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Abstract Glaucoma is a prevalent cause of blindness globally, characterized by the progressive degeneration of retinal ganglion cells (RGCs). Among various factors, glutamate excitotoxicity stands out as a significant contributor of RGCs loss in glaucoma. Our study focused on Ripa-56 and its protective effect against NMDA-induced retinal damage in mice, aiming to delve into the potential underlying mechanism. The R28 cells were categorized into four groups: glutamate (Glu), Glu + Ripa-56, Ripa-56 and Control group. After 24 h of treatment, cell death was assessed by PI / Hoechst staining. Mitochondrial membrane potential changes, apoptosis and reactive oxygen species (ROS) production were analyzed using flow cytometry. The alterations in the expression of RIP-1, p-MLKL, Bcl-2, BAX, Caspase-3, Gpx4 and SLC7A11 were examined using western blot analysis. C57BL/6j mice were randomly divided into NMDA, NMDA + Ripa-56, Ripa-56 and control groups. Histological changes in the retina were evaluated using hematoxylin and eosin (H&E) staining. RGCs survival and the protein expression changes of RIP-1, Caspase-3, Bcl-2, Gpx4 and SLC7A11 were observed using immunofluorescence. Ripa-56 exhibited a significant reduction in the levels of RIP-1, p-MLKL, Caspase-3, and BAX induced by glutamate, while promoting the expression of Bcl-2, Gpx-4, and SLC7A1 in the Ripa-56-treated group. In our study, using an NMDA-induced normal tension glaucoma mice model, we employed immunofluorescence and H&E staining to observe that Ripa-56 treatment effectively ameliorated retinal ganglion cell loss, mitigating the decrease in retinal ganglion cell layer and bipolar cell layer thickness caused by NMDA. In this study, we have observed that Ripa-56 possesses remarkable anti- necroptotic, anti-apoptotic and anti-ferroptosis properties. It demonstrates the ability to combat not only glutamate-induced excitotoxicity in R28 cells, but also NMDA-induced retinal excitotoxicity in mice. Therefore, Ripa-56 could be used as a potential retinal protective agent.

Fast and versatile beam forming and steering technologies are now crucial for various emerging applications, including wireless optical communications and optical switches. However, these technologies often rely on expensive components, such as spatial light modulators (SLMs) and optical phase arrays (OPAs), which come with complex and power-consuming control systems. In response to this challenge, we propose a dynamic beam-switching method inspired by the mode-hopping effect of lasers. As a proof of concept, we introduce the dynamic beam switching metasurface (DBSM) design, featuring an in-plane mechanical actuation system. Our numerical analyses, based on the finite element method (FEM), demonstrate that the proposed DBSM exhibits versatile beam forming and steering functionalities. These include beam splitting and omnidirectional beam steering. Moreover, we anticipate that the tuning speed of the DBSM will reach the kilohertz (kHz) range or even higher when utilizing a microelectromechanical systems (MEMS) actuator, building upon pioneering research in this field. We envision it holds promising applications in areas such as light detection and ranging (LiDAR), optical wireless communication devices, and optical switches.

Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogen-activated protein kinase (MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.

Abstract Background Malnutrition and subsequent alterations in body composition (BC), particularly sarcopenia, are common but not yet elucidated in patients with inflammatory bowel disease (IBD); we aimed to detail the changes in BC and the characteristics of co‐occurrence of malnutrition and sarcopenia in IBD patients and to investigate its effect on quality of life. Methods This study was a multicentre, prospective, observational study involving four tertiary referral hospitals in China. The following data were collected from consecutive IBD inpatients: demographic information, medical history, recent weight change, handgrip strength (HGS) and BC parameters by bioelectrical impedance analysis (BIA). Nutritional assessments were performed through stepwise screening (Nutritional Risk Screening 2002) and diagnosis (World Health Organization‐related body mass index [BMI], subjective global assessment, European Society for Clinical Nutrition and Metabolism 2015 and Global Leadership Initiative on Malnutrition [GLIM] criteria). The quality of life was assessed by the Inflammatory Bowel Disease Questionnaire. IBD patients were compared with 1:1 sex‐, age‐ and BMI‐matched healthy controls (MHC). Results A total of 238 IBD patients (177 Crohn's disease [CD] and 61 ulcerative colitis [UC]), 68.5% male, with a mean age of 38.5 ± 14.0 years and a mean BMI of 19.8 ± 3.5 kg/m2, were recruited. Compared with MHC (n = 122), IBD patients showed significant deterioration in BC and physical function, characterized by muscle depletion (appendicular skeletal muscle mass index [ASMI], 8.0 ± 1.3 vs. 6.7 ± 1.2 kg/m2, Δ% −15.0% [−22.0%, −10.0%], P

Neurodegenerative diseases refer to a battery of medical conditions that affect the survival and function of neurons in the brain, which are mainly presented with progressive loss of cognitive and/or motor function. Acupuncture showed benign effects in improving neurological deficits, especially on movement and cognitive function impairment. Here, we reviewed the therapeutic mechanisms of acupuncture at the neural circuit level in movement and cognition disorders, summarizing the influence of acupuncture in the dopaminergic system, glutamatergic system, γ-amino butyric acid-ergic (GABAergic) system, serotonergic system, cholinergic system, and glial cells at the circuit and synaptic levels. These findings can provide targets for clinical treatment and perspectives for further studies.

PurposeIn the realm of pain management, traditional Chinese medicine, specifically acupuncture, has garnered increasing attention. This meta-analysis pioneers the evaluation of acupuncture’s effectiveness in treating insomnia among hypertensive patients.MethodsWe conducted a comprehensive search across several databases—PubMed, Web of Science, Cochrane Library, WANFANG, China National Knowledge Infrastructure (CNKI), Sinomed, and the Chinese Journal of Science and Technology (VIP). Additionally, forward and backward articles of studies published from the inception of these databases until 10 September 2023, were reviewed. This systematic review and meta-analysis included all randomized controlled trials (RCTs) focusing on acupuncture for insomnia in hypertensive patients, without imposing language or date restrictions. We rigorously assessed all outcome measures reported in these trials. The evidence was synthesized by calculating the difference between mean differences (MD) in symptom change. The quality of the evidence was determined using the Cochrane Risk of Bias tool. This study is registered with PROSPERO under number CRD42023461760.ResultsOur analysis included 16 RCTs, comprising 1,309 patients. The findings revealed that acupuncture was significantly more effective than the control group in reducing insomnia symptoms, as indicated by a greater decrease in the PSQI score (MD = −3.1, 95% CI [−3.77 to −2.62], p

Abstract Introduction MicroRNA‐223 (miR‐223) has emerged as a promising noninvasive biomarker for Crohn's disease (CD). However, it is unclear which tissue derived miRNA‐223 can more accurately estimate CD disease activity. Materials and Methods To collect serum, terminal ileal mucosa biopsy and fecal samples from CD patients and healthy controls. The CD Activity Index (CDAI) score, Montreal classification, maintenance medicines, peripheral blood inflammatory markers, fecal calprotectin (FC) and the Simple Endoscopic Score for CD (SES‐CD) were recorded. To compare the expression of miR‐223 in the serum, intestinal tissue, and feces. Results MiR‐223 expression levels in the serum, intestinal tissue and feces of CD patients were significantly higher than those of controls. The level of miR‐223 in the serum, intestinal tissue and feces increased significantly in active CD patients compared with that in inactive CD patients. The levels of serum, intestinal tissue and fecal miR‐223 were correlated with the CDAI. Serum miR‐223 was also correlated with C‐reactive protein (CRP) and IL‐6, tissue miR‐223 correlated with IL‐6 and FC, and fecal miR‐223 correlated with FC. In terms of the association with FC, fecal miR‐223 had a higher Spearman r value than tissue miR‐223. The area under the curve (AUC) values of serum, tissue and fecal miR‐223 to diagnose CD were similar to those of CRP and FC (AUC > 0.8). The AUC values of tissue and fecal miR‐223 to evaluate CD disease activity were 0.832 and 0.818, respectively, and were higher than serum miR‐223, CRP and FC. Fecal miR‐223 had a higher specificity of 92.3%. Conclusions Fecal miR‐223 might be a novel, noninvasive biomarker for estimating the disease activity of CD patients.

