患儿疑诊PCP即停化疗，并予复方磺胺甲恶唑片联合卡泊芬净抗卡氏肺孢子虫治疗和甲基强的松龙抗炎，同时予粒细胞刺激因子、丙种球蛋白等支持治疗；期间所有儿童均因呼吸窘迫转入PICU，予无创或有创机械通气治疗。4例患儿治愈，1例患儿死亡.ALL患儿出现高热、呼吸困难、LDH及BDG升高，肺部弥漫斑片影或实变时，应高度怀疑PCP，尽快完善呼吸道标本的病原体检测。TMP/SMZ是抗PCP的一线用药，卡泊芬净静滴联合TMP/SMZ口服治疗NH-PCP可能有更好的疗效，糖皮质激素辅助治疗中重度NH-PCP可能使患者获益.

The aim of this study was to investigate the transgenerational associations between exposure to famine in early life and obesity.This study used the longitudinal data from the China Health and Nutrition Survey from 1989 to 2015. A total of 1113 fathers and 1207 mothers (946 mother-father pairs) born in 1955 to 1966 and 1895 adult offspring were included. Offspring were classified into subgroups according to the famine exposure of their parents (unexposed, maternal exposed, paternal exposed, parental exposed) and exposure timing (during fetal development, childhood).Maternal exposure to famine in early life was associated with elevated levels of BMI, waist circumference, overweight, and central obesity of their children, whereas paternal exposure was inversely associated with these measurements. Compared with children of unexposed parents (P0M0), the maternal exposed group (P0M1) had higher mean BMI, by 1.3 kg/mFetal and early childhood exposure to famine in parents may be associated with their children's risk of obesity during adulthood. A better understanding of the transgenerational associations is important for developing strategies to reduce obesity risk in future generations.

Objective To investigate the risk factors for, and outcomes of, preoperative asymptomatic pulmonary embolism (PE) in patients ≥60 years old following delayed operation for hip fracture. Methods From March 2017 to December 2018, 90 patients aged ≥60 years with hip fracture who suffered a delay in surgery were recruited to this prospective study following admission to our hospital. Computed tomography pulmonary angiography (CTPA) was used to detect preoperative asymptomatic PE and calculated its incidence. Time from injury to admission, baseline characteristics, medical comorbidities, and blood biomarker levels were evaluated as potential risk factors. Logistic regression analysis was used to identify risk factors. Mortality and major bleeding events were recorded and compared between individuals with PE and without. Data were analyzed by t‐test, Mann–Whitney U test, χ 2 test, Fisher's exact test, and logistic regression analysis. Results The incidence of preoperative asymptomatic PE was 18.9% (17/90 patients). In the univariate analysis, the risk factors for preoperative asymptomatic PE were male sex, hypertension, cerebrovascular accident, smoking, plasma D‐dimer level, potassium level, urea level, creatinine level, and cysteine level. Multivariate logistic regression analysis showed that the risk of preoperative asymptomatic PE was higher in patients with hypertension (odds ratio [OR] = 10.048; 95% confidence interval [CI], 1.118–90.333), cerebrovascular accident (OR = 20.135; 95% CI, 1.875–216.164), smoking (OR = 48.741; 95% CI, 4.155–571.788), high plasma D‐dimer levels (OR = 1.200; 95% CI, 1.062–157.300), and high plasma potassium levels (OR = 12.928; 95% CI, 1.062–157.300). All patients were followed up for 21.0 months (range, 2 to 36 months). Mortality within the first year postoperatively was higher in patients with PE (29.41% vs 9.59%, P = 0.046). Conclusions In view of the high incidence of preoperative asymptomatic PE and the inferior prognosis in individuals with PE, routine CTPA examination for preoperative asymptomatic PE could be useful for patients aged ≥60 years with hip fracture for whom surgery is delayed., The overall incidence of preoperative asymptomatic PE was 18.9% in patients ≥60 years old following delayed operation for hip fracture. Individuals with preoperative asymptomatic PE have an inferior prognosis. Hypertension, cerebrovascular accident, smoking, high plasma D‐dimer levels, and high plasma potassium levels were associated with preoperative asymptomatic PE in these patients.

Objective To observe the efficacy and safety of telitacicept in refractory childhood-onset systemic lupus erythematosus (cSLE). Methods A self-controlled before–after trial. Children with active SLE, aged 5–18 years, who cannot tolerate side effects of glucocorticoid, were enrolled in our study. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. Results Among the 15 cases of refractory cSLE, three were males (20%) and 12 were females (80%). The median age and weight were 13 years old and 52 kg, respectively. The median duration of disease was 30 months. 5–26 weeks (80 or 160 mg per week) after administration of telitacicept, 66.7% ( n=10) reached SRI-4 response. 12 cases reduced their glucocorticoid intake from 40 mg/d to 17.5 mg/d. The urinary protein after treatment declined in 8 cases whose 24-h proteinuria was >0.5 g at baseline. The urinary protein in two of the eight cases turned negative and plasma albumin in five of the eight cases rose to normal. In addition, three of these eight cases demonstrated varying degrees of improvement in renal impairment, whose estimated glomerular filtration rate (eGFR, ml/min·1.73 m2) rose from 17.4 to 26.6, 40.7 to 48.2, and 63.2 to 146.0, respectively. There were mild to moderate adverse events after treatment. Conclusion Telitacicept combined with the standard treatment may significantly increase the SRI-4 response rate and reduce the glucocorticoid dosage in refractory cSLE, and also shown efficacy on lupus nephritis. The related adverse drug events were controllable.

