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Prescriptions for biologic therapy for treatment of Crohn's disease (CD) and ulcerative colitis (UC) have increased during the past two decades; however, trends are less clear regarding corticosteroid prescriptions in this context. We designed a cross-sectional study using the IQVIA Ambulatory Electronic Medical Records databases. Weighted linear regressions by age group were used to estimate annual percentage change from 2011 to 2020 in prescriptions for biologics and for corticosteroids among patients with or without biologic prescriptions within the same calendar year. Using 2019 data, we compared patient demographic and lifestyle risk factors using χ2 test for biologic prescriptions and corticosteroids with or without biologics prescriptions. There was an 11% (CD) and 16% (UC) annual increase in the percentage of patients prescribed biologics during the study period. The percentage of patients with biologics prescriptions prescribed corticosteroids decreased by 2% (CD) and 3% (UC) annually after 2015, while the percentage remained unchanged for corticosteroid prescriptions among patients without biologics. In 2019, differences in medication prescriptions existed by patient's demographic and lifestyle factors for patients with CD (n=52,892) and UC (n=52,280), including a higher percentage prescribed biologics among younger patients, men, those with fewer comorbidities, and current alcohol drinkers, and a higher percentage prescribed corticosteroids without biologics among women, those with more comorbidities, and a history of smoking. While medications continue to evolve during the biologic era, it is important to continue to monitor trends and differences in prescription patterns to assess progress toward optimizing treatment for patients with CD or UC.

Immune cell infiltration plays an essential role in the occurrence and development of colon cancer. However, the main tumor-associated immune cell infiltration and its gene regulation in colon cancer still need to be further clarified in order to provide a new perspective for diagnosing and treating this disease. For this study, single-cell RNA sequencing (scRNA-seq) expression profiles and TCGA colon cancer data sets were first acquired from the GEO database. Then, Seurat, Monocle, LIMMA, Clusterprofile, GSVA and GSEABase algorithms were used to systematically examine the data. Potential target drugs corresponding to target genes were analyzed in the Drugbank database and detected by molecular docking. Immunohistochemistry was used to assess the level of C1QC expression in the tissue microarray. Single cell analysis suggested that neutrophil activation might be the critical regulatory pathway in colon cancer and that macrophages were the main cell population involved. Subsequent functional enrichment analysis on differential genes in macrophages suggested that C1QC may be a critical regulatory factor in the occurrence and progression of colon cancer, and was closely related to the survival of patients. According to the drug target prediction, palivizumab is a targeted drug for C1QC, and molecular docking demonstrated that palivizumab binds to C1QC. Additionally, tissue-microarray based immunohistochemical analysis showed that C1QC was highly expressed in colon cancer tissue, and the prognosis of colon cancer patients with high C1QC expression was worse, closely related to age, lymphatic metastasis and the TNM stage (Tumor, Nodes and Metastases). Our findings suggest that C1QC may regulate the macrophages in colon cancer immune infiltration, which is expected to be a potential immunotherapy target for colon cancer, and beneficial for the diagnosis and prognosis of colon cancer patients.

Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited.We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications.Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation.In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

Hypoxia-activated prodrugs (HAPs) have drawn increasing attention for improving the antitumor effects while minimizing side effects. However, the heterogeneous distribution of the hypoxic region in tumors severely impedes the curative effect of HAPs. Additionally, most HAPs are not amenable to optical imaging, and it is difficult to precisely trace them in tissues. Herein, we carefully designed and synthesized a multifunctional therapeutic

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia, and amnestic mild cognitive impairment (aMCI) has been defined as a transitional stage between normal aging and AD. Accumulating evidence has shown that altered functional connectivity (FC) and structural connectivity (SC) in the default mode network (DMN) is the prominent hallmarks of AD. However, the relationship between the changes in SC and FC of the DMN is not yet clear. In the present study, we derived the FC and SC matrices of the DMN with functional magnetic resonance imaging (fMRI) and diffusion-weighted imaging (DWI) data and further assessed FC and SC abnormalities within a discovery dataset of 120 participants (39 normal controls, 34 patients with aMCI and 47 patients with AD), as well as a replication dataset of 122 participants (43 normal controls, 37 patients with aMCI and 42 patients with AD). Disrupted SC and FC were found among DMN components (e.g., the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and hippocampus) in patients in the aMCI and AD groups in the discovery dataset; most of the disrupted connections were also identified in the replication dataset. More importantly, some SC and FC elements were significantly correlated with the cognitive ability of patients with aMCI and AD. In addition, we found structural-functional decoupling between the PCC and the right hippocampus in patients in the aMCI and AD groups. These findings of the alteration of DMN connectivity in neurodegenerative cohorts deepen our understanding of the pathophysiological mechanisms of AD.

Motivation Detecting synthetic lethality (SL) is a promising strategy for identifying anti-cancer drug targets. Targeting SL partners of a primary gene mutated in cancer is selectively lethal to cancer cells. Due to high cost of wet-lab experiments and availability of gold standard SL data, supervised machine learning for SL prediction has been popular. However, most of the methods are based on binary classification and thus limited by the lack of reliable negative data. Contrastive learning can train models without any negative sample and is thus promising for finding novel SLs. Results We propose NSF4SL, a negative-sample-free SL prediction model based on a contrastive learning framework. It captures the characteristics of positive SL samples by using two branches of neural networks that interact with each other to learn SL-related gene representations. Moreover, a feature-wise data augmentation strategy is used to mitigate the sparsity of SL data. NSF4SL significantly outperforms all baselines which require negative samples, even in challenging experimental settings. To the best of our knowledge, this is the first time that SL prediction is formulated as a gene ranking problem, which is more practical than the current formulation as binary classification. NSF4SL is the first contrastive learning method for SL prediction and its success points to a new direction of machine-learning methods for identifying novel SLs. Availability and implementation Our source code is available at https://github.com/JieZheng-ShanghaiTech/NSF4SL. Supplementary information Supplementary data are available at Bioinformatics online.

Background: Colorectal cancer (CRC) is a common malignancy of digestive tract. Pinocembrin (PINO) has been discovered to have proapoptotic effect on CRC. This study aimed to elucidate how other biological behaviors of CRC cells were affected under PINO treatment. Materials & Methods: The effect of PINO on HT29 and HCT116 cells were detected through treatment of different concentrations of PINO. The role of LACTB in PINO treatment was investigated by transfection of siRNA-LACTB. Cell counting kit-8 assay, wound healing assay, and Transwell assay were conducted to evaluate the proliferation, migration, and invasiveness of CRC cells, respectively. Western blot or quantitative reverse transcription-polymerase chain reaction was carried out to measure the expressions of LACTB, matrix metalloproteinase (MMP)-2, E-cadherin, and N-cadherin. Results: Gradient PINO inhibited the viability, migration, invasiveness, and expressions of MMP-2 and N-cadherin in CRC cells, while promoted E-cadherin and LACTB expressions. Silencing LACTB promoted the viability, migration, invasiveness, and expressions of MMP-2 and N-cadherin in CRC cells and inhibited E-cadherin expression. PINO counteracted the effect of silenced LACTB, and yet silencing LACTB partially abolished the effect of PINO on CRC cells. Conclusion: PINO inhibited the proliferation, migration, invasiveness, and epithelial-to-mesenchymal transition of CRC cells by regulating LACTB.

