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Antiviral therapy improves the clinical outcomes of patients with chronic hepatitis B (CHB), including those with cirrhosis. In the present study, we validated the Baveno VII definition of recompensation and explored the criteria for stable improvement of liver function tests in entecavir-treated patients with CHB-related decompensated cirrhosis.In this multicentre prospective study, patients with decompensated (ascites) CHB-related cirrhosis were enrolled and treated with entecavir for 120 weeks. Patients were followed up for clinical events, viral and biochemical tests, and ultrasonography every 6 months. The recompensation rate per Baveno VII criteria was calculated. Multivariate regression models were used to identify the predictors of recompensation. Finally, the criteria for stable improvement of liver function tests were explored.Of the 320 recruited patients, 283 completed the 120-week study, with 261/283 (92.2%) achieving HBV DNA levels20 IU/ml and 171/283 (60.4%) achieving resolution of ascites, encephalopathy, and absence of recurrent variceal bleeding for at least 12 months. We identified model for end-stage liver disease10 and/or liver function tests within Child-Pugh Class A (albumin35 g/L, international normalised ratio1.50 and total bilirubin34 μmol/L) as the criteria for stable improvement of liver function tests. Accordingly, 56.2% (159/283) of patients fulfilled the Baveno VII definition of recompensation with a stable improvement of liver function tests defined by the current study.Our study defined the criteria for a stable improvement of liver function tests required by the Baveno VII definition of recompensation in patients with CHB-related decompensated cirrhosis on antiviral therapy. The criteria derived from this multicentre prospective study warrant further validation in patients with cirrhosis of other aetiologies.Decompensation of cirrhosis marks the point at which the liver is no longer able to function normally (and symptoms become apparent). Recently the idea of recompensation was proposed for individuals who may experience an improvement in liver function if the underlying cause of their liver disease is addressed (e.g. antivirals for viral cirrhosis). Herein, we show that over 50% of patients with hepatitis B-related decompensated cirrhosis treated with antivirals could recompensate and we propose laboratory criteria which could be used to define recompensation.

Malaria control programs in Africa encounter daunting challenges that hinder progressive steps toward elimination of the disease. These challenges include widespread insecticide resistance in mosquito vectors, increasing outdoor malaria transmission, lack of vector surveillance and control tools suitable for outdoor biting vectors, weakness in malaria surveillance, and an inadequate number of skilled healthcare personnel. Ecological and epidemiological changes induced by environmental modifications resulting from water resource development projects pose additional barriers to malaria control. Cognizant of these challenges, our International Center of Excellence for Malaria Research (ICEMR) works in close collaboration with relevant government ministries and agencies to align its research efforts with the objectives and strategies of the national malaria control and elimination programs for the benefit of local communities. Our overall goal is to assess the impact of water resource development projects, shifting agricultural practices, and vector interventions on Plasmodium falciparum and P. vivax malaria in Kenya and Ethiopia. From 2017 to date, the ICEMR has advanced knowledge of malaria epidemiology, transmission, immunology, and pathogenesis, and developed tools to enhance vector surveillance and control, improved clinical malaria surveillance and diagnostic methods, and strengthened the capacity of local healthcare providers. Research findings from the ICEMR will inform health policy and strategic planning by ministries of health in their quest to sustain malaria control and achieve elimination goals.

Jie Yang,1 Anhui Wang,2 Lei Shang,3 Chao Sun,1 Xin Jia,1 Liming Hou,1 Rong Xu,1 Xiaoming Wang1 1Department of Geriatrics, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of China; 2Department of Epidemiology, Air Force Medical University, Xi’an, 710032, People’s Republic of China; 3Department of Health Statistics, Air Force Medical University, Xi’an, 710032, People’s Republic of ChinaCorrespondence: Xiaoming Wang, Department of Geriatrics, Xijing Hospital, Air Force Medical University, 127 Changle West Road, Xi’an, 710032, People’s Republic of China, Tel +86-29-84775543, Email xmwang@fmmu.edu.cnObjective: The purpose of this study was to explore the effects of Chinese dietary habits and patterns on frailty among elderly people in Xi’an the community. We also sought to provide dietary suggestions for prevention of frailty.Methods: A cross-sectional survey was conducted and participants were divided into three groups: non-frail group, pre-frail group, and frail group. Our sample included 100 individuals randomly selected from each group for the dietary survey. Information regarding general socio-demographic characteristics and the types and quantity of food intake in the past 3 days was collected by a questionnaire. Factor analysis was used to identify dietary patterns; multiple logistic regression analysis was used to explore the correlation between dietary pattern and frailty.Results: (1) 1693 elderly individuals were screened. The prevalence of pre-frailty and frailty was 41.0% and 16.2%, respectively. (2) Two dietary patterns were defined: ordinary dietary pattern and high-fat dietary pattern. Compared with the high-fat diet, the intake of iron, vitamin E, polyunsaturated fatty acids, and legume protein was significantly lower in the ordinary diet (P < 0.05). (3) Multivariate regression analysis showed that the ordinary dietary pattern score was positively correlated with frailty, which was consistent after adjusting for confounding factors (P < 0.05).Conclusion: The low-fat and low-protein diet was positively correlated with the risk of frailty. Appropriate increase in fat and protein intake can help improve the frailty of the elderly in China.Keywords: elderly, frailty, dietary pattern, nutrients, protein

Background Long noncoding RNA ANRIL has been found to be involved in the pathogenesis of diabetic kidney disease (DKD) and is expected to be a new target for prevention of DKD. However, the circulating expression and clinical significance of ANRIL in DKD patients is uncertain. This study aims to explore this issue. Methods The study consisted of 20 healthy controls, 22 T2DM patients (normalbuminuria) and 66 DKD patients (grouped as follows: microalbuminuria, n = 23; macroalbuminuria, n = 22 and renal dysfunction, n = 21). The expressions of ANRIL in peripheral whole blood of all participants were measured by RT-qPCR. Results The expression of ANRIL was significantly up-regulated in DKD patients (microalbuminuria, macroalbuminuria and renal dysfunction groups) than that in healthy control group. ANRIL was also over-expressed in macroalbuminuria and renal dysfunction groups in comparison with normalbuminuria group. ANRIL expression was positively correlated with Scr, BUN, CysC, urine β2-MG and urine α1-MG; while negatively correlated with eGFR in DKD patients. In addition, ANRIL was the risk factor for DKD with OR value of 1.681. The AUC of ANRIL in identifying DKD was 0.922, and the sensitivity and specificity of DKD diagnosis were 83.3% and 90.5%, respectively. Conclusion Our results indicated that highly expressed ANRIL in peripheral blood is associated with progression of DKD. Circulating ANRIL is an independent risk factor of DKD and has a highly predictive value in identifying DKD.

