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ObjectiveA method for calculating and selecting the minimum specific energy consumption working point is developed to solve the problem of high energy consumption in the short-distance slurry transport of dredgers.MethodsBased on the relevant models of pump pressure, pipeline resistance, critical flow velocity and pump cavitation established in previous research, the minimum energy consumption per cubic meter of particles is taken as the goal, and the pump speed which is most familiar and easily controlled by the workers is taken as the optimization variable. A double optimization method combining the minimum energy consumption search of the transport system and the optimization of multiple pump speeds is adopted to calculate and select the minimum energy consumption working point of the dredger with multiple pumps in a series, and the algorithm is verified by taking the construction of the "Xin Hai Lang" dredger with three different types of centrifugal pumps under specific working conditions as a case. ResultsThe calculation results show that the specific-energy consumption of the working point optimized by this algorithm model is 11.8% lower than that of the maximum production working point. Conclusions The application of these research results can effectively make up for existing optimization methods that aim at production capacity (max. production), providing feasible references for energy saving and emission reduction in dredging projects.

This study investigated the study motivation and psychological responses of pre-second-year Ph.D. students from a comprehensive university in Malaysia. To gain an understanding of the challenges faced by students, we conducted group interviews with 15 pre-second-year students: Malay, Chinese, and Malaysian Chinese. The interview transcripts were analyzed thematically using Atlas. The results revealed three significant challenges: The passion for pursuing a Ph.D. diminishes over time.; The stark contrast between self-expectations and the harshness of reality; The challenges of reality give birth to the hope for pursuing a Ph.D. The finding suggests some implications for educators and students regarding active learning.

Abstract Background Abnormalities in T cell activation play an important role in the pathogenesis of myocarditis, and persistent T cell responses can lead to autoimmunity and chronic cardiac inflammation, as well as even dilated cardiomyopathy. Although previous work has examined the role of T cells in myocarditis in animal models, the specific mechanism for human cardiomyocytes has not been investigated. Methods In this study, we constructed the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and established the T cell-mediated cardiac injury model by co-culturing with activated CD4 + T or CD8 + T cells that were isolated from peripheral mononuclear blood to elucidate the pathogenesis of myocardial cell injury caused by inflammation. Results By combination of quantitative proteomics with tissue and cell immunofluorescence examination, we established a proteome profile of inflammatory myocardia from hiPSC-CMs with obvious cardiomyocyte injury and increased levels of lactate dehydrogenase content, creatine kinase isoenzyme MB and cardiac troponin. A series of molecular dysfunctions of hiPSC-CMs was observed and indicated that CD4 + cells could produce direct cardiomyocyte injury by activating the NOD-like receptor signals pathway. Conclusions The data presented in our study established a proteome map of inflammatory myocardial based on hiPSC-CMs injury model. These results can provide guidance in the discovery of improved clinical treatments for myocarditis.

Abstract Background The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent. Methods Clinical trials evaluating KRASG12C inhibitors for advanced solid tumors were searched from PubMed, Embase, and Cochrane Library online databases up to 31st December 2023. The characteristics of the studies and the results of objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate, and treatment-related adverse events (trAEs) were extracted. Results Ten studies with 925 heavily pretreated advanced patients harboring KRASG12C mutation were included. For total population, the pooled analysis of ORR was 28.6% (95%CI, 21.2-36.6%), DCR was 85.5% (95%CI, 82.2-88.6%), PFS rate at 6 months (PFS6) was 49.6% (95%CI, 41.4-57.9%), PFS rate at 12 months (PFS12) was 26.7% (95%CI, 19.8-34.1%), OS rates at 6 months (OS6) was 76.2% (95%CI, 68.8-82.9%), OS rates at 12 months (OS12) was 47.8% (95%CI, 38.6-57.0%). The pooled analysis of any grade trAEs was 79.3% (95%CI, 66.2-90.0%) and grade three or more trAEs was 24.4% (95%CI, 16.7-32.9%). The median time to response and DoR results from individual data were 1.39 months (95%CI, 1.37–1.41 months) and 10.54 months (95%CI, 7.72–13.36 months). Sotorasib had significantly lower pooled incidences of any trAEs (OR, 0.07, 95%CI, 0.03–0.14) and grade three or more trAES (OR, 0.34, 95%CI, 0.24–0.49) compared with adagrasib. Conclusions KRASG12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors; however, most of the pooled results were heterogeneous. Sotorasib has shown better safety results.

ABSTRACT Objectives The calculation of left ventricular mass varies in different studies, and reference values of the voltage‐to‐mass ratio for diagnosing cardiac amyloidosis (CA) are lacking. This study aimed to determine the value of the voltage‐to‐mass ratio in diagnosing CA and provide an optimal cut‐off value for different calculation methods. Methods We reviewed the electrocardiograms and echocardiograms of 213 consecutive biopsy‐proven CA patients, 236 hypertrophic cardiomyopathy (HCM) patients, 100 hypertensive heart disease patients, and 181 healthy controls. Left ventricular mass was calculated using linear and cross‐sectional area (CSA) methods. The voltage‐to‐mass ratios were compared between the CA group and other groups. The voltage‐to‐mass ratio obtained was used to build multivariate logistic regression models that predicted the log odds of developing CA. Results The CA group had a significantly lower voltage‐to‐mass ratio than the HCM, hypertensive heart disease, and healthy control groups. The voltage‐to‐mass ratio was an independent factor significantly associated with the CA diagnosis after adjusting for baseline characteristics. Linear and CSA methods yielded areas under the ROC curve of 0.86 and 0.90, respectively. Using the CSA method, the optimal cut‐off was 16.42 mV/mm2/m2, with 89.0% sensitivity and 80.8% specificity. Conclusion The voltage‐to‐mass ratio could differentiate patients with CA, HCM, and hypertensive heart disease from healthy controls, potentially providing an accurate and non‐invasive alternative to current expensive and invasive diagnostic techniques.

Abstract The clogging phenomenon finds extensive application in both industrial processes and daily life events. While this broad spectrum of application motivated extensive research to identify the general factors underlying the clogging mechanism, it results in a fragmented and system-specific understanding of the entire clogging process. Therefore, it is essential to establish a holistic understanding of all contributing factors of clogging based on the microscopic physical mechanisms. In this paper, we experimentally investigate clogging of granular materials in a two-dimensional hopper flow and present a self-consistent physical mechanism of clogging based on precursory chain structures. These chain structures follow a specific modified restricted random walk, and clogging occurs when they are mechanically stable enough to withstand the flow fluctuations. We introduce a single-particle model that can explain the arch-forming probability. Our results provide insight into the microscopic mechanism behind clogging and a broader understanding of the dynamics of dense granular flow.