ABSTRACTPolyunsaturated fatty acids (PUFAs) have been shown to exacerbate Crohn’s disease (CD) by promoting lipid peroxidation (LPO) of intestinal epithelial cells (IECs). Dysbiosis of the gut microbiota may play a crucial role in this process. CD patients often exhibit an increased abundance of Escherichia coli (E. coli) in the gut, and the colonization of adherent-invasive E. coli (AIEC) is implicated in the initiation of intestinal inflammation in CD. However, the impact of AIEC on LPO remains unclear. In this study, we observed that AIEC colonization in the terminal ileum of CD patients was associated with decreased levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) in the intestinal epithelium, along with elevated levels of 4-Hydroxynonenal (4-HNE). In vitro experiments demonstrated that AIEC infection reduced the levels of GPX4 and FTH, increased LPO, and induced ferroptosis in IECs. Furthermore, arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation in AIEC-infected IECs significantly aggravated LPO and ferroptosis. However, overexpression of GPX4 rescued AIEC-induced LPO and ferroptosis in IECs. Our results further confirmed that AIEC with AA supplementation, associated with excessive LPO and cell death in IECs, worsened colitis in the DSS mouse model and induced enteritis in the antibiotic cocktail pre-treatment mouse model in vivo. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, alleviated AIEC with AA supplementation-induced enteritis in mice, accompanied by reduced LPO and cell death in IECs. Our findings suggest that AIEC, in combination with PUFA supplementation, can induce and exacerbate intestinal inflammation, primarily through increased LPO and ferroptosis in IECs.

ABSTRACTThe interaction between adherent-invasive Escherichia coli (AIEC) and intestinal macrophages is implicated in the pathogenesis of Crohn’s disease (CD). However, its role in intestinal fibrogenesis and the underlying molecular mechanisms are poorly understood. In addition, miRNAs such as let-7b may participate in AIEC-macrophage interactions. In this study, we identified that the colonization of AIEC in the ileum was associated with enhanced intestinal fibrosis and reduced let-7b expression by enrolling a prospective cohort of CD patients undergoing ileocolectomy. Besides, AIEC-infected IL-10−/− mice presented more severe intestinal fibrosis and could be improved by exogenous let-7b. Mechanistically, intestinal macrophages were found to be the main target of let-7b. Transferring let-7b-overexpressing macrophages to AIEC-infected IL-10−/− mice significantly alleviated intestinal fibrosis. In vitro, AIEC suppressed exosomal let-7b derived from intestinal epithelial cells (IECs), instead of the direct inhibition of let-7b in macrophages, to promote macrophages to a fibrotic phenotype. Finally, TGFβR1 was identified as one target of let-7b that regulates macrophage polarization. Overall, the results of our work indicate that AIEC is associated with enhanced intestinal fibrosis in CD. AIEC could inhibit exosomal let-7b from IECs to promote intestinal macrophages to a fibrotic phenotype and then contributed to fibrogenesis. Thus, anti-AIEC or let-7b therapy may serve as novel therapeutic approaches to ameliorate intestinal fibrosis.

Background/Aims The aim of this study was to analyze the chronological changes in postoperative complications in surgical ulcerative colitis patients over the past decade in China and to investigate the potential parameters that contributed to the changes. Methods Ulcerative colitis patients who underwent surgery during 2008–2017 were retrospectively enrolled from 13 hospitals in China. Postoperative complications were compared among different operation years. Risk factors for complications were identified by logistic regression analysis. Results A total of 446 surgical ulcerative colitis patients were analyzed. Fewer short-term complications (24.8% vs. 41.0%, P=0.001) and more laparoscopic surgeries (66.4% vs. 25.0%, P

IntroductionDiffusion Tensor Imaging (DTI) indicators of different white matter (WM) fibers and brain region lesions for post-stroke aphasia (PSA) are inconsistent in existing studies. Our study examines the consistency and differences between PSA tests performed with DTI. In addition, obtaining consistent and independent conclusions between studies was made possible by utilizing DTI in PSA assessment.MethodsIn order to gather relevant studies using DTI for diagnosing PSA, we searched the Web of Science, PubMed, Embase, and CNKI databases. Based on the screening and evaluation of the included studies, the meta-analysis was used to conduct a quantitative analysis. Narrative descriptions were provided for studies that met the inclusion criteria but lacked data.ResultsFirst, we reported on the left hemisphere. The meta-analysis showed that fractional anisotropy (FA) of the arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF), inferior frontal-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and uncinate fasciculus (UF) were decreased in the PSA group in comparison with the healthy controls (p

Objective: To develop novel multiparametric models based on computed tomography enterography (CTE) scores to identify endoscopic activity and surgical risk in patients with Crohn's disease (CD). Methods: We analyzed 171 patients from 3 hospitals. Correlations between CTE outcomes and endoscopic scores were assessed using Spearman's rank correlation analysis. Predictive models for moderate to severe CD were developed, and receiver operating characteristic (ROC) curves were constructed to determine the area under the ROC curve (AUC). A combined nomogram based on CTE scores and clinical variables was also developed for predicting moderate to severe CD and surgery. Results: CTE scores were significantly correlated with endoscopy scores at the segment level. The global CTE score was an independent predictor of severe (HR = 1.231, 95% CI: 1.048–1.446, p = 0.012) and moderate-to-severe Simplified Endoscopic Scores for Crohn's Disease (SES-CD) (HR = 1.202, 95% CI: 1.090–1.325, p

Background and aimsMalnutrition is strongly linked to adverse outcomes in patients with Crohn’s disease (CD). In this study, our objective was to validate the Global Leadership Initiative on Malnutrition (GLIM) criteria and develop a fast and accurate diagnostic approach for identifying malnutrition in CD patients.MethodsThis study assessed 177 CD patients from four general hospitals. The efficacy of the GLIM criteria for the diagnosis of CD malnutrition was compared. By analyzing the independent factors, a nomogram model was derived and internally validated to predict the diagnosis of malnutrition in patients with CD. Model performance was assessed using discrimination and calibration, decision curves, and net benefit analyses.ResultsCompared with the SGA criteria, the GLIM criteria was consistent in sensitivity (88.89%) and specificity (78.43%) [AUC = 0.84; 95% Confidence Interval (CI): 0.77–0.89]. The Harvey-Bradshaw index(HBI) score (OR: 1.58; 95% CI: 1.15–2.18), body mass index (OR: 0.41; 95% CI: 0.27–0.64), and mid-upper arm circumference (OR: 0.68; 95% CI: 0.47–0.9) were independent factors associated with malnutrition. The nomogram was developed based on these indicators showing good discrimination in malnutrition diagnosis (AUC = 0.953; 95% CI: 0.922–0.984), with agreement after calibration curve and decision curve analysis.ConclusionThe GLIM criteria are appropriate for diagnosing malnutrition in CD patients. The HBI score may be used to diagnose malnutrition in patients with CD and become a possible selection for the GLIM etiologic criteria of inflammation. The HBM nomogram could be a simple, rapid, and efficient method for diagnosing malnutrition in CD patients.