OBJECTIVE: The N-myc downstream-regulated gene 1 (NDRG1) has been discovered as a significant gene in the progression of cancers. However, the regulatory mechanism of NDRG1 remained obscure in prostate cancer (PCa). METHODS: The miR-96-5p and NDRG1 expression levels were evaluated in PCa cell lines, prostate tissues, and validated public databases by real-time PCR, western blot analysis, and immunohistochemistry. The function of miR-96-5p and NDRG1 were investigated by wound healing and transwell assays in vitro, and mouse xenograft assay in vivo. The candidate pathway regulated by NDRG1 was conducted by the next-generation gene sequencing technique. Immunofluorescence and luciferase assay was used to detect the relation between miR-96-5p, NDRG1, and NF-κB pathway. RESULTS: Overexpressing NDRG1 suppresses the migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and inhibits metastasis in vivo. Moreover, miR-96-5p contributes to NDRG1 deficiency and promotes PCa cell migration and invasion. Furthermore, NDRG1 loss activates the NF-κB pathway, which stimulates p65 and IKBa phosphorylation and induces EMT in PCa. CONCLUSIONS: MiR-96-5p promotes the migration and invasion of PCa by targeting NDRG1 and regulating the NF-κB pathway.

Anti-mitochondrial autoantibodies (AMAs) are highly specific for the diagnosis of primary biliary cholangitis (PBC) but are also occasionally found in other diseases. In the present study, we evaluated the incidence of and predictors for PBC development in AMA-positive patients with other liver or non-liver diseases at baseline. In this retrospective study, we screened patients who tested positive for AMA and/or anti-mitochondrial M2 antibody (AMA-M2) at Beijing Friendship Hospital, Capital Medical University, from October 2005 to January 2017. They were categorized by their diagnosis at the baseline as patients with PBC or non-PBC cases. We followed up on the non-PBC cases through telephone interviews and reviewing of medical records to obtain laboratory results and clinical outcomes. In total, 139 patients were AMA-positive but did not fulfill the diagnostic criteria of PBC at baseline, including 51 patients with non-PBC liver diseases and 88 cases with non-liver diseases. The titers of AMA-M2, alkaline phosphatase, gamma-glutamyl transpeptidase, and immunoglobulin M were significantly higher in patients with PBC compared to those with non-PBC liver diseases and non-liver diseases. After a median follow-up of 4.6 (interquartile range: 2.4-7.6) years, 4.3% (6 of 139) developed PBC, with an accumulative 5-year incidence rate of 4.2%. None of the patients with non-PBC liver diseases developed PBC, whereas the 5-year incidence rate of PBC was 7.8% among 88 patients with non-liver diseases. Lower alanine aminotransferase and higher immunoglobulin M were independent predictors for developing PBC. Conclusion: Our results suggest a low risk of developing PBC over time in AMA-positive patients with other liver and non-liver diseases.

Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity.Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function.

Knowledge of insect dispersal is relevant to the control of agricultural pests, vector-borne transmission of human and veterinary pathogens, and insect biodiversity. Previous studies in a malaria endemic area of the Sahel region in West Africa revealed high-altitude, long-distance migration of insects and various mosquito species. The objective of the current study was to assess whether similar behavior is exhibited by mosquitoes and other insects around the Lake Victoria basin region of Kenya in East Africa. Insects were sampled monthly from dusk to dawn over 1 year using sticky nets suspended on a tethered helium-filled balloon. A total of 17,883 insects were caught on nets tethered at 90, 120, and 160 m above ground level; 818 insects were caught in control nets. Small insects (0.5 cm, n = 2,334) and mosquitoes (n = 299). Seven orders were identified; dipteran was the most common. Barcoding molecular assays of 184 mosquitoes identified 7 genera, with Culex being the most common (65.8%) and Anopheles being the least common (5.4%). The survival rate of mosquitoes, experimentally exposed to high-altitude overnight, was significantly lower than controls maintained in the laboratory (19% vs. 85%). There were no significant differences in mosquito survival and oviposition rate according to capture height. These data suggest that windborne dispersal activity of mosquito vectors of malaria and other diseases occurs on a broad scale in sub-Saharan Africa.

AML cells are arranged in a hierarchy with stem/progenitor cells giving rise to more differentiated bulk cells. Despite the importance of stem/progenitors in the pathogenesis of AML, the determinants of the AML stem/progenitor state are not fully understood. Through a comparison of genes that are significant for growth and viability of AML cells by way of a CRISPR screen, with genes that are differentially expressed in leukemia stem cells (LSC), we identified importin 11 (IPO11) as a novel target in AML. Importin 11 (IPO11) is a member of the importin β family of proteins that mediate transport of proteins across the nuclear membrane. In AML, knockdown of IPO11 decreased growth, reduced engraftment potential of LSC, and induced differentiation. Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.

The purpose of this study was to conduct initial characterization of membrane vesicles isolated from human placenta by agitation of villous tissue (apical and basal) as well as vesicles obtained following dual perfusion of placental lobule. The morphology, physical and biological properties of the isolated vesicles were determined by electron microscopy, dynamic light scattering, and immunoblotting as well as nanoflow liquid chromatography-mass spectrometry proteomics analysis. CD-1 male mice were used to test the biocompatibility of the vesicles in vivo and assess the biodistribution of fluorescently labeled apical and perfusion vesicles. The vesicles obtained following placental perfusion and the apical vesicles had Z-average diameters of 199±23 nm and 246±24 nm, respectively, and demonstrated nanocarrier stability, low toxicity, and low immunogenicity. On the other hand, administration of basal vesicles resulted in animal demise with LD50 of 0.85 μgprotein/g. Both fluorescently labeled apical and perfusion vesicles were detected in the lungs, liver, kidneys, and spleen of CD-1 mice within 24 h of administration. However, there were differences in organ distribution of these vesicles over 24 hours time period. These data suggest that placental apical and perfusion vesicles have a potential for further development as biological vehicles for drug delivery.

Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the uptake transporters that contribute to the placental disposition of pravastatin. Our data revealed the expression of organic anion transporting polypeptide 1A2 (OATP1A2) and OATP2A1 in the apical, and OATP2B1 and OATP5A1 in the basolateral membranes of the placenta, while organic anion transporter 4 (OAT4) exhibited higher expression in basolateral membrane but was detected in both membranes. Preloading placental membrane vesicles with glutarate increased the uptake of pravastatin suggesting involvement of glutarate-dependent transporters such as OAT4. In the HEK293 cells overexpressing individual uptake transporters, OATP2A1, OATP1A2 and OAT4 were determined to accept pravastatin as a substrate at physiological pH, while the uptake of pravastatin by OATP2B1 (known to interact with pravastatin at acidic pH) and OATP5A1 was not detected at pH 7.4. These findings led us to propose that OATP1A2 and OATP2A1 are responsible for the placental uptake of pravastatin from the maternal circulation, while OAT4 mediates the passage of the drug across placental basolateral membrane in the fetal-to-maternal direction.