Abstract When unperturbed, granular materials form stable structures that resemble the ones of other amorphous solids like metallic or colloidal glasses. Whether or not granular materials under shear have an elastic response is not known, and also the influence of particle surface roughness on the yielding transition has so far remained elusive. Here we use X-ray tomography to determine the three-dimensional microscopic dynamics of two granular systems that have different roughness and that are driven by cyclic shear. Both systems, and for all shear amplitudes Γ considered, show a cross-over from creep to diffusive dynamics, indicating that rough granular materials have no elastic response and always yield, in stark contrast to simple glasses. For the system with small roughness, we observe a clear dynamic change at Γ ≈ 0.1, accompanied by a pronounced slowing down and dynamical heterogeneity. For the large roughness system, the dynamics evolves instead continuously as a function of Γ. We rationalize this roughness dependence using the potential energy landscape of the systems: The roughness induces to this landscape a micro-corrugation with a new length scale, whose ratio over the particle size is the relevant parameter. Our results reveal the unexpected richness in relaxation mechanisms for real granular materials.

Abstract Aims A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well‐known HR‐lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. Methods and results This multicentre, single‐arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment‐emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor–neprilysin inhibitor (ARNI) or beta‐blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P

BackgroundRare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population. ObjectiveThis study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants. MethodsA nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership. ResultsThe study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: “extremely high burden” (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), “overall high burden” (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and “overall low burden” (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an “extremely high burden” than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the “overall high burden” group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity. ConclusionsThis study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.

The increased use of plastics and the associated environmental impact has catalyzed research on the development of bio-derived polymers. Bio-based polyesters have gained increased attention due to the abundance of their starting materials and ease of processing. Lignin is naturally occurring in biomass with rich carbon content, whose functionality and rigidity make it an ideal bio-derived candidate for bio-based polyesters. Herein, a lignin-based polyester with good thermal stability and self-repairability was synthesized from carboxylated lignin and epoxidized soybean oil. The synthesized lignin/epoxidized soybean oil (ESO) vitrimer was brittle such that its mechanical performance could not be recorded. However, when polyethylene glycol (PEG) was incorporated as a plasticizer, polymer samples exhibited acceptable ductility. From thermomechanical analysis of the synthesized polyesters, the plasticizer did not impair thermal stability of polymers, but greatly enhanced mechanical properties. Notably, all samples exhibited stability at high temperatures, and good glass transition temperatures (51.0 ± 0.9–78.0 ± 1.2 °C). The highest tensile strength (3.983 ± 0.1 MPa) and storage modulus (1463.67 ± 12.6 MPa) were recorded for the polyester containing 6 % w/w PEG. Moreover, the polymer samples exhibited self-healing capability at 180 °C. This work expands on valorization of lignin through the synthesis of bio-derived materials.

Abstract Objective Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. Methods and results We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p

Background: Coronary thrombosis events continue to be the leading cause of morbidity and mortality worldwide. Recently, emerging evidence has highlighted the role of gut microbiota in cardiovascular disease, but few studies have systematically investigated the gut microbiota variation associated with atherothrombosis. Methods: We conducted multi-omics analysis (metagenomics sequencing and serum metabolomics) on 146 subjects from Peking Union Medical College Hospital-Coronary Artery Disease (PUMCH-CAD) cohort. We analyzed the key strains and metabolic pathways related to coronary artery disease (CAD) development, explored the bacterial functional pathway which contributes to atherothrombosis at strain level in depth. Single strain colonization procedures on germ free mice demonstrated the promotion of platelet activation and thrombotic phenotypes of the disordered gut microbiota. Results: Gut microbiome and serum metabolome shifts were apparent in cases of CAD progression, Bacteroides spp. disturbed the development of CAD by participating in lipopolysaccharide (LPS), menaquinone and methanogenesis pathways. Particularly, coronary thrombosis is characterized by increased circulatory levels of L-tryptophan, which correlate with Bacteroides thetaiotaomicron that has enriched biosynthetic potential. In germ free mice we demonstrate that Bacteroides thetaiotaomicron colonization could induce thrombosis, aggravate platelet hyperreactivity and augment fecal levels of L-tryptophan. Conclusions: The disordered gut microbiota of CAD contributed to the occurrence and development of atherothrombosis. The key members of the bacterial and metabolic features may become biomarkers for predicting the cardiovascular thrombosis event. Targeting the microbial pathway may have the potential to reduce the incidence of cardiovascular disorders. Clinical Trial Registration: ChiCTR2000033897, https://www.chictr.org.cn/showproj.html?proj=55023.

Abstract Background Immune checkpoint inhibitors (ICIs) are widely used in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, the toxicity profiles are inconclusive. Methods Clinical trials evaluating ICIs for R/M HNSCC were searched from online databases. The characteristics of the studies and the results of incidences of any grade treatment‐related adverse events (trAEs), grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment, and specific trAEs were extracted. Results Twenty studies with 3756 patients were included. The pooled incidences of any grade trAEs, grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment for overall population were 62.07% (95% CI, 59.07%–65.02%), 13.82% (95% CI, 11.23%–16.62%), 0.39% (95% CI, 0.15%–0.71%), 3.99% (95% CI, 2.36%–5.95%), respectively. Programmed cell death protein 1 (PD‐1) inhibitors monotherapy and ICIs combination therapy had significantly higher incidences of any grade trAEs (odds ratio [OR], 1.25, 95% CI, 1.05–1.49 and 1.36, 95% CI, 1.15–1.60, respectively), grade three or more trAEs (OR, 1.41, 95% CI, 1.08–1.84 and 1.79, 95% CI, 1.39–2.30, respectively), trAEs leading to discontinuation of treatment (OR, 3.98, 95% CI, 2.06–7.70 and 10.14, 95% CI, 5.49–18.70, respectively) compared with programmed death‐ligand 1 (PD‐L1) inhibitors monotherapy. ICIs combination therapy had a significantly higher incidence of grade three or more trAEs compared with PD‐1 inhibitors monotherapy (OR, 1.27, 95% CI, 1.03–1.55); however, the incidences of any grade trAEs and trAEs leading to discontinuation of treatment were not significant different. Conclusions Our study suggests that the incidences of grade three or more trAEs, treatment‐related deaths, and trAEs leading to discontinuation of treatment are low in R/M HNSCC patients treated with ICIs. PD‐L1 inhibitors monotherapy may be safer compared with PD‐1 inhibitors monotherapy and ICIs combination therapy.

Medium optimization and development for selective bacterial cultures are essential for isolating and functionalizing individual bacteria in microbial communities; nevertheless, it remains challenging due to the unknown mechanisms between bacterial growth and medium components. The present study first tried combining machine learning (ML) with active learning to fine-tune the medium components for the selective culture of two divergent bacteria, i.e., Lactobacillus plantarum and Escherichia coli. ML models considering multiple growth parameters of the two bacterial strains were constructed to predict the fine-tuned medium combinations for higher specificity of bacterial growth. The growth parameters were designed as the exponential growth rate (r) and maximal growth yield (K), which were calculated according to the growth curves. The eleven chemical components in the commercially available medium MRS were subjected to medium optimization and specialization. High-throughput growth assays of both strains grown separately were performed to obtain thousands of growth curves in more than one hundred medium combinations, and the resultant datasets linking the growth parameters to the medium combinations were used for the ML training. Repeated rounds of active learning (i.e., ML model construction, medium prediction, and experimental verification) successfully improved the specific growth of a single strain out of the two. Both r and K showed maximized differentiation between the two strains. A further analysis of all the data accumulated in active learning identified the decision-making medium components for growth specificity and the differentiated, determinative manner of growth decisions of the two strains. In summary, this study demonstrated the efficiency and practicality of active learning in medium optimization for selective cultures and offered novel insights into the contribution of the chemical components to specific bacterial growth.