A new indole diterpene, 26-dihydroxyaflavininyl acetate (1), along with five known analogs (2–6) were isolated from the liquid fermentation of Aspergillus flavus GZWMJZ-288, an endophyte from Garcinia multiflora. The structures of these compounds were identified through NMR, MS, chemical reaction, and X-ray diffraction experiments. Enzyme inhibition activity screening found that compounds 1, 4, and 6 have a good binding affinity with NPC1L1, among which compound 6 exhibited a stronger binding ability than ezetimibe at a concentration of 10 µM. Moreover, compound 5 showed inhibitory activity against α-glucosidase with an IC50 value of 29.22 ± 0.83 µM, which is 13 times stronger than that of acarbose. The results suggest that these aflavinine analogs may serve as lead compounds for the development of drugs targeting NPC1L1 and α-glucosidase. The binding modes of the bioactive compounds with NPC1L1 and α-glucosidase were also performed through in silico docking studies.

Background Temporary stoma formation is common in Crohn’s disease (CD), while stoma reversal is associated with postoperative morbidity. This study aimed to evaluate the postoperative outcomes of split stoma reversal, SSR (i.e., exteriorization of proximal and distal ends of the stoma through a small common opening) and end stoma closure, ESC (i.e., the proximal stump externalized, and distal end localized abdominally.Methods Patients with CD who underwent stoma reversal surgeries between January 2017 and December 2021 were included. Demographic, clinical, and postoperative data were collected and analyzed to evaluate outcomes of reversal surgery.Results A total of 255 patients who underwent stoma reversal surgeries met the inclusion criteria. SSR was superior to ESC in terms of operative time (80.0 vs. 120.0, p = 0.0004), intraoperative blood loss volume (20.0 vs. 100.0, p = 0.0002), incision length (3.0 vs. 15.0, p

Abstract This study aimed to at explore exploring the biological functions of dysregulated circRNA in Crohn’s disease (CD) pathogenesis, with the overarching goal of and providing potential novel therapeutic targets. CircRNA microarray and quantitative real time-polymerase chain reaction (qRT-PCR) analyses were performed to investigate and verify the candidate dysregulated circRNA. The Next, clinical, in vivo, and in vitro studies were performed to investigate explore the biological function and mechanisms of the candidate circRNA in CD. The therapeutic effect of poly (lactic-co-glycolic acid)-microspheres (PLGA MSs)-carried oe-circGMCL1 in experimental colitis models of IL-10 knock-out mice was assessed. CircGMCL1 was identified as the candidate circRNA by microarray and qRT-PCR analyses. Results showed that circGMCL1 expression was negatively correlated with CD-associated inflammatory indices, suggesting that it is a CD-associated circRNA. Microarray and bioinformatics analyses identified miR-124-3p and Annexin 7 (ANXA7) as its downstream mechanisms. The in vitro studies revealed that circGMCL1 mediates its effects on autophagy and NLRP3 inflammasome-mediated pyroptosis in epithelial cells through the ceRNA network. Moreover, the in vivo studies identified the therapeutic effect of PLGA MSs-carried oe-circGMCL1 in experimental colitis models. This study suggests that circGMCL1 protects intestinal barrier function against Crohn’s colitis through alleviating NLRP3 inflammasome-mediated epithelial pyroptosis by promoting autophagy through regulating ANXA7 via sponging miR-124-3p. Therefore, circGMCL1 can serve as a potential biological therapeutic target for Crohn’s colitis.

Nonenzymatic reactions play an important part in the formation of some natural products possessing complex skeletons. Here, the authors report the discovery of eight chimeric medermycin-type natural products and their nonenzymatic construction.

Stroke-induced depression is a common complication and an important risk factor for disability. Besides psychiatric symptoms, depressed patients may also exhibit a variety of gastrointestinal symptoms, and even take gastrointestinal symptoms as the primary reason for medical treatment. It is well documented that stress may disrupt the balance of the gut microbiome in patients suffering from post-stroke depression (PSD), and that disruption of the gut microbiome is closely related to the severity of the condition in depressed patients. Therefore, maintaining the balance of intestinal microbiota can be the focus of research on the mechanism of acupuncture in the treatment of PSD. Furthermore, stroke can be effectively treated with acupuncture at all stages and it may act as a special microecological regulator by regulating intestinal microbiota as well. In this article, we reviewed the studies on changing intestinal microbiota after acupuncture treatment and examined the existing problems and development prospects of acupuncture, microbiome, and poststroke depression, in order to provide new ideas for future acupuncture research.

In a case of thalamencephalic and mesencephalic injury secondary to electrical trauma, a 29-year-old patient has been receiving manual acupuncture for 17 months in National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion. As a result of treatment, the patient's self-care ability and quality of life have greatly improved. In order to fully understand how acupuncture can benefit neurological sequelae resulting from electrical trauma, further research is needed. Additionally, there should be consideration given to the promotion of acupuncture therapy in the neurological sequelae of electric shock.

Analyzing the photomicrographs of coal and conducting maceral analysis are essential steps in understanding the coal’s characteristics, quality, and potential uses. However, due to limitations of equipment and technology, the obtained coal photomicrographs may have low resolution, failing to show clear details. In this study, we introduce a novel Generative Adversarial Network (GAN) to restore high-definition coal photomicrographs. Compared to traditional image restoration methods, the lightweight GAN-based network generates more explicit and realistic results. In particular, we employ the Wide Residual Block to eliminate the influence of artifacts and improve non-linear fitting ability. Moreover, we adopt a multi-scale attention block embedded in the generator network to capture long-range feature correlations across multiple scales. Experimental results on 468 photomicrographs demonstrate that the proposed method achieves a peak signal-to-noise ratio of 31.12 dB and a structural similarity index of 0.906, significantly higher than state-of-the-art super-resolution reconstruction approaches.

IntroductionAccording to several studies, a specific dietary pattern can reduce the risk of dementia and cognitive impairment. However, the robustness of these results has not been tested. The study intends to investigate the association between nutrition intake and cognitive impairment in middle-aged and older adults (≥45-years) and provide reliable, evidence-based references for healthcare decision-makers, researchers, and policymakers.Review questionAre the dietary characteristics of community-dwelling adults (≥45-years) associated with the occurrence of cognitive impairment?ObjectivesThe primary objective of this protocol is to synthesize the longitudinal observational evidence on the relationship between nutrition intake patterns and the incidence of cognitive impairment in middle-aged and older adults (≥45-years), and to provide detailed dietary recommendations for the prevention of cognitive impairment in this population.Methods and analysisCohort studies conducted among adults (≥45-years) will be included. The following electronic databases will be searched for relevant records published by July 2023, with a restriction on language to English: Pubmed, Medline, Embase, Web of science, Cochrane Library. The studies will be selected, the data will be extracted, and the bias risk will be assessed by two independent investigators. The Meta-analysis of Observational Studies in Epidemiology guidelines will be followed to summarize observational studies, and the protocol will adhere to the recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Endnote X9 will be used to manage data screening. We will use Review Manager 5.4 and Stata 16.0 to conduct data analysis, and a random-effects model will be applied to pool clinically homogenous studies. The results will be presented based on the form of nutrition intake. For assessing publication bias, Egger's test and visual inspection of funnel plots will be utilized.Ethics and disseminationAs this study does not involve primary data, ethical approval is not required. The final report will be published in a peer-reviewed journal.Prospero registration numberA registration number of DOI 10.17605/OSF.IO/NAKC3 was assigned to it on October 15, 2022 on Prospero.