The aim of this network meta-analysis was to evaluate the comparative effects of neuropsychological interventions for cancer-related cognitive impairment (CRCI), and to rank the best intervention options for adult cancer patients with CRCI. Twenty-seven eligible randomized controlled trials (RCTs) were searched, and a total of six interventions identified: cognitive behavioral therapies (CBT), cognitive rehabilitation (CR), cognitive training (CT), meditation/mindfulness-based interventions, psychoeducation, and supportive care. In terms of effectiveness, the relative effect size of CBT, CR, and CT in managing subjective cognition had statistically significant differences - 0.94 (0.43-1.44), 0.54 (0.03-1.05), and 0.47 (0.13-0.81), respectively. The most effective interventions to manage the objective cognition of attention were meditation or mindfulness-based interventions: intervention effect size was 0.58 (0.24-0.91). The relative effect size of CT had a statistically significant difference in managing verbal memory, and the intervention effect size was 1.16 (0.12-2.20). The relative effect size of psychoeducation in managing executive function compared with control had a statistically significant difference, which was 0.56 (0.26-0.86). For managing information processing speed, the most effective intervention was CT and the effect size was -0.58 (-1.09--0.06). This network meta-analysis found that CT is the most effective intervention for managing the objective cognition of verbal memory and processing speed; meditation/mindfulness-based interventions may be the best option for enhancing attention; psychoeducation is the most effective intervention for managing executive function; CT may be the best option for managing verbal fluency as the intervention ranking probability. For the management of subjective cognition, CBT may be the most effective intervention.

Irrigation not only helps to improve food security but also creates numerous water bodies for mosquito production. This study assessed the effect of irrigation on malaria vector bionomics and transmission in a semi-arid site with ongoing malaria vector control program. The effectiveness of CDC light traps in the surveillance of malaria vectors was also evaluated relative to the human landing catches (HLCs) method. Adult mosquitoes were sampled in two study sites representing irrigated and non-irrigated agroecosystems in western Kenya using a variety of trapping methods. The mosquito samples were identified to species and assayed for host blood meal source and Plasmodium spp. sporozoite infection using polymerase chain reaction. Anopheles arabiensis was the dominant malaria vector in the two study sites and occurred in significantly higher densities in irrigated study site compared to the non-irrigated study site. The difference in indoor resting density of An. arabiensis during the dry and wet seasons was not significant. Other species, including An. funestus, An. coustani, and An. pharoensis, were collected. The An. funestus indoor resting density was 0.23 in irrigated study site while almost none of this species was collected in the non-irrigated study site. The human blood index (HBI) for An. arabiensis in the irrigated study site was 3.44% and significantly higher than 0.00% for the non-irrigated study site. In the irrigated study site, the HBI of An. arabiensis was 3.90% and 5.20% indoor and outdoor, respectively. The HBI of An. funestus was 49.43% and significantly higher compared to 3.44% for An. arabiensis in the irrigated study site. The annual entomologic inoculation rate for An. arabiensis in the irrigated study site was 0.41 and 0.30 infective bites/person/year indoor and outdoor, respectively, whereas no transmission was observed in the non-irrigated study site. The CDC light trap performed consistently with HLC in terms of vector density. These findings demonstrate that irrigated agriculture may increase the risk of malaria transmission in irrigated areas compared to the non-irrigated areas and highlight the need to complement the existing malaria vector interventions with novel tools targeting the larvae and both indoor and outdoor biting vector populations. Graphical abstract

The impact of fine particulate matter (PM2.5) on public health has received increasing attention. Through various biochemical mechanisms, PM2.5 alters the normal structure and function of the airway epithelium, causing epithelial barrier dysfunction. Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) has been implicated in various respiratory diseases; however, its role in PM2.5-induced epithelial barrier dysfunction remains unclear. Herein, we assessed the regulatory effects of Shp2 on PM2.5-mediated epithelial barrier function and tight junction (TJ) protein expression in both mice and human pulmonary epithelial (16HBE) cells. We observed that Shp2 levels were upregulated and claudin-4 levels were downregulated after PM2.5 stimulation in vivo and in vitro. Mice were exposed to PM2.5 to induce acute lung injury, and disrupted epithelial barrier function, with decreased transepithelial electrical resistance (TER) and increased paracellular flux that was observed in 16HBE cells. In contrast, the selective inhibition or knockdown of Shp2 retained airway epithelial barrier function and reversed claudin-4 downregulation that triggered by PM2.5, and these effects may occur through the ERK1/2 MAPK signaling pathway. These data highlight an important role of Shp2 in PM2.5-induced airway epithelial barrier dysfunction and suggest a possible new course of therapy for PM2.5-induced respiratory diseases.

Purpose Many studies identified that the preoperative neutrophil-to-lymphocyte ratio (PNLR) was associated with patient prognosis in non-muscle-invasive bladder cancer (NMIBC). We hypothesized that PNLR could be prognostic in patients with histological variants of NMIBC (VH-NMIBC). Materials and Methods This retrospective study included patients with VH-NMIBC admitted at our center between January 2009 and May 2019. The best cut-off value of NLR was measured by the receiver operating characteristic curve and Youden index. The Kaplan-Meier method and Cox proportional hazard regression models were employed to evaluate the association between PNLR and disease prognosis, including recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results A total of 243 patients with VH-NMIBC were enrolled in our study. According to the Kaplan-Meier method results, patients with PNLR ≥2.2 were associated with poor RFS (p, Graphical Abstract

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.

