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OBJECTIVE. To test the hypothesis that an altered gut microbiota (dysbiosis) plays a role in obesity-associated osteoarthritis (OA). METHODS. Stool and blood samples were collected from 92 participants with BMI ≥ 30 kg/m(2) recruited from the Johnston County Osteoarthritis Project. OA cases (n=50) had hand plus knee OA (Kellgren-Lawrence [KL] grade ≥2 or arthroplasty). Controls (N=42) had no hand OA and KL grade 0–1 knees. Compositional analysis of stool samples was carried out by 16S rRNA amplicon sequencing. Alpha and beta diversity and differences in taxa relative abundances were determined. Blood samples were used for multiplex cytokine analysis and measures of lipopolysaccharide (LPS) and LPS binding protein. Germ-free mice were gavaged with case or control pooled fecal samples and placed on a 40% fat, high sucrose diet for 40 weeks. Knee OA was evaluated histologically. RESULTS. OA cases were slightly older with more females and higher BMI, WOMAC pain and KL grades than controls. There were no significant differences in alpha or beta diversity or genus level composition between cases and controls. Cases had higher plasma levels of osteopontin (p=0.01) and serum LPS (p

Western diet consumption during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes persist in adulthood following healthy dietary intervention is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar or both sugar and fat on metabolic outcomes, HPC function, and gut microbiota.Adolescent female rats (PN 26) were fed a standard chow diet (CHOW), chow with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing various foods high in fat and/or sugar. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated. In a subsequent experiment, these outcomes were evaluated following a 5-week dietary intervention where CAF and SUG groups were maintained on standard chow alone.Both CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to the CHOW group. However, impaired peripheral glucose regulation was only observed in the SUG group. When examined following a healthy dietary intervention in a separate experiment, metabolic dysfunction was not observed in either the CAF or SUG group, whereas HPC-dependent memory impairments were observed in the CAF but not the SUG group. In both groups the composition of the gut microbiota remained distinct from CHOW rats after the dietary intervention.While the metabolic impairments associated with adolescent junk food diet consumption are not present in adulthood following dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.

Introduction Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps. Material and methods Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance. Results Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown. Conclusion International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns.

We herein report a facile method to fabricate a multifunctional cancer theranostic nanoplatform via Fe3+-driven assembly of photosensitizer (chlorine e6, Ce6)-decorated red emissive carbon dots (Ce...

The upper aerodigestive tract (UAT) is the first line of defense against environmental stresses such as antigens, microbes, inhalants, foods, etc., and mucins, intracellular junctions, epithelial cells, and immune cells are the major constituents of this defensive mucosal barrier. Laryngopharyngeal reflux (LPR) is recognized as an independent risk factor for UAT mucosal disorders, and in this review, we describe the components and functions of the mucosal barrier and the results of LPR-induced mucosal inflammation in the UAT. We discuss the interactions between the refluxate and the mucosal components and the mechanisms through which these damaging events disrupt and alter the mucosal barriers. In addition, we discuss the dynamic alterations in the mucosal barrier that might be potential therapeutic targets for LPR-induced disorders.

Summary Background Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. Methods This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18–75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0–3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1–14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov , NCT02022098 , and is still active but not recruiting. Findings Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6–29·4) in the Debio 1143 group and 24·2 months (6·6–26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 20–48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13–6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3–4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. Interpretation To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. Funding Debiopharm.

Chlamydia pneumonia (C.pn) is a common respiratory pathogen that is involved in human cardiovascular diseases and promotes the development of atherosclerosis in hyperlipidemic animal models. C.pn reportedly up-regulated lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells. Recently, the anti-atherosclerotic activity of peroxisome proliferator-activated receptor γ (PPARγ) has been documented. In the present study, we investigated the effect of C.pn on LOX-1 expression in human umbilical vein endothelial cells (HUVECs) and identified the involvement of the PPARγ signaling pathway therein. The results showed that C.pn increased the expression of LOX-1 in HUVECs in a dose- and time-dependent manner. C.pn-induced up-regulation of LOX-1 was mediated by ERK1/2, whereas p38 MAPK and JNK had no effect on this process. C.pn induced apoptosis, inhibited cell proliferation, and decreased the expression PPARγ in HUVECs. Additionally, LOX-1 activity and cell injury caused by C.pn through activation of ERK1/2 was completely inhibited by rosiglitazone, a PPARγ agonist. In conclusion, we inferred that activation of PPARγ in HUVECs suppressed C.pn-induced LOX-1 expression and cell damage by inhibiting ERK1/2 signaling.

There could be an overlap of monogenic diabetes and early-onset type 2 diabetes mellitus. Precise diagnosis of early-onset diabetes has proven valuable for understanding the mechanism of diabetes and selecting optimal therapy. The majority of maturity onset diabetes of the young (MODY) pathogenic genes in China is still unknown. In this study, a family with suspected MODY was enrolled. Whole-exome sequencing (WES) was used to analyze the variants of the proband. Variants were filtered according to their frequency, location, functional consequences, and bioinformatics software. Candidate pathogenic variants were validated by Sanger sequencing and tested for cosegregation in other members of the family and nonrelated healthy controls. KEGG (Kyoto Encyclopedia of Genes and Genomes) and PPI (protein-protein interaction) analysis were conducted using the DAVID (Database for Annotation, Visualization, and Integrated Discovery) and the STRING online analysis tools for the candidate pathogenic gene. A total of 123291 variants including 105344 SNPs and 17947 InDels were found in WES. A likely pathogenic rare missense heterozygous mutation in diabetes genes (c.2137C > T, p.His713Tyr in IRS1) was identified, which was a cosegregate in this family and not in nonrelated healthy controls. The position of the mutation in the aminoacid sequence of the gene is highly conserved among the species. 2 significantly enriched KEGG pathways were identified including bta04930, type II diabetes mellitus (GCK, INS, PDX1, ABCC8, and IRS1), and bta04910, insulin signaling pathway (GCK, INS, and IRS1). PPI analysis displayed that IRS1 interacts with 3 known pathogenic proteins including INS, KCNJ11, and GCK. We conclude that WES could be an initial option for genetic testing in patients with early-onset diabetes. IRS1 p.His713Tyr is implicated as a possible pathogenic mutation in monogenic diabetes, which might require further validation, and the precise molecular mechanism underlying the influence of IRS1 p.His713Tyr on the development of diabetes remains to be determined in the further prospective studies.

As nanomedicine-based clinical strategies have continued to develop, the possibility of combining chemotherapy and singlet oxygen-dependent photodynamic therapy (PDT) to treat pancreatic cancer (PaC) has emerged as a viable therapeutic modality. The efficacy of such an approach, however, is likely to be constrained by the mechanisms of drug release and tumor oxygen levels. In the present study, we developed an Fe(III)-complexed porous coordination network (PCN) which we then used to encapsulate PTX (PCN-Fe(III)-PTX) nanoparticles (NPs) in order to treat PaC via a combination of chemotherapy and PDT. The resultant NPs were able to release drug in response to both laser irradiation and pH changes to promote drug accumulation within tumors. Furthermore, through a Fe(III)-based Fenton-like reaction these NPs were able to convert H2O2 in the tumor site to O2, thereby regulating local hypoxic conditions and enhancing the efficacy of PDT approaches. Also these NPs were suitable for use as a T1-MRI weighted contrast agent, making them viable for monitoring therapeutic efficacy upon treatment. Our results in both cell line and animal models of PaC suggest that these NPs represent an ideal agent for mediating effective MRI-guided chemotherapy-PDT, giving them great promise for the clinical treatment of PaC.