Pregnancy is a condition of broad interest across many medical and health services research domains, but one not easily identified in healthcare claims data. Our objective was to establish an algorithm to identify pregnant women and their pregnancies in claims data. We identified pregnancy-related diagnosis, procedure, and diagnosis-related group codes, accounting for the transition to International Statistical Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis and procedure codes, in health encounter reporting on 10/1/2015. We selected women in Merative MarketScan commercial databases aged 15-49 years with pregnancy-related claims, and their infants, during 2008-2019. Pregnancies, pregnancy outcomes, and gestational ages were assigned using the constellation of service dates, code types, pregnancy outcomes, and linkage to infant records. We describe pregnancy outcomes and gestational ages, as well as maternal age, census region, and health plan type. In a sensitivity analysis, we compared our algorithm-assigned date of last menstrual period (LMP) to fertility procedure-based LMP (date of procedure + 14 days) among women with embryo transfer or insemination procedures. Among 5,812,699 identified pregnancies, most (77.9%) were livebirths, followed by spontaneous abortions (16.2%); 3,274,353 (72.2%) livebirths could be linked to infants. Most pregnancies were among women 25-34 years (59.1%), living in the South (39.1%) and Midwest (22.4%), with large employer-sponsored insurance (52.0%). Outcome distributions were similar across ICD-9 and ICD-10 eras, with some variation in gestational age distribution observed. Sensitivity analyses supported our algorithm's framework; algorithm- and fertility procedure-derived LMP estimates were within a week of each other (mean difference: -4 days [IQR: -13 to 6 days]; n = 107,870). We have developed an algorithm to identify pregnancies, their gestational age, and outcomes, across ICD-9 and ICD-10 eras using administrative data. This algorithm may be useful to reproductive health researchers investigating a broad range of pregnancy and infant outcomes.

Neural plasticity promotes the reorganization of language networks and is an essential recovery mechanism for poststroke aphasia (PSA). Neuroplasticity may be a pivotal bridge to elucidate the potential recovery mechanisms of acupuncture for aphasia. Therefore, understanding the neuroplasticity mechanism of acupuncture in PSA is crucial. However, the underlying therapeutic mechanism of neuroplasticity in PSA after acupuncture needs to be explored. Excitotoxicity after brain injury affects the activity of neurotransmitters and disrupts the transmission of normal neuron information. Thus, a helpful strategy of acupuncture might be to improve PSA by affecting the availability of these neurotransmitters and glutamate receptors at synapses. In addition, the regulation of neuroplasticity by acupuncture may also be related to the regulation of astrocytes. Considering the guiding significance of acupuncture for clinical treatment, it is necessary to carry out further study about the influence of acupuncture on the recovery of aphasia after stroke. This study summarizes the current research on the neural mechanism of acupuncture in treating PSA. It seeks to elucidate the potential effect of acupuncture on the recovery of PSA from the perspective of synaptic plasticity and integrity of gray and white matter.

The COVID-19 pandemic has disrupted HIV prevention, care, and transmission opportunities. This likely varies by geography, given differences in COVID-19 burden and mandates over time, and by age, given different likelihoods of severe COVID-19 consequences. We consider changes in sexual behavior, HIV testing, pre-exposure prophylaxis (PrEP) use and antiretroviral therapy (ART) use among men who have sex with men (MSM) over the first year of the COVID-19 epidemic, comparing the Atlanta metropolitan area and New York City (NYC). We use two continuous time-series datasets and one panel dataset, assessing changes over time within city and comparing across cities, and disaggregate major findings by age. For clinical results, ART use showed by far the smallest reductions, and testing the largest. Disruptions occurred concurrently between cities, despite the major wave of COVID-19, and government mandates, occurring later in Atlanta. Test positivity increased in NYC only. In both cities, younger MSM saw the greatest reductions in testing and PrEP use, but the smallest in sexual behavior. Reduced clinical service usage would be unconcerning if stemming solely from reductions in exposure; however, the patterns for young MSM suggest that the COVID-19 epidemic likely generated new conditions for increased HIV transmission, especially in this cohort.

Defect modulation and understanding its impact on electrode materials remain challenging. Here, authors introduce twin boundaries into spinel cathode and demonstrate that their presence enables fast lithium ion diffusion.

Under the guidance of global natural product social molecular networking, three new indolocarbazoles named streptocarbazoles F–H (1-3), along with staurosporine (4) were isolated from the marine-derived Streptomyces sp. OUCMDZ-5380. Structures of streptocarbazoles F–H were, respectively, determined as N-demethyl-N-hexanoylstaurosporine (1), N-demethyl-N-(2-methyl-3-methoxypyridin-4-yl) staurosporine staurosporine (2), and 4-(N-demethylstaurosporine-N-yl)-1,2-dimethyl-3-methoxypyridinium (3) by spectroscopic analysis and electronic circular dichroism comparison with staurosporine. Compared with staurosporine (4), streptocarbazoles F–H (1-3) showed a selective antiproliferation of the acute myeloid leukemia cell line MV4-11 with the IC50 values of 0.81, 0.55, and 1.88 μM, respectively.

Two new 4-hydroxy-2-pyridone alkaloids furanpydone A and B (1 and 2), along with two known compounds N-hydroxyapiosporamide (3) and apiosporamide (4) were isolated from the endophytic fungus Arthrinium sp. GZWMJZ-606 in Houttuynia cordata Thunb. Furanpydone A and B had unusual 5-(7-oxabicyclo[2.2.1]heptane)-4-hydroxy-2-pyridone skeleton. Their structures including absolute configurations were determined on the basis of spectroscopic analysis, as well as the X-ray diffraction experiment. Compound 1 showed inhibitory activity against ten cancer cell lines (MKN-45, HCT116, K562, A549, DU145, SF126, A-375, 786O, 5637, and PATU8988T) with IC50 values from 4.35 to 9.72 µM. Compounds 1, 3 and 4 showed moderate inhibitory effects against four Gram-positive strains (Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus Subtilis, Clostridium perfringens) and one Gram-negative strain (Ralstonia solanacarum) with MIC values from 1.56 to 25 µM. However, compounds 1–4 showed no obvious inhibitory activity against two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and two pathogenic fungi (Candida albicans and Candida glabrata) at 50 µM. These results show that compounds 1–4 are expected to be developed as lead compounds for antibacterial or anti-tumor drugs.

Abstract Introduction The pathogenesis of inflammatory bowel disease (IBD) has not yet been clarified and is closely related to several pro‐inflammatory factors. MicroRNA‐233 (miR‐223) might be involved in the development of IBD; however, the mechanism underlying its pathogenesis is unclear. In this study, we attempted to determine the role of miR‐223 in dextran sodium sulfate (DSS)‐induced colitis and explore the involvement of the IL‐6/STAT3 pathway in the development of intestinal mucosal inflammation. Materials and Methods Except control (WT) group, male C57BL/6 mice were provided DSS, then treated for with miR‐223 agomir or antagomir including DSS group, DSS + miR‐223 agomir (DSS + A) group, and DSS + miR‐223 antagomir (DSS + AN) group. The colitis symptoms were observed, the disease activity index (DAI) score were recorded daily, and colonic inflammation was evaluated by histopathological scoring. The expression of myeloperoxidase (MPO), cytokines and IL‐6/STAT3 pathway‐related proteins were measured. Results miR‐223 expression in the terminal ileum and colon was increased in the DSS group compared with the WT group. Colitis symptoms were significantly alleviated in the DSS + A group and exacerbated in the DSS + AN group after administration of the miR‐223 agomir and antagomir, respectively. MPO, tumor necrosis factor‐α, IL‐6, and IL‐17 were decreased and IL‐10 was increased in the DSS + A group, but these changes were reversed in the DSS + AN group. Gp130, p‐STAT3, Bcl‐2, and Bcl‐xl in the colon declined in the DSS + A group, but these levels increased in the DSS + AN group. Conclusions The upregulation of miR‐223 by agomir administration alleviated colonic inflammation in a DSS‐induced colitis model, which was likely mediated by inhibiting the production of pro‐inflammatory cytokines via the IL‐6/STAT3 signaling pathway. These findings provide evidence that miR‐223 might have potential therapeutic implications in IBD.

