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Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Abstract Background Fluid overload (FO) after resuscitation is frequent and contributes to adverse outcomes among postinjury open abdomen (OA) patients. Bioelectrical impedance analysis (BIA) is a promising tool for monitoring fluid status and FO. Therefore, we sought to investigate the efficacy of BIA-directed fluid resuscitation among OA patients. Methods A pragmatic, prospective, randomized, observer-blind, single-center trial was performed for all trauma patients requiring OA between January 2013 and December 2017 to a national referral center. A total of 140 postinjury OA patients were randomly assigned in a 1:1 ratio to receive either a BIA-directed fluid resuscitation (BIA) protocol that included fluid administration with monitoring of hemodynamic parameters and different degrees of interventions to achieve a negative fluid balance targeting the hydration level (HL) measured by BIA or a traditional fluid resuscitation (TRD) in which clinicians determined the fluid resuscitation regimen according to traditional parameters during 30 days of ICU management. The primary outcome was the 30-day primary fascial closure (PFC) rate. The secondary outcomes included the time to PFC, postoperative 7-day cumulative fluid balance (CFB) and adverse events within 30 days after OA. The Kaplan–Meier method and the log-rank test were utilized for PFC after OA. A generalized linear regression model for the time to PFC and CFB was built. Results A total of 134 patients completed the trial (BIA, n = 66; TRD, n = 68). The BIA patients were significantly more likely to achieve PFC than the TRD patients (83.33% vs. 55.88%, P

Ammonia stress and nitrite stress can induce immune depression and oxidative stress in Litopenaeus vannami (L. vannamei). Earlier reports showed that L. vannamei immunity, resistance to ammonia stress, and resistance to nitrite stress improved after Tian–Dong–Tang–Gan Powder (TDTGP) treatment, but the mechanism is not clear. In this study, three thousand L. vannamei were fed different doses of TDTGP for 35 days and then subjected to ammonia and nitrite stress treatments for 72 h. Transcriptome and 16-Seq ribosomal RNA gene sequencing (16S rRNA-seq) were used to analyze hepatopancreas gene expression and changes in gut microbiota abundance in each group. The results showed that after TDTGP treatment, hepatopancreas mRNA expression levels of immunity- and antioxidant-related genes were increased, the abundance of Vibrionaceae in the gut microbiota was decreased, and the abundance of Rhodobacteraceae and Flavobacteriaceae was increased. In addition, after TDTGP treatment, the effects of ammonia and nitrite stress on the mRNA expression of Pu, cat-4, PPAF2, HO, Hsp90b1, etc. were reduced and the disruption of the gut microbiota was alleviated. In short, TDTGP can regulate the immunity and antioxidant of L. vannamei by increasing the expression levels of immunity- and antioxidant-related genes and regulating the abundance of Rhodobacteraceae and Flavobacteriaceae in the gut microbiota.