Objective. By observing the effect of N-acetylcysteine (NAC) on the proliferation and collagen synthesis of rat cardiac fibroblasts (CFs) to explore the effect of NAC on cardiac remodeling (CR). Methods. In vivo, first, the Sprague Dawley (SD) rat myocardial hypertrophy model was constructed, and the effect of NAC on cardiac structure and function was detected by echocardiography, serological testing, and Masson staining. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression level of antioxidant enzymes, and flow cytometry was used to detect the intracellular reactive oxygen species (ROS) content. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2 ′ -deoxyuridine (EdU) staining were used to detect cell proliferation, and the expression level of the NF-κB signaling pathway was detected. Results. Compared with the control group, the model group had disordered cardiac structure, reduced cardiac function, and obvious oxidative stress (OS) response. However, after NAC treatment, it could obviously improve the rat cardiac structure and cardiac function and alleviate redox imbalance and cardiology remodeling. At the same time, NAC can inhibit the activation of the NF-κB signaling pathway and reduce the proliferation level of CFs and the amount of 3H proline incorporated. Conclusions. NAC can inhibit AngII-induced CF proliferation and collagen synthesis through the NF-κB signaling pathway, alleviate the OS response of myocardial tissue, inhibit the fibrosis of myocardial tissue, and thus slow down the pathological remodeling of the heart.

The aim of the current cohort study was to explore the relationship between return to work (RTW) after cervical cancer treatment and different medical and occupational covariates. We also investigated the effect of RTW on all-cause mortality and survival outcomes of cervical cancer survivors. Data were collected between 2004 and 2015 from the database of the Taiwan Cancer Registry, Labor Insurance Database, and National Health Insurance Research Database. The associations between independent variables and RTW were analyzed by Cox proportional hazard models. A total of 4945 workers (82.3%) who returned to work within 5 years after being diagnosed with cervical cancer. Patients who underwent surgical treatment were more likely to RTW by the 5th year compared to other groups, with a hazard ratio (HR) of 1.21 (95% CI: 1.01~1.44). Small company size and a monthly income greater than NT 38,200 were inversely associated with RTW (HR = 0.91, 95% CI: 0.84~0.98 and HR = 0.48, 95% CI: 0.44~0.53). Furthermore, RTW showed a statistically significant decrease in the risk of all-cause mortality in the fully adjusted HR, (HR = 0.42, p &lt, 0.001). Some medical and occupational factors are associated with RTW in cervical cancer survivors. Returning to work may have a beneficial effect on the survival of patients with cervical cancer.

OBJECTIVES/HYPOTHESIS Vocal fold (VF) fibroblasts are the central target for developing new strategies for the treatment of VF scarring and fibrosis. Asiatic acid (AA) is a triterpenoid derivate with antifibrotic properties. However, the effect of AA in VF scarring is poorly understood. The objective of this study was to investigate the potential application of AA as a therapeutic treatment in VF scarring. STUDY DESIGN Xxxxx. METHODS The functional expression of SMAD7 was knocked down with recombinant adenoviruses and adeno-associated viruses carrying shRNAs in the in vitro and in vivo models, which were constructed to investigate AA's antifibrotic function. The expression of collagens and SMADs in cultured human and rabbit cell lines and animal models was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry labeling, respectively. Cell migration capacity and contraction in VF fibroblast cell lines were also evaluated. RESULTS AA downregulated the downstream fibrotic activation in a dose-dependent manner. Meanwhile, AA attenuated VF scarring/fibrosis by reducing collagen deposition. Furthermore, the antifibrotic effects of AA were associated with the upregulation of SMAD7. In contrast, knockdown of SMAD7 inhibited the effect of AA on transforming growth factor-beta-1 (TGF-β1) stimulation, which suggests a central role for SMAD7 in AA-induced antifibrotic activities during VF fibrosis. CONCLUSION We concluded that AA, which is a novel therapeutic candidate for preventing VF scarring/fibrosis, might exert its antifibrotic effect via the TGF-β1/SMAD signaling pathway. LEVEL OF EVIDENCE N/A Laryngoscope, 2021.

Background The vaginal microbiome has been associated with adverse pregnancy outcomes, but information on the impact of diet on microbiome composition is largely unexamined. Objective To estimate the association between prenatal diet and vaginal microbiota composition overall and by race. Methods We leveraged a racially diverse prenatal cohort of North Carolina women enrolled between 1995 and 2001 to conduct this analysis using cross-sectional data. Women completed food frequency questionnaires about diet in the previous 3 months and foods were categorised into subgroups: fruits, vegetables, nuts/seeds, whole grains, low-fat dairy, sweetened beverages and red meat. We additionally assessed dietary vitamin D, fibre and yogurt consumption. Stored vaginal swabs collected in mid-pregnancy were sequenced using 16S taxonomic profiling. Women were categorised into three groups based on predominance of species: Lactobacillus iners, Lactobacillus miscellaneous and Bacterial Vaginosis (BV)-associated bacteria. Adjusted Poisson models with robust variance estimators were run to assess the risk of being in a specific vagitype compared to the referent. Race-stratified models (Black/White) were also run. Results In this study of 634 women, higher consumption of dairy was associated with increased likelihood of membership in the L. crispatus group compared to the L. iners group in a dose-dependent manner (RR quartile 4 vs. 1: 2.01 [95% CI: 1.36, 2.95]). Increased intake of fruit, vitamin D, fibre and yogurt was also associated with increased likelihood of membership in L. crispatus compared to L. iners, but only among black women. Statistical heterogeneity was only detected for fibre intake. There were no detected associations between any other food groups or risk of membership in the BV group. Conclusions Higher consumption of low-fat dairy was associated with increased likelihood of membership in a beneficial vagitype, potentially driven by probiotics.

Simple Summary Triple-negative breast cancer (TNBC) with negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) is considered to be associated with poorer outcomes and a higher risk of recurrence or metastasis owing to a lack of effective targeted therapeutic drugs. The epidermal growth factor receptor (EGFR) functions is a driver of disease progression in most of TNBC that represents a viable target that can be leveraged to guide the intra-tumoral delivery of chemotherapeutic drugs in TNBC patients. Moreover, ultrasound-mediated cavitation (UMC) strategies increase tissue permeability and extravasation through nuclei-dependent cavitation via sonoporation, thus enabling drugs to better enter target tissues. In this research, a combination of active, targeting nano-micelles and UMC was able to inhibit TNBC tumor growth effectively at lower concentrations while reducing treatment-related toxicity. Thus, this is a very promising treatment strategy in the clinical therapy with TNBC and other cancer types. Abstract Triple-negative breast cancer (TNBC) is highly recurring and metastatic breast cancer with overexpressing epidermal growth factor receptor (EGFR). Herein, a series of in vitro and in vivo analyses were used to explore the therapeutic effect of EGFR-targeting nano-micelles (PLGA-PEG/DOX@anti-EGFR) combined with ultrasound-mediated cavitation (UMC). The prepared nano-micelle drug carriers have good biocompatibility and can greatly increase the drug accumulation in tumor regions, thereby reducing off-target toxicity while enhancing anti-tumor efficacy. Moreover, an in vivo analysis of the practical utility of this treatment modality was conducted by using SonoVueTM microbubbles to achieve cavitation under different power intensity levels, with an ultrasonic power intensity of 0.5 W/cm2 maximizing the intra-tumoral blood perfusion. Relative to PLGA-PEG@DOX/anti-EGFR nano-micelles treatment alone, the combination with UMC was better able to suppress tumor growth even at low concentrations. As such, combining actively targeted drug-carrier molecules with UMC represents an effective approach to enhancing therapeutic efficacy while reducing the adverse, systemic effects associated with DOX and other chemotherapeutic drugs, and it can be considered as a promising clinical prospect in the treatment of TNBC.