Improving physical, mental and cognitive health is a strategic choice to help developing countries cross the middle-income trap. This paper used data from the 2019 China Rural Children Health and Nutrition Survey (n = 826), and used the Ordered Probit (Oprobit), Logit and ordinary least squares (OLS) analytical methods to systematically analyze the implications of parental migration on multidimensional health. The results indicate that parental migration significantly harms the physical and mental health of rural children, and that mobile phone addiction has a significant moderating effect. Moreover, parental migration has a greater impact on the physical health, mental health and cognitive ability of boys and rural children with low family income, while parents with higher nutrition knowledge and education can effectively improve the physical health and cognitive ability of their children. In conclusion, in order to improve the multidimensional health of rural children, the government should strengthen the policy of care and support for children whose parents migrate. Schools and families should pay attention to the supervision of rural children’s mobile phone addiction.

Abstract Background People bypass primary healthcare (PHC) institutions to seek expensive healthcare at high-level hospitals, leading to escalating medical costs and inefficient use of resources. In 2009, China launched nationwide synergic policies on primary care strengthening, to tackle access to healthcare and financial protection. This study aimed to assess the impact of the two policy areas, health insurance and health workforce, on healthcare seeking behavior. Methods Drawing on national survey data before (2008) and after (2013) the policies, we linked individual-level data on healthcare-seeking behavior with county-level data on health workforce and health insurance. We constructed a multilevel zero-inflated negative binomial regression to examine the impacts of average reimbursement rate (ARR) of health insurance and the density of registered physicians on outpatient/inpatient visits, and multilevel multinomial logistic regression for the impacts on choice of outpatient/inpatient care providers. Results Although the increase in health insurance ARR and physician density have positive impacts on individuals’ healthcare use, their impacts might be weakened during 2008 and 2013, and the negative impacts of investment of those in PHC institutions on likelihood of visiting hospitals was larger. The negative impacts of ARR at PHC institutions on likelihood of visiting county-, municipal- and higher-level hospitals in 2013 was 28 percentage points, 66 percentage points and 33 percentage points larger than these in 2008. Conclusions Primary care strengthening requires synergic policies. Effective mechanisms for coordination across multisectoral actions are necessities for deepening those policies to ensure efficient delivery of healthcare without experiencing financial risks.

The organic soil is widely distributed around Dianchi Lake in Kunming, which is rich in the humic group (HG). In order to explore the effect of HG on the strength development of organic soil, this paper adopts the method of adding humic acid (HA) reagent into the undisturbed cohesive soil (blending method) and soaking it in fulvic acid (FA) solution (steeping method) to simulate the organic soil. Then, the effect of HG on soil is analyzed by the unconfined compressive strength (UCS) and the scanning electron microscope (SEM) tests. The UCS test shows that HA can significantly reduce the UCS of the samples, and it continues to decrease with the increase of the HA reagent content. FA can substantially enhance the UCS of the samples, which continues to increase with the concentration of FA solution (decreasing the pH value). Under each HG condition, the steeping of FA can significantly increase the UCS of the sample when the content of the HA reagent is less than 10%, and the growth rate of the UCS decreases when it is greater than 10%. With the increase of steeping age, the UCS of the 5% HA samples continued to increase and gradually became stable, and when the content of the HA reagent is more than 5%, the UCS curve first increases and then decreases. The SEM test shows that adding HA reagent can significantly increase the pore size, improve the connectivity between the pores, and weaken the connection of the soil structure. The steeping of FA can reduce the pore size, weaken the connectivity between the pores, and strengthen the connection of the sample structure.

The objective of this study was to compare the efficacy of exclusive enteral nutrition (EEN) and corticosteroids on the gut microbiome in Crohn’s disease. Methods. Data were collected for 16 patients newly diagnosed with CD as the test group and 10 healthy volunteers as the control group. The 16 patients were randomly divided into the EEN group and the corticosteroids group. For subsequent analysis, 6 patients in the EEN group with follow-up were enrolled to compare the 0-month, 1-month, and 3-month outcomes. We analyzed and compared gut microbiota between different groups in 3 stages. To evaluate the clinical outcome of treatment, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin (HB), albumin (ALB), and Crohn’s disease activity (CDAI) were recorded. Results. There are significant differences in microbiota between patients with CD and healthy people, and there are intuitive differences in the main components of the microbiota. 16 patients were included in stage 2, in which both corticosteroids and EEN can induce CD remission well. However, corticosteroids have a greater impact on inflammatory indicators, while EEN has a more obvious effect on nutritional indicators. Principal component analysis suggests that there are different compositional changes in the gut microbiome after corticosteroids and EEN treatment. After 3 months of dynamic observation, we found that EEN can effectively maintain CD remission, reduce inflammatory indicators, and improve nutritional indicators. Conclusions. Both EEN and corticosteroids can increase the diversity of the microbiome in inducing CD remission, while they have different effects on the proportion of microbiome species. This trial is registered with NCT02056418.

Background. Aphasia is a common symptom in stroke patients, presenting with the impairment of spontaneous speech, repetition, naming, auditory comprehension, reading, and writing function. Multiple rehabilitation methods have been suggested for the recovery of poststroke aphasia, including medication treatment, behavioral therapy, and stimulation approach. Acupuncture has been proven to have a beneficial effect on improving speech functions in repetition, oral speech, reading, comprehension, and writing ability. Neuroimaging technology provides a visualized way to explore cerebral neural activity, which helps reveal the therapeutic effect of acupuncture therapy. In this systematic review, we aim to reveal and summarize the neuroimaging mechanism of acupuncture therapy on poststroke aphasia to provide the foundation for further study. Methods. Seven electronic databases were searched including PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, the Wanfang databases, and the Chinese Scientific Journal Database. After screening the studies according to the inclusion and exclusion criteria, we summarized the neuroimaging mechanism of acupuncture on poststroke aphasia, as well as the utilization of acupuncture therapy and the methodological characteristics. Result. After searching, 885 articles were retrieved. After removing the literature studies, animal studies, and case reports, 16 studies were included in the final analysis. For the acupuncture type, 10 studies used manual acupuncture and 5 studies used electroacupuncture, while body acupuncture (10 studies), scalp acupuncture (7 studies), and tongue acupuncture (8 studies) were applied for poststroke aphasia patients. Based on blood oxygen level-dependent (BOLD) and diffusion tensor imaging (DTI) technologies, 4 neuroimaging analysis methods were used including amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), seed-based analysis, and independent component analysis (ICA). Two studies reported the instant acupuncture effect, and 14 studies reported the constant acupuncture’s effect on poststroke aphasia patients. 5 studies analyzed the correlation between the neuroimaging outcomes and the clinical language scales. Conclusion. In this systematic review, we found that the mechanism of acupuncture’s effect might be associated with the activation and functional connectivity of language-related brain areas, such as brain areas around Broca’s area and Wernicke’s area in the left inferior temporal gyrus, supramarginal gyrus, middle frontal gyrus, and inferior frontal gyrus. However, these studies were still in the preliminary stage. Multicenter randomized controlled trials (RCT) with large sample sizes were needed to verify current evidence, as well as to explore deeply the neuroimaging mechanisms of acupuncture’s effects.