Background Malaria in western Kenya is currently characterized by sustained high Plasmodial transmission and infection resurgence, despite positive responses in some areas following intensified malaria control interventions since 2006. This study aimed to evaluate long-term changes in malaria transmission profiles and to assess patterns of asymptomatic malaria infections in school children aged 5–15 years at three sites in western Kenya with heterogeneous malaria transmission and simultaneous malaria control interventions. Methods The study was conducted from 2018 to 2019 and is based on data taken every third year from 2005 to 2014 during a longitudinal parasitological and mosquito adult surveillance and malaria control programme that was initiated in 2002 in the villages of Kombewa, Iguhu, and Marani. Plasmodium spp. infections were determined using microscopy. Mosquito samples were identified to species and host blood meal source and sporozoite infections were assayed using polymerase chain reaction. Results Plasmodium falciparum was the only malaria parasite evaluated during this study (2018–2019). Asymptomatic malaria parasite prevalence in school children decreased in all sites from 2005 to 2008. However, since 2011, parasite prevalence has resurged by > 40% in Kombewa and Marani. Malaria vector densities showed similar reductions from 2005 to 2008 in all sites, rose steadily until 2014, and decreased again. Overall, Kombewa had a higher risk of infection compared to Iguhu (χ2 = 552.52, df = 1, P χ2 = 1127.99, df = 1, P χ2 = 617.59, df = 2, P χ2 = 27.17, df = 1, P Conclusions Malaria prevalence in western Kenya remains high and has resurged in some sites despite continuous intervention efforts. Targeting malaria interventions to those with asymptomatic infections who serve as human reservoirs might decrease malaria transmission and prevent resurgences. Longitudinal monitoring enables detection of changes in parasitological and entomological profiles and provides core baseline data for the evaluation of vector interventions and guidance for future planning of malaria control. Graphical abstract

Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles. Results Predicted exposure (AUC0-6h ) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure-response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.

Background This study aimed to analyze the safety of circular lateral anastomosis and cross-lateral anastomosis in laparoscopic radical resection of right-sided colon cancer. Methods From January 2018 to March 2021, 147 patients with right-sided colon cancer were admitted to the Department of General Surgery, Cancer Hospital, Zhengzhou University. The experimental group comprised patients with circular lateral anastomosis, whereas the control group comprised patients with cruciform lateral anastomosis. The general clinical data, intraoperative features, and postoperative results of the two groups were compared and analyzed. Results Both groups successfully underwent laparoscopic lateral ileocolic anastomosis, with significant differences in anastomotic leakage (χ2=4.520, P < 0.05). By contrast, body mass index (t = 1.568, P = 0.119), histological typing (χ2 = 2.067, P = 0.559), intraoperative bleeding (t = 0.418, P = 0.677), and intestinal obstruction (χ2 = 2.564, P = 0.109) were not significantly different between the groups (P > 0.05). Conclusions In laparoscopic-assisted radical hemicolectomy for right-sided colon cancer, the incidence of postoperative anastomotic leakage was lower with circular lateral anastomosis than with cross-lateral anastomosis, and circular lateral anastomosis was superior to cross-lateral anastomosis in terms of reducing the length of hospital stay and improving patients' postoperative quality of life.

Clear cell renal cell carcinoma (CCRCC) is a common renal malignancy known for its lethality and chromosome 3p aberrancies associated with loss of VHL. It has been shown that additional prognostic molecular markers exist in other transcriptional modifiers such as BAP1 and SETD2. Molecular heterogeneity has been described between primary and metastatic sites as well as genetic diversity in spatial tumor analysis; however, morphologic and proteogenomic heterogeneity information is lacking. We assessed 77 nephrectomy specimens with a diagnosis of CCRCC for morphologic architectural patterns including nodular growth patterns and variations in WHO/ISUP grade. Evaluation of highly heterogeneous areas with immunohistochemical (IHC) staining for BAP1, UCHL1, SETD2, and CAIX was performed and correlated with morphologic and histology data. Ultimately, high variability in the morphologic and histological findings matched the complexity of the IHC findings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional regulators BAP1 and SETD2 within the tumor. High-grade morphology, such as eosinophilia, were areas enriched for alteration of biomarker expression. This highly complex data set of morphologic and biomarker characteristics highlights the heterogeneity of morphology amongst high-grade CCRCC tumors.

Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload. Methods Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro. Results Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level. Conclusions Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload.

The effects of PADI4 and GAA on the senescence of Alzheimer's cells were explored in the present work. HT22 cells were treated with Aβ25-35 to establish an Alzheimer's model and were then treated with different concentrations of GAA and transfected with a siPADI4 lentiviral vector. GAA could reverse the effects of Aβ25-35 on inhibiting cell viability and promoting apoptosis and senescence. siPADI4 reduced Aβ25-35-induced cell viability and upregulated Aβ25-35-induced cell apoptosis and senescence, as well as partially reversed the effect of GAA on cells, and these results were confirmed by detecting the expressions of senescence- and apoptosis-related proteins. In addition, siPADI4 was found to promote the phosphorylation of Akt and mTOR, which was partially reversed by GAA. In conclusion, PADI4 mediates autophagy and participates in the role of GAA monomers in delaying the senescence of Alzheimer's cells through the Akt/mTOR pathway.

Malaria risk factor assessment is a critical step in determining cost-effective intervention strategies and operational plans in a regional setting. We develop a multi-indicator multistep approach to model the malaria risks at the population level in western Kenya. We used a combination of cross-sectional seasonal malaria infection prevalence, vector density, and cohort surveillance of malaria incidence at the village level to classify villages into malaria risk groups through unsupervised classification. Generalized boosted multinomial logistics regression analysis was performed to determine village-level risk factors using environmental, biological, socioeconomic, and climatic features. Thirty-six villages in western Kenya were first classified into two to five operational groups based on different combinations of malaria risk indicators. Risk assessment indicated that altitude accounted for 45–65% of all importance value relative to all other factors; all other variable importance values were < 6% in all models. After adjusting by altitude, villages were classified into three groups within distinct geographic areas regardless of the combination of risk indicators. Risk analysis based on altitude-adjusted classification indicated that factors related to larval habitat abundance accounted for 63% of all importance value, followed by geographic features related to the ponding effect (17%), vegetation cover or greenness (15%), and the number of bed nets combined with February temperature (5%). These results suggest that altitude is the intrinsic factor in determining malaria transmission risk in western Kenya. Malaria vector larval habitat management, such as habitat reduction and larviciding, may be an important supplement to the current first-line vector control tools in the study area.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

LncRNAs play an important role in the regulation of the killing effect of cytotoxic CD8 + T cells in various cancers. However, the role and underlying mechanisms of UCA1 in the killing effect of cytotoxic CD8 + T cells in anaplastic thyroid carcinoma (ATC) are not clear. UCA1, miR-148a, and PD-L1 expression were detected by quantitative real-time PCR and/or Western blot. The ratio of PD-L1+ATC cells/ATC cells was determined using flow cytometry. The ability of CD8 + T cells to kill target ATC cells was detected by Chromium-51 (51Cr) release assay. The targeted relationship between UCA1 and miR-148a was confirmed by dual-luciferase reporter gene assay. UCA1 and PD-L1 expression levels were elevated in ATC tissues and cells. Silencing UCA1 and PD-L1 enhanced the killing effect of cytotoxic CD8 + T cells on ATC cells. UCA1 negatively regulated the expression of miR-148a, and miR-148a targeted PD-L1 to down-regulate its expression. Besides, we found that UCA1 attenuated the killing effect of cytotoxic CD8 + T cells and reduced cytokine secretion through PD-L1 and miR-148a. Finally, silencing UCA1 or PD-L1 in ATC cells restored the suppression of the killing effect of CD8 + T cells in vivo. UCA1 attenuated the killing effect of cytotoxic CD8 + T cells on ATC cells through the miR-148a/PD-L1 pathway.