Accumulating evidence indicates the association between obesity and lung function. However, no previous study has examined whether obesity affects lung function in normal weight participants with high body fat. We hypothesized that subjects with normal weight obesity (NWO) were inversely associated with lung function in Taiwan. The study sample was composed of participants who attended health examinations at the Tri-Service General Hospital from 2010 to 2016. A total of 7801 eligible participants who were classified as NWO were divided into quartiles by percentage body fat (PBF), which was measured by bioelectrical impedance analysis (BIA). A multivariable linear regression was performed to assess the association between PBF quartiles and pulmonary function. The relationship between PBF and the presence of obstructive and restrictive lung diseases was analyzed by a logistic regression. PBF quartiles were closely associated with reduced forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in all adjusted models. This relationship remained significant in the male population, and a dose-dependent effect was observed. Increased PBF was associated with increased risks for the presence of restrictive lung diseases. These results presented a novel finding that body fat exhibited an inverse association with pulmonary function in NWO subjects. More comprehensive management of subjects with normal weight but high body fat, which might contribute to metabolic dysfunction and impaired pulmonary function, is needed.

Osteoporosis is one of the major complications in chronic hepatitis B virus (HBV) and hepatitis C (HCV) infection. However, few studies had examined the relationship between hepatic viral infection with bone loss. Our aim was to investigate the association between hepatic viral infection with bone mineral density (BMD) in a cross-sectional study. Participants who attended the health examinations at the Tri-Service General Hospital (TSGH), Taiwan, were enrolled in the study. Diagnosis of viral hepatitis was confirmed by the serum viral markers of hepatitis B surface antigen (HBsAg) and anti-HCV, and BMD measurement was performed by the bone densitometry. Subjects were divided into four groups by the presence of viral markers. The association between hepatic viral infection and BMD was examined by a multivariate linear regression model. HBV infection was inversely associated with BMD after full adjusting with β values of −0.17 (95% CI: −0.29, −0.05) (p β = −0.16, 95% CI = −0.31, −0.01) (p

Constructing nanocarriers with high drug loading capacity is a challenge, which limits the effective delivery of drugs to solid tumors. Here, we reported a one-pot synthesis of hollow nanoparticles (NPs) encapsulated by doxorubicin (DOX) and modified with polydopamine (PDA) to form PDA@DOX NPs for breast cancer treatment. PDA@DOX NPs demonstrated exceptionally high capacity (53.16%) for loading DOX. In addition, when PDA@DOX NPs were administered systemically, they exhibited responsive aggregation in the tumor sites and demonstrated a good controlled release effect for DOX due to the weak acidic environment of the tumor sites and targeting near-infrared (NIR) light irradiation. The PDA outer layer absorbed the near-infrared (NIR) light and facilitated simultaneous generation of heat energy for destroying the tumor cells to release the drug upon NIR irradiation. Moreover, this NIR-activated combined/synergistic therapy exhibited remarkably complete tumor growth suppression in a breast cancer mouse model. Importantly, NPs exhibited a good ultrasound performance both in vitro and in vivo, which could monitor the treatment process. In conclusion, this NIR-activated PDA@DOX NP system is demonstrated as a good US-guided combination (chemotherapy + PTT) therapy platform with high loading capacity and controlled drug release characteristics, which is promising for the treatment of breast cancer.

BACKGROUND There are few data on the prevalence of gestational diabetes (GDM) in pregnant women living with HIV (WLHIV) in sub-Saharan Africa, particularly those using integrase strand transfer inhibitors such as dolutegravir (DTG). METHODS We prospectively enrolled pregnant WLHIV and pregnant women without HIV ≥18 years old in Gaborone, Botswana, excluding those with pre-existing diabetes. We screened for GDM using a 75 g oral glucose tolerance test (OGTT) performed at 24-28 weeks' gestation or at the earliest prenatal visit for those presenting after 28 weeks. Logistic regression models were fitted to assess the association between maternal HIV infection and GDM. Subgroup analyses were performed among WLHIV to assess the association between maternal antiretroviral therapy (ART) in pregnancy [DTG vs. efavirenz (EFV) with tenofovir/emtricitabine] and GDM. RESULTS Of 486 pregnant women, 66.5% were WLHIV, and they were older than women without HIV (median age 30 vs. 25 years, P

ObjectiveConsumption of a Western diet during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes are reversible in adulthood following intervention with a healthy diet is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar alone, or sugar and fat on metabolic outcomes, HPC-dependent memory, and gut microbiota.MethodsAdolescent female rats (PN 26) were fed a standard chow diet (CTL), a chow diet with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing a variety of fat- and/or sugar-enriched foods. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated both before and after a 5-week dietary intervention period where all groups were fed a diet of water standard chow.ResultsPrior to the dietary intervention both the CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to controls. However, impaired peripheral glucose regulation was only observed in the SUG group. The dietary intervention reversed the metabolic dysfunction in both the CAF and SUG groups, whereas HPC-dependent memory impairments were reversed in the SUG, but not the CAF group. The composition of the gut microbiota remained distinct from controls in both groups after dietary intervention.ConclusionsWhile the metabolic impairments associated with adolescent cafeteria diet consumption are reversible in adulthood with dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.

In tropical and subtropical regions, mosquito-borne dengue virus (DENV) infections can lead to severe dengue, also known as dengue hemorrhage fever, which causes bleeding, thrombocytopenia, and blood plasma leakage and increases mortality. Although DENV-induced platelet cell death was linked to disease severity, the role of responsible viral factors and the elicitation mechanism of abnormal platelet activation and cell death remain unclear. DENV and virion-surface envelope protein domain III (EIII), a cellular binding moiety of the virus particle, highly increase during the viremia stage. Our previous report suggested that exposure to such viremia EIII levels can lead to cell death of endothelial cells, neutrophils, and megakaryocytes. Here we found that both DENV and EIII could induce abnormal platelet activation and predominantly necrotic cell death pyroptosis. Blockages of EIII-induced platelet signaling using the competitive inhibitor chondroitin sulfate B or selective Nlrp3 inflammasome inhibitors OLT1177 and Z-WHED-FMK markedly ameliorated DENV- and EIII-induced thrombocytopenia, platelet activation, and cell death. These results suggest that EIII could be considered as a virulence factor of DENV, and that Nlrp3 inflammasome is a feasible target for developing therapeutic approaches against dengue-induced platelet defects.