Abstract Background The structures of the mesentery including adipose tissue, nerves, and lymphatics play an important role in the pathogenesis and disease progression of Crohn’s disease (CD). Conventional surgical resection for CD usually does not involve resecting the mesentery en bloc with the specimen. This contrasts with complete mesocolic excision (CME) in colorectal cancer, which involves radical resection of the mesentery. Preliminary evidence from smaller studies suggests that applying the principle of mesocolic excision to CD surgery may reduce the risk of postoperative recurrence. This randomized controlled trial is designed to test whether applying the principles of mesocolic excision to CD results in reduced postoperative recurrence. It also aims to evaluate intra- and postoperative morbidity between the two approaches. Methods This international, multicenter, randomized controlled trial will randomize patients (n = 116) scheduled to undergo primary ileocolic resection to either receive extensive mesenteric excision (EME) or conventional ileocolic resection with limited mesenteric excision (LME). Five sites will recruit patients in three countries. In the EME group, the mesentery is resected following CME, while avoiding the root region, i.e., 1 cm from the root of the ileocolic artery and vein. In the LME group, the mesentery is retained, i.e., “close shave” or

Abstract Calotropis procera fiber (CPF) is the fruit fiber of C. procera and belongs to a typical cellulosic fiber. In this study, Calotropis procera fiber (CPF) was first purified in the pretreatment process including delignification and bleaching before the isolation of cellulose nanocrystal. Chemical composition of Calotropis procera fiber was determined according to TAPPI standard method. It was composed of 64.0 wt% cellulose, 19.5 wt% hemicelluloses, and 9.7 wt% of lignin. The morphology of the Calotropis procera fiber and fiber after each pretreatment process was also investigated. Cellulose nanocrystal was extracted by classical sulfuric acid hydrolysis of the pretreated Calotropis procera fiber. TEM and SEM were used to analyze the morphologies of the obtained CNC. The crystallinity, thermal stability and suspension stability of the CNC were also investigated. The interesting results proved that this under-utilized biomass could be exploited as a new source of cellulose raw material for the production of cellulose nanocrystal.

Objective: To evaluate the influence of the abdominal incision length on the gastrointestinal function recovery post-operatively.Background: Gut motility recovers more quickly after the minimally invasive laparoscopic surgery compared than after the traditional open surgery; however, whether the minimal abdominal incision contributes to the faster gut motility recovery is controversial and lacks solid clinical evidence.Methods: A registry-based secondary cohort analysis was conducted to evaluate the association between the abdominal incision length and gut motility recovery post-operatively based on a multicenter, prospective, and observational study of the prolonged post-operative ileus (PPOI) incidence and the risk factors in the patients with the major abdominal surgery. The incision length, in the centimeters, was the exposure. The primary outcome measures were the PPOI incidence and its association with the incision length. The secondary outcome included the days to the first passage of flatus and the days to the first passage of stool.Results: Overall, 1,840 patients, including 287 (15.7%) patients with the PPOI, were recruited. The PPOI incidence was 17.6% and 13.3% in the long-incision (>18 cm) and short-incision patients ( ≤ 18 cm), respectively. The incidence of the PPOI increased by 1.1% (1.0–1.1) by each centimeter increment of the incision length after adjusting for the confounding factors. In comparison to the short-incision patients, the long-incision patients had prolonged passage of stool (4.46 vs. 4.95 days, p < 0.001). Each centimeter increment of the incision length contributed to a 2% increased risk of delay in the first bowel movement [hazard ratio (HR) 0.980 (0.967, 0.994)].Conclusion: A long abdominal incision length independently contributed to the prolonged gut function recovery post-operatively mainly by delaying the time to the first bowel movement, but not influencing the time to first passage of flatus.

Background: The coronavirus disease 2019 (COVID-19) pandemic has lasted much longer than an influenza season, but the main signs, symptoms, and some imaging findings are similar in COVID-19 and influenza patients. The aim of the current study was to construct an accurate and robust model for initial screening and differential diagnosis of COVID-19 and influenza A.Methods: All patients in the study were diagnosed at Fuyang No. 2 People's Hospital, and they included 151 with COVID-19 and 155 with influenza A. The patients were randomly assigned to training set or a testing set at a 4:1 ratio. Predictor variables were selected based on importance, assessed by random forest algorithms, and analyzed to develop classification and regression tree models.Results: In the optimal model A, the best single predictor of COVID-19 patients was a normal or high level of low-density lipoprotein cholesterol, followed by low level of creatine kinase, then the presence of

Four new drimane sesquiterpenoids (1–4) and three known ones (5–7) were isolated from the fermentation broth of the mangrove-derived Aspergillus ustus 094102. Compound 5 was further resolved as four purified compounds 5a–5d. By means of extensive spectroscopic and ECD analysis as well as the chemical transformation, their structures were identified as (2R,3R,5S,9R,10S)-2,3,9,11-tetrahydroxydrim-7-en-6-one (ustusol F, 1), (2R,3R,5R,9S,10R)-2,3,11-trihydroxydrim-7-en-6-one (9-deoxyustusol F, 2), (3S,5R,9R,10R)-3,11,12-trihydroxydrim-7-en-6-one (ustusol G, 3), (5S,6R,9S,10S, 11R,2′E,4′E)-(11-dideoxy-11-hydroxystrobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate H, 4), ((5S,6R,9S,10S)-strobilactone A-6-yl) (2E,4E)-6,7-dihydroxyocta-2,4-dienoate (ustusolate I, 5), (2′E,4′E;6′,7′-erythro)-ustusolate I (5a) and (2′E,4′E;ent-6′,7′-erythro)-ustusolate I (5b), (2′E,4′E,6′R,7′R)-ustusolate I (5c) and (2′E,4′E,6′S,7′S)-ustusolate I (5d), (5S,6R,9S,10S,2′E,4′E)-(strobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate J, 6), and (2S,5S,9R,10S)-2,9,11-trihydroxydrim-7-en-6-one (ustusol B, 7), respectively. Compound 5 showed antiproliferation against the human tumor cells CAL-62 and MG-63 with the IC50 values of 16.3 and 10.1 µM, respectively.

One new (1) and fifteen known (2–16) p-terphenyls were isolated from a solid culture of the endophytic fungus Aspergillus sp. GZWMJZ-055 by adding the leaves of its host Eucommia ulmoides. Furthermore, nine p-terphenyls (17–25) were synthesized from the main compounds (5–7), among which derivatives 18, 19, 21, 22, and 25 are new p-terphenyls. Compounds 15 and 16 were also, respectively, synthesized from compounds 6 and 7 by oxidative cyclization of air in the presence of silica gel. These p-terphenyls especially those with 4,2′,4″-trihydroxy (4–7, 20, 21) or 4, 4″-dihydroxy-1,2,1′,2′-furan (15, 16) substituted nucleus, exhibited significant antioxidant and α-glucosidase inhibitory activities and lower cytotoxicity to caco-2 cells. The results indicated their potential use as lead compounds or dietary supplements for treating or preventing the diabetes.

PRAS40 (Prolin-rich Akt substrate of 40 kDa) is a critical protein, which directly connects PI3K/Akt and mTORC1 pathway. It plays an indispensable role in the development of various diseases. However, the relationship between PRAS40 and head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, our study indicated that high expression of PRAS40 mRNA is a favorable prognostic factor in HNSCC patients by analyzing 498 clinical and mRNA data. Moreover, we confirmed that CRISPR/Cas9 induced PRAS40-knockout would promote colony formation, cell migration, and invasion in several HNSCC cell lines. RNA-seq was employed to investigate the further possible mechanisms involving the above regulations by PRAS40 in HNSCC cells. The molecular landscape contributed by 253 differentially expressed mRNA after PRAS40-knockout was enriched in TGF-beta, PI3K-Akt, P53, mTOR, NF-κB signaling pathway. Partial molecular alternations within these pathways were validated by qPCR or Western blotting. Besides, we found that high expression of PRAS40 in HNSC patients would present more CD8+ T and T follicular helper cells, but less Th17 cells than the patients with low expression of PRAS40. The altered molecular pathways and tumor-infiltrating immune cells might associate with the mechanism of PRAS40 being a suppressor in HNSCC cells, which would provide a potential prognostic predictor and therapeutic target in HNSCC patients.