Hypoxia plays a significant role in tumor progression. This study aimed to develop a hypoxia-related long noncoding RNA (lncRNA) signature for predicting survival outcomes of patients with bladder cancer (BC). The transcriptome and clinicopathologic data were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis and Lasso regression analysis were used to screened lncRNAs. Ten lncRNAs were screened out and included into the hypoxia lncRNA signature. The risk score based on hypoxia lncRNA signature could accurately predict the survival outcomes of BC patients. Immune infiltration analysis showed that six types of immune cells had significant different infiltration. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, FGFR3, and RB1 were significantly different. Gene Set Enrichment Analysis (GSEA) showed that cancer-associated pathways belonged to the high risk groups and immune-related signal pathways were enriched into the low risk group. Then, we constructed a predictive model with the risk score, age, and clinical stage, which showed a robust prognostic performance. An lncRNA-mRNA coexpression network was constructed, which contained 62 lncRNA-mRNA links among 10 lncRNAs and 40 related mRNAs. In summary, the hypoxia lncRNA signature could accurately predict prognosis, chemotherapy and immunotherapy response in patients with BC and was relevant to clinicopathologic parameters and immune cell infiltration., Graphical Abstract

Background Perioperative myocardial injury after noncardiac surgery affects more than 10% of individuals, with increased morbidity and mortality. Perioperative cardiac risk assessment targets the identification of this high-risk population using preoperative natriuretic peptides and postoperative troponin measurements. Our objective was to assess the use of these biomarkers in the province of Alberta. Methods A retrospective cohort of all patients who underwent noncardiac surgery in Alberta from January 2013 to December 2017 was created using linked provincial administrative databases. Inclusion criteria were modified from recommendations for perioperative cardiac screening including: patients with a Revised Cardiac Risk Index score ≥ 1 and age 65 years or older, or 45 years of age or older with history of cardiovascular disease, with planned overnight hospital stay. Results In our cohort of 59,506 patients, only 6.8% underwent preoperative natriuretic peptide screening. Rates of appropriate preoperative natriuretic peptide testing increased marginally from 5.7% to 8.8% over the study period. Postoperative troponin was measured at least once in 19.5% of patients. Patients with elevated perioperative screening biomarkers showed increased 6-month mortality, and increased hospitalizations for heart failure and acute coronary syndromes. Conclusions The use of biomarkers to assist in cardiac risk stratification and postoperative monitoring remains low. Addressing access to these tests and improving physician education regarding the asymptomatic nature of postoperative cardiac events might improve compliance with national guidelines.

Background Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.

PurposeThis study aimed to explore a visual model for predicting the prognosis of patients with parathyroid carcinoma (PC) and analyze related biochemistries in different groups of stage.MethodsThe training dataset of 342 patients with PC was obtained from the Surveillance, Epidemiology, and End Results (SEER) database, and the validation dataset included 59 patients from The First Affiliated Hospital of Zhengzhou University. Univariate and multivariate Cox regression analyses were performed to evaluate significant independent prognostic factors. Based on those factors, nomograms and Web-based probability calculators were constructed to evaluate the overall survival (OS) and the cancer-specific survival (CSS) at 3, 5, and 8 years. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram in the training set and validation set. Moreover, biochemistries from the validation set were retrospectively analyzed in different groups of stage by Kruskal–Wallis test.ResultsAge, marital status, tumor size, stage, lymph node status, and radiation were identified as prognostic factors of OS. In contrast, only tumor size and stage were predictive for CSS. The nomogram was developed based on these independent factors. The C-index, ROC curve, calibration curve, and DCA of the nomogram in both training and validation sets showed that the nomogram had good predictive value, stability, and clinical benefit in predicting 3-, 5-, and 8-year OS and CSS in PC patients. Among the 59 PC patients from our hospital, lower albumin (ALB) levels and higher postoperative parathyroid hormone (PTH) levels were found in patients with distant metastasis (Distant vs. Regional ALB levels: p = 0.037; Distant vs. Local ALB levels: p = 0.046; Distant vs. Regional postoperative PTH levels: p = 0.002; Distant vs. Local postoperative PTH: p = 0.002).ConclusionThe established nomogram application can provide accurate prognostics for patients with PC in the Chinese population, but it must be validated on prospectively collected real-world data.

Nitrite (NO

The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

The purpose of this study was to assess residual dizziness (RD) after successful canalith repositioning maneuvre (CRM) treatment in patients with benign paroxysmal positional vertigo (BPPV) using Dizziness Handicap Inventory (DHI) questionnaire and Visual Analog Scale (VAS).One hundred sixty BPPV patients after successful CRM treatment were recruited. All patients were divided into the residual dizziness (RD) group and without RD group. The DHI questionnaire and VAS before CRM and follow-up were asked to complete. For analysis of the improvement in symptom, we defined ∆DHI and ∆VAS as the difference between the baseline score and the follow-up score.High incidence of RD was observed in the older patients (p 0.001). The incidence of hypertension in the RD group was also significantly higher than that of the without RD group (p = 0.022). The ∆DHI-P, ∆DHI-E, ∆DHI-F, ∆DHI-T, and ∆VAS scores in the without RD group were significantly higher than that of the RD group (p 0.001). When the cutoff point of the ∆DHI total scores was 17, the sensitivity was 64.86% and the specificity was 73.26% for diagnosing RD. When the cutoff point of the ∆VAS scores was 2.5, the sensitivity was 77.03% and the specificity was 81.40% for diagnosing RD.RD is prone to occur in the older patients and ∆VAS exhibits higher sensitivity and specificity in assessing RD.