Abnormal immune responses and cytokine storm are involved in the development of severe dengue, a life-threatening disease with high mortality. Dengue virus-induced neutrophil NETosis response is associated with cytokine storm; while the role of viral factors on the elicitation of excessive inflammation mains unclear. Here we found that treatments of dengue virus envelope protein domain III (EIII), cellular binding moiety of virion, is sufficient to induce neutrophil NETosis processes in vitro and in vivo. Challenges of EIII in inflammasome Nlrp3−/− and Casp1−/− mutant mice resulted in less inflammation and NETosis responses, as compared to the wild type controls. Blockages of EIII-neutrophil interaction using cell-binding competitive inhibitor or selective Nlrp3 inflammasome inhibitors OLT1177 and Z-WHED-FMK can suppress EIII-induced NETosis response. These results collectively suggest that Nlrp3 inflammsome is a molecular target for treating dengue-elicited inflammatory pathogenesis.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytes in vitro. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIII in vitro. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome–deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.

Background and Aims: Changes in the esophageal microbiome have been reported in children with eosinophilic esophagitis (EoE), but few data exist for adults. We aimed to determine whether the esophageal microbiome differs in adults with and without EoE. Methods: In a prospective cohort study, adults undergoing outpatient endoscopy were enrolled as incident EoE cases or non-EoE controls. Clinical, endoscopic, and histologic data were collected. An esophageal biopsy was utilized for microbiome analysis. Bacterial DNA was extracted and the V3-V4 region of the 16S rRNA gene was amplified and sequenced. Analyses were performed comparing microbiome features for cases and controls, and within cases for disease features, with correction for multiple hypothesis testing. Results: A total of 24 incident EoE cases (mean age 40 years; 63% male; 100% white; 97 eos/hpf) and 25 controls (mean age 48, 36% male; 76% white; 1 eos/hpf) were analyzed. Principal coordinate analysis ordination failed to distinguish cases from controls. There were no microbiome differences within EoE cases based on clinical phenotype, presence of atopy, or endoscopic features. Use of proton pump inhibitors (PPIs), however, was significantly associated with 5 taxa including SR1 at the phylum level and Burkholderia at the genus level. Conclusions: There were no significant differences in the esophageal microbiome between newly diagnosed EoE cases and non-EoE controls in adults, or within EoE cases based on clinical features. However, given the strong rationale for the esophageal microbiome in EoE pathogenesis, future studies should explicitly consider the presence of PPIs as a confounding feature.

Ultraviolet (UV) radiation from sunlight has various adverse effects, thus, UV blockage is recommended for preventing sunburn. Common sunscreen ingredients, such as nanosized titanium dioxide and zinc oxide, offer effective protection and enhance cosmetic appearance, however, health concerns have been raised regarding their photocatalytic activity, which generates reactive oxygen species under UV illumination. Silver nanoparticles (AgNPs) are known as safe materials for use in a wide spectrum of biomedical applications. In vitro studies have revealed that AgNPs may have a protective effect against UV irradiation, but the effects in animal studies remain unclear. The present study demonstrated that AgNPs effectively protect against UVB-induced skin damage both in cell cultures and mouse models. These results suggested that AgNPs are feasible and safe as sunscreen ingredients for protection against UVB-induced skin damage.

This study aims to analyze the gait characteristics of the elderly patients with lumbar spinal stenosis by an intelligent device for energy expenditure and activity (IDEEA) to assist clinical work. A total of 98 subjects were included in this study from January 2017 to December 2018. A total of 49 elderly outpatients with symptomatic lumbar spinal stenosis in unilateral lower extremity were included as the experimental group, and another 49 healthy subjects matched with gender, age, and body mass index (BMI) were analyzed as the control group. The gait data of the subjects (including single support, double support, SLS/DLS, swing duration, step duration, cycle duration, pulling accel, swing power, ground impact, foot fall, foot off, push off, speed, cadence, step length, and stride length) were collected to compare between the experience group and control group, the affected leg and the healthy leg in experimental group. The results of this study presented that small intermittent claudication occurred in all patients. The time of single support was significantly increased (p < 0.05). Double support, step duration, and pulling accel were increased (p < 0.05), and the Push off, speed, step length, and Stride length were decreased (p < 0.05) in the experimental group compared with the control group. Small intermittent claudication was the basic gait composition of the elderly patients with lumbar spinal stenosis that can reflect the abnormal gait characteristics by IDEEA.

Epidemiological studies suggest a positive association between obesity and fecal short-chain fatty acids (SCFAs) produced by microbial fermentation of dietary carbohydrates, while animal models suggest increased energy harvest through colonic SCFA production in obesity. However, there is a lack of human population-based studies with dietary intake data, plasma SCFAs, gut microbial, and anthropometric data. In 490 Chinese adults aged 30&ndash, 68 years, we examined the associations between key plasma SCFAs (butyrate/isobutyrate, isovalerate, and valerate measured by non-targeted plasma metabolomics) with body mass index (BMI) using multivariable-adjusted linear regression. We then assessed whether overweight (BMI &ge, 24 kg/m2) modified the association between dietary-precursors of SCFAs (insoluble fiber, total carbohydrates, and high-fiber foods) with plasma SCFAs. In a sub-sample (n = 209) with gut metagenome data, we examined the association between gut microbial SCFA-producers with BMI. We found positive associations between butyrate/isobutyrate and BMI (p-value &lt, 0.05). The associations between insoluble fiber and butyrate/isobutyrate differed by overweight (p-value &lt, 0.10). There was no statistical evidence for an association between microbial SCFA-producers and BMI. In sum, plasma SCFAs were positively associated with BMI and that the colonic fermentation of fiber may differ for adults with versus without overweight.

Background Long noncoding (lncRNA) single‐nucleotide polymorphisms (SNPs) are associated with the susceptibility to the development of various malignant tumors. The aim of this study was to investigate the roles of HOX transcript antisense intergenic RNA (HOTAIR) and its SNPs in lung cancer. Methods Initially, the expression of HOTAIR in different tumors was investigated using the online Gene Expression Profiling Interactive Analysis (GEPIA) resource. Three SNPs (rs920778, rs1899663, and rs4759314) of HOTAIR were identified using the MassArray system. Following this, the relationship between these SNPs and susceptibility to lung cancer was investigated. Results Expression of HOTAIR was found to increase in a variety of cancers, including nonsmall cell lung cancer (NSCLC). We found that the genotypes of these SNPs (rs920778, rs1899663, and rs4759314) were not significantly associated with lung cancer type, family history, lymph node metastasis, or lung cancer stage. In gender stratification, the results of rs920778 genotypes showed that, compared to genotype AA, the AG (OR = 0.344, 95% CI: 0.133–0.893, p = .028) and AG + GG (OR = 0.378, 95% CI: 0.153–0.932, p = .035) genotypes of rs920778 are protective factors against NSCLC in females. In smoking stratification, compared with AA of rs920778, the genotype AG + GG (OR = 0.507, 95% CI: 0.263–0.975, p = .042) was a protective factor against NSCLC in nonsmoking people. No statistical differences were observed in the classifications of rs1899663 and rs4759314 genotypes. Linkage disequilibrium analysis revealed a high linkage disequilibrium between the rs920778 and rs1899663 (D′ = 0.99, r 2 = .74), rs920778 and rs4759314 (D′ = 0.85, r 2 = .13), and rs1899663 and rs4759314 (D′ = 0.79, r 2 = .00). Conclusion Our study demonstrated that HOTAIR expression increased in NSCLC, and that the genotypes of rs920778 could be useful in the diagnosis and prognosis of lung cancer., This study investigated the roles of HOTAIR and its SNPs in lung cancer. We found that HOTAIR increased in nonsmall cell lung cancer, and the genotypes of rs920778 are protective factors for female patients and nonsmoking people, which are useful for screening and prognosis for lung cancer.