The bone mass around the prosthesis plays an important role in the stability of the prosthesis. This study aimed to assess the effect of postoperative activity on bone mineral density (BMD) in the proximal tibia 5 years after total knee arthroplasty (TKA). To provide a scientific guidance for postoperative functional exercise.110 patients underwent unilateral primary TKA were divided into three groups based on the University of California Los Angeles (UCLA) activity scale: low activity group (LA group, UCLA = 4, 5); medium activity group (MA group, UCLA = 6, 7); and high activity group (HA group, UCLA = 8, 9). The primary observation was a comparison of the BMD and BMD change percentage (ΔBMD (%)) in the periprosthetic tibia among the LA, MA and HA groups at 1 year, 3 years and 5 years. The secondary observations were radiographic evaluation (prosthetic stability, periprosthetic fractures, aseptic loosening and periprosthetic joint infection) and clinical evaluation (Knee Society Score (KSS), visual analogue score scores and range of motion (ROM)). A one-way ANOVA was used to compare the clinical scores and BMD among the three groups.The BMD of medial region decreased by 10.80%, 12.64%, 13.61% at 1, 3, and 5 years respectively; these were 5.72%, 6.26%, 7.83% in lateral region and 1.42%, 1.78%, 3.28% in diaphyseal region. For medial metaphyseal region, the BMD of the MA group was significantly greater than that of the LA and HA groups at 1 and 3 years (108.9 ± 5.2 vs. 106.1 ± 6.69 vs. 105.4 ± 5.2 and 108.5 ± 6.0 vs. 101.2 ± 6.76 vs. 103.0 ± 6.8, P 0.01 and P 0.001), and the BMD changes (ΔBMD (%)) in the MA group were significantly smaller than those in the LA and HA groups (8.75 ± 5.36 vs. 11.92 ± 5.49 vs. 12.70 ± 5.21 and 9.11 ± 5.11 vs. 16.04 ± 4.79 vs. 14.82 ± 4.26, P 0.01 and P 0.001). Regarding secondary observations, all of the prostheses were assessed as stable, without periprosthetic fractures, aseptic loosening and periprosthetic joint infection. Regarding KSS scores, there was no significant difference among the three groups. However, the VAS and ROM of the HA group were better than those of the MA and LA groups (1.65 ± 0.79 vs. 2.63 ± 0.77 vs. 3.00 ± 1.17, p 0.001, and 111.90 ± 9.17 vs. 110.20 ± 6.78 vs. 102.90 ± 8.48, P 0.001).Medium activity prevented periprosthetic bone loss in the medial metaphyseal region of the tibia after posterior-stabilized TKA, and moderate-intensity exercise is recommended for patients after TKA to reduce periprosthetic bone loss.

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson's disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant K

The evolution of seasonal influenza viruses, which can cause virus antigenic drift to escape human herd immunity, is a significant public health problem. Here, we obtained hemagglutinin (HA), neuraminidase (NA), and polymerase acidic protein (PA) the gene sequences of 84 influenza virus isolates collected in Guangdong Province during the 2019-2020 influenza season. Phylogenetic analyses revealed all these isolates were genetically similar to the viruses of clade 3C2a A1b, specifically those within subclades of A1b 137F (59 cases), A1b 186D (19 cases), and A1b 94 N (6 cases). The influenza virus isolates were distinct from the World Health Organization recommended influenza A vaccine virus for the 2019-2020 Northern Hemisphere season (A/Kansas/14/2017; H3N2). Phylogenies inferred from the individual gene segment sequences revealed that one reassortment event occurred among these clades. The genetic variation involved mutations within viral antigenic epitopes and two N-glycosylation site alterations. The novel mutation sites of G202D and D206N in the HA gene, E344K in the NA gene, and K626R in the PA gene which may affect the spread of the virus were observed. We investigated the evolution of these genes and found that the HA and NA genes were under greater pressure than PA gene. Mutations associated with conferring resistance to NA inhibitors or baloxavir acid were not found. Our results suggest that a rapid evolution of the H3N2 influenza virus occurred, thus continuous monitoring is critical for establishing appropriate vaccine formulations or drug delivery for targeting influenza.

Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS.Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis.Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody.The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.

The increasing burden of non-alcoholic fatty liver disease (NAFLD) worldwide imposes an emerging public health issue. We perform the current study to estimate the global prevalence, incidence, disease progression, and clinical outcomes of NAFLD.A systematic search was conducted in Medline, Embase, Web of Science, Google Scholar, and Cochrane CENTRAL that screened articles in English language published from January 2000 to December 2021. NAFLD prevalence, incidence, rate of disease progression, and outcomes were calculated with the DerSimonian-Laird random effects model with arcsine transformation.Our search identified 59,156 records, of which 578 studies fulfilled our inclusion criteria. The overall prevalence of NAFLD was 29.38% (95% confidence interval [CI] 28.09-30.69) regardless of the diagnostic techniques. Looking at the group in which the diagnosis was made by ultrasound exclusively, the pooled prevalence was 30.49% (95% CI 29.55-31.43). NAFLD has become more prevalent during the year 2011-2021 (31.63%, 95% CI 30.23-33.04) compared with year 2000-2010 (27.94%, 95% CI 26.23-29.69). The pooled estimation of non-alcoholic steatohepatitis prevalence was 8.26% (95% CI 1.13-21.01), 46.49% (95% CI 35.93-57.20), and 46.72% (95% CI 37.57-55.98) in general population, NAFLD patients, and severe/morbidly obese patients, respectively. Based on a total of 110,142 newly developed NAFLD patients, the pooled incident rate was estimated as 46.24 cases per 1000 person-years (95% CI 43.21-49.30). In patients with NAFLD, the incident rate of hepatocellular carcinoma was 1.46 (95% CI 0.90-2.03) cases per 1000 person-years. The overall pooled estimate of NAFLD related mortality was 23.91 (95% CI 13.55-37.18) death per 1000 person-years.The prevalence of NAFLD is increasing globally. It is contributing to poor clinical outcomes including hepatocellular carcinoma and death. Rising awareness and urgent actions are warranted to control the NAFLD pandemic across the globe.PROSPERO, No. CRD42020171104.

We studied brain changes during an N-back task before and after 10 sessions of transcranial direct current stimulation (tDCS) and its relation to cognitive changes. This was a double-blind, sham-controlled, randomized study of tDCS in 27 patients with schizophrenia. They performed an N-back task in a 3 T scanner before and after receiving the 10 tDCS sessions. Cognitive performance outside the fMRI session was assessed using the MATRICS Consensus Cognitive Battery and other tests at baseline and several time points after 10 sessions of tDCS. During the N-back task performed during fMRI scans, comparing the 0-back vs. the 2-back task, the active tDCS group demonstrated a significantly increased activation in the right fusiform, left middle frontal, left inferior frontal gyrus (opercular part) and right inferior frontal gyrus (triangular part) and reduced activation in the left posterior cingulum gyrus with most of these results primarily due to increases in activation during the 0-back rather than 2-back task. There were also significant positive or negative correlations between some of the brain changes and cognitive performance. tDCS modulated prefrontal activation at low working memory load or attention mode, but default mode network at higher working memory load. Changes in brain activation measured during the N-back task were correlated with some dimensions of cognitive function immediately after 10 tDCS sessions and at follow-up times. The results support tDCS could offer a potential novel approach for modulating cortical activity and its relation to cognitive function.

Background: Epigenetic marks (eg, DNA methylation) may capture the effect of gene-environment interactions. DNA methylation is involved in blood pressure (BP) regulation and hypertension development; however, no studies have evaluated its relationship with 24-hour BP phenotypes (daytime, nighttime, and 24-hour average BPs). Methods: We examined the association of whole blood DNA methylation with 24-hour BP phenotypes and clinic BPs in a discovery cohort of 281 Black participants using reduced representation bisulfite sequencing. We developed a deep and region-specific methylation sequencing method, Bisulfite ULtrapLEx Targeted Sequencing and utilized it to validate our findings in a separate validation cohort (n=117). Results: Analysis of 38 215 DNA methylation regions (MRs), derived from 1 549 368 CpG sites across the genome, identified up to 72 regions that were significantly associated with 24-hour BP phenotypes. No MR was significantly associated with clinic BP. Two to 3 MRs were significantly associated with various 24-hour BP phenotypes after adjustment for age, sex, and body mass index. Together, these MRs explained up to 16.5% of the variance of 24-hour average BP, while age, sex, and BMI explained up to 11.0% of the variance. Analysis of one of the MRs in an independent cohort using Bisulfite ULtrapLEx Targeted Sequencing confirmed its association with 24-hour average BP phenotype. Conclusions: We identified several MRs that explain a substantial portion of variances in 24-hour BP phenotypes, which might be excellent markers of cumulative effect of factors influencing 24-hour BP levels. The Bisulfite ULtrapLEx Targeted Sequencing workflow has potential to be suitable for clinical testing and population screenings on a large scale.