This study aimed to investigate the role and mechanism of circular ribonucleic acid nucleoporin 98 (circNUP98) in diabetic nephropathy (DN).Human glomerular mesangial cells (HMCs) were stimulated with high glucose (HG) to imitate the growth environment of cells under the DN condition. Levels of genes and proteins were tested by quantitative reverse transcription polymerase chain reaction and western blot. Cell proliferation, apoptosis and inflammatory response were analyzed by using cell counting kit-8, flow cytometry and enzyme-linked immunosorbent assay analysis, respectively. Oxidative stress and fibrosis were evaluated by detecting the activity of reactive oxygen species, malondialdehyde, superoxide dismutase, fibronectin and collagen IV. The binding interaction between microribonucleic acid (miR)-151-3p and high mobility group AT-hook 2 (HMGA2) or circNUP98 was confirmed using dual-luciferase reporter, pull-down and ribonucleic acid immunoprecipitation assays. Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy, nanoparticle tracking analysis and western blot.CircNUP98 expression was higher in the serum of DN patients and HG-stimulated HMCs. Functionally, circNUP98 knockdown alleviated HG-induced proliferation, fibrosis, inflammatory response and oxidative stress in HMCs. Mechanistically, circNUP98 directly sponged miR-151-3p, which targeted HMGA2. Rescue experiments showed that miR-151-3p reversed the inhibitory effects of circNUP98 knockdown on HG-induced HMC dysfunction. Furthermore, miR-151-3p re-expression also led to an inhibition of the aforementioned biological behaviors, which was attenuated by HMGA2 upregulation. Besides that, CircNUP98 was found to be packaged into exosomes of DN, and exosomal circNUP98 possessed diagnostic value for DN patients.CircNUP98 knockdown alleviates HG-induced proliferation, fibrosis inflammation and oxidative stress in HMCs by regulating the miR-151-3p-HMGA2 axis, which might provide a potential approach for DN therapeutics.

Objective. The accelerate loss of skeletal muscle mass, strength, and function, named sarcopenia, is a progressive and generalised skeletal muscle disorder, and it is always associated with increased outcomes including falls, frailty, and disability. Diabetes mellitus is associated with significant muscle and physical complications. We aimed at clarifying the changes and risk factors of skeletal muscle mass and strength in elderly with type 2 diabetes. Methods. The study consisted of patients with type 2 diabetes ( n = 120 ) and an older general population ( n = 126 ). The skeletal muscle mass and muscle strength, as well as the serum levels of chronic inflammation, oxidative stress, homocysteine, and insulin-like factor-1 were assessed, and the correlation and regression analysis were conducted to evaluate outcomes. Results. T2DM patients exhibited lower muscle strength compared with the non-T2DM subjects ( P < 0.01 ). Among T2DM patients, serum IGF-1 levels were positively correlated with muscle strength ( r = 0.255 , P < 0.01 ) and muscle mass ( r = 0.209 , P < 0.05 ), levels of 8-OHdG were inversely correlated with muscle strength ( r = − 0.252 , P < 0.01 ), and there was a negative association between HCY and muscle mass ( r = − 0.185 , P < 0.05 ). Muscle mass and strength of patients with higher education level were significantly higher than those with lower education level ( P < 0.05 ), in male patients, muscle mass and muscle strength were significantly lower in smokers ( P < 0.01 ), and muscle mass was lower in chronic drinkers ( P < 0.05 ). Conclusions. These findings suggest that diabetic patients may be more susceptible to sarcopenia at an older age. And it also provides evidences that among elderly with diabetes mellitus, oxidative damage and HCY as well as IGF-1 are important predictors of age-dependent sarcopenia.

Volume-regulated anion channel (VRAC) is ubiquitously expressed in vertebrate cells and in various types of cancer cells. Leucine-rich repeat containing 8A (LRRC8A) and its four homologous family members (LRRC8B-E) assemble into heterogeneous VRAC complexes of ~800 kDa. The main components of VRAC, LRRC8A and LRRC8D have been implicated in the proliferation, migration, death, and multidrug resistance of cancer cells through their involvement in various signal pathways. This review summarizes recent findings concerning the involvement of VRAC in cancer development and progression, including the molecular structure, function, and regulation of VRAC and its roles in various cancers, and highlights the remaining challenges in the field. Our aim is to evaluate the potential of VRAC as a therapeutic target for cancer therapies and to discuss the major problems to be solved.

ObjectiveTo estimate the prognostic value of positive surgical margins (PSM) location and perineural invasion (PNI) for biochemical recurrence (BCR) in patients undergoing radical prostatectomy (RP).MethodsAll men with prostate cancer (PCa) who received RP in the second hospital of Tianjin Medical University from 2014 to 2018 were retrospectively identified. All patients met the following criteria: no neoadjuvant or adjuvant treatment, absence of lymph node invasion, or distant metastasis confirmed by surgery or imaging. Comparisons were made between cases with only apex positive (AM), isolated nonapical positive (OM), multiple positive (MM), and negative surgical margins (NSM). Patients were also subdivided according to the Gleason score and pathological tumor stage for analysis.ResultsA total of 416 patients available for analysis, of which 132 (31.7%) were PSM, 43 were AM, 37 were OM, and 52 were MM at a median follow-up of 27 months. The PNI was in 30.5% of patients. BCR occurred in 22.6% of patients during follow-up. Both AM and MM were noticed to be independent predictors of BCR with a hazard ratio of 4.192 (95% CI 2.185–8.042;p< 0.001) and 2.758 (95% CI 1.559–4.880;p< 0.001), respectively, when compared to NSM. Though the correlation was significant in univariate analysis, PNI was not an independent risk factor for BCR (p= 0.369). Subgroup analyses suggested that MM was not particularly predictive for BCR in the Gleason score ConclusionsPSM location was a significant independent predictor of BCR in PCa, especially in patients with AM or MM, while PNI is a non-independent risk factor. Compared with other locations, AM has a higher BCR risk.

Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease., Here the authors present an approach that can reveal the full complement of mRNA isoforms encoded by individual genes, and they identify a major isoform of the retinal degeneration gene CRB1 which functions at the cell-cell junctions of the outer limiting membrane to promote photoreceptor survival.

Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2−/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.

The aim of the present study was to examine the frequency, characteristics, and risk factors of level IIb lymph node metastases in papillary thyroid carcinoma.We reviewed and collected clinical and pathological records for 954 papillary thyroid carcinoma patients with clinically positive lateral neck node metastasis. Univariate and multivariate analyses were performed to detect risk factors for level IIb lymph node metastasis; a predictive model was built based on multivariate analysis and tested in a validation group.Level IIb lymph node metastasis was observed in 137 of 954 patients (14.4%). Univariate and multivariate analyses using the training group indicated that gross extrathyroidal extension of the primary tumor, tumor location in the upper pole, and preoperative distant metastasis were 3 independent risk factors for level IIb lymph node metastasis. This model was built and tested in a validation group, and the area under the curve was 0.840 (P.001). The cutoff of the IIb score was 12, which was tested in the validation group; the sensitivity was 82.1% and the specificity was 95.6%.Level IIb dissection should be performed in select patients with IIb scores ≥12.