MYB protooncogene-like 2 (MYBL2) is a transcription factor that is upregulated and significantly associated with various human cancer types. However, the potential role of MYBL2 in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Therefore, the expression and biological functions of MYBL2 in ccRCC were assessed in the current study using The Cancer Genome Atlas (TCGA). A Wilcoxon signed-rank test was performed to compare MYBL2 expression between ccRCC and normal tissues. Moreover, the association between MYBL2 expression and various clinicopathological factors was estimated using both the Wilcoxon signed-rank test and logistic regression. The differences in prognosis between patients with high- and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis. Finally, gene set enrichment analysis (GSEA) was performed to investigate the biofunctions of MYBL2 in ccRCC. It was revealed that MYBL2 was upregulated in ccRCC, and that the MYBL2 high-expression phenotype was significantly associated with sex, a high histological grade, an advanced clinical stage, tumor stage, lymph node metastasis, distant metastasis and poor overall survival (OS). It was also revealed, via the Cox regression analysis, that the upregulation of MYBL2 expression was able to independently predict a poor prognosis in patients with ccRCC. GSEA indicated that the intestinal immune network for IgA production, primary immunodeficiency, the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, the cytosolic DNA-sensing pathway, the p53 signaling pathway and the chemokine signaling pathway were all enriched in the high-MYBL2 expression datasets. In conclusion, the present findings indicate that MYBL2 may be used as an independent prognostic factor in patients with ccRCC.

What is known and objective Hyperuricemia (HUA) and gout are considerable public health problems because of their increasing incidence and interactions with other diseases. We aimed to evaluate the efficacy and safety of urate-lowering therapies (ULTs) for patients. Methods A systematic literature review was conducted, and a network meta-analysis was performed on the included studies using the Markov Chain Monte Carlo simulation method and a Bayesian statistical framework. We calculated surface under the cumulative ranking curve (SUCRA) values and performed clustered ranking to combine the efficacy and safety results. Results Twenty-two randomized controlled studies were identified for the efficacy analysis, and 20 studies were identified for the safety analysis. Compared with the placebo, the ULTs were efficient and safe. Febuxostat 120 mg/d and allopurinol 200 mg/d had the highest SUCRA scores for efficacy and safety, respectively. Clustered ranking results showed that febuxostat 120 mg/d was the best in terms of efficacy and safety, topiroxostat 120/160 mg/d was similar to febuxostat 80 mg/d in terms of efficacy but safer, and allopurinol was not inferior to topiroxostat. What is new and conclusion Febuxostat had the best efficacy and safety results among the tested agents, and topiroxostat and allopurinol appeared to have fewer adverse events.

HOX transcript antisense intergenic RNA (HOTAIR) is considered a diagnostic biomarker for cancer; however, results of previous studies on HOTAIR are inconsistent. In this meta-analysis, we aimed to investigate the role of HOTAIR in cancer diagnosis. Medline, PubMed, Embase, Ovid, Web of Science and Cochrane databases were searched for relevant literature up to May 2019. Over all, we included 20 studies from 17 articles on the role of HOTAIR in cancer diagnosis (individual diagnosis) and 7 studies from 6 articles on the role of HOTAIR along with other biomarkers in cancer diagnosis (combinative diagnosis). The sensitivity and specificity of HOTAIR-mediated individual diagnosis of cancers were 0.80 (95% confidence interval [CI], 0.74-0.85) and 0.74 (95% CI, 0.66-0.81), respectively. The sensitivity and specificity of HOTAIR-mediated combinative diagnosis of cancer were 0.82 (95% CI, 0.77-0.87) and 0.86 (95% CI, 0.80-0.91), respectively. The areas under the receiver operating characteristic curve for individual and combinative diagnoses was 0.84 (95% CI, 0.81-0.87) and 0.91 (95% CI, 0.88-0.93), respectively, indicating that a combinative diagnosis has a relatively better diagnostic accuracy (z = -2.22, P = 0.01) than individual diagnosis. In conclusion, HOTAIR levels might be a promising biomarker in cancer diagnosis. In addition, using HOTAIR in combination with other biomarkers showed a relatively better diagnostic accuracy than HOTAIR alone.

The association between anthropometric indices with chronic kidney disease (CKD) was examined previously. However, the effect of body fat on renal function was not determined clearly. Our aim was to investigate the association of percent body fat (PBF) and renal function in adult population from health examination in Tri-Service General Hospital (2010–2016). 35087 participants aged 20 years and older were enrolled in the study. PBF was measured by bioelectrical impedance analysis (BIA). Estimation of renal function was performed by Taiwanese MDRD equation. Optimal cut-off values of PBF was accessed by a receiver–operator characteristic (ROC) curve analysis. Multivariate regression models were used in the relationship among changes of PBF, renal function, and future CKD. In terms of baseline PBF for CKD, optimal cut-off values of PBF in males and females were 21.55 and 40.75. The changes of PBF were more closely associated with renal function decline than waist circumference (WC) with β values of −0.173 (95% CI: −0.233, −0.112) and −0.077 (95% CI: −0.104, −0.049), respectively. After stratified by gender, this relationship remained significant in male population with β values of −0.276 (95% CI: −0.371, −0.181) and −0.159 (95% CI: −0.207, −0.112), respectively. Female subjects with increased baseline PBF over cut-off values had increased risk for predicting the future CKD with odd ratios (ORs) of 2.298 (95% CI: 1.006–5.252). Body fat had detrimental impact on renal function and development of CKD in adult population. Measurement of PBF for surveillance of renal function impairment was warranted.

Objective To explore the prediction of aerobic exercise and resistance training on incidental metabolic syndrome (MetS) and diabetes in a Taiwanese cohort. Methods The participant underwent annual health examinations and physical fitness tests, including 2-min push-up, 2-min sit-up, and endurance 3000-m none weight-bearing running exercise test from 2013 to 2015, were recruited. The cohort study involved 27,787 participants aged ≥20 years in military services. Multivariate logistic regression odd ratios models were used to explore the associations between the performance of physical fitness and the development of MetS and diabetes. Results The male participants without MetS at baseline with poor performance in aerobic and resistance exercise tests were likely to develop the MetS and diabetes two years later; while the female participants did not show the same results in statistical significance. Additionally, only poor performance measuring by resistance training exercise test was significantly associated with increased risk of metabolic components numbers at follow-up in all subjects without MetS (all P Conclusions The poor performance in aerobic and resistance exercise tests might be predicting tools for MetS and diabetes in Taiwanese men without MetS at baseline. And resistance exercise displayed a substantial predicting ability in development of metabolic abnormality, MetS and diabetes in our study.