Chronic kidney injury has gradually become a worldwide public health problem currently affecting approximately 10% of the population and can eventually progress to chronic end-stage renal disease characteristic by the result of epithelial atrophy. Interleukin-22 (IL-22) is a cytokine produced by activated immune cells, while acting mainly on epithelial cells ranging from innate immune response to tissue regeneration to maintain barrier integrity and promote wound healing. Accumulating data suggests that IL-22 has emerged as a fundamental mediator of epithelial homeostasis in the kidney through promoting tissue repair and regeneration, inhibiting oxidative stress, and producing antimicrobial peptides. Binding of IL-22 to its transmembrane receptor complex triggers janus kinase/tyrosine kinase 2 phosphorylation, which further activates a number of downstream cascades, including signal transducer and activator of transcription 3, MAP kinase, and protein kinase B, and initiates a wide array of downstream effects. However, the activation of the IL-22 signaling pathways promotes the activation of complement systems and enhances the infiltration of chemokines, which does harm to the kidney and may finally result in chronic renal failure of different autoimmune kidney diseases, including lupus nephritis, and IgA nephropathy. This review describes current knowledge of the basic features of IL-22, including structure, cellular origin and associated signaling pathways. Also, we summarize the latest progress in understanding the physiological and pathological effects of IL-22 in the kidney, suggesting the potential strategies for the specific application of this cytokine in the treatment of kidney disease.

To investigate the correlation between serum vitamin D level and clinical outcomes after repair of rotator cuff tears.A total 122 patients who met the inclusion criteria and were followed up for 12 months from March 2018 to March 2020 were analyzed retrospectively, including 50 males and 72 females with an average age of(62.10±8.39) years old (ranged, 34 to 82 years old). All patients were divided into deficiency group(vitamin D20 μg/L) and control group(vitamin D≥20 μg/L), including 62 cases in the deficiency group, with vitamin D (14.80±3.18) μg/L;60 cases in the control group, with vitamin D(25.17±5.64) μg/L. The two groups were compared in terms of age, gender, body mass index(BMI), tear size, degree of retraction, degree of fatty infiltration, injury factors, postoperative pain VAS score, postoperative shoulder joint function score, and re-tear rate. The age of all patients was divided into two categories:60 years old and ≥60 years old;BMI was divided into24 kg/mThere were no major complications such as joint infection, anchor withdrawal and revision surgery in any of the 122 patients who were followed up on. There were no statistical differences in age, gender, injury factor, BMI, tear size, degree of retraction, degree of fatty infiltration, and duration of disease between the two groups (Vitamin D deficiency is not correlated with clinical function scores and re-tear rate, however it is associated with the early postoperative pain (1 and 3 months) and the quality of rotator cuff healing (Sugaya classification) after surgery.

Background Titanium mesh exposure after cranioplasty is a possible complication and is usually managed by mesh removal and flap transfer, but the advantages of the rigid prosthesis are then lost. This study aimed to present our experience with negative pressure wound therapy combined with soft tissue dilation for retaining the titanium mesh in patients with mesh exposure after cranioplasty. Methods This retrospective study included patients treated between 01/2016 and 05/2019 at the Jiangyin Hospital Affiliated to Southeast University School of Medicine. The wound was cleaned, and a cystic space was created for the tissue dilator, which was used with a self-designed negative pressure dressing. After the target dilation was achieved, the repair was conducted while retaining the titanium mesh. Results Eight patients were included (seven males and one female; 53.6 ± 8.8 (range, 43–65) years of age). The exposed mesh area ranged from 1 × 1 to 4 × 5.5 cm. The thinning scalp area around the exposed mesh ranged from 3.6 × 3.8 to 4 × 5.5 cm. Five patients had positive wound cultures and received sensitive antibiotics. The dilator embedding time was 20–28 days. The time of negative pressure wound therapy was 25–33 days. The hospital stay was 30–41 days. Primary wound healing was achieved in all eight patients. There were no signs of recurrence after 6–18 months of follow-up. The cranial CT scans were unremarkable. Conclusions Negative pressure wound therapy combined with soft tissue dilation for exposed titanium mesh after cranioplasty might help retain the titanium mesh.

Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.