Abstract Background Although some targeted therapies have been shown to be effective in treating HER2‐altered non‐small cell lung cancer (NSCLC), the survival demands have not yet been met due to the high cost and limited availability. This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab, in previously treated patients with HER2‐altered advanced NSCLC. Methods In this retrospective real‐world study, patients with HER2‐altered NSCLC who received pyrotinib plus antiangiogenic agents as a second‐ or later‐line treatment between November 2015 and January 2022 were reviewed. The objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety profiles of patients were analyzed. Results A total of 107 patients were included in the analysis, of which 59 patients (55.1%) had received at least two lines of prior chemotherapy or tyrosine kinase inhibitors. Most of them (87.9%) were identified as harboring HER2 exon 20 insertions. At the data cutoff date (May 13, 2022), the ORR, DCR, median PFS, and median OS were 19.6% (21/107), 94.4% (101/107), 7.13 months (95% confidence interval [CI]: 6.26–8.01), and 19.50 months (95% CI: 12.83–26.17), respectively. There was no difference in the PFS between patients receiving apatinib or anlotinib/bevacizumab (median PFS, 7.13 vs. 6.27 months, hazard ratio [HR] = 1.49, 95% CI: 0.87–2.54, p = 0.15). The most frequent grade 3 or higher treatment‐related adverse events was diarrhea (17.6%), followed by hypertension (11.0%) and nausea (3.3%). No treatment‐related death occurred. Conclusion In this study, pyrotinib plus antiangiogenic agents demonstrated promising efficacy and were tolerable in HER2‐altered NSCLC patients.

Abstract Objectives The purpose of this study was to explore the efficacy and safety of toripalimab combined with anlotinib in patients with advanced non‐small cell lung cancer (NSCLC) who acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Materials and Methods Patients who developed resistance after using first‐ or second‐generation EGFR‐TKIs as their first‐line regimen without EGFR T790M mutation or had disease progression after being treated with third‐generation EGFR‐TKIs as first‐ or second‐line therapy were enrolled. All patients received toripalimab (240 mg/day on Day 1, intravenously) combined with anlotinib (12 mg/day, Days 1–14, orally) once every 3 weeks. Treatment continued until disease progression, or if toxicity was intolerable. The primary endpoint was the objective response rate (ORR) assessed by the investigator. The secondary endpoint was the progression‐free survival (PFS). Results In total, 19 patients were enrolled between May 2020 and October 2021.The ORR was 0%, and a median PFS was 2.1 months (95% CI 0.251–3.949). Grade ≥3 treatment‐related adverse events (AEs) occurred in 11% patients. Common adverse events included hypothyroidism (12/19), fatigue (9/19), and hypertension (8/19). Patients in stable disease (SD) group had lower abundance of EGFR mutation allele frequency (AF) before enrollment than those in progressive disease (PD) group (p = 0.031). Patients without detectable EGFR mutation (EGFR−) had longer PFS compared to the ones with EGFR mutations (p = 0.059). Patients with high levels of soluble programmed cell death ligand 1 (PD‐L1) at baseline also tended to have longer PFS (p = 0.160). Conclusion Toripalimab combined with anlotinib was tolerable in EGFR‐TKI‐resistant advanced NSCLC patients not previously treated with chemotherapy. Patients without detectable EGFR mutation and high soluble PD‐L1 levels may benefit from this chemotherapy‐free treatment.

Anti-AAV neutralizing Abs (NAbs) titer is usually measured by cell-based microneutralization (MN) assay and is crucial for patient screening in AAV-based gene therapy clinical trials. However, achieving uniform operation and comparable results among different laboratories remains challenging. Here, we established a standardized MN assay for anti-AAV9 NAbs in human sera or plasma and transferred the method to the other two research teams. Then, we validated its parameters and tested a set of eight human samples in blind across all laboratories. The end-point titer, defined by a transduction inhibition of 50% (IC50), was calculated using curve-fit modelling. A mouse neutralizing monoclonal antibody in human negative serum was used for system quality control (QC), requiring inter-assay titer variation of

Background: Long-term prognosis of dilated cardiomyopathy (DCM) in the Chinese population is lacking, and the left ventricular (LV) hypertrabeculation phenotype usually overlaps with DCM. Objectives: The study aims to investigate whether the presence of the LV hypertrabeculation phenotype confers additional adverse prognostic information for DCM patients. Methods: We retrospectively reviewed all DCM patients (≥18 years of age at diagnosis) hospitalized in the Peking Union Medical College Hospital between September 2002 and September 2022. The eligible patients were divided into two groups based on echocardiography at diagnosis: the isolated DCM (n = 353), and DCM with the LV hypertrabeculation phenotype (n = 97). The primary endpoint was major adverse cardiac events (MACEs), and multivariate Cox hazards regression models were used to compare the endpoints between the two groups. Results: During a mean follow-up time of 4.6 years, there was no significant difference in the primary endpoint between the isolated DCM and DCM with the LV hypertrabeculation phenotype (p = 0.19). The risk of MACEs in the first 5 years was significantly higher in DCM with the LV hypertrabeculation phenotype than isolated DCM (adjusted HR [95%CI]: 1.83 [1.21–2.77]) and after 5 years the effect of the LV hypertrabeculation phenotype as a prognostic attenuated. Subgroup analysis found a significant interaction for the incidence of MACEs between sex and DCM subtypes (p for interaction = 0.01). Conclusions: DCM with LV hypertrabeculation phenotypes had a higher early (first 5 years) risk of MACEs. For males, the presence of LV hypertrabeculation phenotypes might be an important clue for identifying high-risk DCM patients.