Objective: This study aims to systematically evaluate the efficacy and safety of catgut implantation at acupoints (CIA) treating asthma, extracting data from the published clinical trials. Methods: The Cochrane Library, PubMed, Chinese Biomedical Database (CBM), CNKI, WANFANG and VIP databases were searched up to February 2017. Randomized controlled trials (RCTs) involving CIA or CIA plus conventional medicine treatment (CMT) were selected with CMT as control. We assessed the methodological quality of RCTs using the Cochrane Handbook for Systematic Review of Interventions. The outcome data of trials were analyzed using RevMan5.3. Results: A total of 12 studies ([Formula: see text]) were included. Most of the included studies were assessed to have high risk of bias with low quality of methodology. CIA application significantly improved the overall therapeutic efficacy ([Formula: see text]) and pulmonary function (forced expiratory volume in 1[Formula: see text]s (FEV1) and FEV1%, [Formula: see text] and [Formula: see text]) and reduced the overall scores of TCM symptoms ([Formula: see text]). Further, it significantly relieved several TCM symptoms including shortness of breath, chest distress and cough ([Formula: see text]). However, CIA only exerted a protective tendency for expectoration and wheezing without significant difference and had no effects on recurrence rate (all [Formula: see text]). Conclusions: CIA treatment could improve the overall efficacy and pulmonary function and relief several symptoms. However, the evidence remains weak. Rigorous and larger trials will be the basis of the effectiveness and long-term effects of CIA therapies.

Median survival for recurrent/metastatic head and neck squamous cell cancer (HNSCC) patients is about 10 months after first-line best systemic treatment. We aimed to assess current approaches of oligometastatic HNSCC patients by the analysis of current concept and published data (1995–2017) in this population. Five-year survival rates are over 20% in selected patients who undergo metastasis-directed therapy by either surgery or stereotactic irradiation. Human papillomavirus(+) HNSCC patients have more disseminated metastases but respond more favorably and also benefit from ablative treatments. Treatments of oligometastases are expanding rapidly. Unmet needs include revised imaging follow-up strategies to detect metastases earlier, identification of predictive noninvasive biomarkers for treatment guidance, assessment and corrections of biases in current studies and randomized clinical trials.

Treacher Collins syndrome (TCS) (OMIM 154500) is a rare congenital craniofacial disorder with an autosomal dominant manner of inheritance in most cases. To date, three pathogenic genes (TCOF1, POLR1D and POLR1C) have been identified. In this study, we conducted mutational analysis on Chinese TCS patients to reveal a mutational spectrum of known causative genes and show phenotype-genotype data to provide more information for gene counselling and future studies on the pathogenesis of TCS. Twenty-two TCS patients were recruited from two tertiary referral centres, and Sanger sequencing for the coding exons and exon-intron boundaries of TCOF1, POLR1D and POLR1C was performed. For patients without small variants, further copy number variations (CNVs) analysis was conducted using high-density SNP array platforms. The Sanger sequencing overall mutation detection rate was as high as 86.3% (19/22) for our cohort. Fifteen TCOF1 pathogenic variants, including ten novel mutations, were identified in nineteen patients. No causative mutations in POLR1D and POLR1C genes and no CNVs mutations were detected. A suspected autosomal dominant inheritance case that implies germinal mosaicism was described. Our study confirmed that TCOF1 was the main disease-causing gene for the Chinese TCS population and revealed its mutation spectrum. We also addressed the need for more studies of mosaicism in TCS cases, which could explain the mechanism of autosomal dominant inheritance in TCS cases and benefit the prevention of TCS.

Arsenical drugs have achieved hallmark success in treating patients with acute promyelocytic leukemia, but expanding their clinical utility to solid tumors has proven difficult with the contradiction between the therapeutic efficacy and the systemic toxicity. Here, leveraging efforts from materials science, biocompatible PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity that can selectively and effectively treat solid tumors are synthesized. The intrinsic selective killing effect of AsNDs@PEG is closely related to high oxidative stress in tumor cells, which leads to an activated valence-change of arsenic (from less toxic As0 to severely toxic oxidation states), followed by decreased superoxide dismutase activity and massive reactive oxygen species (ROS) production. These effects occur selectively within cancer cells, causing mitochondrial damage, cell-cycle arrest, and DNA damage. Moreover, AsNDs@PEG when applied in a multi-drug combination strategy with β-elemene, a plant-derived anticancer drug, achieves synergistic antitumor outcomes, and its newly discovered on-demand photothermal properties facilitate the elimination of the tumors without recurrence, potentially further expanding its clinical utility. In line of the practicability for a large-scale fabrication and negligible systemic toxicity of AsNDs@PEG (even at high doses and with repetitive administration), a new-concept arsenical drug with high therapeutic efficacy for selective solid tumor therapy is provided.

Background Loss of soft tissue in heel-calcaneal region is frequently caused by trauma, infection, or tumors. Limited availability of similar tissue becomes challenging, therefore, the use of free tissue transfer offers a solution. Our aim is to describe long term functional outcome of different free tissue transfers for these defects. Patients and methods We retrospectively reviewed 24 consecutive cases of the heel-calcaneal defect between January 2009 and December 2014. The free fasciocutaneous perforator (FCP) flaps were performed in 14 cases and free muscle flaps with skin graft in 10 cases. The postoperative complications, range of motion and ability of ambulation or exercise were administered to evaluate functional results. Results The average follow-up period was 26.5 months. The survival of free flap was 100%. Early complication included venous thrombosis, infection and edge dehiscence was noted in 8 cases. Late complication with insensate ulcers developed in 3 cases (1 cases in FCP flap, 2 cases in muscle flap). All ulcers healed spontaneously without surgical intervention. The postoperative average range of motion of ankle regained 52.79 degree in FCP flap group and 56.4 degree in muscle flap group. The ability of ambulation or exercise returned in 13 cases in FCP group (13/14) and 9 cases in muscle flap group (9/10). No differences of complication rate (P = .403), ROM (P = .363) or functional evaluation (P = .803) could be found between these two groups. Conclusions Both FCP flap and muscle flaps provided the similar and excellent functional results in resurfacing of heel-calcaneal defects after long term follow up.

Dengue virus (DENV) infection can cause severe, life-threatening events, and no specific treatments of DENV infection are currently approved. Although thrombocytopenia is frequently observed in dengue patients, its pathogenesis is still not fully understood. Previous studies have suggested that DENV-induced thrombocytopenia occurs through viral-replication-mediated megakaryopoiesis inhibition in the bone marrow; however, the exact mechanism for megakaryopoiesis suppression remains elusive. In this study, a reductionist approach was applied, in which C57B/6J mice were inoculated with recombinant DENV-envelope protein domain III (DENV-EIII) instead of the full viral particle. Our results demonstrated that DENV-EIII-suppressed megakaryopoiesis is similar to those observed with DENV infection. Furthermore, in agreement with our in vivo analyses, DENV-EIII sufficiently suppressed the megakaryopoiesis of progenitor cells from murine bone marrow and human cord blood in vitro. Additional analyses suggested that autophagy impairment and apoptosis are involved in DENV-EIII-mediated suppression of megakaryopoiesis. These data suggest that, even without viral replication, the binding of DENV-EIII to the cell surface is sufficient to suppress megakaryopoiesis.