The experiment was designed to investigate the modulating effect of Cangpu Wumei powder on the immune function of the organism. Cyclophosphamide was used to induce immunosuppression in mice, and different doses of Cangpu Wumei powder were administered to both immunosuppressed and normal mice via gavage. A total of 128 Kunming mice, half male and half female, were randomly divided into eight groups, with 16 mice in each group: The blank control group, the cyclophosphamide model group, the low-dose Cangpu Wumei powder group (0.8 g/kg BW), the medium-dose Cangpu Wumei powder group (1.6 g/kg BW), the high-dose Cangpu Wumei powder group (3.2 g/kg BW), the cyclophosphamide + low-dose Cangpu Wumei powder group, the cyclophosphamide + medium-dose Cangpu Wumei powder group, and the cyclophosphamide + high-dose Cangpu Wumei powder group. The experimental period lasted for seven days. The results showed that the administration of each dose of Cangpu Wumei powder for seven consecutive days could significantly increase the levels of interleukin-2 (IL-2), interleukin-6 (IL-6), immunoglobulin G (IgG), and interleukin-1β (IL-1β) in the serum of immunosuppressed mice, increase the body weight, spleen index, and thymus index of mice, and repair the atrophy of splenic follicles, unclear thymic structure, and necrosis of lymphocytes induced by cyclophosphamide, with the medium dose showing the best effect. The experiment shows that Cangpu Wumei powder can antagonise the immunosuppression induced by cyclophosphamide, repair the damage of spleen and thymus, and has an immune-enhancing effect. Based on the results of cytokines and histopathologic findings, the best dosage of Cangpu Wumei powder to enhance the immunological function in mice is 1.6 g/kg BW. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β1 (TGF-β1) acts as a tumor promoter in advanced prostate cancer (PCa). We speculated that microRNAs (miRNAs) that are inhibited by TGF-β1 might exert anti-tumor effects. To assess this, we identified several miRNAs downregulated by TGF-β1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA. miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue, and its expression level correlated inversely with aggressive clinical pathological features. Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation, migration, and invasion, and promoted apoptosis. The miR-3691-3p target genes E2F transcription factor 3 (E2F3) and PR domain containing 1, with ZNF domain (PRDM1) were upregulated in miR-3691-3p-overexpressing PCa cells, and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation, migration, and invasion. Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis. Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p, both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue. Our results indicate that TGF-β1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1. These results provide novel insights into the mechanisms by which TGF-β1 contributes to the progression of PCa.

Abstract Background Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. Objectives The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). Methods The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. Results We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. Conclusions Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.

Natural products, characterized by intriguing scaffold diversity and structural complexity, as well as significant agricultural and medicinal activities, have been a valuable source of agrochemicals/drugs development and have historically made a huge contribution to pharmacotherapy. Structurally, bisabolanes are a family of naturally occurring sesquiterpenoids that featured a hexatomic ring core incorporating with eight continuous carbons, which cause high structural variability along the alkyl side chain to form abundant functionalities. Moreover, apart from their interesting structures, bisabolanes have shown multitudinous bioactivities. Bisabolanes are distributed in a variety of marine invertebrates, terrestrial plant, and microbial sources. Interestingly, bisabolanes characterized from marine environment possess unique characteristics both structurally and biologically. A total of 296 newly-discovered bisabolanes were searched. Among them, 94 members were isolated from marine organisms. This review particularly focuses on the new bisabolanes characterized from marine organisms (covering from 2000 to 2021), including marine-derived fungi, algae, soft corals, and sponges, with emphasis on the diversity of their chemical structures as well as the novelty and differences between terrestrial and marine sources. Moreover, a wide range of bioactivities of marine-derived bisabolanes, including antimicrobial, anti-inflammatory, enzyme inhibitory, and cytotoxic properties, are presented herein, which is considered to be a promising resource for the discovery of new drug leads and agrochemicals.

Persistent high-risk HPV infection drives tumorigenesis in various human malignancies, including cervical, oropharyngeal, anal, and vulvar carcinomas. Although HPV-related tumors arise in several different sites, they share many common genetic and epigenetic events. Complex and heterogeneous genomic aberrations and mutations induced by high-risk HPV contribute to the initiation and progression of cervical cancer (CC). However, the associations between high-risk HPV infection and DNA methylation have not been clearly investigated. In the present study, HPV-related gene promoter methylation signature was comprehensively analyzed using multiple interactive platforms. CC patients were successfully classified into high-risk and low-risk groups with significant differences in clinical outcomes based on the HPV-related gene promoter methylation signature. Moreover, the protein levels of ALDH1A2 and clinical prognostic value were confirmed in the CC patients cohort. In summary, our study provides compelling evidence that HPV-related gene promoter methylation signature serves as a strong prognostic signature for CC patients. Clinical investigations in large CC patient cohorts are greatly needed to pave the way to implement epigenetic biomarkers into better clinical management.

Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury (AKI). However, the potential function of MSCs in chronic kidney disease remains elusive. Renal fibrosis is the common endpoint of chronic progressive kidney diseases and causes a considerable health burden worldwide. In this study, the protective effects of bone marrow mesenchymal stem cells (BM-MSCs) were assessed in repeated administration of low-dose cisplatin-induced renal fibrosis mouse model in vivo as well as a TGF-β1-induced fibrotic model in vitro. Differentially expressed miRNAs in mouse renal tubular epithelial cells (mRTECs) regulated by BM-MSCs were screened by high-throughput sequencing. We found microRNA (miR)-146a-5p was the most significant up-regulated miRNA in mRTECs. In addition, the gene Tfdp2 was identified as one target gene of miR-146a-5p by bioinformatics analysis. The expression of Tfdp2 in the treatment of BM-MSCs on cisplatin-induced renal injury was evaluated by immunohistochemistry analysis. Our results indicate that BM-MSC attenuates cisplatin-induced renal fibrosis by regulating the miR-146a-5p/Tfdp2 axis in mRTECs.

Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), have been found in a variety of tumor entities and play distinct roles in the pathogenesis and development of various cancers including head and neck cancer (HNC). HNC is a heterogeneous disease arising from the mucosal epithelia of the upper aerodigestive tract, including different anatomic sites, distinct histopathologic types, as well as human papillomavirus (HPV)-positive and negative subgroups. Despite advances in multi-disciplinary treatment for HNC, the long-term survival rate of patients with HNC remains low. Emerging evidence has revealed the members of UCHs are associated with the pathogenesis and clinical prognosis of HNC, which highlights the prognostic and therapeutic implications of UCHs for patients with HNC. In this review, we summarize the physiological and pathological functions of the UCHs family, which provides enlightenment of potential mechanisms of UCHs family in HNC pathogenesis and highlights the potential consideration of UCHs as attractive drug targets.

The management of enterocutaneous fistulas (ECF) can be challenging because of massive fluid loss, which can lead to electrolyte imbalance, severe dehydration, malnutrition and sepsis. Nutritional support plays a key role in the management and successful closure of ECF. The principle of nutritional support for patients with ECF should be giving enteral nutrition (EN) priority, supplemented by parenteral nutrition if necessary. Although total parenteral nutrition (TPN) may be indicated, use of enteral feeding should be advocated as early as possible if patients are tolerant to it, which can protect gut mucosal barrier and prevent bacterial translocation. A variety of methods of enteral nutrition have been developed such as fistuloclysis and relay perfusion. ECF can also be occluded by special devices and then EN can be implemented, including fibrin glue application, Over-The-Scope Clip placement and three-dimensional (3D)-printed patient-personalized fistula stent implantation. However, those above should not be conducted in acute fistulas, because tissues are edematous and perforation could easily occur.

Background: Intestinal fistula is one of the common complications of Crohn's disease (CD) that might require surgical treatment. The clinical characteristics and outcomes of CD with intestinal fistula are much different from CD alone. This study was to investigate whether the coagulation status of CD is changed by intestinal fistula. Methods: Data were retrospectively analyzed for 190 patients with a definitive diagnosis of CD who were registered at the Jinling Hospital between January 2014 and September 2015. Baseline clinical characteristics and laboratory indices of initial admission and 7 days after intestinal fistula resections were collected. Student's t-test and the Wilcoxon rank-sum test were used to compare differences between the two groups. Results: Compared with CD patients without intestinal fistula, prothrombin time (PT) in patients with intestinal fistula was significantly longer (12.13 ± 1.27 s vs. 13.18 ± 1.51 s, P < 0.001 in overall cohort; 11.56 ± 1.21 s vs. 12.61 ± 0.73 s, P = 0.001 in females; and 12.51 ± 1.17 s vs. 13.37 ± 1.66 s, P = 0.003 in males). Platelet (PLT) count was much lower in intestinal fistula group than in nonintestinal fistula group (262.53 ± 94.36 × 109/L vs. 310.36 ± 131.91 × 109/L, P = 0.009). Multivariate logistic regression showed that intestinal fistula was significantly associated with a prolonged PT (odds ratio [OR] = 1.900, P < 0.001), a reduced amount of PLT (OR = 0.996, P = 0.024), and an increased operation history (OR = 5.408, P < 0.001). Among 65 CD patients receiving intestinal fistula resections, PT was obviously shorter after operation than baseline (12.28 ± 1.16 s vs. 13.02 ± 1.64 s, P = 0.006). Conclusions: Intestinal fistula was significantly associated with impaired coagulation status in patients complicated with CD. Coagulation status could be improved after intestinal fistula resections.