The present study aimed to evaluate the status of iodine nutrition and thyroid function in adults, to understand the distribution of thyroid disease in people with autoimmune thyroid disease (AITD) in different water iodine areas and to explore the relationship between serum iodine, urine iodine and thyroid function in people with AITD. A cross-sectional survey was conducted in areas of Shandong Province with different water iodine levels, and subsequently 1225 adults were enrolled from iodine-deficient (ID), iodine-adequate (IA) and iodine-excess (IE) areas. Urinary iodine, water iodine, salt iodine, serum iodine and thyroid function were measured. According to the urine iodine concentration, the ID and IA areas were defined as iodine sufficient and the IE area as iodine excessive. Urine iodine, serum iodine, free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were comparatively higher in the IE area. The positive rate of thyroglobulin antibody (19·1 %) and the prevalence of AITD (21·8 %) were higher in the ID areas; the prevalence of subclinical hypothyroidism was lowest in the ID areas (7·3 %) and highest in the IE area (16·3 %). Among the AITD population, urinary iodine concentration, free triiodothyronine, FT4 and TSH had a non-linear correlation with serum iodine; abnormal TSH level, serum iodine concentration > 110 µg/l and goitre were risk factors for AITD in adults, especially females. Our data collectively suggest that universal salt iodisation has improved the iodine nutritional status of the population in ID areas in China. Non-step-by-step iodine fortification may induce the transformation of thyroid autoimmune diseases from recessive-to-dominant in susceptible people. Moreover, enhanced monitoring of thyroid function in people with AITD is important.

This meta-analysis aims to systematically measure the immediate efficacy of the Gufoni maneuver for horizontal canal benign paroxysmal positional vertigo (HC-BPPV).A extensive search electronic databases, including PubMed, Embase, Web of Science and Cochrane library, were searched until to September 1, 2018 for relevant articles. We selected only randomized clinical trials studying with treatment of HC-BPPV employ by the Gufoni maneuver.Five randomized clinical trials were included in the current meta-analysis with a total of 714 HC-BPPV patients. The meta-analysis revealed that Gufoni maneuver had a higher immediate recovery rate than sham maneuver in treatment of HC-BPPV (risk ratio = 2.68, 95% CI, 1.54-4.65, p 0.01). No difference was observed in immediate recovery rate between Gufoni maneuver and other maneuvers (risk ratio = 1.18, 95% CI, 0.99-1.41, p = 0.06). And Gufoni maneuver had a similar otolith switch rate with other maneuvers (risk ratio = 2.13, 95% CI, 0.56-8.07, p = 0.27).Gufoni maneuver has a satisfactory immediate efficacy for HC-BPPV and does not increase otolith switch rate.

Numerous protein-based multifunctional nanomaterials have been studied for biomedical applications. However, the inherent immunogenicity and activation of the complement system of protein-based nanomaterials may cause immunological responses, further leading to hypersensitivity and/or allergic reactions in patients. Herein, carboxymethyl chitosan (CMC) and KMnO

IntroductionContinuous renal replacement therapy (CRRT) is a continuous form of dialysis used to support critically ill patients with acute kidney injury. The ideal delivery of CRRT requires ongoing monitoring and reporting to adjust practice and deliver optimal therapy. However, this practice occurs variably.MethodsQUALITY CRRT is a multicentre, prospective, stepped-wedged, interrupted time series (ITS) evaluation of the effectiveness, safety and cost of implementing a multifaceted CRRT quality assurance and improvement programme across an entire healthcare system. This study will focus on the standardisation of CRRT programmes with similar structure, process and outcome metrics by the reporting of CRRT key performance indicators (KPIs). The primary outcome will be the quarterly performance of CRRT KPIs. Secondary outcomes will include patient-centred outcomes and economic outcomes. Analysis will compare pre-implementation and post-implementation groups as well as for the performance of KPIs using an ITS methodology. The health economic evaluation will include a within-study analysis and a longer-term model-based analysis.DiscussionThe effective delivery of CRRT to critically ill patients ideally requires a standardised approach of best practice assessment and ongoing audit and feedback of standardised performance measures. QUALITY CRRT will test the application of this strategy stakeholder engagement and stepped-wedged implementation across an entire healthcare system.Ethics and disseminationThis study has received ethics approval. We will plan to publish the results in a peer-reviewed journal.Trial registration numberNCT04221932.Protocol version1.0 (15 June 2020).

Urinary tract infections (UTI) are recognized as one of the most common infectious diseases worldwide, and uropathogenic Escherichia coli (UPEC) is the main causative agent of UTI. Dendrobium officinale polysaccharides (DOPs), the main effective ingredient in Dendrobium officinale, have been reported to possess an anti-inflammatory role. Whether DOPs can attenuate the inflammatory injury (pyroptosis) induced by UPEC remains unknown. The present study aimed to assess the protective effect and potential mechanism of DOPs in UPEC-induced pyroptosis. Cell viability of THP-1 differentiated macrophage cells with DOPs was determined using MTT assay. Pyroptosis by UPEC in macrophage cells with or not DOPs pre-treatment was evaluated with flow cytometry analysis, lactate dehydrogenase (LDH) assay, and proinflammatory cytokines secretion. Expression level of key proteins in the NLRP3/Caspase-1/GSDMD pyroptotic pathway was analyzed with western blot. Furthermore the effect of DOPs on ROS activation was investigated. Results indicated that DOPs attenuated UPEC-induced cell damage in macrophage cells, inhibited the activation of NLRP3 mediated inflammasome, subsequently decreased induction and activation of caspase-1/GSDMD, and reduced the secretion of pro-inflammatory cytokine (IL-1β et al.). Moreover, pretreatment with DOPs significantly reduces ROS production, an important/putative pyroptosis stimulus signal. These results suggested that DOPs successfully mitigate UPEC-promoted pyroptosis in macrophage cells. The protective effects of DOPs are associated with the inhibition of the NLRP3/Caspase-1/GSDMD pathway and ROS signal activation.

Frailty is an established risk factor for adverse outcomes following non-cardiac surgery. The Hospital Frailty Risk Score (HFRS) is a recently described frailty assessment tool that harnesses administrative data and is composed of 109 International Classification of Disease variables. We aimed to examine the incremental prognostic utility of the HFRS in a generalizable surgical population. Using linked administrative databases, a retrospective cohort of patients admitted for non-cardiac surgery between October 1st, 2008 and September 30th, 2019 in Alberta, Canada was created. Our primary outcome was a composite of death, myocardial infarction or cardiac arrest at 30-days. Multivariable logistic regression was undertaken to assess the impact of HFRS on outcomes after adjusting for age, sex, components of the Charlson Comorbidity Index (CCI), Revised Cardiac Risk Index (RCRI) and peri-operative biomarkers. The final cohort consisted of 712,808 non-cardiac surgeries, of which 55·1% were female and the average age was 53·4 +/- 22·4 years. Using the HFRS, 86.3% were considered low risk, 10·7% were considered intermediate risk and 3·1% were considered high risk for frailty. Intermediate and high HFRS scores were associated with increased risk of the primary outcome with an adjusted odds ratio of 1·61 (95% CI 1·50–1.74) and 1·55 (95% CI 1·38–1·73). Intermediate and high HFRS were also associated with increased adjusted odds of prolonged hospital stay, in-hospital mortality, and 1-year mortality. The HFRS is a minimally onerous frailty assessment tool that can complement perioperative risk stratification in identifying patients at high risk of short- and long-term adverse events.