Context Icariin has attracted increasing attention because of its wide variety of pharmacological effects. Objective This study investigates whether icariin could promote fracture healing in young and old rats and its mechanisms. Materials and methods A Wistar rat model for the tibia fracture in relatively young and old rats, respectively, was established. The rats were divided into four groups: model group, L-icariin (50 mg/kg icariin), M-icariin (100 mg/kg icariin) and H-icariin (200 mg/kg icariin), and intragastric administration of icariin was performed for 10 days or 20 days. In addition, isolated and cultured rat bone mesenchymal stem cells (rBMSCs) from young and old rats were cultured with 5% and 20% of icariin-containing serum, respectively, then cell viability and alkaline phosphatase (ALP) activity were measured. Results Icariin administration induced the expression of Runx2, Osterix, BMP-2, p-Smad5 and osteocalcin secretion (young rats: model: 2.50 ± 0.71; L-icariin: 10.10 ± 1.55; M-icariin: 24.95 ± 2.19; H-icariin: 36.80 ± 2.26; old rats: model: 1.55 ± 0.49; L-icariin:6.55 ± 0.50; M-icariin: 15.00 ± 0.85; H-icariin:20.50 ± 2.27) at the fracture site, and increased the levels of bone formation markers (OC, BAP, NTX-1 and CTX-1) in a dose-dependent manner. In vitro, icariin treatment promoted rBMSC viability, increased ALP activity and the expression of BMP-2/Smad5/Runx2 pathway proteins. Discussion and conclusions Icariin may accelerate fracture healing by activating the BMP-2/Smad5/Runx2 pathway in relatively young and old rats. The research on the mechanism of icariin to promote fracture healing can provide a theoretical basis for the clinical application and promotion of icariin.

Background Central line-associated bloodstream infections (CLABSI) are largely preventable when evidence-based guidelines are followed. However, it is not clear how well these guidelines are followed in intensive care units (ICUs) in China. This study aimed to evaluate Chinese ICU nurses’ knowledge and practice of evidence-based guidelines for prevention of CLABSIs issued by the Centers for Disease Control and Prevention, US and the Department of Health UK. Method Nurses completed online questionnaires regarding their knowledge and practice of evidence-based guidelines for the prevention of CLABSIs from June to July 2019. The questionnaire consisted of 11 questions, and a score of 1 was given for a correct answer (total score = 0–11). Results A total of 835 ICU nurses from at least 104 hospitals completed the questionnaires, and 777 were from hospitals in Guangdong Province. The mean score of 11 questions related to evidence-based guidelines for preventing CLABSIs was 4.02. Individual total scores were significantly associated with sex, length of time as an ICU nurse, educational level, professional title, establishment, hospital grade, and incidence of CLABSIs at the participant’s ICU. Importantly, only 43% of nurses reported always using maximum barrier precautions, 14% of nurses reported never using 2% chlorhexidine gluconate for antisepsis at the insertion site, only 40% reported prompt removal of the catheter when it was no longer necessary, and 33% reported frequently and routinely changing catheters even if there was no suspicion of a CLABSI. Conclusion Chinese ICU nurses in Guangdong Province lack of knowledge and practice of evidence-based guidelines for the prevention of CLABSIs. National health administrations should adopt policies to train ICU nurses to prevent CLABSIs.

Recent evidence suggests that hypoxia preconditioning can alter the microRNA (miRNA) profile of extracellular vesicles (EVs) and has better neuroprotective effects when enriched miRs are delivered to recipients. However, the roles of exosomal miRNAs in regulating ischaemia-reperfusion (IR)-induced pain hypersensitivity are largely unknown. Thus, we isolated EVs from normoxia-conditioned neurons (Nor-VSC EVs) and Hypo-VSC EVs by ultracentrifugation. After the initial screening by a microarray analysis and quantitative RT-PCR (qRT-PCR), miR-126-3p, which was detected as the most altered miR in the Hypo-VSC EVs, was further confirmed by applying GW4869 to inhibit exosomal secretion. Moreover, transfection with a miR-126 mimic obviously increased miR-126-3p expression in Nor-VSC EVs, whereas a miR-126 inhibitor prevented the increase in miR-126-3p in Hypo-VSC EVs. A rat model of pain was established by performing 8-min occlusion of the aorta. Following IR, compared with the Nor-VSC EVs- or antagomir-126-injected rats, the Hypo-VSC EVs-injected rats displayed improved pain hypersensitivity demonstrated as higher PWT and PWL values. Mechanistically, PIK3R2 is a target of miR-126-3p and might be a modulator of the phosphoinositide 3-kinase (PI3K)/Akt pathway as the PIK3R2 and PI3K immunoreactivities in each group were changed in opposite directions. Compared with the controls, higher protein levels of PI3K and phosphorylated Akt but lower levels of phosphorylated nuclear factor-κ B (NF-κB), tumour necrosis factor (TNF)-α and interleukin (IL)-1β were detected in the spinal cords of the Hypo-VSC EVs-injected rats, and these effects were impaired by an injection of Hypo-VSC EVs combined with antagomir-126. Collectively, the miR-126-3p-enriched Hypo-VSC EVs attenuated IR-induced pain hypersensitivity by restoring miR-126-3p expression in the injured spinal cord and subsequently modulating PIK3R2-mediated PI3K/Akt and NF-κB signalling pathways.

HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.