Though the same types of complication were found in both elective cesarean section (ElCS) and emergence cesarean section (EmCS), the aim of this study is to compare the rates of maternal and fetal morbidity and mortality between ElCS and EmCS. Full-text articles involved in the maternal and fetal complications and outcomes of ElCS and EmCS were searched in multiple database. Review Manager 5.0 was adopted for meta-analysis, sensitivity analysis, and bias analysis. Funnel plots and Egger’s tests were also applied with STATA 10.0 software to assess possible publication bias. Totally nine articles were included in this study. Among these articles, seven, three, and four studies were involved in the maternal complication, fetal complication, and fetal outcomes, respectively. The combined analyses showed that both rates of maternal complication and fetal complication in EmCS were higher than those in ElCS. The rates of infection, fever, UTI (urinary tract infection), wound dehiscence, DIC (disseminated intravascular coagulation), and reoperation of postpartum women with EmCS were much higher than those with ElCS. Larger infant mortality rate of EmCS was also observed. Emergency cesarean sections showed significantly more maternal and fetal complications and mortality than elective cesarean sections in this study. Certain plans should be worked out by obstetric practitioners to avoid the post-operative complications.

Inflammatory bowel disease (IBD) is an intestinal immune-dysfunctional disease worldwide whose prevalence increasing in Asia including China. It is a chronic disease of the gastrointestinal tract with unknown cause. Exosomes are small vesicles in various body fluids. They have diameters of 40–120 nm, and one of their functions is long-distance transfer of various substances. In this study, we investigated the contents of salivary exosomes in patients with IBD and in healthy controls to explore a new biomarker in patients with IBD. In this study, whole saliva was obtained from patients with IBD (ulcerative colitis (UC), n = 37; Crohn’s disease (CD), n = 11) and apparently healthy individuals (HC, n = 10). Salivary exosomes were extracted from samples, and the proteins within the exosomes were identified by liquid chromatograph-mass spectrometer (LC-MS/MS). The results showed that more than 2000 proteins were detected in salivary exosomes from patients with IBD. Through gene ontology analysis, we found that proteasome subunit alpha type 7 (PSMA7) showed especially marked differences between patients with IBD and the healthy controls, in that its expression level was much higher in the CD and UC groups. This exosomal protein is related to proteasome activity and inflammatory responses. So we conclude that in this research, salivary exosomal PSMA7 was present at high levels in salivary exosomes from subjects with IBD. It can be a very promising biomarker to release the patients from the pain of colonoscopy. Electronic supplementary material The online version of this article (doi:10.1007/s13238-017-0413-7) contains supplementary material, which is available to authorized users.

Background Tartrate-resistant phosphatase isoform 5a is expressed in tumor-associated macrophages and is a biomarker of chronic inflammation. Herein, we correlated serum tartrate-resistant phosphatase isoform 5a levels with metabolic syndrome status and made comparisons with traditional markers of inflammation, including c-reactive protein and interleukin-6. Methods One hundred healthy volunteers were randomly selected, and cut-off points for metabolic syndrome related inflammatory biomarkers were determined using receiver operating characteristic curves. Linear and logistic regression models were subsequently used to correlate inflammatory markers with the risk of metabolic syndrome. Results Twenty-two participants met the criteria for metabolic syndrome, and serum tartrate-resistant phosphatase isoform 5a levels of >5.8 μg/L were associated with metabolic syndrome (c-statistics, 0.730; p = 0.001; 95% confidence interval, 0.618-0.842). In addition, 1 μg/L increases in tartrate-resistant phosphatase isoform 5a levels were indicative of a 1.860 fold increase in the risk of metabolic syndrome (p = 0.012). Conclusions Elevated serum tartrate-resistant phosphatase isoform 5a levels are associated with the risk of metabolic syndrome, with a cut-off level of 5.8 μg/L.

The prevalence of obesity was increasing and became a growing problem worldwide. Obesity increased the risk of developing metabolic abnormalities and was associated adverse health outcomes. Our aim was to examine the associations among different combinations of obesity phenotypes (high body mass index > 27 kg/m2 (O), high waist circumference (male > 90 cm, female > 80 cm) (W), fatty liver (F) and percentage body fat in top 40% (P)) and cardiometabolic diseases (type 2 diabetes mellitus (DM), hypertension (HTN), metabolic syndrome (MetS)). A total of 48426 eligible subjects were categorized based on the different definitions. After adjusting for all covariables, participants with O + F + P combination were more likely associated with the presence of DM. Participants with O + W combination were more associated with the presence of HTN than others. Participants with O + W + F + P had higher risk for the presence of MetS than others. The study addressed the associations between different obesity phenotypes and DM and HTN in the adult population. Better understanding the pathophysiological mechanisms underlined individual vulnerability and progression of cardiometabolic insults.

Background The optimal dosage for cryoablation of atrial fibrillation (Cryo-AF) is still unknown. To evaluate the efficacy of an individualized freeze duration, we compared the clinical outcome of patients treated with a time-to-pulmonary vein isolation (TT-PVI) or temperature-guided ablation protocol to the outcome of patients treated with a conventional ablation protocol. Methods A total of 164 consecutive patients were included in the study. One method employed was a conventional dosing protocol (at least 2 applications of 180 s each) (the Cryo-AFConventional group n = 84), and the second method had a shorter protocol that was based on the TT-PVI or achievement of − 40 °C within 60 s (the Cryo-AFDosing group n = 80) Results We treated 656 pulmonary veins (PVs) with 1420 cryotherapy applications. The mean number of applications per patient was 8.7 ± 0.8, with no difference between groups (Cryo-AFConventional, 8.7 ± 0.8 versus Cryo-AFDosing,8.6 ± 0.8; P = 0.359). The Cryo-AFDosing group required significantly less total cryotherapy application time (990.60 ± 137.77versus 1501.58 ± 89.60 s; P P Conventional group. Additionally, the Cryo-AFDosing group required significantly less total procedure time (95.03 ± 6.50 versus 112.43 ± 7.11 min; P Conventional and Cryo-AFDosing groups were similar in that 2.98 and 0.94% of the initially isolated veins were reconnected, respectively, (P = 0.061). There was no difference in the recurrence rate of free atrial arrhythmia after a 1-year follow-up, which were 78.75% in the Cryo-AFDosing group versus 78.57% in the Cryo-AFConventional group (P = 0.978). Conclusion A novel Cryo-AF dosing protocol guided by temperature or the TT-PVI can be used to individualize an ablation strategy. This new protocol can lead to a significant reduction in duration of the procedure, the cryoenergy dosage and the left atrial dwell time. The procedure had equal safety and similar acute and 1-year follow-up outcomes compared to the conventional approach.