Abstract Background Genetic testing can facilitate the diagnosis and subsequent therapeutic management of rare diseases. However, there is a lack of data on the use of genetic testing for rare diseases. This study aims to describe the utilization rate and troubles encountered by clinicians in treating rare diseases with genetic testing. Methods A cross-sectional electronic questionnaire survey was conducted between June and October 2022 among the medical staff from the hospitals covering all provinces, municipalities, and autonomous regions of China. The survey on genetic testing focused on whether genetic testing was used in the diagnosis and treatment of rare diseases, the specific methods of genetic testing, and the problems encountered when using genetic testing. Results A total of 20,132 physicians who had treated rare diseases were included, of whom 35.5% were from the central region, 36.7% were from the eastern region, and 27.8% were from the western region. The total utilization rate of genetic testing for rare diseases was 76.0% (95%CI: 75.4–76.6). The use of genetic testing was highest in the Eastern region (79.2% [95% CI: 78.3–80.1]), followed by the Central (75.9% [95% CI: 74.9–76.9]) and Western regions (71.9% [95% CI: 70.7–73.1]). More than 90% (94.1% [95%CI: 93.4–94.8]) of pediatricians had used genetic testing to treat rare diseases, with surgeons having the lowest use of genetic testing (58.3% [95% CI: 56.6–60.0]). Physicians’ departments and education levels affect the use of genetic testing. Most physicians have used a variety of genetic tests in the management of rare diseases, the most popular methods were “Whole-exome sequencing (Proband)” and “Whole-exome sequencing (families of three or more)”. Doctors have encountered many problems with the use of genetic testing in the diagnosis and treatment of rare diseases, among which the high price was the main concern of medical workers. Conclusion Three-quarters of physicians used genetic testing in rare disease practice, and there were regional differences in the use of genetic testing. Recognition of the utilization of genetic testing can help identify patterns of resource utilization in different regions and provide a more comprehensive picture of the epidemiology of rare diseases in jurisdictions.

Abstract Background Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China’s national database of rare diseases during the same period. Results A total of 120 rare diseases were included in this study. From 2016 to 2019, the number of patients with rare diseases estimated using search data and those obtained from the case database showed an increasing trend. Rare diseases can be ranked by the number of search estimated patients and reported patients, and the rankings of each disease in both search and reported case data were generally stable. Furthermore, the disease rankings in the search data were relatively consistent with the reported case data in each year, with more than 50% of rare diseases having a ranking difference of -20 to 20 between the two systems. In addition, the relationship between the disease rankings in the two systems was generally stable over time. Based on the relationship between the disease rankings in the search and reported case data, rare diseases can be classified into two categories. Conclusion Online search queries may provide an important new resource for detecting rare diseases. Rare diseases can be classified into two categories to guide different epidemiological research strategies.

Abstract Background Coronary artery ectasia is defined as a local or diffuse dilatation of the coronary artery more than 1.5 times the diameter of the adjacent normal segment. The etiology of coronary artery ectasia is diverse, and rarely complicated with immunoglobulin G4-related disease (IgG4-related disease). A limited number of cases have been reported, with insidious onset, slow progression but poor prognosis. Case presentation we report a patient with coronary artery ectasia combined with IgG4-related disease. He has been diagnosed with IgG4-related disease 5 years after his first percutaneous coronary intervention (PCI). Despite routine treatment with steroids, he develops a large coronary aneurysm and eventually died. Conclusions It is suggested that a thorough evaluation should be performed when coronary artery ectasia is diagnosed. The factors such as manifestations of coronary artery thickening, typical imaging features, other aortas involvement, increased serum IgG4 level, etc. should be considered for early diagnosis of key etiologies.

Background and aims: Quantitative analysis of plasma N-glycome is a promising method for identifying disease biomarkers. This study aimed to investigate the impact of using blood collection tubes with different anticoagulants on plasma N-glycome. Materials and methods: We used a robust mass spectrometry method to profile plasma N-glycomes in two cohorts of healthy volunteers (cohort 1, n = 16; cohort 2, n = 53). The influence of three commonly used blood collection tubes on fully characterized N-glycomic profiles were explored. Results: Principal component analysis revealed distinct clustering of blood samples based on the collection tubes. Pairwise comparisons demonstrated significant differences between EDTA and heparin plasma in 55 out of 82 quantified N-glycan traits, and between EDTA and citrate plasma in 62 out of 82 traits. These differences encompassed various N-glycan features, including glycan type, sialylation, galactosylation, fucosylation, and bisection. Trends in N-glycan variations in citrate and heparin plasma were largely consistent compared to EDTA plasma. In correlation analysis (EDTA vs. heparin; EDTA vs. citrate), Pearson's correlation coefficients were consistently higher than 0.7 for the majority of N-glycan traits. Conclusion: Sample matrix variations impact plasma N-glycome measurements. Caution is crucial when comparing samples from different plasma collection tubes in glycomics projects.

Abstract Objectives Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort. Methods Patients having TG levels (5.6–22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). Results Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%, P

Introduction: Acute myocardial infarction (AMI) accounts for the majority of deaths caused by coronary artery disease (CAD). Early warning of AMI, especially for patients with stable coronary artery disease (sCAD), is urgently needed. Our previous study showed that alterations in the gut microbiota were correlated with CAD severity. Objectives: Herein, we tried to discover accurate and convenient biomarkers for AMI by combination of gut microbiota and fecal/blood/urinary metabolomics. Methods: We recruited 190 volunteers including 93 sCAD patients, 49 AMI patients, and 48 subjects with normal coronary artery (NCA), and measured their blood biochemical parameters, 16S rRNA-based gut microbiota and NMR-based fecal/blood/urinary metabolites. We further selected 20 subjects from each group and analyzed their gut microbiota by whole-metagenome shotgun sequencing. Results: Multi-omic analyses revealed that AMI patients exhibited specific changes in gut microbiota and serum/urinary/fecal metabolites as compared to subjects with sCAD or NCA. Fourteen bacterial genera and 30 metabolites (11 in feces, 10 in blood, 9 in urine) were closely related to AMI phenotypes and could accurately distinguish AMI patients from sCAD patients. Some species belonging to Alistipes, Streptococcus, Ruminococcus, Lactobacillus and Faecalibacterium were effective to distinguish AMI from sCAD and their predictive ability was confirmed in an independent cohort of CAD patients. We further selected nine indicators including 4 bacterial genera, 3 fecal and 2 urinary metabolites as a noninvasive biomarker set which can distinguish AMI from sCAD with an AUC of 0.932. Conclusion: Combination of gut microbiota and fecal/urinary metabolites provided a set of potential useful and noninvasive predictive biomarker for AMI from sCAD.

Transplanting cell cultured brown adipocytes (BAs) represents a promising approach to prevent and treat obesity (OB) and its associated metabolic disorders, including type 2 diabetes mellitus (T2DM). However, transplanted BAs have a very low survival rate in vivo. The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells. There is a critical need for novel methods that can avoid cell death during cell preparation, transplantation, and in vivo. Here, we reported that preparing BAs as injectable microtissues could overcome the problem. We found that 3D culture promoted BA differentiation and UCP-1 expression, and the optimal initial cell aggregate size was 100 μm. The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved. Fabricated microtissues could survive in vivo for long term. They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced OB and T2DM mice. Transplanted microtissues impacted multiple organs, secreted protein factors, and influenced the secretion of endogenous adipokines. To our best knowledge, this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice. The proposal of transplanting fabricated BA microtissues, the microtissue fabrication method, and the demonstration of efficacy in T2DM mice are all new. Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability, storage, purity, safety, dosage, survival, and efficacy.