Carrier screening of Duchenne muscular dystrophy (DMD) has not been widely evaluated. To identify definite DMD female carriers prior to or in early pregnancy, we studied a large population of reproductive age females and provided informed reproductive options to DMD carriers. 37268 females were recruited from the Hangzhou Family Planning Publicity and Technology Guidance Station/Hangzhou Health Service Center for Children and Women, Hangzhou, China, between October 10, 2017, and December 16, 2018. CK activity was measured with follow-up serum DMD genetic testing in subjects with hyperCKemia, defined as CK>200 U/L. The calculated upper reference limit (97.5th percentile) of serum creatine kinase (CK) for females aged 20-50 years in this study was near the reference limit recommended by the manufacturer (200 U/L), above which was defined as hyperCKemia. 427 females (1.2%) harbored initially elevated CK, among which 281 females (response rate of 65.8%) accepted CK retesting. DMD genetic testing was conducted on 62 subjects with sustained serum CK>200 U/L and 16 females with a family history of DMD. Finally, 6 subjects were confirmed to be DMD definite carriers. The estimated DMD female carrier rate in this study was 1 : 4088 (adjusting for response rate), an underestimated rate, since only 50% to 70% of DMD female carriers manifest elevated serum CK, and carriers in this study may have been missed due to lack of follow-up or inability to detect all DMD pathogenic variants by current genetic testing.

Mosapride significantly improves intestinal motility in liver cirrhosis, ultimately leading to the reduction in plasma endotoxin levels and bacterial translocation.To investigate the effects of mosapride on intestinal microecology in cirrhotic rats and its potential mechanisms.Forty-five healthy male Sprague-Dawley rats that were pathogen-free (weight 200-220 g) were randomly divided into a control group (n = 15), model group (n = 15) and mosapride group (n = 15). Then, the pathological changes in the liver and intestine were determined through tissue staining and using transmission electron microscope (TEM). Bacterial translocation was examined. High throughput 16S rRNA sequencing was performed to determine the changes of gut microbiota in each group.Compared with the model group, mosapride treatment induced no attenuation in hepatic morphology and pathology changes. The TEM indicated no differences in intestinal structure in both groups. There was a significant decline in the rate of gut microbiota translocation in the mosapride group compared with the model group. There were intestinal microbiota changes in the mosapride group compared with that of the model group, including Bacteroidetes, Prevotellaceae, Alloprevotella, Ruminiclostridium, Negativicutes, Selenomonadales, Veillonellaceae, Anaerovibrio, Campylobacterales, Epsilonbacteraeota, Helicobacter, Oscillibacter, Verrucomicrobiales, Akkermansia, Intestinimonas, Eubacterium, Clostridiaceae, Clostridium, Bacteroides, Tyzzerella, Actinobacteria, and Bifidobacteriales. Among these bacteria, Alloprevotella showed a strong correlation with the other bacteria.Taken together, we concluded that mosapride may reduce intestinal bacterial translocation through regulating the gut microbiota in rats with hepatic cirrhosis.

To explore the genotype mutation characteristics of patients with glucose-6-phosphate dehydrogenase(G6PD) deficiency in Wuhan.A total of 1 321 neonates with positive screening and outpatients were received G6PD mutation detection, 12 kinds of common G6PD mutation in Chinese people was detected by using multicolor melting curve analysis (MMCA) method, for those with negative results, the enzyme activity and clinical information were analyzed, sequencing was recommended after informed consent when it is necessary.Among 1321 patients, a total of 768 mutations were detected out, with a detection rate of 58.1%. A total of 18 types of G6PD genotypes were identified, including c.1388GA, c.1376GT, c.95GA, c.1024CT, c.871GA, c.392GT, c.487GA, c.1360CT, c.1004CA, c.517TC, c.592CT, c.94CG, c.152CT, c.320AG, c.1028AG, c.1316GA, c.1327GC and c.1376GC, including 683 male hemizygotes, 3 female homozygotes, 80 female heterozygotes and 2 female compound heterozygous.A total of 18 types of G6PD mutations are identified in the reaserch, and c.94CG, c.1028AG and c.1327GC are first reported in Chinese population. The most common G6PD mutation types in Wuhan are c.1388GA, c.1376GT, c.95GA.武汉地区葡萄糖-6-磷酸脱氢酶缺乏症患者基因突变分析.探讨武汉地区葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症患者的基因突变特征.对湖北省妇幼保健院1 321例筛查阳性的新生儿及门诊患者进行G6PD基因检测，首选多色探针熔解曲线法(MMCA)检测中国人群常见的12种G6PD基因突变，对于MMCA法未检出者，分析其酶活性和临床信息，必要时进行测序检测.在1 321例受检者中共检出768例突变，检出率58.1%。共检出18种G6PD基因变异类型，包括c.1388GA、c.1376GT、c.95GA、c.1024CT、c.871GA、c.392GT、c.487 GA 、c.1360CT、c.1004CA、c.517TC、 c.592CT 、c.94CG、c.152CT、c.320AG、c.1028AG、c.1316GA、c.1327GC和c.1376GC，其中男性半合子683例，女性纯合子3例，女性杂合子80例，女性复杂杂合2例.本研究共检出18种G6PD基因变异类型，并首次在中国人群中报道了c.94CG、c.1028AG和c.1327GC突变类型。武汉地区人群常见G6PD基因突变类型为c.1388GA、c.1376GT和c.95GA.

Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimers dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression. Funding Agencies|StratNeuro (the Strategic Research Area Neuroscience-Karolinska Institutet, Umea University); StratNeuro (Kungliga Tekniska hogskolan); Center for Innovative Medicine Foundation (CIMED) [FoUI-963369]; Swedish Research Council [2019-01059, 2022-01428, 2016-02317, 2020-02014]; Stockholm County Council; Karolinska Institutet; Swedish Heart and Lung Foundation [20190587]; Westman Foundation

The purpose of this multicenter study was to compare the differential diagnostic value of the 2015 American Thyroid Association (ATA) and 2017 American College of Radiology (ACR) practice guidelines and elastography in thyroid nodules. This study also investigated whether the diagnostic value of practice guidelines can be improved, and the unnecessary biopsy rate decreased in combination with elastography. A total of 498 thyroid nodules were evaluated using the ATA and the ACR guidelines. Strain elastography, acoustic radiation force impulse imaging and point-shear wave elastography were used to assess the nodules. The suspicious levels were downgraded or upgraded after combination and unnecessary biopsy rates were calculated, respectively. The diagnostic performance of the practice guidelines was better than that of elastography. The ACR guidelines had a lower unnecessary biopsy rate and similar diagnostic performance compared with the ATA guidelines. The unnecessary biopsy rates significantly decreased when the ACR guidelines were combined with elastography, but the rates did not decrease when the ATA guidelines were combined with elastography.

Background Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. Objective Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. Methods We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naive subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Results Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11-1.31] and lower probability of DPP-4i (0.72 [0.66-0.79]), GLP-1a (0.51 [0.41-0.63]), and SGLT-2i dispensation (0.44 [0.36-0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (-0.58%), GLP-1a (-0.13%), and SGLT-2i (-0.21%) dispensation in dementia patients compared to dementia-free controls. Conclusion Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects.

Background and aim Endoscopic submucosal dissection (ESD) has a high en bloc resection rate and is widely performed for large colorectal lesions. However, colorectal ESD is associated with a high frequency of adverse events (AEs), and the efficacy of prophylactic endoscopic closure after ESD for preventing AEs is still controversial. This meta-analysis was conducted to assess the efficacy of closure on AEs following colorectal ESD. Methods We searched PubMed, Embase, and the Cochrane Library for eligible studies. The chi-square-based Q statistics and the I2 test were used to test for heterogeneity. Pooling was conducted using a fixed or random effects model. Results We identified eight eligible studies that compared the effects of closure vs non-closure with respect to delayed bleeding, delayed perforation, and post-ESD coagulation syndrome. Compared with non-closure (5.2%), closure was associated with a lower incidence (0.9%) of delayed bleeding (pooled odd ratios [ORs]:0.19, 95% CI: 0.08-0.49) following ESD. The pooled ORs showed no significant differences in incidence of delayed perforation (pooled OR: 0.22; 95% CI: 0.05-1.03) or post-ESD coagulation syndrome (pooled OR:0.75; 95% CI: 0.26-2.18) between the closure and non-closure groups. Conclusion Prophylactic endoscopic closure may reduce the incidence of delayed bleeding following ESD of colorectal lesions. Future studies are needed to further illuminate risk factors and stratify high risk subjects for a cost-effective preventive strategy.

By responding to environmental and intracellular stimuli, ion channels play critical roles in sperm function regulation. Although the importance of ion channel in male reproduction has drawn increasing attention in many species, the knowledge about ion channels in zebrafish sperm is limited. Here, we show zebrafish sperm motility could be suppressed by general calcium channel blockers rather than by general potassium channel blockers. Further investigation found that sperm motility was not only suppressed by antagonist for the transient receptor potential vanilloid channel, subtype 1 (Trpv1), but also restored by its agonist, suggesting functional presence of Trpv1 in zebrafish spermatozoa. As a consequence, the suppression of sperm motility by Trpv1 antagonist could reduce in vitro fertilization rate. Western blot and immunofluorescence analysis proved that Trpv1 was mainly distributed in the neck and tail regions of zebrafish sperm. Additionally, neither antagonist nor agonist of Trpv1 exhibited effect on the motility of trpv1−/− zebrafish sperm. To our knowledge, this is one of the limited studies showing the importance of ion channels in regulating zebrafish sperm function, and may enrich our understanding on male reproductive physiology of zebrafish and offer novel regulatory target for fish breeding and sperm cryopreservation.