Chronic obstructive pulmonary disease (COPD) accounts for the majority of deaths from chronic lower respiratory diseases, the fourth leading cause of death in the United States in 2019.* COPD mortality rates are decreasing overall. Although rates in men remain higher than those in women, declines have occurred among men but not women (1). To examine the geographic variation in sex-specific trends in age-adjusted COPD mortality rates among adults aged ≥25 years, CDC analyzed 1999-2019 death certificate data, by urban-rural status

Background The extent of interstitial fibrosis in the kidney not only correlates with renal function at the time of biopsy but also predicts future renal outcome. However, its assessment by pathologists lacks good agreement. The aim of this study is to construct a machine learning-based model that enables automatic and reliable assessment of interstitial fibrosis in human kidney biopsies. Methods Validated cortex, glomerulus and tubule segmentation algorithms were incorporated into a single model to assess the extent of interstitial fibrosis. The model performances were compared with expert renal pathologists and correlated with patients’ renal functional data. Results Compared with human raters, the model had the best agreement [intraclass correlation coefficient (ICC) 0.90] to the reference in 50 test cases. The model also had a low mean bias and the narrowest 95% limits of agreement. The model was robust against colour variation on images obtained at different times, through different scanners, or from outside institutions with excellent ICCs of 0.92–0.97. The model showed significantly better test-retest reliability (ICC 0.98) than humans (ICC 0.76–0.94) and the amount of interstitial fibrosis inferred by the model strongly correlated with 405 patients’ serum creatinine (r = 0.65–0.67) and estimated glomerular filtration rate (r = −0.74 to −0.76). Conclusions This study demonstrated that a trained machine learning-based model can faithfully simulate the whole process of interstitial fibrosis assessment, which traditionally can only be carried out by renal pathologists. Our data suggested that such a model may provide more reliable results, thus enabling precision medicine.

Glioblastoma (GBM), the most aggressive primary heterogeneous primary brain tumor, is a glioma subtype that originates from the glial cells of the central nervous system. Glioblastoma stem cells (GSCs), situated at the top of the hierarchy, initiate and maintain the tumor and are largely accountable for GBM resistance to the mainstay treatment and recurrence. The LIM homeobox transcription factor islet 1 (ISL1) induces tumorigenicity in various tumors; however, its function in GSCs has been less reported. We aimed to generate GSCs from surgical specimens of human GBM and investigate the effect of ISL1 knockdown on GSCs. We established patient-derived GSCs, determined cancer stem cell marker expression, and immunostained GSCs to assess cell viability and apoptosis. We demonstrated that ISL1 deletion decreased the GSC viability and proliferation, and upregulated apoptosis. Moreover, we performed enzyme-linked immunosorbent assay and western blotting and found that ISL1 knockdown affected the expression of sonic hedgehog (SHH) and its downstream regulator GLI1, and further validated these results by supplementing the cells with recombinant SHH. Our results suggested that ISL1 played a critical role in regulating GBM growth and that an ISL1/SHH/GLI1 pathway was required for the maintenance of GBM progression and malignancy. The regulation of GSC growth through ISL1 might be a mechanism of interest for future therapeutic studies.

PURPOSE: To develop deep learning models to perform automated diagnosis and quantitative classification of age-related cataract from anterior segment photographs. DESIGN: DeepLensNet was trained by applying deep learning models to the Age-Related Eye Disease Study (AREDS) dataset. PARTICIPANTS: A total of 18 999 photographs (6333 triplets) from longitudinal follow-up of 1137 eyes (576 AREDS participants). METHODS: Deep learning models were trained to detect and quantify nuclear sclerosis (NS; scale 0.9–7.1) from 45-degree slit-lamp photographs and cortical lens opacity (CLO; scale 0%–100%) and posterior subcapsular cataract (PSC; scale 0%–100%) from retroillumination photographs. DeepLensNet performance was compared with that of 14 ophthalmologists and 24 medical students. MAIN OUTCOME MEASURES: Mean squared error (MSE). RESULTS: On the full test set, mean MSE for DeepLensNet was 0.23 (standard deviation [SD], 0.01) for NS, 13.1 (SD, 1.6) for CLO, and 16.6 (SD, 2.4) for PSC. On a subset of the test set (substantially enriched for positive cases of CLO and PSC), for NS, mean MSE for DeepLensNet was 0.23 (SD, 0.02), compared with 0.98 (SD, 0.24; P = 0.000001) for the ophthalmologists and 1.24 (SD, 0.34; P = 0.000005) for the medical students. For CLO, mean MSE was 53.5 (SD, 14.8), compared with 134.9 (SD, 89.9; P = 0.003) for the ophthalmologists and 433.6 (SD, 962.1; P = 0.0007) for the medical students. For PSC, mean MSE was 171.9 (SD, 38.9), compared with 176.8 (SD, 98.0; P = 0.67) for the ophthalmologists and 398.2 (SD, 645.4; P = 0.18) for the medical students. In external validation on the Singapore Malay Eye Study (sampled to reflect the cataract severity distribution in AREDS), the MSE for DeepSeeNet was 1.27 for NS and 25.5 for PSC. CONCLUSIONS: DeepLensNet performed automated and quantitative classification of cataract severity for all 3 types of age-related cataract. For the 2 most common types (NS and CLO), the accuracy was significantly superior to that of ophthalmologists; for the least common type (PSC), it was similar. DeepLensNet may have wide potential applications in both clinical and research domains. In the future, such approaches may increase the accessibility of cataract assessment globally. The code and models are available at https://github.com/ncbi/deeplensnet.

Malnutrition is associated with poor prognosis in a wide range of illnesses. However, its long-term prognostic impact in general coronary artery disease (CAD) patients is not well known. We aim to report the prevalence and long-term mortality of malnutrition in the whole general population.In this retrospective cohort study, the controlling nutritional status (CONUT) score was applied to 46,485 consecutive patients undergoing coronary angiography (CAG) and diagnosed with CAD from January 2007 to July 2018. Patients were stratified as having no malnutrition (n = 19,780), mild (n = 21,092), moderate (n = 5286) and severe malnutrition (n = 327), based on CONUT score. Overall, mean age was 63.1 ± 10.7 years, and 75.8% of patients (n = 35,250) were male. 45.4% of patients were mildly malnourished and 12.1% were moderately or severely malnourished. During a median follow-up of 5.1 years (interquartile range: 3.0-7.7 years), 6093 (17.3%) patients died. After adjusting for confounders, malnutrition risk was associated with significantly increased risk for all-cause death (mild vs. normal, HR = 1.19,95% confidence interval [CI]: 1.12 to 1.28; moderate vs. normal, HR = 1.42,95% CI: 1.30 to 1.55; severe vs. Normal, HR = 1.95, 95% CI: 1.57 to 2.41) (p for trend0.001). The similar result on all-cause mortality was also found in different subgroups stratified by gender, chronic kidney disease, anemia, percutaneous coronary intervention.Malnutrition is a common complication among patients with CAD, and is strongly associated with increased mortality. Further studies need to explore the efficacy of nutritional interventions on long-term prognosis among CAD patients. This study was registered at Clinicaltrials.gov as NCT04407936.