Ischemic stroke (IS), chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) account for a large burden of premature deaths. However, few studies have investigated the associations between fine particular matter (PM2.5) components and mortality of IS, COPD and DM. We aimed to examine these associations in Beijing, China. Data on daily mortality, air pollutants and meteorological factors from 2008 to 2011 in Beijing were collected. Daily concentrations of five PM2.5 components, namely, sulfate ion (SO42−), ammonium ion (NH4+), nitrate ion (NO3−), organic matter (OM) and black carbon (BC), were obtained from the Tracking Air Pollution (TAP) database in China. The association between PM2.5 components and daily deaths was explored using a quasi-Poisson regression with the distributed lag nonlinear model (DLNM). The average daily concentrations of SO42−, NH4+, NO3−, OM and BC were 11.24, 8.37, 12.00, 17.34 and 3.32 μg/m3, respectively. After adjusting for temperature, relative humidity, pressure, particulate matter less than 10 μm in aerodynamic diameter (PM10), nitrogen dioxide (NO2) and sulfur dioxide (SO2), an IQR increase in OM at lag day 2 and lag day 6 was associated with an increased DM mortality risk (RR 1.038; 95% CI: 1.005–1.071) and COPD mortality risk (RR 1.013; 95% CI: 1.001–1.026). An IQR increase in BC at lag day 0 and lag day 6 was associated with increased COPD mortality risk (RR 1.228; 95% CI: 1.017–1.48, RR 1.059; 95% CI: 1.001–1.121). Cumulative exposure to SO42− and NH4+ was associated with an increased mortality risk for IS, with the highest effect found for lag of 0–7 days (RR 1.085; 95% CI: 1.010–1.167, RR 1.083; 95% CI: 1.003–1.169). These effects varied by sex and age group. This study demonstrated associations of short-term exposure to PM2.5 components with increased risk of IS, COPD and DM mortality in the general population. Our study also highlighted susceptible subgroups.

BackgroundRare diseases (RDs) affect millions of people worldwide, and these diseases can severely impact the health-related quality of life (HRQoL) of those affected. Despite this, there is a lack of research measuring HRQoL using the EQ-5D-5L, which is one of the most widely used generic preference-based instruments to measure HRQoL in populations living with RDs. ObjectiveThis study aimed to measure HRQoL using the EQ-5D-5L in a large number of patients with various types of RDs in China, and to examine the relationship between respondents’ socioeconomic characteristics and preference-based health utility scores. MethodsThe data used in this study were obtained from a web-based survey conducted in China. The survey aimed to explore and understand the health and socioeconomic status of patients with RDs in China. We recruited registered and eligible members, including patients or their primary caregivers, from 33 RD patient associations to complete the questionnaires via their internal social networks. HRQoL was measured using the EQ-5D-5L utility score, which was calculated based on an established Chinese value set. Utility scores have been presented based on demographics and disease-related information. Univariate linear regression analysis was used to assess the differences in the EQ-5D-5L utility scores between subgroups. ResultsA total of 12,502 respondents completed the questionnaire and provided valid responses, including 6919 self-completed respondents and 5583 proxy-completed respondents. Data from 10,102 participants over the age of 12 years were elicited for analysis. Among patients with RDs, 65.3% (6599/10,102), 47.5% (4799/10,102), 47.0% (4746/10,102), 24.8% (2506/10,102), and 18.4% (1855/10,102) reported no problems for “self-care,” “usual activities,” “mobility,” “pain/discomfort,” and “anxiety/depression,” respectively. A full health state was reported by 6.0% (413/6902) and 9.2% (295/3200) of self- and proxy-completed patients, respectively. Among self-completed patients, 69.9% (4826/6902) and 50.4% (3478/6902) reported no problems for “self-care” and “usual activities,” respectively, whereas only 17.7% (1223/6902) reported problems for “anxiety/depression.” Proxy-completed respondents showed a higher proportion of reporting extreme problems than self-completed respondents in all 5 dimensions. The mean utility scores reported by self- and proxy-completed respondents were 0.691 and 0.590, respectively. Different types of caregivers reported different utility scores, and among them, proxy-completed (mother) respondents reported the highest mean utility score. ConclusionsThe establishment of a normative profile for RD patients can facilitate patients’ adaptation and assess the effectiveness of interventions to improve the HRQoL and well-being of this population. Differences between self- and proxy-completed HRQoL assessed by the EQ-5D-5L have been identified in this study. This finding highlights the importance of incorporating perspectives from both patients and their proxies in clinical practice. Further development of the patient cohort is necessary to assess long-term changes in HRQoL in the RD population.

Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.

Abstract Background Currently, survival benefit of immunotherapy in advanced non‐small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first‐line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real‐world evidence. Patients and Methods A retrospective real‐world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first‐line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator‐assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. Results A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first‐line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression‐free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR = 0.60, 95% CI: 0.40–0.90, p = 0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR = 0.83, 95% CI: 0.44–1.56, p = 0.30) than C + I. There was no PFS difference between C + I and C, despite of PD‐L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. Conclusion First‐line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins.

Abstract Severe neurological symptoms are associated with Coronavirus disease 2019 (COVID-19). However, the morphologic features, pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection. In this study, neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining, ultrastructural examination under electron microscopy, and an image threshold method, in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals. Differentially expressed proteins were identified by quantitative proteomic assays. Histopathological findings included neurophagocytosis, microglia nodules, satellite phenomena, extensive edema, focal hemorrhage, and infarction, as well as infiltrating mononuclear cells. Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes, severe damage of the blood–brain barrier (BBB) and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+ monocytes and occasionally CD4+/CD8+ T lymphocytes. Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses, autophagy and cellular metabolism in COVID-19 patient brains compared with control brains. Proteins involved in brain development, neuroprotection, and extracellular matrix proteins of the basement membrane were downregulated, potentially caused by the activation of transforming growth factor β receptor and vascular endothelial growth factor signaling pathways. Thus, our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis (CAME) and suggest potential therapeutic targets.

Abstract Background Heterosis is widely used in agriculture. However, its molecular mechanisms are still unclear in plants. Here, we develop, sequence, and record the phenotypes of 418 hybrids from crosses between two testers and 265 rice varieties from a mini-core collection. Results Phenotypic analysis shows that heterosis is dependent on genetic backgrounds and environments. By genome-wide association study of 418 hybrids and their parents, we find that nonadditive QTLs are the main genetic contributors to heterosis. We show that nonadditive QTLs are more sensitive to the genetic background and environment than additive ones. Further simulations and experimental analysis support a novel mechanism, homo-insufficiency under insufficient background (HoIIB), underlying heterosis. We propose heterosis in most cases is not due to heterozygote advantage but homozygote disadvantage under the insufficient genetic background. Conclusion The HoIIB model elucidates that genetic background insufficiency is the intrinsic mechanism of background dependence, and also the core mechanism of nonadditive effects and heterosis. This model can explain most known hypotheses and phenomena about heterosis, and thus provides a novel theory for hybrid rice breeding in future.

