Abstract
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating ...SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.
Methods
The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug’s safety profile.
Results
Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.
Conclusions
Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. Hydroxychloroquine sulfate 400 mg given twice daily for 1 day, followed by 200 mg twice daily for 4 more days, is recommended to treat SARS-CoV-2 infection.
Background
Amyotrophic lateral sclerosis (ALS) is a global disease, which adversely affects the life quality of patients and significantly increases the burden of families and society. We aimed to ...assess the changing incidence, prevalence of ALS around the world.
Methods
We searched Medline, Embase, Web of Science, and Cochrane library to identify articles published until September 9, 2018. Each included study was independently reviewed for methodological quality by two reviewers. We used a random-effects model to summarize individual studies and assessed heterogeneity (
I
2
) with the
χ
2
test on Cochrane’s Q statistic.
Results
We identified 124 studies that were eligible for final inclusion, including 110 studies of incidence and 58 studies of prevalence. The overall crude worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92–4.96) per 1,00,000 population and 1.59 (95% CI 1.39–1.81) per 1,00,000 person-years, respectively. ALS prevalence and incidence increased by age until the age of 70–79. Since 1957, incidence has been significantly rising year by year, and this upward trend was weakened after standardization. The longest survival time were in Asia (ranging from 3.74 years in South Asia to 9.23 years in West Asia).
Conclusions
With the aggravation of population aging and the rapid growth of economy, developing regions following the development pattern of the developed regions may suffer rising ALS prevalence and incidence which may increase their disease burden as well. These data highlight the need for research into underlying mechanism and innovations in health-care systems.
UEBMI covers working and retired employees in cities (i.e., employers and employees from government agencies and institutions, state-owned enterprises, private businesses, social organizations, and ...other private entities), and URBMI covers citizens without employment in cities (i.e., children, students, elderly people, and unemployed residents). ...indicators of osteoporosis such as bone density or imaging information are seldom available in the medical insurance databases. ...consistent with previous publications on hip fracture incidence 8,9,11,16,29, in this study, hip-fracture-related indicators such as the incidence of hip fracture and associated costs in patients aged 55 years and above were used as surrogate indexes for determining the burden of osteoporosis or osteoporotic fractures. Additionally, we included specific symptoms and signs (hip pain, shorting and external rotation of the affected leg), special examination (hip X-ray), and particular treatments (open reduction and internal fixation of femoral neck fracture, open reduction and internal fixation of intertrochanteric fracture). Exclusion criteria for case identification were the following: (1) pathological fracture, (2) old hip fracture, (3) femoral shaft fracture, (4) distal femoral fracture, (5) subtrochanteric fracture, (6) complications and sequelae of hip fracture (non-union, delayed union, malunion, osteomyelitis, osteoarthritis, and anchylosis), (7) prosthesis complications, (8) osteonecrosis of the femoral head, (9) hip dislocation, and (10) removal of internal fixation devices.
Abstract Purpose The goal of this study was to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on lipid profiles in patients with type 2 diabetes. Methods The MEDLINE, ...Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from inception through October 31, 2013. Randomized controlled trials with available data were selected if they compared GLP-1 RAs with placebo and traditional antidiabetic drugs with a duration ≥8 weeks. The weighted mean difference for changes in lipid profiles was estimated by using the random effects model, and a network meta-analysis was performed to supplement direct comparisons. Findings Thirty-five trials with 13 treatments were included in the analysis. GLP-1 RAs decreased HDL-C with a range of –0.06 mmol/L (95% CI, –0.11 to –0.01) to –0.13 mmol/L (95% CI, –0.17 to –0.10) compared with thiazolidinediones, whereas thiazolidinediones were associated with a significant increase in HDL-C compared with placebo (0.09 mmol/L 95% CI, 0.06 to 0.12). A significant reduction in LDL-C was detected for all GLP-1 RAs versus placebo (range, –0.08 to –0.16 mmol/L), insulin (range, –0.10 to –0.19 mmol/L), and thiazolidinediones (range, –0.16 to –0.24 mmol/L). Exenatide, liraglutide 1.8 mg once daily, and taspoglutide decreased total cholesterol with a range of –0.16 mmol/L (95% CI, –0.26 to –0.06) to –0.27 mmol/L (95% CI, –0.41 to –0.12) versus placebo and thiazolidinediones (range, –0.26 to –0.37 mmol/L). The decreased effect was more evident in exenatide long-acting release and liraglutide 1.8 mg once daily. A significant reduction in triglyceride levels was observed with liraglutide 1.8 mg once daily (–0.30 mmol/L 95% CI, –0.49 to –0.11) and taspoglutide 20 mg once weekly (–0.17 mmol/L 95% CI, –0.31 to –0.01) versus placebo. Implications GLP-1 RAs were associated with modest reductions in LDL-C, total cholesterol, and triglycerides but no significant improvement in HDL-C. Further evidence is needed to determine if improvements in lipid profiles might translate into reductions in cardiovascular outcomes.