Despite being potentially useful extremophile resources, there have been few reports on acid-tolerant fungi and their bioactive metabolites. Acidophilic/aciduric fungi (n = 237) were isolated from Thai mangrove sediments in an acidic medium. Using fungal identification technology (including morphologic observation, chemical screening, and sequence comparisons) all the isolates were identified and 41 representative isolates were selected for analysis of the phylogenetic relationships (ITS rDNA, β-tubulin, calmodulin, and actin gene sequences). There were seven genera identified – Penicillium; Aspergillus; Talaromyces; Cladosporium; Allophoma; Alternaria; and Trichoderma – in four taxonomic orders of the phylum Ascomycota, and Penicillium, Aspergillus, and Talaromyces were the dominant genera. Acidity tolerance was evaluated and 95% of the isolates could grow under extremely acidic conditions (pH 2). Six strains were classed as acidophilic fungi that cannot survive under pH 7, all of which had an extraordinarily close genetic relationship and belonged to the genus Talaromyces. This is the first report on the acidophilic characteristics of this genus. The antimicrobial, anti-tumor, and antiviral activities of the fermentation extracts were evaluated. Nearly three-quarters of the extracts showed cytotoxic activity, while less than a quarter showed antimicrobial or anti-H1N1 activity. The typical aciduric fungus Penicillium oxalicum OUCMDZ-5207 showed similar growth but completely different chemical diversity at pH 3 and 7. The metabolites of OUCMDZ-5207 that were obtained only at pH 3 were identified as tetrahydroauroglaucin (1), flavoglaucin (2), and auroglaucin (3), among which auroglaucin showed strong selective inhibition of A549 cells with an IC50 value of 5.67 μM. These results suggest that acid stress can activate silent gene clusters to expand the diversity of secondary metabolites, and the bioprospecting of aciduric/acidophilic microorganism resources in Thai mangrove sediments may lead to the discovery of compounds with potential medicinal applications.

The global shrimp industry has suffered bacterial diseases caused mainly by Vibrio species. The typical vibriosis, acute hepatopancreatic necrosis disease (AHPND), has resulted in mass mortality and devastating economic losses. Thus, therapeutic strategies are highly needed to decrease the risk of vibriosis outbreaks. Herein, we initially identified that the growth of the causative agent of AHPND, Vibrio parahaemolyticus (VPAHPND) and other vibrios in Pacific white shrimp (Litopenaeus vannamei) was inhibited by a Bacillus subtilis strain BSXE-1601. The natural products amicoumacins A, B, and C were purified from the cell-free supernatant from the strain BSXE-1601, but only amicoumacin A was demonstrated to be responsible for this anti-Vibrio activity. Our discovery provided the first evidence that amicoumacin A was highly active against shrimp pathogens, including the representative strain VPAHPND. Furthermore, we elucidated the amicoumacin A biosynthetic gene cluster by whole genome sequencing of the B. subtilis strain BSXE-1601. In addition to amicoumacin A, the strain BSXE-1601 genome harbored other genes encoding bacillibactin, fengycin, surfactin, bacilysin, and subtilosin A, all of which have previously reported antagonistic activities against pathogenic strains. The whole-genome analysis provided unequivocal evidence in support of the huge potential of the strain BSXE-1601 to produce diverse biologically antagonistic natural products, which may facilitate further studies on the effective therapeutics for detrimental diseases in shrimp.

R-Pyrisulfoxin C (1), S-pyrisulfoxin D [(+)-2], R-pyrisulfoxin D [(–)-2], pyrisulfoxin E (13), S-pyrisulfoxin F [(+)-14], and R-pyrisulfoxin F [(–)-14], six new caerulomycin derivatives with a 2,2′-bipyridine skeleton, were obtained from the cultures of the endophytic Streptomyces albolongus EA12432 with Aconitum carmichaeli (Ranunculaceae). Additionally, the racemic pyrisulfoxins A [(±)-3] and B [(±)-4] were further purified as optically pure compounds and identified the configurations for the first time. The racemic pyrisulfoxin D [(±)-2] displayed significant cytotoxicity against a series of cancer cell lines with IC50 values ranging from 0.92 to 9.71 μM. Compounds 7, 8, and (±)-3 showed cytotoxicity against the HCT-116, HT-29, BXPC-3, P6C, and MCF-7 cell lines. Notably, compounds 7 and 8 have a strong inhibition both on the proliferation of human colon cancer cells HCT-116 and HT-29 with IC50 values ranging from 0.048 to 0.2 μM (doxorubicin, 0.21 and 0.16 μM), and compound 1 showed a selective inhibition on the proliferation of the gastric carcinoma cell lines, N87, with an IC50 value of 8.09 μM. Optically pure compounds R(–)-14 and S(+)-14 showed weak cytotoxicity against HCT-116 and MCF-7 cell lines with the IC50 values of 14.7 μM and 10.4 μM, respectively. Interestingly, compounds 1 and (±)-2 didn't show cytotoxic activity against two human normal cell lines, HEK-293F and L02, with IC50 values >100 μM.

BACKGROUND:In 2015, there were approximately 40,000 new HIV diagnoses in the United States. Pre-exposure prophylaxis (PrEP) is an effective strategy that reduces the risk of HIV acquisition; however, uptake among those who can benefit from it has lagged. In this study, we 1) compared the characteristics of patients who were prescribed PrEP with individuals newly diagnosed with HIV infection, 2) identified the specialties of practitioners prescribing PrEP, 3) identified metropolitan statistical areas (MSAs) within the US where there is relatively low uptake of PrEP, and 4) reported median amounts paid by patients and third-party payors for PrEP. METHODS AND FINDINGS:We analyzed prescription drug claims for individuals prescribed PrEP in the Integrated Dataverse (IDV) from Symphony Health for the period of September 2015 to August 2016 to describe PrEP patients, prescribers, relative uptake, and payment methods in the US. Data were available for 75,839 individuals prescribed PrEP, and findings were extrapolated to approximately 101,000 individuals, which is less than 10% of the 1.1 million adults for whom PrEP was indicated. Compared to individuals with newly diagnosed HIV infection, PrEP patients were more likely to be non-Hispanic white (45% versus 26.2%), older (25% versus 19% at ages 35-44), male (94% versus 81%), and not reside in the South (30% versus 52% reside in the South).Using a ratio of the number of PrEP patients within an MSA to the number of newly diagnosed individuals with HIV infection, we found MSAs with relatively low uptake of PrEP were concentrated in the South. Of the approximately 24,000 providers who prescribed PrEP, two-thirds reported primary care as their specialty. Compared to the types of payment methods that people living with diagnosed HIV (PLWH) used to pay for their antiretroviral treatment in 2015 to 2016 reported in the Centers for Disease Control and Prevention (CDC) HIV Surveillance Special Report, PrEP patients were more likely to have used commercial health insurance (80% versus 35%) and less likely to have used public healthcare coverage or a publicly sponsored assistance program to pay for PrEP (12% versus 45% for Medicaid). Third-party payors covered 95% of the costs of PrEP. Overall, we estimated the median annual per patient out-of-pocket spending on PrEP was approximately US$72. Limitations of this study include missing information on prescription claims of patients not included in the database, and for those included, some patients were missing information on patient diagnosis, race/ethnicity, educational attainment, and income (34%-36%). CONCLUSIONS:Our findings indicate that in 2015-2016, many individuals in the US who could benefit from being on PrEP were not receiving this HIV prevention medication, and those prescribed PrEP had a significantly different distribution of characteristics from the broader population that is at risk for acquiring HIV. PrEP patients were more likely to pay for PrEP using commercial or private insurance, whereas PLWH were more likely to pay for their antiretroviral treatment using publicly sponsored programs. Addressing the affordability of PrEP and otherwise promoting its use among those with indications for PrEP represents an important opportunity to help end the HIV epidemic.