BACKGROUND: Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus are the three most important human liver fluke species in the Opisthorchiidae family, infecting approximately 25 million people worldwide. Drug treatment is needed to control morbidity and is also useful in lowering transmission. Several drugs used in various regimens are available to treat these infections, but their comparative efficacy is uncertain. We aimed to compare the efficacy in terms of cure rate and egg reduction rate of currently registered drugs against human liver fluke infection. METHODS: We conducted a systematic review using readily available electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, KoreaMed, China National Knowledge Infrastructure, and Wanfang Data) without language restrictions from inception until June 29, 2021. Clinical trials with pairwise comparison of drugs (praziquantel, albendazole, mebendazole, tribendimidine, or combinations of these drugs) against C sinensis, O viverrini, and O felineus were eligible, including trials comparing these drugs or their combinations with placebo. We compared efficacy in terms of cure rate by network meta-analysis. We conducted mixed binomial regression analyses for each species to derive predicted median cure rates for each drug regimen. The models included treatment and infection intensity as fixed factors, year of publication as covariate, and random effects of the different studies assumed to be normally distributed. We also assessed the quality of the included studies. This study was registered with PROSPERO (CRD42018109232). FINDINGS: Overall, 26 trials from 25 studies were included, of which 18 involved C sinensis, seven studied O viverrini, and one focused on O felineus. These trials included a total of 3340 participants. The two long-term treatment courses against C sinensis infection using 400 mg of albendazole (400 mg twice a day for 5 days and 400 mg twice a day for 7 days) resulted in cure rates of 100%, while two other multiple-dose regimens of albendazole resulted in high predicted cure rates: 300 mg twice a day for 5 days (93.9% [95% CI 49.6-99.6]) and 400 mg twice a day for 3 days (91.0% [50.9-99.0]). The WHO-recommended praziquantel regimen (25 mg/kg three times a day for 2 days) also showed a high predicted cure rate (98.5% [85.4-99.9]) in C sinensis infection, and predicted cure rates were above 90% for several other multiple-dose praziquantel regimens, including 20 mg/kg three times a day for 3 days (97.6% [74.7-99.8]), 14 mg/kg three times a day for 5 days (93.9% [44.8-99.7]), and 20 mg/kg twice a day for 3 days (91.0% [50.9-99.0]). In O viverrini infection, the regimen of 50 mg/kg and 25 mg/kg of praziquantel given in a single day showed the highest predicted cure rate (93.8% [85.7-97.5]), while a single dose of 50 mg/kg praziquantel also resulted in a high predicted cure rate (92.1% [64.9-98.6]). The single dose of 400 mg tribendimidine showed a high predicted cure rate of 89.8% (77.5-95.8). A low quality of evidence was demonstrated in most studies, especially those published before 2000. Selection bias due to poor random sequence generation and allocation concealment was high, and performance and detection biases were frequently unreported. INTERPRETATION: Praziquantel shows high efficacy against clonorchiasis and opisthorchiasis. Tribendimidine might serve as a treatment alternative and warrants further investigation. Although albendazole is efficacious when long treatment schedules (5 days or 7 days) are applied, limited size of studies and high risk of bias affect the interpretation of results. More high-quality studies are needed to promote the establishment of treatment guidelines for human liver fluke infection. FUNDING: Fourth Round of Three-Year Public Health Action Plan (2015-2017; Shanghai, China) and Swiss National Science Foundation.

Identification of cognition status and its associated factors permit targeted interventions. This study aimed to: (i) investigate cognitive function of Chinese older adults using a large, nationally representative cohort; and (ii) explore its associated factors from aspects of socio-demographic, health behaviour, physical and mental health.Data on 2665 adults aged 65 and older from the China Health and Retirement Longitudinal Study wave 4 in 2018 were analyzed. Information on self-reported cognition status, socio-demographic characteristics, health behaviour, physical and mental health status were obtained. Hierarchical regression analyses were conducted to explore associated factors.The cognition score was 24.8, with 41.1% of Chinese older adults identified as cognitively impaired. Better cognition was associated with being married, more education, living in a city/town or urban-rural integration zone, moderate night-time sleep (5-9 h) and post-lunch napping (less than 90 min), moderate/light physical activity for 30 min to 2 h every day, socially active and good health status; while worse cognition was associated with older age, intensive physical activity every day and more than 4 h a day, greater dependency in activities of daily living and depression.Cognitive impairment is a common health problem in Chinese older adults. Its associated factors are multifaceted, including socio-demographic characteristics, health behaviour and physical and mental health status. Developing interventions focused on these factors may be an important part of optimising cognition in these populations.

Background and aims Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. The aim of the present study was to characterize the clinical features and therapeutic response of patients with IgG4-RD and identify risk factors for disease relapse. Methods We collected baseline data of eligible patients with IgG4-RD and analyzed clinical features by interview and review of medical records. The patients who received glucocorticoids (GC) therapy with at least 3 months follow-up were used to characterize the therapeutic response and identify risk factors for relapse. Result Totally 127 IgG4-RD patients, including 92 males and 35 females, were enrolled in the present study. The median age of onset was 63.0 years, ranging from 23 to 86. The pancreas, bile duct and lymph nodes were the most frequently involved organs. The serum IgG4 level was elevated in 94.5% of the patients and was correlated with the number of organs involved. Patients classified as head and neck limited group were more likely to be female. Compared to Mikulicz syndrome and systemic involvement group, pancreato-hepatobiliary group had higher aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin and lower IgG4 level. Mikulicz syndrome and systemic involvement group had the highest IgG4-RD RI score, IgG level. Among 92 patients who received medical therapy with at least 3 months follow-up, 76 received GC alone or in combination with immunomodulator (IM) and 16 patients did not take GC. 74 out of the 76 patients (97.3%) achieved remission, with 59 of them remained in remission and 15 of them relapsed. Whereas 16 patients did not take GC, among them, 6 patients achieved remission with one relapsed. On multivariate analysis, higher initial score of ACR/EULAR IgG4-RD Classification Criteria and GC withdrawal were independent predictors for relapse. Conclusion Four phenotypes of IgG4-RD showed different demographic and serological features. GC + IM therapy was safe and effective and might protect patients from relapse. The independent risk factors of relapse were GC withdrawal and higher score of ACR/EULAR IgG4-RD Classification Criteria.