Treatment options for early gastric cancer have evolved toward achieving accurate evaluation of lymph node metastasis. This study aimed to investigate risk factors of lymph node metastasis in patients with early gastric cancer and establish a risk score model to guide the selection of optimal treatment.The clinicopathological characteristics of 351 patients with early gastric cancer from January 2016 to December 2018 were reviewed retrospectively. On the basis of the independent risk factors determined by multivariate binary logistic regression analysis, we established a risk score model for predicting lymph node metastasis and then verified it. The receiver operating characteristic curves were plotted using the test and validation sets. The area under the receiver operating characteristic curve was used to assess the discriminant ability of the model.Lymph node metastasis was observed in 10.5% (37/351) of early gastric cancer cases. Patients with early gastric cancer were grouped based on the independent risk factors for lymph node metastasis (tumor size, depth, histological type, and lymphovascular involvement) determined by multivariate analysis. A 7-point risk score model was established to predict the risk of lymph node metastasis. The area under the receiver operating characteristic curve in the development and validation sets were 0.839 (95% confidence interval, 0.769%-0.910%) and 0.820 (95% confidence interval, 0.711%-0.930%), respectively.A feasible risk score model for lymph node metastasis was established to guide the optimal treatment of patients with early gastric cancer early gastric cancer.

Available evidence is incomplete and inconsistent in the outcomes of heart failure (HF) patients with preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). There are also limited data on the proportions and long-term prognosis among the three HF phenotypes in China. We aimed to characterize the 5 year prognosis in three HF phenotypes according to EF in a cohort of hospitalized HF patients undergoing coronary angiography in southern China.Hospitalized patients with HF were enrolled from the Cardiorenal ImprovemeNt registry (CIN; ClinicalTrials.gov NCT04407936) between January 2007 and December 2014. HF phenotypes were defined as HFpEF (EF ≥ 50%), HFmrEF (EF 41-49%), and HFrEF (EF ≤ 40%). Kaplan-Meier and Cox proportional hazards models were constructed to examine differences in 5 year outcomes in HF patients with different phenotypes. A total of 4880 HF patients [mean age: 61.8 ± 10.3, male: 3156 (64.7%)] were included: 2768 (57%) had HFpEF, 1015 (21%) had HFmrEF, and 1097 (22%) had HFrEF. Patients with HFrEF were older than those with HFpEF (62.5 ± 10.6 vs. 61.3 ± 10.1, P 0.001) and more likely to be male (78.0% vs. 55.9%, P 0.001). With 5 year follow-up through the end of December 2019, 1624 (27.6%) patients died. Controlling confounding variables, declined EF category was independently associated with increased 5 year mortality {HFrEF 25.2% vs. HFpEF 13.4%, adjusted hazard ratio [aHR]: 1.85 [95% confidence interval (CI): 1.45 to 2.35]; HFmrEF 18.1% vs. HFpEF 13.4%, aHR: 1.40 [95% CI: 1.08 to 1.81]; HFrEF 25.2% vs. HFmrEF 18.1%, aHR: 1.32 [95% CI: 1.02 to 1.71]}.In this Chinese cohort, patients with HFrEF account for less than a fourth of HF patients. One-sixth individuals with HF died in 5 years. HFrEF was associated with a nearly two-fold increased risk of 5 year mortality than HFpEF. Further studies are needed to prospectively evaluate the efficacy of improving treatment on outcomes in all three HF phenotypes.

The application of artificial intelligence (AI) in medicine and ophthalmology has experienced exponential breakthroughs in recent years in diagnosis, prognosis, and aiding clinical decision-making. The use of digital data has also heralded the need for privacy-preserving technology to protect patient confidentiality and to guard against threats such as adversarial attacks. Hence, this review aims to outline novel AI-based systems for ophthalmology use, privacy-preserving measures, potential challenges, and future directions of each.Several key AI algorithms used to improve disease detection and outcomes include: Data-driven, imagedriven, natural language processing (NLP)-driven, genomics-driven, and multimodality algorithms. However, deep learning systems are susceptible to adversarial attacks, and use of data for training models is associated with privacy concerns. Several data protection methods address these concerns in the form of blockchain technology, federated learning, and generative adversarial networks.AI-applications have vast potential to meet many eyecare needs, consequently reducing burden on scarce healthcare resources. A pertinent challenge would be to maintain data privacy and confidentiality while supporting AI endeavors, where data protection methods would need to rapidly evolve with AI technology needs. Ultimately, for AI to succeed in medicine and ophthalmology, a balance would need to be found between innovation and privacy.

Fetalhyperechogenickidneys (HEK)are associated with a wide range of etiologies and prognoses. Prenatal counselling and management can be extremely challenging, especially for isolated HEK.A total of 28 pregnancies were screened by ultrasonography with HEK from March 1, 2016 to December 31, 2020. Genetic testings for aneuploidy and copy number variations (CNVs) are routine during the investigation for etiologies of fetal HEK in our unit. Trio-whole exome sequencing(WES) was offered to the family when karyotyping and microarray were not diagnostic.A systematic review (SR) was conducted to use the authoritative literature retrieval databases describing genetic testings' results in prenatal HEK cases.In the 28 HEK fetuses, 2 (7.14%) cases were identified with chromosome abnormalities and 6 (21.43%) cases were detected with pathogenic CNVs. Through trio-WES analysis, pathogenic or likely pathogenic variations were detected in the following genes: PKD1, BBS2, BBS9, HNF1B, PKHD1 and ETFA in another 10 (35.71%) fetuses. And the remaining 10 (35.71%) cases were undiagnosed. The pooled data from all reviewed studies indicate that HNF1B gene heterozygous deletion or mutation are the most common genetic causes associated with HEK.This is the first study to accurately describe the genotype ratio at different levels of genetic testing associated with fetal HEK. Our study has suggested that trio-WES could improve the detection rate and efficiency ofidentification genetic pathologies in fetuseswith isolated HEK. The WES results provide new evidences to guide prenatal counseling and management.

Pneumonia is one of the most common treatable causes of death, and early diagnosis allows for early intervention. Automated diagnosis of pneumonia can therefore improve outcomes. However, it is challenging to develop high-performance deep learning models due to the lack of well-annotated data for training. This paper proposes a novel method, called Deep Supervised Domain Adaptation (DSDA), to automatically diagnose pneumonia from chest X-ray images. Specifically, we propose to transfer the knowledge from a publicly available large-scale source dataset (ChestX-ray14) to a well-annotated but small-scale target dataset (the TTSH dataset). DSDA aligns the distributions of the source domain and the target domain according to the underlying semantics of the training samples. It includes two task-specific sub-networks for the source domain and the target domain, respectively. These two sub-networks share the feature extraction layers and are trained in an end-to-end manner. Unlike most existing domain adaptation approaches that perform the same tasks in the source domain and the target domain, we attempt to transfer the knowledge from a multi-label classification task in the source domain to a binary classification task in the target domain. To evaluate the effectiveness of our method, we compare it with several existing peer methods. The experimental results show that our method can achieve promising performance for automated pneumonia diagnosis.

Disseminated Rhizomucor pusillus infection is a very rare but fatal complication in immunocompromised patients, because of aggressive clinical process with delayed diagnosis by routine laboratory tests. Recently, cell-free DNA next-generation sequencing (cfDNA NGS) has been used for the timely detection of infectious pathogens including mucormycosis. Herein, we described an 18-year-old male with Philadelphia-like acute lymphoblastic leukemia who received a timely diagnosis of R. pusillus infection by cell-free DNA next-generation sequencing, and confirmed by silver staining and qPCR on biopsy tissue. To the best of our knowledge, this was the first case of disseminated R. pusillus infection detected by cfDNA NGS and confirmed by histology in an adult leukemia patient. In addition, this case was supposed to be the most extensive R. pusillus infection diagnosed, involving the lung, skin, liver, kidney, spleen and brain, and the only one case who survived the infection had a favorable outcome through treatment with liposome amphotericin B sequential posaconazole. This case suggested that cfDNA NGS could be used to successfully detect rare pathogen infections, and this was especially important for R. pusillus because timely diagnosis and effective treatment could improve the prognosis of this kind of patient.