Abstract Background The application of immune checkpoint inhibitors (ICIs) represents a breakthrough in the current landscape for the treatment of extensive‐stage small‐cell lung cancer (ES‐SCLC), but the real‐world outcome is limited. This study aimed to investigate the treatment options and efficacy evaluation of first‐line, second‐line, and subsequent‐line immunotherapy in routine practice. Methods A retrospective analysis of ES‐SCLC patients treated with ICIs was conducted between May 2016 and September 2021. Objective response rate, disease control rate, progression‐free survival (PFS) and overall survival were assessed between groups to explore the value of ICIs at different treatment time periods. PFS1 and PFS2 were defined as the duration from initial therapy to disease progression or death in first‐line or second‐line treatment. Results Ninety‐six patients with ES‐SCLC were included. PFS1 was prolonged in patients treated with first‐line ICIs‐combined therapy (median PFS1 7.20 months vs. 5.30 months, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.36–087, p = 0.0085). For patients who progressed after first‐line ICIs treatment (N = 22), PFS1 + PFS2 was longer in the second‐line ICIs continuation group with no significant difference (median PFS1 + PFS2 11.27 months vs. 7.20 months, HR 0.45, 95% CI 0.14–1.51, p = 0.19). For patients who experienced a progression event after first‐line chemotherapy (N = 50), PFS2 and PFS1 + PFS2 were prolonged in patients who accepted second‐line ICIs‐combined therapy without significant difference (median PFS2 4.00 months vs. 2.43 months, HR 0.59, 95% CI 0.33–1.05, p = 0.070; median PFS1 + PFS2 11.30 months vs. 8.70 months, HR 0.53, 95% CI 0.29–0.98, p = 0.056). Conclusion First‐line ICIs plus chemotherapy should be applied in the clinical practice of ES‐SCLC. If patients did not receive ICIs plus chemotherapy in first‐line treatment, therapies that include ICIs in second‐line treatment should be considered.

Abstract Background Immune checkpoint inhibitor (ICI) combined with chemotherapy is one of the standards of care for advanced non–small cell lung cancer (NSCLC) without driver mutations. However, the biomarker of combination therapy is still unknown. Although previous studies have confirmed that low allele frequency adjusted blood‐based tumor mutational burden (LAF‐bTMB) is associated with the efficacy of ICI monotherapy, there has been no report on the correlation between the efficacy of LAF‐bTMB and ICI combined chemotherapy. This study aimed to explore whether LAF‐bTMB can be used as a predictive biomarker for the efficacy of immunotherapy combined with chemotherapy in advanced NSCLC. Methods This study enrolled patients diagnosed with advanced NSCLC and who received ICI combined with chemotherapy for first‐line therapy from May 2020 to December 2021 at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Clinical information, treatment information, survival data, and peripheral blood samples of every patient before treatment were collected. Next‐generation sequencing was performed on plasma samples to estimate bTMB and LAF‐bTMB. Results A total of 42 patients with NSCLC were enrolled. In this cohort, 19 patients achieved partial response (PR), and the objective response rate (ORR) was 45.2%. The median progression‐free survival (PFS) of all patients was 13.4 months (95% CI, 7.49–19.72). Both PFS and the overall survival (OS) were significantly longer in the responder (R) group than in the non‐responder (NR) group (median PFS, 16.4 months vs. 7.2 months, p = 0.028; median OS, NE vs. 9.3 months, p = 0.016). There was no significant difference in bTMB and LAF‐BTMB between the R and NR group. The ORR of patients with LAF‐bTMB≤8muts/Mb was significantly higher than that of patients with LAF‐bTMB >8muts/Mb (ORR, 61% vs. 26%, respectively, p = 0.033). When LAF‐bTMB ≤8muts/Mb or > 20muts/Mb, ORR was significantly higher than that of patients with LAF‐bTMB between 8 and 20muts/Mb (ORR were 57% and 21%, p = 0.047). No correlation has been found between LAF‐bTMB and PFS or OS. Conclusions This study confirmed that neither bTMB nor LAF‐bTMB is feasible as a potential predictor of first‐line immunochemotherapy for advanced NSCLC. More suitable biomarkers need to be explored to screen patients with better efficacy of immunotherapy combined with chemotherapy in the future.

Abstract Background There is growing evidence that patients recovering after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have a variety of acute sequelae including newly diagnosed diabetes. However, the risk of diabetes in the post-acute phase is unclear. To solve this question, we aimed to determine if there was any association between status post-coronavirus disease (COVID-19) infection and a new diagnosis of diabetes. Methods We performed a systematic review and meta-analysis of cohort studies assessing new-onset diabetes after COVID-19. PubMed, Embase, Web of Science, and Cochrane databases were all searched from inception to June 10, 2022. Three evaluators independently extracted individual study data and assessed the risk of bias. Random-effects models estimated the pooled incidence and relative risk (RR) of diabetes compared to non-COVID-19 after COVID-19. Results Nine studies with nearly 40 million participants were included. Overall, the incidence of diabetes after COVID-19 was 15.53 (7.91–25.64) per 1000 person-years, and the relative risk of diabetes after COVID-19 infection was elevated (RR 1.62 [1.45–1.80]). The relative risk of type 1 diabetes was RR=1.48 (1.26–1.75) and type 2 diabetes was RR=1.70 (1.32–2.19), compared to non-COVID-19 patients. At all ages, there was a statistically significant positive association between infection with COVID-19 and the risk of diabetes: 65 years: RR=1.68 (1.22–2.30). The relative risk of diabetes in different gender groups was about 2 (males: RR=2.08 [1.27–3.40]; females: RR=1.99 [1.47–2.80]). The risk of diabetes increased 1.17-fold (1.02–1.34) after COVID-19 infection compared to patients with general upper respiratory tract infections. Patients with severe COVID-19 were at higher risk (RR=1.67 [1.25–2.23]) of diabetes after COVID-19. The risk (RR=1.95 [1.85–2.06]) of diabetes was highest in the first 3 months after COVID-19. These results remained after taking confounding factors into account. Conclusions After COVID-19, patients of all ages and genders had an elevated incidence and relative risk for a new diagnosis of diabetes. Particular attention should be paid during the first 3 months of follow-up after COVID-19 for new-onset diabetes.

Abstract Heart disease is the leading cause of death in the United States. A person who has type-2 diabetes is twice as likely to have heart disease than someone who doesn’t have diabetes. Therefore, analyzing factors associated with both diseases and their interrelationships is essential for cardiovascular disease control and public health. In this article, we propose a Multi-scale Geographically Weighted Regression (MGWR) approach to observe spatial variations of environmental and demographic risk factors such as alcohol consumption behavior, lack of physical activity, obesity rate, urbanization rate, and income from 2005 to 2015 in the United States. The MGWR model has applied to eight census divisions of the United States at the county level: New England, Middle Atlantic, East North Central, West North Central, South Atlantic, East South Central, West South Central, and Mountain. Results illustrate that there are notable differences in the spatial variation of the risk factors behind these two diseases. In particular, obesity has been a leading factor that associate with diabetes in the east, south-central, and south Atlantic regions of the U.S. On the other hand, smoking and alcohol consumption was the primary concern in the northern part of the U.S., in 2005. In 2015, alcohol consumption levels decreased, but the smoking level remained the same in those regions, which showed a significant impact on diabetes in the neighboring regions. Between 2005 and 2015, lack of physical exercise has become a significant risk factor associated with diabetes in the Northeast and West parts of the U.S. The proposed MGWR produced high goodness to fit (R2) for most of the areas in the United States.