Background: Most studies on enhanced recovery after surgery (ERAS) for gastric cancer exclude patients who received neoadjuvant chemotherapy. Here, we aimed to evaluate whether patients who received neoadjuvant chemotherapy can be enrolled into the ERAS program for locally advanced gastric cancer. Methods: From April 2015 to July 2017, 114 patients who received neoadjuvant chemotherapy for locally advanced gastric cancer were randomized into ERAS and standard care (SC) groups. Postoperative length of stay, complications, bowel function, and nutritional status were recorded. Results: The postoperative length of stay of the ERAS group was shorter compared with that of the SC group (5.9 ± 5.6 vs. 8.1 ± 5.3 days, P = 0.037). The postoperative complication rate was 9.3% in the ERAS group and 11.5% in the SC group (P = 0.700). The time to first flatus (2.7 ± 2.0 vs. 4.5 ± 4.6 days, P = 0.010) and time to a semi-liquid diet (3.2 ± 2.1 vs. 6.3 ± 4.9 days, P < 0.001) in the ERAS group were shorter compared with those in the SC group. On the 10th day after surgery, the values of weight, total protein, albumin, and prealbumin of the ERAS group were lower compared with those of the SC group. Conclusions: Patients who received neoadjuvant chemotherapy could be enrolled into ERAS programs for locally advanced gastric cancer. The nutritional status of these patients was not adversely affected.

Abstract Background Rabies is a global fatal infectious viral disease that is characterized by a high mortality after onset of clinical symptoms. Recently, there has been an increase in the incidence of rabies in China. The aim of this study was to investigate the incidence of human rabies and characterize the rabies virus nucleoprotein gene in dogs sampled from Fujian Province, Southeast China from 2002 to 2012. Methods Data pertaining to human rabies cases in Fujian Province during the period from 2002 through 2012 were collected, and the epidemiological profiles were described. The saliva and brain specimens were collected from dogs in Quanzhou, Longyan and Sanming cities of the province, and the rabies virus antigen was determined in the canine saliva specimens using an ELISA assay. Rabies virus RNA was extracted from canine brain specimens, and rabies virus nucleoprotein gene was amplified using a nested RT-PCR assay, followed by sequencing and genotyping. Results A total of 226 human rabies cases were reported in Fujian Province from 2002 to 2012, in which 197 cases were detected in three cities of Quanzhou, Longyan and Sanming. ELISA assay revealed positive rabies virus antigen in six of eight rabid dogs and 165 of 3492 seemingly healthy dogs. The full-length gene fragment of the rabies virus nucleoprotein gene was amplified from the brain specimens of seven rabid dogs and 12 seemingly healthy dogs. Sequence alignment and phylogenetic analysis revealed that these 19 rabies virus nucleoprotein genes all belonged to genotype I, and were classified into three genetic groups. Sequencing analysis showed a 99.7% to 100% intra-group and an 86.4% to 89.3% inter-group homology. Conclusions This study is the first description pertaining to the epidemiological characteristics of human rabies cases and characterization of the rabies virus nucleoprotein gene in dogs in Fujian Province, Southeast China. Our findings may provide valuable knowledge for the development of strategies targeting the prevention and control of rabies.

Anomalous origin of the right coronary artery from pulmonary artery (ARCAPA) is a rare congenital anomaly of the coronary circulation, which can be easily missed by echocardiography. Interrupted aortic arch (IAA) is another rare congenital cardiac abnormality that typically presents in the first few weeks of life. We present a case of ARCAPA associated with IAA diagnosed with the help of multidetector computed tomography angiography, in a 7-year-old boy.