Objectives Early acute kidney injury (AKI) after burn contributes to disastrous prognoses for severely burned patients. Burn-induced renal oxidative stress and secondary proinflammatory mediator release contribute to early AKI development, and Toll-like receptor (TLR) 4 regulates inflammation. Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that plays a vital role in protecting against ischemia-induced organ injury via its antioxidant properties and regulation of inflammation. We investigated the potential effect of HO-1 induction in preventing burn-induced early AKI and its related mechanism. Methods A classic major-burn rat model was established using a 100 °C water bath, and hemin was injected intraperitoneally immediately after the injury to induce HO-1. Histological staining and blood tests were used to assess AKI progression based on structural changes and function. Renal levels of HO-1, oxidative stress, proinflammatory mediators and TLR4-related signals were detected using ELISA, immunostaining, qRT-PCR, and western blotting. The selective TLR4 inhibitor TAK242 and TLR4 inducer LPS were introduced to determine the roles of HO-1 in burn-related renal inflammation and the TLR4 pathway. Results Hemin improved burn-induced renal histological damage and dysfunction, and this beneficial effect was related to reduced renal oxidative stress and the release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and intracellular adhesion molecule-1 (ICAM-1). Hemin downregulated the expression of TLR4 and the subsequent phosphorylation of IKKα/β, IκBα, and NF-κB p65;. TAK242 exerted an effect similar to but weaker than hemin; and LPS reversed the antiinflammatory effect of hemin and the regulation of TLR4 signals. These results suggested that the TLR4 signaling pathway mediated the HO-1-facilitated regulation of renal inflammation after burn. Conclusion The present study demonstrated that HO-1 induction prevented burn-induced early AKI by targeting renal inflammation, which was mediated via regulation of the TLR4/NF-κB signaling pathway.

Progestin resistance is a critical factor that prevents patients with endometrial cancer (EC) from receiving conservative therapy. However, the etiology remains elusive. Cancer stem cells (CSCs) may be a contributing factor to progestin resistance in EC. These cells share similar stemness properties with embryonic stem cells that have a multipotent but differential naïve phenotype. Embryonic stem cells are programed to self-renew, to differentiate and to show plasticity toward a normal cellular phenotype in their defined microenvironment. However, whether this microenvironment may promote CSC differentiation toward a better responsive phenotype and reverse progestin resistance has not yet been clarified. In the current study, we found that progestin resistance of endometrial CSCs can be improved or reversed by using in vitro fertilization (IVF)-generated embryonic sac-derived fluid containing the embryonic microenvironment. Furthermore, suppression or reversal of progestin resistance was mediated by placental alkaline phosphatase (ALPP), a factor secreted into the embryonic microenvironment by IVF-generated blastocysts. ALPP significantly reversed progestin resistance by facilitating endometrial CSC differentiation through downregulating the stemness genes NANOG, OCT4 and SOX2. We further showed that the downregulation of NANOG, OCT4 and SOX2 by ALPP was carried out by TET1/2-mediated epigenetic modulation of the promoter regions of these genes. Such changes at the molecular level initiated endometrial CSC differentiation and promoted a better responsive endometrial cancer phenotype. In fact, their response to progestin treatment was similar to that of well-differentiated endometrioid carcinoma cells without CSCs. ALPP could be a novel target in the process to overcome progestin resistance, and such findings may provide a new approach for the conservative treatment of endometrial cancer.

Hospice care (HC) is specialized medical care for terminal patients who are nearing the end of life. Interdisciplinary collaborative hospice care (ICHC) is where experts from different disciplines and patients/caregivers form a treatment team to establish shared patient care goals. However, the ICHC efficacy has not been frequently studied in the terminal geriatric cancer patient (TGCP) population. This study aimed to gain insight into ICHC provided to TGCPs by an ICHC team and identify factors to ameliorate multidimensional HC.166 TGCPs were randomized by a computer-generated random number table using an allocation ratio of 1:1. The patients were divided into the ICHC group and life-sustaining treatment (LST) group. The scores of these questionnaires, such as EORTC, QLQ-C30, Hamilton anxiety scale, the median survival time (MST), symptoms improvement, the median average daily cost of drugs (MADDC), the median total cost of drugs (MTDC) in the last 2 days, and medical care satisfaction were observed in both groups.After treatment, the improvement of emotional function and symptoms in the ICHC group were statistically higher than those in the LST group (P 0.05). The MADDC and the MTDC in the last 2 days were statistically lower in the ICHC group than those in the LSTs group (P 0.01). In addition, the overall satisfaction situation and the cooperation ability in the ICHC group were statistically higher than those in the LST group (P 0.01).The ICHC could provide TGCPs with coordinated, comfortable, high-quality, and humanistic care.

Tumor-induced osteomalacia TIO is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 FGF23 by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density aBMD in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral distal radius and tibia and axial lumbar spine skeleton using high-resolution peripheral quantitative computed tomography HR-pQCT and trabecular bone score TBS and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry DXA or HR-pQCT scans were enrolled. Compared with age-, sex- and BMI-matched healthy controls, TIO patients n=113 had lower vBMD, damaged microstructure and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS

Gait abnormalities have been widely investigated in the diagnosis and treatment of neurodegenerative diseases. However, it is still a great challenge to achieve a comfortable, convenient, sensitive and high-pressure resistant flexible gait detection sensor for real-time health monitoring. In this work, a polyaniline (PANI)@(polyacrylic acid (PAA)-polyvinyl alcohol (PVA)) (PANI@(PVA-PAA)) ternary network hydrogel with a uniaxially oriented porous featured structure was successfully prepared using a simple freeze-thaw method and

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis. Supplementary Information The online version contains supplementary material available at 10.1007/s12265-021-10147-3.

Hepatitis B surface antigen (HBsAg) seroconversion is considered the optimal outcome of the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-α) improves the seroconversion rate in patients with chronic hepatitis B (CHB).Flow cytometry was performed using circulating T follicular helper (TFH) cells from 15 healthy individuals and 45 patients with CHB presenting different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)] to the standard 48-week regimen of PEG-IFN-α monotherapy to examine the significance of circulating TFH cells in the therapeutic response of patients with CHB to PEG-IFN-α. In addition, the capacities of different TFH subsets to activate B cells and stimulate IgG production were assessed by performing coculture experiments.Longitudinal analysis revealed specific and significant increases in the numbers of CD40LTFH cells, particularly those with CD40L expression, stimulate B-cell differentiation and improve the HBsAg seroconversion rate in patients with CHB treated with PEG-IFN-α monotherapy.