In mainland China, dialysis for children with end-stage renal disease (ESRD) was not introduced until the 1980s. To describe the development of pediatric dialysis in different regions of China, a national pediatric dialysis network, namely, International Pediatric Dialysis Network-China (IPDN-China) ( www.pedpd.org.cn ), was launched in 2012. Original and updated information from the renal centers registered with the IPDN-China was collected between 2012 and 2016 from two sources, namely, the registry and the survey, and demographic features were analyzed. Due to promotion by the IPDN-China, the number of registered renal centers increased from 12 to 39 between 2012 and 2016, with a significant increase in the coverage of the Chinese administrative divisions (from 26.5 to 67.6%) (p < 0.01); and the coverage of the pediatric (0~14 years old) population increased to nearly 90% in 2016. The distribution of renal centers indicated that East China had the highest average number of registered centers per million population (pmp) 0~14-year-old age group. Seventeen relatively large dialysis centers were distributed across 14 divisions. Various modalities of renal replacement therapy (RRT) were available in most centers. The IPDN-China has promoted collaborations between dieticians, psychologists, and social workers on dialysis teams to provide better service to children with ESRD and their families. The proportion of centers with all three types of paramedic support (i.e., dieticians, psychologists, and social workers) as well as the proportion of centers with a partial paramedic team significantly increased between 2012 (25.0%) and 2016 (69.2%) (p < 0.05). In terms of the point prevalent cases of patients (aged < 18 years), data from the survey of 39 registered centers revealed that the number of children with ESRD who were on RRT was 578 (49% received a kidney transplant) at the end of 2016, which was more than that reported in previous surveys. Data from the registry showed that 349 dialysis patients had been enrolled as of the end of 2016. The median age at RRT start was 9.5 years, and the leading cause of ESRD was congenital abnormalities of the kidney and urinary tract (CAKUT). The IPDN-China has helped to promote the development of pediatric dialysis for ESRD in China by improving the organization of care for dialysis patients and increasing the availability and the quality of RRT for patients who need it. To improve knowledge about the epidemiology and outcomes of pediatric RRT around the country, a sustained effort needs to be made by the IPDN-China to increase the enrollment of dialysis patients and increase the number of registered centers in the future.

Background In persons with CKD, adherence to plant-based diets is associated with lower risk of CKD progression and death, but underlying mechanisms are poorly characterized. We here explore associations between adherence to plant-based diets and measures of insulin sensitivity and inflammation in men with CKD stages 3–5. Methods Cross-sectional study including 418 men free from diabetes, aged 70–71 years and with cystatin-C estimated glomerular filtration rate (eGFR) 2 and not receiving kidney-specific dietetic advice. Information from 7-day food records was used to evaluate the adherence to a plant-based diet index (PBDi), which scores positively the intake of plant-foods and negatively animal-foods. Insulin sensitivity and glucose disposal rate were assessed with the gold-standard hyperinsulinemic euglycemic glucose clamp technique. Inflammation was evaluated by serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6. Associations were explored through linear regression and restricted cubic splines. Results The majority of men had CKD stage 3a. Hypertension and cardiovascular disease were the most common comorbidities. The median PBDi was 38 (range 14–55). Across higher quintiles of PBDi (i.e. higher adherence), participants were less often smokers, consumed less alcohol, had lower BMI and higher eGFR (P for trend Conclusion In elderly men with non-dialysis CKD stages 3–5, adherence to a plant-based diet was associated with higher insulin sensitivity and lower inflammation, supporting a possible role of plant-based diets in the prevention of metabolic complications of CKD. Graphic abstract

The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus.Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) andThe initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the

Background Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents’ characteristics and cases outcomes. Methods A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. Results Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025–.529). Conclusions When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

This study evaluates the effectiveness of traditional Chinese opera on older adults with dementia; those who met the inclusion criteria were categorized into intervention (n = 21) and control (n = 22) groups. Traditional Chinese opera was organized for the intervention group for 12 weeks. The Mini-Mental State Examination (MMSE), the Chinese version of the neuropsychiatric inventory (CNPI), and Quality of Life in Alzheimer's disease (QOL-AD) assessed the effectiveness at the pre-test stage and after 6 and 12 weeks of the intervention, and generalized estimated equation was used for statistical analysis. Statistically significant (P 0.05) differences were observed between the intervention and control groups in terms of MMSE, CNPI, and QOL-AD. Traditional Chinese opera can potentially be an effective therapy for improving the cognitive function of older adults with dementia, reducing their behavioral and psychiatric symptoms and enhancing their quality of life.

Background Despite the availability of free tuberculosis (TB) diagnosis and treatment, TB care still generates substantial costs that push people into poverty. We investigated out-of-pocket (OOP) payments for TB care and assessed the resulting economic burden and economic consequences for those with varying levels of household income in eastern China. Methods A cross-sectional study was conducted among TB patients in the national TB programme networks in eastern China. TB-related direct OOP costs, time loss, and coping strategies were investigated across households in different economic strata. Analysis of Variance was used to examine the differences in various costs, and Kruskal-Wallis tests were used to compare the difference in total costs as a percentage of annual household income. Results Among 435 patients, the mean OOP total costs of TB care were USD 2389.5. In the lower-income quartile, OOP payments were lower, but costs as a percentage of reported annual household income were higher. Medical costs and costs prior to treatment accounted for 66.4 and 48.9% of the total costs, respectively. The lower the household income was, the higher the proportion of medical costs to total costs before TB treatment, but the lower the proportion of medical costs patients spent in the intensive phase. TB care caused 25.8% of TB-affected households to fall below the poverty line and caused the poverty gap (PG) to increase by United States Dollar (USD) 145.6. Patients in the poorest households had the highest poverty headcount ratio (70.2%) and PG (USD 236.1), but those in moderately poor households had the largest increase in the poverty headcount ratio (36.2%) and PG (USD 177.8) due to TB care. Patients from poor households were more likely to borrow money to cope with the costs of TB care; however, there were fewer social consequences, except for food insecurity, in poor households. Conclusions Medical and pretreatment costs lead to high costs of TB care, especially among patients from the poorest households. It is necessary to train health system staff in general hospitals to promptly identify and refer TB patients. Pro-poor programmes are also needed to protect TB patients from the medical poverty trap.