Background Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody is the first ICPI which has shown remarkable benefits in the clinical treatment of cancers. However, the increased activity of the immune system also causes some side effects called immune-related adverse events (irAEs). Colitis is one of the most common irAEs related to anti-CTLA-4 immunotherapy. Results We identified that CD4+ T cells were the primary responders in CTLA-4 blockade and that the expansion of gut-homing CD4+ T cells by anti-CTLA-4 therapy was independent of CD103. We used dextran sulfate sodium (DSS)-induced colitis mice as our model and tested the possibility of using a trafficking-blocking antibody to treat anti-CTLA-4 antibody-induced irAEs. We found that blocking T cell homing increased colitis severity in the context of CTLA-4 blockade and that gut-trafficking blockade had different effects on different Th subsets and could facilitate the proliferation of Th17 cells in the lamina propria (LP). Conclusions Our data reveals the fundamental mechanism underlying trafficking-blocking antibody therapy for CTLA-4 blockade-induced colitis and provide a caution in regard to apply trafficking-blocking antibody treatment under CTLA-4 blockade condition.

Thrombocytopenia is usually associated with liver injury, elevated plasma aspartate aminotransferase and alanine aminotransferase levels, and high antiplatelet immunoglobulin (Ig) titers, although the mechanism behind these effects remains elusive. Deciphering the mechanism behind acute liver disease–associated thrombocytopenia may help solve difficulties in routine patient care, such as liver biopsy, antiviral therapy, and surgery. To determine whether liver damage is sufficient per se to elicit thrombocytopenia, thioacetamide (TAA)-induced hepatitis rodent models were employed. The analysis results indicated that TAA treatment transiently induced an elevation of antiplatelet antibody titer in both rats and mice. B-cell-deficient (BCD) mice, which have loss of antibody expression, exhibited markedly less thrombocytopenia and liver damage than wild-type controls. Because TAA still induces liver damage in BCD mice, this suggests that antiplatelet Ig is one of the pathogenic factors, which play exacerbating role in the acute phase of TAA-induced hepatitis. TNF-α was differentially regulated in wild-type versus BCD mice during TAA treatment, and anti-TNF treatment drastically ameliorated antiplatelet Ig induction, thrombocytopenia, and liver injury, suggesting that the TNF pathway plays a critical role in the disease progression.

Patients with cervical lymphadenopathy of unknown primary carcinoma (CUP) usually undergo neck dissection and irradiation. There is an ongoing controversy regarding the extent of nodal and mucosal volumes to be irradiated. We assessed outcomes after bilateral or unilateral nodal irradiation.This retrospective multicentre study included patients with CUP and squamous cellular carcinoma who underwent radiotherapy (RT) between 2000 and 2015.Of 350 patients, 74.5% had unilateral disease and 25.5% had bilateral disease. Of 297 patients with available data on disease and irradiation sides, 61 (20.5%) patients had unilateral disease and unilateral irradiation, 155 (52.2%), unilateral disease and bilateral irradiation and 81 (27.3%), bilateral disease and bilateral irradiation. Thirty-four (9.7%) and 217 (62.0%) patients received neoadjuvant and/or concomitant chemotherapy, respectively. Median follow-up was 37 months. Three-year local, regional, locoregional failure rates and CUP-specific survival were 5.6%, 11.7%, 15.0% and 84.7%, respectively. In patients with unilateral disease, the 3-year cumulative incidence of regional/local relapse was 7.7%/4.3% after bilateral irradiation versus 16.9%/11.1% after unilateral irradiation (hazard ratio = 0.56/0.61, p = 0.17/0.32). The cumulative incidence of CUP-specific deaths was 9.2% after bilateral irradiation and 15.5% after unilateral irradiation (p = 0.92). In multivariate analysis, mucosal irradiation was associated with better local control, whereas no neck dissection, ≥N2b and interruption of RT for more than 4 days were associated with poorer regional control. Toxicity was higher after bilateral irradiation (p 0.05). No positron-emission tomography-computed tomography, largest node diameter, ≥N2b, neoadjuvant chemotherapy and interruption of RT were associated with poorer cause-specific survival.Bilateral nodal irradiation yielded non-significant better nodal and mucosal control rates but was associated with higher rates of severe toxicity.

Emerging studies have shed light on the association between Helicobacter pylori (HP) infection and cardiometabolic risk. However, there is no evidence to support a causal link for the relationship in the general population. Our aim was to determine whether HP infection is associated with the risks of incident type II diabetes mellitus (DM) in a population-based cohort consisting of adults from the general population. A total of 69235 adults enrolled in the study obtained health examinations at the Tri-Service General Hospital in Taiwan from 2010 to 2016. HP infection detection was performed by rapid urease tests (RUTs), and endoscopic examinations were used to diagnose gastroesophageal reflux disease (GERD), gastric ulcers (GUs) and duodenal ulcers (DUs). Cross-sectional and longitudinal analyses were performed to examine the association between HP infection and cardiometabolic diseases using logistic regression and Cox regression in a large population-based study. HP infection was significantly associated with the presence of metabolic syndrome (MetS) (OR = 1.26, 95%CI: 1.00-1.57) and DM (OR = 1.59, 95%CI: 1.17-2.17) only in male subjects, and abnormal endoscopic findings were also correlated with cardiometabolic diseases. Our findings demonstrated that participants with HP infection had an elevated risk of developing incident DM (HR = 1.54, 95%CI: 1.11-2.13). In addition, endoscopic findings of a DU (HR = 1.63, 95%CI: 1.02-2.63), rather than GERD or a GU, were also predictive of incident DM. In this cohort, HP infection was a statistically significant predictor of incident DM among male population.

Hair cells are specialized sensory epithelia cells that receive mechanical sound waves and convert them into neural signals for hearing, and these cells can be killed or damaged by ototoxic drugs, including many aminoglycoside antibiotics, platinum-based anticancer agents, and loop diuretics, leading to drug-induced hearing loss. Studies of therapeutic approaches to drug-induced hearing loss have been hampered by the limited understanding of the biological mechanisms that protect and regenerate hair cells. This review briefly discusses some of the most common ototoxic drugs and describes recent research concerning the mechanisms of ototoxic drug-induced hearing loss. It also highlights current developments in potential therapies and explores current clinical treatments for patients with hearing impairments.

Background: Vitamin D deficiency became increasingly common worldwide and was related to various disorders. However, there was little information concerning the relationship between serum 25-hydroxyvitamin D (25(OH) D) level and shift work. The aim of this paper was to investigate the relation between serum 25(OH) D level and shift work in the American citizens. Methods: From the 2005–2006 NHANES, a total of 3025 participants were included. The relation between serum 25(OH) D level and shift work was investigated through the regression models. Results: There was an inverse relationship between serum 25(OH) D level and female shift worker in the fully adjusted models (β coefficient = −8.774, 95% confidence intervals [CI] = −16.83–−0.71, P = 0.03). Additionally, a negative correlation was presented between serum 25OHD level and Mexican American (β coefficient = −9.825, 95% CI = −19.31–−0.33, P = 0.04). No significant differences in serum 25(OH) D level were presented among indoor/outdoor works or manual/nonmanual works. However, long working hours (>40 h/week) were remarkably correlated with low serum 25(OH) D level (β coefficient = −8.007, 95% CI = −15.32–−0.68, P = 0.03). Conclusions: Our study concluded there was an inverse correlation between serum 25(OH) D level and shift work, especially in female population.