Introduction The incidence of insomnia is getting higher and higher. Long-term insomnia seriously affects people’s health. Drug use is usually accompanied with adverse events. Both acupuncture and cognitive behavioral therapy for insomnia (CBT-I) have been proven to be safe and effective non-pharmacological treatments for insomnia. As the insomniacs’ bad sleep behavior and wrong cognition have not been effectively corrected, acupuncture has a quick effect, high patient compliance but unstable long-term efficacy, while CBT-I is complex, time-consuming, and expensive; additionally, patient compliance is low, and the number of trained therapists is limited, making it difficult to carry out. Therefore, this study aims to use the insomnia TCM system to construct a convenient and feasible traditional Chinese medicine e-aid cognitive behavioral therapy for insomnia (TCM-eCBT-I) for Chinese people, and combine the advantages of acupuncture and TCM-eCBT-I for maintaining long-term efficacy, and three treatments will be evaluated to provide clinicians with a more effective clinical protocol Methods and analysis This study is a single-center, open-label, randomized controlled trial. Ninety subjects will be recruited and randomly assigned to three groups: the acupuncture group, the TCM-eCBT-I group, and the acupuncture combined with TCM-eCBT-I group, in a ratio of 1:1:1. We will evaluate the Pittsburgh Sleep Quality Index (PSQI) and Dysfunctional Beliefs and Attitudes About Sleep Scale (DBAS), Insomnia Severity Index (ISI), sleep diary, Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Fatigue Scale-14 Scale (FS-14) scales. All adverse reactions will be assessed through the ADVERSE event table. All outcomes will be evaluated online at 0 weeks, 4 weeks, 8 weeks, 16 weeks, and 28weeks. Ethics and dissemination This study has been approved by the Institutional Review Board of the Affiliated Hospital of Nanjing University of Chinese Medicine (2020 NL-018-02). Informed consent will be obtained from all the subjects. The results will be shared with sleep researchers, public, and relevant academic institutions through high-impact peer-reviewed publications. Trial registration Chinese Clinical Trial Registry ChiCTR2000032960. Registered on 17 May 2020

Background Although it has been suggested that loneliness is a risk factor for adverse health outcomes, living arrangement may confound the association. This study aimed to investigate whether the associations of loneliness with adverse health outcomes differ in community-dwelling older adults according to different living arrangements. Methods In the 2008/2009 wave of Chinese Longitudinal Healthy Longevity Survey, 13,738 community-dwelling older adults (≥65 years) were included for analyses. Living arrangements and loneliness were assessed. Health outcomes including cognitive and physical functions were assessed using MMSE, ADL/IADL scales and Frailty Index in the 2008/2009 and 2011/2012 waves; mortality was assessed in the 3-year follow-up from 2008/2009 to 2011/2012. The effect modificaitons of loneliness on adverse health outcomes by living arrangements were estimated using logistic regression or Cox proportional hazards regression models. Results Living alone older adults were significantly more likely to be lonely at baseline (52% vs 29.5%, OR = 1.90, 95% CI = 1.67–2.16, P P P P = 0.002, respectively). In contrast, among the living alone older adults, loneliness was only significantly associated with higher prevalence of frailty (OR = 1.42, 95% CI = 1.07–1.90, P = 0.017). Living arrangement significantly modified the associations of loneliness with prevalent cognitive impairment and 3-year mortality (P values for interaction = 0.005 and 0.026, respectively). Conclusions Living arrangement modifies the associations of loneliness with adverse health outcomes in community-dwelling older adults, and those who lived with others but felt lonely had worse cognitive and physical functions as well as higher mortality. Special attention should be paid to this population and more social services should be developed to reduce adverse health outcomes, in order to improve their quality of life and promote successful aging.

Introduction: Apart from their recognized lipid-lowering effect, Hedan tablets, a mixture of Chinese herbal medicines, have demonstrated a certain weight-loss effect in clinical practice. The aim of this randomized, double-blind, placebo-controlled study was to verify the effect of Hedan tablets on body weight (BW) and insulin resistance (IR) in patients with metabolic syndrome (MetS). Methods: A total of 62 eligible patients with MetS were divided into two groups: the treatment group (Hedan tablets at 4.38 g/day tid) and the control group (placebo treatment). Both groups attended follow-ups at 8, 16, and 24 weeks during the process. The parameters of the assessment include lipid level, BW, triglyceride (TG) to high-density lipoprotein cholesterol (HDLc) ratio (TG/HDLc), homeostasis model assessment for IR (HOMA-IR) index, and adiponectin. Results: Patients in the treatment group showed a significant decrease in BW compared to those in the control group (−4.47 vs. 0.06 kg) after 8 weeks of treatment. A significant decrease in body mass index (BMI) was also observed in the treatment group after 16 weeks of treatment (−1.79 vs. −0.03 kg/m2). In the treatment group, 20 out of 31 (64.5%) patients lost 5–10% BW and 4 out of 31 (12.9%) patients lost over 10% BW after 24 weeks of treatment. Although there were no significant changes in the patients’ HOMA-IR, the treatment group showed a significant reduction in TG/HDLc (−0.98 vs. −0.19) after 8 weeks of treatment and a significant increase in adiponectin (6.87 vs. −0.43) after 16 weeks of treatment. Discussion/Conclusion: The Hedan tablets significantly improve BW, BMI, TG/HDLc, and adiponectin in patients with MetS. Thus, Hedan tablets may be used as an adjunct to existing MetS management methods.

Background High-sensitivity C-reactive protein (hs-CRP) plays an important role in hypoalbuminemia as a representative of inflammation, which is closely associated with poor prognosis among patients with coronary artery disease (CAD). The present study aimed to evaluate the independent and joint effects of high hs-CRP levels and hypoalbuminemia on long-term mortality among CAD patients. Methods A total of 1449 CAD patients were included from a prospective, multicenter, observational cohort study (REICIN, NCT01402232) of patients referred for coronary angiography (CAG). The primary endpoint was long-term all-cause death. Results During a median follow-up of 2.9 (2.0–3.0) years, a total of 107 (7.4%) patients died. The long-term mortality was higher among CAD patients with high hs-CRP levels (> 3 mg/L) than those with the low hs-CRP levels (≤ 3 mg/L; 10.7% versus 4.1%; hazard ratio [HR] 2.49; 95% confidence interval [CI] 1.48–4.17). Similarly, CAD patients with hypoalbuminemia had higher mortality than those without hypoalbuminemia (12.2% versus 4.9%; HR 1.93; 95% CI 1.20–3.08). When hs-CRP and albumin were combined, CAD patients with high hs-CRP levels (> 3 mg/L) and with hypoalbuminemia were at the highest risk of death compared with their reference group (hs-CRP ≤ 3 mg/L and albumin > 35 g/L; HR 3.79; 95% CI 1.91–7.52). Conclusions High hs-CRP levels and hypoalbuminemia were independently and jointly associated with long-term mortality among CAD patients. Patients with high hs-CRP levels and hypoalbuminemia had the highest risk of long-term mortality compared with other groups.

Background Recombinant protein subunit vaccination is considered to be a safe, fast and reliable technique when combating emerging and re-emerging diseases such as coronavirus disease 2019 (COVID-19). Typically, such subunit vaccines require the addition of adjuvants to attain adequate immunogenicity. AS01, which contains adjuvants MPL and saponin QS21, is a liposome-based vaccine adjuvant system that is one of the leading candidates. However, the adjuvant effect of AS01 in COVID-19 vaccines is not well described yet. Methods In this study, we utilized a mixture of AS01 as the adjuvant for an S1 protein-based COVID-19 vaccine. Results The adjuvanted vaccine induced robust immunoglobulin G (IgG) binding antibody and virus-neutralizing antibody responses. Importantly, two doses induced similar levels of IgG binding antibody and neutralizing antibody responses compared with three doses and the antibody responses weakened only slightly over time up to six weeks after immunization. Conclusion These results suggested that two doses may be enough for a clinical vaccine strategy design using MPL & QS21 adjuvanted recombinant protein, especially in consideration of the limited production capacity of COVID-19 vaccine in a public health emergency.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder. Half of the patients would slowly progress to end-stage renal disease. However, the potential target for ADPKD treatment is still lacking. Methods Four ADPKD patients and two healthy family members were included in this study. The peripheral blood samples were obtained and tested by the whole exome sequencing (WES). The autosomal mutations in ADPKD patients were retained as candidate sites. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein–protein interaction network (PPI) analyses were performed by clusterProfiler R package. A dataset containing 18 ADPKD patients and three normal samples were downloaded from the Gene Expression Omnibus (GEO) database and analyzed using the limma R package. Results A total of six mutant genes were identified based on the dominant genetic pattern and most of them had not been reported to be associated with ADPKD. Furthermore, 19 harmful genes were selected according to the harmfulness of mutation. GO and KEGG enrichment analyses showed that the processes of single-organism cellular process, response to stimulus, plasma membrane, cell periphery, and anion binding as well as cyclic adenosine monophosphate (cAMP) signaling pathway and pathways in cancer were significantly enriched. Through integrating PPI and gene expression analyses, acyl-CoA thioesterase 13 (ACOT13), which has not been reported to be related to ADPKD, and prostaglandin E receptor 2 (PTGER2) were identified as potential genes associated with ADPKD. Conclusions Through combination of WES, gene expression, and PPI network analyses, we identified ACOT13 and PTGER2 as potential ADPKD-related genes.