With urban residents’ increasing reliance on metro systems for commuting and other daily activities, extreme weather events such as heavy rainfall and flooding impacting the metro system services are becoming increasingly of concern. Plans for such emergency interruptions require a thorough understanding of the potential outcomes on both the system and individual component scales. However, due to the complex dynamics, constraints, and interactions of the elements involved (e.g., disaster, infrastructure, service operation, and travel behavior), there is still no framework that comprehensively evaluates the system performance across different spatiotemporal scales and is flexible enough to handle increasingly detailed travel behavior, transit service, and disaster information data. Built on an agent-based model (ABM) framework, this study adopts a data-driven ABM simulation approach informed by actual metro operation and travel demand data to investigate the impact of flood-induced station closures on travelers as well as the overall system response. A before-after comparison is conducted where the traveler behaviors in disaster scenarios are obtained from a discrete choice model of alternative stations and routes. A case study of the Shanghai Metro is used to demonstrate the ability of the proposed approach in evaluating the impacts of flood-induced station closures on individual traveler behavior under normal operation and a series of water level rise scenarios of up to 5m. It was found that, when the flood-induced station closures only affect a few river-side stations in the city center, the travelers experience only minor disruptions to their trips due to the availability of unaffected stations nearby as a backup. However, as the water level increases and more stations (mainly in the suburban area) are affected, up to 25% of trips are no longer being fulfilled due to the loss of entrances, exits, or transfer links. The system experiences overall less crowdedness in terms of passenger volume and platform waiting time with a few exceptions of increased passenger load due to concentrations of passenger flows to alternative stations under flooding-induced station closures. The proposed approach can be adapted to other disaster scenarios to reveal the disaster impacts on both aggregated and disaggregated levels and guide the design of more spatio- and temporally-targeted emergency plans for metro systems.

Abstract Background There are about 7000 rare diseases worldwide, of which only 5% of the diseases can be treated with medicines, showing that it’s important to improve patient access to orphan drugs. Recently, China has actively worked to set up a national system for rare diseases to improve the diagnosis and treatment capabilities and ensure the accessibility of drugs. However, the benefits of the system have yet not to be measured. This study aimed to provide an overview of orphan drug access based on the Compendium of China’s First List of Rare Diseases and National Network to Collaborate on Diagnosis and Treatment of Rare Diseases, expecting to map a blueprint for orphan drug access in China. Methods Framework of China’s national system for rare diseases was summarized. We surveyed the availability and affordability of 79 approved orphan drugs based on the Compendium of China’s First List of Rare Diseases in 30 leading provincial institutions from 2017 to 2020. The availability was measured annually at 3 levels (market, hospital and drug), and affordability was reflected by comparing costs of daily defined dose with per capita income of urban and rural residents, with the National Basic Medical Insurance considered. Results The market availability of orphan drugs in China showed an upward trend. As of 2020, the median hospital-level availability was 41.1% (increased by 1.5 times), highly available drugs increased by 16.5%. There were 64/74 orphan drugs that were affordable to rural/urban residents with the National Basic Medical Insurance considered (an increase of 14.1%), and the urban–rural gap of affordability ratio was narrowed (down by 6.0%). Comprehensive analysis showed the proportions of drugs with better availability and affordability in urban and rural areas by 2020 were 39.4% and 32.3%, respectively, which had increased but were still at a low level. Conclusions China’s national system for rare diseases has made great progress in orphan drug access, indicating that it’s been functioning under the joint reformation of medical treatment, medical insurance and medicines supply. The list of rare diseases will be updated and collaboration in networks will be enhanced to further improve the system.

Abstract Background Hereditary transthyretin amyloidosis (hATTR) is a progressive and fatal disease with heterogenous clinical presentations, limited diagnosis and poor prognosis. This retrospective analysis study aimed to report the genotypes and phenotypes of herediary transthyretin amyloidosis (hATTR) in Chinese through a systematic review of published literature. Methods The systematic review included structured searches of peer-reviewed literature published from 2007 to 2020 of following online reference databases: PubMed, Web of Science and the literature database in China. Extracted data included sample size, personal information (sex, age, natural course, family history), mutation type, clinical milestones and reason of death. Results We described 126 Chinese patients with hereditary transthyretin amyloidosis identified through a systematic review of 30 studies. The most common genotype in the Chinese population was Gly83Arg (25, 19.8%), which most likely presented visual and neurological abnormalities without reported death. The second and third most common genotypes were Val30Met (20, 15.9%) and Val30Ala (10, 7.9%). Peripheral neurological manifestations (91, 72%) were dominant in 126 patients. The followed manifestation was autonomic neurological abnormalities (73, 58%). Half of the cases were reported to have visual disorders, and nearly one-third of the cases presented cardiac abnormalities. Among all 126 reported patients, 46.03% were classified as neurological type, 30.16% as mixed type and only 2.38% as cardiac type. In addition. Chinese patients were mostly early onset, with age of onset at 41.8 (SD: 8.9) years, and the median time from onset to death was 7.5 [IQR: 5.3] years. Patients with cardiac involvement had a shorter survival duration (log Rank (Mantel-Cox), χ2 = 26.885, P

Abstract Background Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. Methods HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). Results Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. Conclusions Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .

A large number of investigator-initiated clinical trials (IIT) were conducted in China, some of them should play an important supporting role in new drug development. Due to the large number, small scale and uneven quality of IIT in China, especially a big gap between the IIT and industry-sponsored trials in terms of protocol design, quality management and ethical review, many IIT can’t be used to support the new drug development. Therefore, it is necessary for regulatory authorities, sponsors, research institutions, ethics committees and researchers to improve their understanding of the role of IIT. In order to support the new drug development with high-quality IIT, formulating supervising system, establishing an effective quality management system, enhancing the training of researchers and improving the ability of ethical review should be implemented effectively.

Abstract Two-dimensional high-throughput data have become increasingly common in functional genomics studies, which raises new challenges in data analysis. Here, we introduce a new statistic called Zeta, initially developed to identify global splicing regulators from a two-dimensional RNAi screen, a high-throughput screen coupled with high-throughput functional readouts, and ZetaSuite, a software package to facilitate general application of the Zeta statistics. We compare our approach with existing methods using multiple benchmarked datasets and then demonstrate the broad utility of ZetaSuite in processing public data from large-scale cancer dependency screens and single-cell transcriptomics studies to elucidate novel biological insights.