Background: Isolated colonic Crohn’s disease (cCD) responds less well to induction therapy with exclusive enteral nutrition (EEN) compared with ileal or ileocolonic disease in adult patients; therefore, we aimed to identify the factors that influence the response to EEN and develop a predictive nomogram model to optimize the use of EEN in cCD patients. Materials and methods: Eighty-five cCD patients treated with EEN as first-line therapy at our center between 1 June 2012 and 30 June 2018 were retrospectively analyzed as the primary cohort. The primary endpoint was clinical remission after EEN therapy. Potential predictive factors for the efficacy of EEN were assessed by univariate and multivariate analyses, and a nomogram to predict the response to EEN therapy in cCD patients was designed. Another 19 cCD patients were retrospectively included in the validation cohort to verify the accuracy of the nomogram model. Results: The clinical remission rates for the primary cohort and validation cohort were 52.9% and 47.4%, respectively. Pancolitis was the greatest contributor to the risk of failure to respond to EEN [odds ratio (OR) = 4.896; 95% confidence interval (CI) = 1.223–19.607; p = 0.025], lean body mass index (LBMI), colonic lesion features, simple endoscopic scores for Crohn’s disease, C-reactive protein before treatment and ∆prealbumin were also related to the efficacy of EEN in cCD. The nomogram model showed robust discrimination, with an area under the receiving operating characteristic curve of 0.906. Conclusion: Several predictive factors for response to EEN therapy in cCD adult patients were identified, and a promising nomogram that can predict the effect of EEN in cCD was developed.

Background/AimsResection of the diseased segment and suture of the victim segment is recommended for enteroenteric fistula in Crohn's disease (CD). The main difficulty in this procedure remains reliable diagnosis of the victim segment, especially for fistulas found intraoperatively and inaccessible on endoscopic examination. We aimed to explore whether intraoperative inspection alone is reliable.MethodsPatients undergoing conservative surgery between 2011 and 2016 for enteroenteric fistulas complicating CD were identified from a prospectively maintained database. Patients were divided according to whether the victim segment was evaluated by preoperative endoscopy + intraoperative inspection (PI group) or by intraoperative inspection alone (I group). Outcomes were compared.ResultsOf 65 patients eligible for the study, 37 were in in the PI group and 28 were in the I group. The baseline characteristics were similar between the groups, except for the rate of emergency surgery (0/37 in PI group vs. 5/28 in I group, P=0.012). Fistulas involved more small intestines (4/37 in PI group vs. 15/28 in I group, P0.05).ConclusionsFor fistulas found intraoperatively and inaccessible on endoscopic examination, intraoperative inspection was a reliable guide when choosing between en bloc resection and a conservative procedure.

Abstract Background China has a high burden of diabetes mellitus (DM), and a large proportion of DM patients remain untreated for various reasons, including low availability of primary health care providers. DM patient management is one of the priorities in China’s national essential public health programs. Shortage of health workforce has been a major barrier to improving access to health care for DM patients. This study examines the impact of the health workforce on outpatient utilization of DM patients. Methods Data were collected from China National Health Service Surveys in 2008 and 2013, covering 94 rural counties and 156 urban districts, respectively, with a total of 15,984 DM patients. Household data and facility-based data at county/district level were merged. The health workforce was measured by number of physicians per 1,000 population in county hospitals and primary health centers (PHCs), respectively. Health care seeking behavior was measured by health care utilization and distribution of health providers of the DM patients. Multilevel zero-inflated negative binomial regression was used to analyze the impact of the health workforce on outpatient visits by DM patients, and a multilevel, multinomial logit model was used to examine the impact of the health workforce on choice of health providers by DM patients. Results An increase in the number of physicians at both county hospitals and PHCs was associated with increased outpatient visits by DM patients, particularly more physicians at PHCs. With increased numbers of physicians at PHCs, outpatient visits among residents with DM in rural and western areas of China increased more than those in urban and eastern areas. More physicians at PHCs had a positive impact on improving the likelihood of outpatient visits at PHCs. The positive influence of increasing the number of physicians available to DM patients in rural and western areas was greater than that for urban and eastern DM patients. Conclusions The health workforce is a key component of any healthcare system and is critical in improving health care accessibility. Strategies to increase coverage of health workforce at PHCs are crucial to achieving adequate levels of health services for DM patients. Allocation of health workforce should focus on PHCs in rural and low-income areas.

Abstract Background Since 1968, China has trained about 1.5 million barefoot doctors in a few years’ time to provide basic health services to 0.8 billion rural population. China’s Ministry of Health stopped using the term of barefoot doctor in 1985, and changed policy to develop village doctors. Since then, village doctors have kept on playing an irreplaceable role in China’s rural health, even though the number of village doctors has fluctuated over the years and they face serious challenges. United Nations declared Sustainable Development Goals in 2015 to achieve universal health coverage by 2030. Under this context, development of Community Health workers (CHWs) has become an emerging policy priority in many resource-poor developing countries. China’s experiences and lessons learnt in developing and maintaining village doctors may be useful for these developing countries. Methods This paper aims to synthesis lessons learnt from the Chinese CHW experiences. It summarizes China’s experiences in exploring and using strategic partnership between the community and the formal health system to develop CHWs in the two stages, the barefoot doctor stage (1968 –1985) and the village doctor stage (1985-now). Chinese and English literature were searched from PubMed, CNKI and Wanfang. The information extracted from the selected articles were synthesized according to the four partnership strategies for communities and health system to support CHW development, namely 1) joint ownership and design of CHW programmes; 2) collaborative supervision and constructive feedback; 3) a balanced package of incentives, both financial and non-financial; and 4) a practical monitoring system incorporating data from the health system and community. Results The study found that the townships and villages provided an institutional basis for barefoot doctor policy, while the formal health system, including urban hospitals, county health schools, township health centers, and mobile medical teams provided training to the barefoot doctors. But After 1985, the formal health system played a more dominant role in the CHW system including both selection and training of village doctors. China applied various mechanisms to compensate village doctors in different stages. During 1960s and 1970s, the main income source of barefoot doctors was from their villages’ collective economy. After 1985 when the rural collective economy collapsed and barefoot doctors were transformed to village doctors, they depended on user fees, especially from drug sale revenues. In the new century, especially after the new round of health system reform in 2009, government subsidy has become an increasing source of village doctors’ income. Conclusion The barefoot doctor policy has played a significant role in providing basic human resources for health and basic health services to rural populations when rural area had great shortages of health resources. The key experiences for this great achievement are the intersection between the community and the formal health system, and sustained and stable financial compensation to the community health workers.

Abstract The gut microbiota is involved in various physiological functions, and disturbances in the host-microbiome have been proven to contribute to the dysfunction of gut; however, whether microbiota participates in the pathogenesis of constipation remains unclear. In this study, we extracted and analyzed microbiota in feces from constipated donors who had undergone effective therapy with fecal microbiota transplantation, transplanted microbiota into pseudo-germ-free mice, and measured gut motility. These mice presented with lower pellet frequency and water percentage, smaller pellet size, delayed gastrointestinal transit time, and weaker spontaneous contractions of colonic smooth muscle. To determine the mechanism underlying delayed gut motility, microbial metabolites were measured. Short chain fatty acids and secondary bile acids were decreased in mice receiving microbiota from constipated donors. Moreover, the compositional changes of gut microbiota in constipated patients were identified, including the operational taxonomic unit, and the species richness and α diversity were much greater than those in healthy volunteers. These findings suggest that alterations of the microbiome might affect gut motility via altered microbial-derived metabolites in the development of constipation, and the restoration of disturbed microbiota might improve the clinical phenotype. This study indicates that regulating the intestinal environment may be a novel therapy strategy for constipation.