Background Isthmus-originating papillary thyroid carcinoma has unique clinicopathological characteristics. There are no specific guidelines regarding the extent of surgery for isthmic papillary thyroid carcinoma. We aimed to evaluate the characteristics of clinically lymph node–negative patients with solitary isthmic papillary thyroid carcinoma and to determine the best surgical protocol for these patients. Methods A total of 904 patients diagnosed with solitary papillary thyroid carcinoma who underwent surgery were retrospectively reviewed. These patients were divided into the isthmic group (246 patients) or lobar group (658 patients). We compared the 2 groups and conducted a multivariate analysis to assess risk factors for ipsilateral and contralateral central lymph node metastasis in isthmic papillary thyroid carcinoma patients. Nomograms for predicting central lymph node metastasis in isthmic papillary thyroid carcinoma patients were developed and internal calibration was performed for these models. Results Isthmic papillary thyroid carcinoma patients have a significantly higher incidence of extrathyroidal extension and central lymph node metastasis than do lobar papillary thyroid carcinoma patients. For isthmic papillary thyroid carcinoma patients, sex, BRAF V600E mutation, chronic lymphocytic thyroiditis, tumor size, margin, and extrathyroidal extension were independent risk factors of ipsilateral central lymph node metastasis. Body mass index, BRAF V600E mutation, tumor size, location, and extrathyroidal extension were independent risk factors of contralateral central lymph node metastasis. All the above factors were incorporated into nomograms, which showed the perfect discriminative ability. Conclusion Based on the predictive nomograms, we proposed a risk stratification scheme and corresponding individualized surgical treatment based on different nomogram scores. In the debate about prophylactic central neck dissection among clinically lymph node-negative patients with solitary isthmic papillary thyroid carcinoma, our nomograms provide the balance to avoid overtreatment and undertreatment through personal risk assessment.

Background Scrub typhus is caused by O. tsutsugamushi and spreads through mite larvae biting the skin. Classic symptoms of the disease are eschar and lymphadenopathy. Previous reports have revealed clinical manifestations of scrub typhus, including gastrointestinal symptoms, meningoencephalitis, ocular flutter, pneumonitis, acute respiratory distress syndrome, and acute kidney injury. However, cases of scrub typhus presenting as a urinary tract infection (UTI) with high D-dimer levels could be easily misdiagnosed when clinical attention is insufficient, resulting in difficulty in making a timely diagnosis of the infection. Metagenomics next-generation sequencing (mNGS) is a revolutionary and highly sensitive method that may help in diagnosing atypical cases, even when trace amounts of pathogens are present. Case presentation A 52-year-old female presented with a 10-day history of fever, chills, headache and myalgia. She was initially diagnosed with influenza at a local clinic. Various antibacterials were used on the 2nd–12th day onwards; however, her symptoms persisted and were followed by increased urination duration, frequency, urgency and dysuria for 2 days. Orientia tsutsugamushi was confirmed as the pathogen responsible for the infection through mNGS analysis of her blood samples from Day 13 onwards. The patient’s temperature changed remarkably 24 h after the initiation of doxycycline. Over the next 48 h (i.e., Day 15 onwards), the patient showed clinical improvement. She recovered and was discharged from the hospital. Conclusions Scrub typhus can present atypical clinical symptoms, such as UTIs, in a febrile patient. mNGS may be a useful method for identifying O. tsutsugamushi infection in patients with atypical clinical manifestations.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3–6. Here we define a critical role of IL-27–IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK–PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy. Therapeutic administration of IL-27—serum levels of which are decreased in individuals with obesity—improves thermogenesis, protects against diet-induced obesity and ameliorates insulin resistance in mouse models of obesity.

Aims It has been reported that the G‐alpha interacting protein (GAIP) interacting protein, C terminus 1 (GIPC1/GIPC) engages in vesicular trafficking, receptor transport and expression, and endocytosis. However, its role in epilepsy is unclear. Therefore, in this study, we aimed to explore the role of GIPC1 in epilepsy and its possible underlying mechanism. Methods The expression patterns of GIPC1 in patients with temporal lobe epilepsy (TLE) and in mice with kainic acid (KA)‐induced epilepsy were detected. Behavioral video monitoring and hippocampal local field potential (LFP) recordings were carried out to determine the role of GIPC1 in epileptogenesis after overexpression of GIPC1. Coimmunoprecipitation (Co‐IP) assay and high‐resolution immunofluorescence staining were conducted to investigate the relationship between GIPC1 and metabotropic glutamate receptor 7 (mGluR7). In addition, the expression of mGluR7 after overexpression of GIPC1 was measured, and behavioral video monitoring and LFP recordings after antagonism of mGluR7 were performed to explore the possible mechanism mediated by GIPC1. Results GIPC1 was downregulated in the brain tissues of patients with TLE and mice with KA‐induced epilepsy. After overexpression of GIPC1, prolonged latency period, decreased epileptic seizures and reduced seizure severity in behavioral analyses, and fewer and shorter abnormal brain discharges in LFP recordings of KA‐induced epileptic mice were observed. The result of the Co‐IP assay showed the interaction between GIPC1 and mGluR7, and the high‐resolution immunofluorescence staining also showed the colocalization of these two proteins. Additionally, along with GIPC1 overexpression, the total and cell membrane expression levels of mGluR7 were also increased. And after antagonism of mGluR7, increased epileptic seizures and aggravated seizure severity in behavioral analyses and more and longer abnormal brain discharges in LFP recordings were observed. Conclusion GIPC1 regulates epileptogenesis by interacting with mGluR7 and increasing its expression.

Excessive alcohol use* is associated with disease, injury, and poor pregnancy outcomes and is responsible for approximately 95,000 deaths in the United States each year (1). Binge drinking (five or more drinks on at least one occasion for men or four or more drinks for women) is the most common and costly pattern of excessive alcohol use (2). CDC analyzed data from the 2018 Behavioral Risk Factor Surveillance System (BRFSS) to estimate past 30-day binge drinking prevalence, frequency, and intensity (number of drinks per occasion), overall and by select characteristics and state. The overall unadjusted prevalence of binge drinking during the past 30 days was 16.6%, representing an estimated 38.5 million U.S. adults aged ≥18 years; prevalence was highest (26.0%) among those aged 25-34 years. The age-standardized binge drinking prevalence was higher among men (22.5%) than among women (12.6%), increased with income, and was highest among non-Hispanic White adults and adults in the Midwest Census region. State-level age-standardized binge drinking prevalence ranged from 10.5% (Utah) to 25.8% (Wisconsin). Among adults who reported binge drinking, 25.0% did so at least weekly, on average, and 25.0% consumed at least eight drinks on an occasion. To reduce binge drinking, the Community Preventive Services Task Force recommends increasing alcohol taxes and implementing strategies that strengthen regulations to reduce alcohol availability.† The U.S. Preventive Services Task Force recommends clinicians screen adults for alcohol misuse in primary care settings and provide counseling as needed.§.