ObjectiveSingle-pill amlodipine besylate (AML) plus losartan (LOS) has been used to treat inadequately controlled hypertension after antihypertensive monotherapy; however, relevant data in China are limited. This study aimed to compare the efficacy and safety of single-pill AML/LOS and LOS alone in Chinese patients with inadequately controlled hypertension after LOS treatment.MethodsIn this multicenter, double-blind, randomized, controlled phase III clinical trial, patients with inadequately controlled hypertension after 4 weeks of LOS treatment were randomized to receive daily single-pill AML/LOS (5/100 mg, AML/LOS group, N = 154) or LOS (100 mg, LOS group, N = 153) tablets for 8 weeks. At weeks 4 and 8 of treatment, sitting diastolic and systolic blood pressure (sitDBP and sitSBP, respectively) and the BP target achievement rate were assessed.ResultsAt week 8, the sitDBP change from baseline was greater in the AML/LOS group than in the LOS group (−8.84 ± 6.86 vs. −2.65 ± 7.62 mmHg, P

Introduction Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease commonly caused by pathogenic genetic variants encoding sarcomere proteins. Mavacamten, a first-in-class allosteric inhibitor of cardiac-specific myosin, has demonstrated efficacy and safety in international clinical trials of patients with symptomatic obstructive HCM (oHCM) but clinical evidence for mavacamten in the Chinese population is lacking.Methods and analysis EXPLORER-CN is a multicentre, phase III, randomised, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of mavacamten in Chinese adults with symptomatic oHCM. The study will enrol approximately 81 participants with symptomatic oHCM. Eligible participants are randomised 2:1 to receive once-daily, oral mavacamten (starting dose 2.5 mg/day), or matching placebo, for 30 weeks, followed by a long-term extension (LTE) period of 48 weeks with active treatment for all subjects. The mavacamten dose will be adjusted by pharmacokinetic (PK)/pharmacodynamic (PD) parameters during the double-blinded, placebo-controlled period and PD-only during the LTE period. The primary efficacy endpoint is change from baseline to week 30 in Valsalva left ventricular outflow tract (LVOT) peak gradient determined by Doppler echocardiography. Secondary efficacy endpoints are change in resting LVOT peak gradient, proportion of participants achieving a Valsalva LVOT peak gradient

Dental caries is a common oral disease. In many cases, disruption of the ecological balance of the oral cavity can result in the occurrence of dental caries. There are many cariogenic microbiota and factors, and their identification allows us to take corresponding prevention and control measures. With the development of microbiology, the caries-causing bacteria have evolved from the traditional single Streptococcus mutans to the discovery of oral symbiotic bacteria. Thus it is necessary to systematically organized the association of polymicrobial interactions with dental caries development. In terms of ecology, caries occurs due to an ecological imbalance of the microbiota, caused by the growth and reproduction of cariogenic microbiota due to external factors or the disruption of homeostasis by one’s own factors. To reduce the occurrence of dental caries effectively, and considering the latest scientific viewpoints, caries may be viewed from the perspective of ecology, and preventive measures can be taken; hence, this article systematically summarizes the prevention and treatment of dental caries from the aspects of ecological perspectives, in particular the ecological biofilm formation, bacterial quorum sensing, the main cariogenic microbiota, and preventive measures.

BackgroundAs rare diseases (RDs) receive increasing attention, obtaining accurate RD incidence estimates has become an essential concern in public health. Since RDs are difficult to diagnose, include diverse types, and have scarce cases, traditional epidemiological methods are costly in RD registries. With the development of the internet, users have become accustomed to searching for disease-related information through search engines before seeking medical treatment. Therefore, online search data provide a new source for estimating RD incidences. ObjectiveThe aim of this study was to estimate the incidences of multiple RDs in distinct regions of China with online search data. MethodsOur research scale included 15 RDs in China from 2016 to 2019. The online search data were obtained from Sogou, one of the top 3 commercial search engines in China. By matching to multilevel keywords related to 15 RDs during the 4 years, we retrieved keyword-matched RD-related queries. The queries used before and after the keyword-matched queries formed the basis of the RD-related search sessions. A two-step method was developed to estimate RD incidences with users’ intents conveyed by the sessions. In the first step, a combination of long short-term memory and multilayer perceptron algorithms was used to predict whether the intents of search sessions were RD-concerned, news-concerned, or others. The second step utilized a linear regression (LR) model to estimate the incidences of multiple RDs in distinct regions based on the RD- and news-concerned session numbers. For evaluation, the estimated incidences were compared with RD incidences collected from China’s national multicenter clinical database of RDs. The root mean square error (RMSE) and relative error rate (RER) were used as the evaluation metrics. ResultsThe RD-related online data included 2,749,257 queries and 1,769,986 sessions from 1,380,186 users from 2016 to 2019. The best LR model with sessions as the input estimated the RD incidences with an RMSE of 0.017 (95% CI 0.016-0.017) and an RER of 0.365 (95% CI 0.341-0.388). The best LR model with queries as input had an RMSE of 0.023 (95% CI 0.017-0.029) and an RER of 0.511 (95% CI 0.377-0.645). Compared with queries, using session intents achieved an error decrease of 28.57% in terms of the RER (P=.01). Analysis of different RDs and regions showed that session input was more suitable for estimating the incidences of most diseases (14 of 15 RDs). Moreover, examples focusing on two RDs showed that news-concerned session intents reflected news of an outbreak and helped correct the overestimation of incidences. Experiments on RD types further indicated that type had no significant influence on the RD estimation task. ConclusionsThis work sheds light on a novel method for rapid estimation of RD incidences in the internet era, and demonstrates that search session intents were especially helpful for the estimation. The proposed two-step estimation method could be a valuable supplement to the traditional registry for understanding RDs, planning policies, and allocating medical resources. The utilization of search sessions in disease detection and estimation could be transferred to infoveillance of large-scale epidemics or chronic diseases.

Abstract. Objective:. Cardiac damage is commonly reported in patients with coronavirus disease 2019 (COVID-19) but its prevalence and impact on the long-term survival of patients remain uncertain. This study aimed to explore the prevalence of myocardial injury and assess its prognostic value in patients with COVID-19. Methods:. A single-center, retrospective cohort study was performed at the Affiliated Hospital of Jianghan University. Data from 766 patients with confirmed COVID-19 who were hospitalized from December 27, 2019 to April 25, 2020 were collected. Demographic, clinical, laboratory, electrocardiogram, treatment data and all-cause mortality during follow-up were collected and analyzed. Results:. Of the 766 patients with moderate to critically ill COVID-19, 86 (11.2%) died after a mean follow-up of 72.8 days. Myocardial injury occurred in 94 (12.3%) patients. The mortality rate was 64.9% (61/94) and 3.7% (25/672) in patients with and without myocardial injury, respectively. Cox regression showed that myocardial injury was an independent risk factor for mortality (hazard ratio: 8.76, 95% confidence interval: 4.76–16.11, P