In China, food safety problems have occurred frequently in the past ten years, causing great concern for the public. Adolescents, with higher exposure to problematic food, represent a unique target ...for interventions aimed at risk reduction. To understand their food safety knowledge, attitude and practice, a cross-sectional survey using paper questionnaire was carried out among 4,220 students (median age of 14 years, 50.3% females) from nine secondary schools in 3 districts of Beijing. The findings showed that the majority of respondents (42.0%) had a high knowledge level. Significant association was found between food safety knowledge score (median = 11, IQR:9-13) and demographic characteristics of region, school type, residence type, habit of smoking and alcohol use, academic record and parents' education background. In terms of attitude and practice, only 17% of those surveyed regarded China's food safety situation as good, 53.6% regarded it as worrying; almost all students (96.5%) did pay attention to food safety; 95.3% of the students had worried about the safety of the food provided by the small restaurants and street peddlers, but in reality, as many as 69.4% often or occasionally bought food from peddlers around their campuses and nearly half continued the consumption of such food in spite of worrying about its safety problems. Overall, the food safety knowledge among Beijing secondary school students was relatively good. They did not show much confidence in the country's food safety situation, but many aware of the safety issues did not bother to change or take action. The study suggests that more systematic and targeted education on food safety is necessary for this age group.
Biomedical named entity recognition (BioNER) is a basic and important medical information extraction task to extract medical entities with special meaning from medical texts. In recent years, deep ...learning has become the main research direction of BioNER due to its excellent data-driven context coding ability. However, in BioNER task, deep learning has the problem of poor generalization and instability.
we propose the hierarchical shared transfer learning, which combines multi-task learning and fine-tuning, and realizes the multi-level information fusion between the underlying entity features and the upper data features. We select 14 datasets containing 4 types of entities for training and evaluate the model. The experimental results showed that the F1-scores of the five gold standard datasets BC5CDR-chemical, BC5CDR-disease, BC2GM, BC4CHEMD, NCBI-disease and LINNAEUS were increased by 0.57, 0.90, 0.42, 0.77, 0.98 and - 2.16 compared to the single-task XLNet-CRF model. BC5CDR-chemical, BC5CDR-disease and BC4CHEMD achieved state-of-the-art results.The reasons why LINNAEUS's multi-task results are lower than single-task results are discussed at the dataset level.
Compared with using multi-task learning and fine-tuning alone, the model has more accurate recognition ability of medical entities, and has higher generalization and stability.
Large-scale and population-based studies of heart failure (HF) incidence and prevalence are scarce in China. The study sought to estimate the prevalence, incidence, and cost of HF in China.
We ...conducted a population-based study using records of 50.0 million individuals ≥25 years old from the national urban employee basic medical insurance from 6 provinces in China in 2017. Incident cases were individuals with a diagnosis of HF (International Classification of Diseases code, and text of diagnosis) in 2017 with a 4-year disease-free period (2013-2016). We calculated standardized rates by applying age standardization to the 2010 Chinese census population.
The age-standardized prevalence and incidence were 1.10% (1.10% among men and women) and 275 per 100 000 person-years (287 among men and 261 among women), respectively, accounting for 12.1 million patients with HF and 3.0 million patients with incident HF ≥25 years old. Both prevalence and incidence increased with increasing age (0.57%, 3.86%, and 7.55% for prevalence and 158, 892, and 1655 per 100 000 person-years for incidence among persons who were 25-64, 65-79, and ≥80 years of age, respectively). The inpatient mean cost per-capita was $4406.8 and the proportion with ≥3 hospitalizations among those hospitalized was 40.5%. The outpatient mean cost per-capita was $892.3.