The numerous health benefits of physical activity include reduced risk for chronic disease and improved mental health and quality of life (1). Physical activity can improve physical function and reduce pain and fall risk among adults with arthritis, a group of approximately 100 conditions affecting joints and surrounding tissues (most commonly osteoarthritis, fibromyalgia, gout, rheumatoid arthritis, and lupus) (1). Despite these benefits, the 54.6 million U.S. adults currently living with arthritis are generally less active than adults without arthritis, and only 36.2% of adults with arthritis are aerobically active (i.e., meet aerobic physical activity guidelines*) (2). Little is known about which physical activities adults with arthritis engage in. CDC analyzed 2019 Behavioral Risk Factor Surveillance System (BRFSS) data to examine the most common nonwork-related physical activities among adults with arthritis who reported any physical activity during the past month, nationally and by state. In 2019, 67.2% of adults with arthritis reported engaging in physical activity in the past month; among these persons, the most commonly reported activities were walking (70.8%), gardening (13.3%), and weightlifting (7.3%). In 45 U.S. states, at least two thirds of adults with arthritis who engaged in physical activity reported walking. Health care providers can help inactive adults with arthritis become active and, by encouraging physical activity and referring these persons to evidence-based physical activity programs, improve their health and quality of life.

Oxaliplatin is a crucial component of the combinatorial chemotherapeutic standard of care for advanced colorectal cancer (CRC). Unfortunately, a serious barrier to effective oxaliplatin treatment is drug resistance due to epithelial-mesenchymal transitioning (EMT). Interestingly, stable oxaliplatin-resistant CRC cell lines show differential expression of miR-1915-3p; thus, this microRNA may represent a potential modifier of oxaliplatin resistance in CRC cells. miR-1915-3p was over-expressed in oxaliplatin-resistant CRC cells and a non-tumorigenic intestinal cell line (FHC) via lentiviral transduction. Extracellular vesicles (EVs) were purified from transduced FHC cells and co-incubated with CRC cells. Expression levels of miR-1915-3p and other RNA species were assessed by RT-qPCR, while protein expression levels were assessed by Western blotting. The effects of miR-1915-3p on CRC viability were evaluated by proliferation, apoptosis assays, and Transwell assays. Effects of miR-1915-3p over-expression on in vivo oxaliplatin sensitivity was tested via murine xenograft models. miRNA-1915-3p decreased EMT marker expression in oxaliplatin-resistant CRC cell lines and in vivo. FHC cells were able to produce and secrete miR-1915-3p-containing EVs, which we employed to mediate miR-1915-3p delivery to oxaliplatin-resistant CRC cells and increase their oxaliplatin sensitivity in vivo and in vitro. Mechanistically, miR-1915-3p overexpression downregulated the EMT-promoting oncogenes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and ubiquitin carboxyl-terminal hydrolase 2 (USP2) as well as upregulated E-cadherin (a cell adhesion mediator). miR-1915-3p’s effects on chemosensitivity and EMT were mediated by its regulation of PFKFB3 and USP2. Exosomal delivery of miR-1915-3p can improve the chemotherapeutic efficacy of oxaliplatin in CRC cells by suppressing the EMT-promoting oncogenes PFKFB3 and USP2.

This meta-analysis aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on blood pressure in patients with essential hypertension to explore more suitable training.PubMed, EBSCO, Cochrane Library, Web of Science, CNKI, and VIP databases were searched for randomized controlled trials published between January 2002 and November 2022. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were selected as the effect scale indices for the evaluation of the differences in post-intervention systolic blood pressure (SBP), and diastolic blood pressure (DBP), heart rate, maximum oxygen uptake (VO2max), and flow-mediated vasodilation. All these were compared using Review Manager 5.3 and Stata 14.0.A total of 13 randomized controlled trials and 442 patients were included. The meta-analyses revealed no statistically significant differences between HIIT and MICT in improving SBP and DBP in patients with hypertension. Subgroup analyses revealed that HIIT was better than MICT in reducing SBP during daytime monitoring (WMD = -4.14, 95%CI: [-6.98, -1.30], P .001). In addition, HIIT increased flow-mediated vasodilation more than MICT in hypertensive patients (WMD = 2.75, 95%CI: [0.43, 5.07], P = .02).HIIT and MICT have similar effects on the overall resting SBP and DBP in patients with hypertension and prehypertension. However, HIIT is better than MICT at reducing SBP during daytime monitoring. In addition, HIIT can improve vasodilation.

Background The triglyceride glucose (TyG) index is an alternative to insulin resistance (IR) as an early indicator of worsening heart failure (HF). Patients with secondary mitral regurgitation (sMR) often experience progressive deterioration of cardiac function. This study aimed to investigate the relationship between the TyG index and worsening of HF in significant sMR (grade ≥ 2) following percutaneous coronary intervention (PCI). Methods This study enrolled participants with significant sMR following PCI from a multicenter cohort study. The patients were divided into the following 3 groups according to tertiles of TyG index: T1, TyG ≤ 8.51; T2, TyG > 8.51 to ≤ 8.98; and T3, TyG > 8.98. The main clinical outcome was worsening HF including unplanned rehospitalization or unscheduled physician office/emergency department visit due to HF and unplanned mitral valve surgery. Results A total of 922 patients (mean ± SD age, 64.1 ± 11.0 years; 79.6% male) were enrolled. The incidence of worsening HF was 15.5% in T1, 15.7% in T2, and 26.4% in T3. In the multivariable model, the highest TyG tertile (T3 group) was more strongly correlated with worsening HF than the lowest tertile (T1 group) after adjusting for confounders (adjusted hazard ratio, 2.44; 95% confidence interval, 1.59–3.72; P Conclusions Elevated preprocedural TyG index is a significant and independent risk factor for worsening HF in sMR following PCI that can be used for risk stratification.

OBJECTIVE: To develop the birth weight curves of the Chinese Han (26-41 weeks of gestation) and Zhuang (28-41 weeks of gestation) singleton neonates in 11 cities of China, as well as the birth weight means of full-term neonates of 14 Chinese ethnic groups. METHODS: The live singleton neonates who were born in 11 maternal and child health care hospitals from 11 cities of China between January 2017 and December 2020 were classified according to the mother's ethnic group. Birth weight means were calculated for the full-term neonates of each ethnic group. For the Han and Zhuang singleton neonates with a large sample size, the Lambda-Mu-Sigma (LMS) method was used to establish the birth weight percentile curves of the Han and Zhuang singleton neonates with different gestational ages. RESULTS: A total of 105 365 live singleton neonates were included, among whom the Han neonates had the highest number of 84 851 (26-41 weeks of gestation), followed by the Zhuang neonates (12 803 neonates with a gestational age of 28-41 weeks). The neonates of the other Chinese ethnic groups enrolled were live full-term singleton neonates, with a sample size of more than 100 neonates for each ethnic group. The 3rd-97th percentile curves of birth weight were established for the Han singleton neonates with a gestational age of 26-41 weeks and the Zhuang singleton neonates with a gestational age of 28-41 weeks. The birth weight curves of the Han singleton neonates at each gestational age were higher than those of the Zhuang singleton neonates. Birth weight means (3 199-3 499 g) and standard deviations were determined for 14 Chinese ethnic groups, i.e., Li, Mulao, Zhuang, Yao, Dong, Miao, Han, Buyi, Mongolian, Tujia, Yi, Hui, Man, and Korean ethnic groups. The Li ethnic group had the lowest birth weight, followed by the Mulao, Zhuang, Yao, Dong, Miao, Han, Buyi, Mongolian, Tujia, Yi, Hui, Man, and Korean ethnic groups. CONCLUSIONS: The 3rd-97th percentile curves of birth weight are developed for the Han (26-41 weeks of gestation) and Zhuang (28-41 weeks of gestation) singleton neonates in 11 cities of China, and birth weight means are determined for the full-term neonates of 14 Chinese ethnic groups in 11 cities of China, which provides a reference for evaluating the intrauterine growth of neonates in these ethnic groups.