The impact of myeloid sarcoma (MS) on clinical outcome of pediatric acute myeloid leukemia (AML) patients remains controversial. Moreover, little is known about the role of stem cell transplantation (SCT) in such patients. Clinical data of patients with AML under 18 years of age were retrieved from the TARGET dataset. We analyzed the prevalence, clinical profile, molecular characteristics, and prognosis of MS in these patients. Among 884 pediatric patients with AML, the frequency of MS was 12.3%. Pediatric AML with MS was associated with age under 1-year, abnormal cytogenetics, and KMT2A rearrangement. Moreover, MS was associated with a low complete remission rate, high induction death, poor 5-year EFS, and OS. KMT2A rearrangement had a negative impact on clinical outcome in AML patients with MS. In addition, SCT had no significant effect on the survival of AML patients with MS. Multivariate analysis revealed that MS was an unfavorable prognostic factor in pediatric AML in terms of EFS (Hazard ratio 1.670, P

The deposition of pathological tau is a common feature in several neurodegenerative tauopathies. Although equal ratios of tau isoforms with 3 (3R) and 4 (4R) microtubule-binding repeats are expressed in the adult human brain, the pathological tau from different tauopathies have distinct isoform compositions and cell type specificities. The underlying mechanisms of tauopathies are unknown, partially due to the lack of proper models. Here, we generate a new transgenic mouse line expressing equal ratios of 3R and 4R human tau isoforms (6hTau mice). Intracerebral injections of distinct human tauopathy brain-derived tau strains into 6hTau mice recapitulate the deposition of pathological tau with distinct tau isoform compositions and cell type specificities as in human tauopathies. Moreover, through in vivo propagation of these tau strains among different mouse lines, we demonstrate that the transmission of distinct tau strains is independent of strain isoform compositions, but instead intrinsic to unique pathological conformations., Although normal human brains express 6 tau isoforms in equal ratio with 3 or 4 microtubule-binding repeat domains (3R and 4R), tau inclusions from different human tauopathy brains, now considered as different strains, have distinct isoform compositions and strain properties and the relationship between these two parts is unclear. Here the authors generate a new transgenic mouse line expressing 6 human tau isoforms with equal 3R and 4R ratios, recapitulate distinct human tau strains in mouse brains with similar isoform compositions and cell type specificities, and further show the strain transmission pattern is independent of its isoform composition.

The purpose of this study was to determine the effects of Kinesin family member 3A (KIF3A) on primary cilia and myofibroblast differentiation during silicosis by regulating Sonic hedgehog (SHH) signalling. Methods: Changes in primary cilia during silicosis and myofibroblast differentiation were detected in silicotic patients, experimental silicotic rats, and a myofibroblast differentiation model induced by SiO2. We also explored the mechanisms underlying KIF3A regulation of Glioma-associated oncogene homologs (GLIs) involved in myofibroblast differentiation. Results: Primary cilia (marked by ARL13B and Ac-α-Tub) and ciliary-related proteins (IFT 88 and KIF3A) were increased initially and then decreased as silicosis progressed. Loss and shedding of primary cilia were also found during silicosis. Treatment of MRC-5 fibroblasts with silica and then transfection of KIF3A-siRNA blocked activation of SHH signalling, but increased GLI2FL as a transcriptional activator of SRF, and reduced the inhibitory effect of GLI3R on ACTA2. Conclusion: Our findings indicate that primary cilia are markedly altered during silicosis and the loss of KIF3A may promote myofibroblast differentiation induced by SiO2.

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Purpose To describe the sonographic (ultrasound-US) features of retained surgical sponges (RSSs) and compare them with the pathological findings. Methods Ultrasound features of RSSs in nine patients (seven women and two men) identified between June 1996 and July 2015 were retrospectively analyzed. Patient characteristics including gender and age, location of the sponge, time interval until diagnosis, clinical presentation, and patient complaints were evaluated. Results The US appearances of RSSs could be classified into three types. Type I (five cases): an echogenic arc with a strong posterior shadow; type II (two cases): US appearance mimicked a cystic teratoma; type III (two cases): a cystic mass with zigzag-shaped internal contents. CT and/or MRI showed a mass with density/signal intensity similar to that of the adjacent soft tissues. Conclusion The characteristic US findings along with a history of surgery can help reach a correct diagnosis of RSS.

Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by amyloid plaque accumulations, intracellular tangles and neuronal loss in certain brain regions. It has been shown that a disturbance of normal iron metabolism contributes to the pathophysiology of AD. However, the mechanism underlying abnormal iron load in the brain of AD patients is unclear. The frontal cortex, an important brain structure for executive function, is one of the regions affected by AD. We investigated the beneficial effects of active compounds of Epimedium, Astragaoside and Puerarin on iron metabolism in the frontal cortex of six-month-old APPswe/PS1ΔE9 (APP/PS1) double transgenic mouse, a model of AD. Treatment with the active compounds reduced cognitive and memory deficits and damaged cell ultrastructure in APP/PS1 mice. These beneficial effects were associated with changes in expression levels of iron metabolism proteins in the frontal cortex, including divalent metal transporter with iron response element (DMT1-with IRE), divalent metal transporter without iron response element (DMT1-without IRE), transferrin (TF) and transferring receptor 1 (TfR1); three release proteins including the exporter ferroportin 1 (Fpn1), ceruloplasmin (CP) and hephaestin (HEPH), one increased storage iron protein ferritin and one iron regulating hormone hepcidin. These findings suggest that the active compounds improve cognition and memory in brain neurodegenerative disorders and these beneficial effects are associated with reduced impairment of iron metabolism. This study may provide a new strategy for developing novel drugs to treat AD.

What is known and objectives Tacrolimus, an immunosuppressant, has been used to treat paediatric systemic lupus erythematosus, but the optimal initial regimen is not clear. The purpose of this study was to explore the optimal initial dose of tacrolimus for children with systemic lupus erythematosus using population pharmacokinetics and pharmacogenomics. Methods Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non-linear mixed-effects modelling (NONMEM) analysis. Results and discussion The results showed that weight, the CYP3A5 genotype and combined treatment with Wuzhi capsule can affect tacrolimus clearance in children with systemic lupus erythematosus. Furthermore, at the same weight, the ratios of tacrolimus clearance were 1:2.49:0.57:1.4193 from people who were CYP3A5*3/*3 and did not take Wuzhi capsule, people who had the CYP3A5*1 allele and did not take Wuzhi capsule, people who were CYP3A5*3/*3 and took Wuzhi capsule, and people who had the CYP3A5*1 allele and took Wuzhi capsule, respectively. In addition, we found that 0.10 mg/kg split into two doses was suitable for people with weights from 10 to 60 kg who were CYP3A5*3/*3 and did not take Wuzhi capsule, who were CYP3A5*3/*3 and took Wuzhi capsule, and who had the CYP3A5*1 allele and took Wuzhi capsule. In people who had the CYP3A5*1 allele and did not take Wuzhi capsule, 0.15 mg/kg split into two doses was appropriate for those with weights from 10 to 40 kg and 0.10 mg/kg split into two doses was appropriate for those with weights from 40 to 60 kg. What is new and conclusion This study is the first study to recommend an optimal initial regimen of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration of Wuzhi capsule.

Novel sunscreen products based on bioadhesive/gel systems that can prevent the skin penetration behaviors of UV filters have attracted increasing attention in recent years. However, integration is very difficult to achieve and control on the wet surface of the skin under sweaty/dynamic physiological conditions, resulting in functional failure. Herein, we demonstrated the fabrication of a novel dual-network hydrogel sunscreen (DNHS) based on poly-γ-glutamic acid (γ-PGA) and tannic acid (TA), which demonstrated prominent UV protection properties across broad UVA and UVB regions (360-275 nm). Due to a three-dimensional network microstructure and a highly hydrated nature that mimics the extracellular matrix of natural skin, DNHS can perfectly match the skin surface without irritation and sensitization. In addition, the intermolecular hydrogen bond interactions of γ-PGA and TA provide an important driving force for coacervation, which endows the DNHS with remarkable self-recovery properties (within 60 s). Moreover, due to the multiple interfacial interactions between γ-PGA/TA and the protein-rich skin tissue surfaces, DNHS simultaneously possesses excellent skin-integration and water-resistance capacities, and it can be readily removed on demand. Our results highlight the potential of the DNHS to be used in next-generation sunscreens by providing long-term and stable UV protection functions even under sweaty/dynamic physiological conditions.

Prolonged exposure to an emotional face biases our judgement of subsequent face stimulus toward the opposite emotion. This emotion aftereffect has been suggested to occur as early as 35 ms exposure duration in cartoon faces. In the current study, we are interested in investigating the time-course of brief emotional face adaptation, and the relationship between brief emotional face adaptation and prolonged emotional face adaptation. We adapted the subjects from 17 ms to 1000 ms with a happy or angry adapting face. We found that a facial emotion adaptation aftereffect started from 17 ms adapting duration for angry face adaptation, and from 50 ms for happy face adaptation. Factor analysis on the adaptation effects highlighted three different components: brief angry adaptation (17 ms, 34 ms, and 50 ms), prolonged angry adaptation (100 ms and 1000 ms), and happy face adaptation (from 17 ms to 1000 ms). We found that the brief angry face adaptation was negatively associated with the awareness of the adapting face, and the prolonged angry face adaptation was stronger in subjects who perceived the angry adapting face as more negative in valence. Together, these findings suggest that (1) facial emotion adaptation can be induced by brief (17 ms) adapting face presentation; (2) brief angry face adaptation may be related to early visual processing, whereas prolonged angry face adaptation may be related to adaptation at later and higher-level visual emotional processing; and (3) brief and prolonged adaptations may adapt different neural populations. Our findings thus shed light on the current understanding of the neural mechanisms of emotional face adaptation.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6–13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3–7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P