HF has placed a considerable burden on health systems in China, and strategies aimed at the prevention and treatment of HF are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ChiCTR2000029094.
To evaluate and compare the relative performance of the tree-based scan statistic (TreeScan) with the crude cohort study, Bayesian confidence propagation neural network (BCPNN) and Gamma Poisson ...Shrinker (GPS) in detecting statin-related adverse events (AEs) in an electronic healthcare database.
Data from a Chinese healthcare database from 2010 to 2016 were evaluated. We identified statin users based on prescription information in their out-/in-patient records, and AEs were defined according to the ICD-10 codes in patients' diagnosis records. TreeScan was applied to detect AE signals related to statin use and was compared with 3 other methods based on sensitivity, specificity, positive predictive value, negative predictive value, accuracy, the Youden index, area under the precision-recall curve and the area under the receiver operating characteristic curve.
A total of 224 187 patients were enrolled and divided into 85 758 statin users and 138 429 nonusers. TreeScan generated 29 positive signals, of which 9 were known AEs. The sensitivities of TreeScan, BCPNN and GPS were all 69.2%, which was higher than that of the crude cohort study (46%). The specificity (82.3%), positive predictive value (31.0%), negative predictive value (95.9%), accuracy (81.0%), Youden index (51.5%) and area under the receiver operating characteristic curve (75.8%) of TreeScan were the highest among the 4 methods.
TreeScan outperformed the crude cohort, BCPNN and GPS in detecting statin-related AEs in an electronic healthcare database. Therefore, it can be used as a complementary tool for other signal detection methods in drug safety surveillance.
Background Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by integrating plasma ...proteome and transcriptome. Methods We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), summary-based MR (SMR) (for mRNA), and colocalization (for coding genes) to identify potential multi-omics biomarkers for CKD and combined the protein-protein interaction, Gene Ontology (GO), and single-cell annotation to explore the potential biological roles. The outcomes included CKD, extensive kidney function phenotypes, and different CKD clinical types (IgA nephropathy, chronic glomerulonephritis, chronic tubulointerstitial nephritis, membranous nephropathy, nephrotic syndrome, and diabetic nephropathy). Results Leveraging pQTLs of 3032 proteins from 3 large-scale GWASs and corresponding blood- and tissue-specific eQTLs, we identified 32 proteins associated with CKD, which were validated across diverse CKD datasets, kidney function indicators, and clinical types. Notably, 12 proteins with prior MR support, including fibroblast growth factor 5 (FGF5), isopentenyl-diphosphate delta-isomerase 2 (IDI2), inhibin beta C chain (INHBC), butyrophilin subfamily 3 member A2 (BTN3A2), BTN3A3, uromodulin (UMOD), complement component 4A (C4a), C4b, centrosomal protein of 170 kDa (CEP170), serologically defined colon cancer antigen 8 (SDCCAG8), MHC class I polypeptide-related sequence B (MICB), and liver-expressed antimicrobial peptide 2 (LEAP2), were confirmed. To our knowledge, 20 novel causal proteins have not been previously reported. Five novel proteins, namely, GCKR (OR 1.17, 95% CI 1.10-1.24), IGFBP-5 (OR 0.43, 95% CI 0.29-0.62), sRAGE (OR 1.14, 95% CI 1.07-1.22), GNPTG (OR 0.90, 95% CI 0.86-0.95), and YOD1 (OR 1.39, 95% CI 1.18-1.64,) passed the MR, SMR, and colocalization analysis. The other 15 proteins were also candidate targets (GATM, AIF1L, DQA2, PFKFB2, NFATC1, activin AC, Apo A-IV, MFAP4, DJC10, C2CD2L, TCEA2, HLA-E, PLD3, AIF1, and GMPR1). These proteins interact with each other, and their coding genes were mainly enrichment in immunity-related pathways or presented specificity across tissues, kidney-related tissue cells, and kidney single cells. Conclusions Our integrated analysis of plasma proteome and transcriptome data identifies 32 potential therapeutic targets for CKD, kidney function, and specific CKD clinical types, offering potential targets for the development of novel immunotherapies, combination therapies, or targeted interventions. Keywords: Chronic kidney disease, Kidney function, Mendelian randomization, Proteome, Transcriptome, Therapeutic targets
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