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42.
《BONE》2016
Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p = 1.20 × 10− 8, FHS p = 0.05 for trochanter BMD; rs9287237, discovery p = 3.55 × 10− 7, FHS p = 9.20 × 10− 3 for trochanter BMD, GEFOS p = 0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p = 7.48 × 10− 7, FHS p = 0.10 for inter-trochanter BMD, GEFOS p = 0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p = 3.09 × 10− 6, FHS p = 8.50 × 10− 3, GEFOS p = 1.23 × 10− 24 for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p = 1.64 × 10− 6, GEFOS p = 1.69 × 10− 3 for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p = 8.79 × 10− 7, GEFOS p = 2.61 × 10− 7 for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis. 相似文献
43.
《Seminars in arthritis and rheumatism》2021,51(3):513-522
The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets. 相似文献
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IntroductionEarly prediction of patients' prognosis in the emergency department (ED) is important. Patients' conditions such as dehydration help predict prognosis. The ratio of serum blood urea nitrogen to creatinine (BUN/Cr ratio) and inferior vena cava (IVC) diameter is often used to determine dehydration. Also, serum albumin levels reflect nutritional conditions such as dehydration. In this study, we evaluated the performance of BUN/Cr ratio, IVC diameter ratio, and BUN/Albumin ratio as predictive markers for in-hospital mortality and ICU admission among various diseases in ED.Material and methodsThis retrospective cohort study utilized data from patients who had abdominal and pelvic computed tomography (APCT) performed at our institution from 2015 to 2018. The measurement of IVC diameter from computed tomography, the BUN/Cr ratio, and the BUN/Albumin ratio were calculated. Differences in the performance among the BUN/Cr ratio, the IVC diameter ratio, and the BUN/Albumin ratio for predicting outcomes were evaluated by the area under the receiver operating characteristic (AUROC) curve.ResultsA total of 914 patients were enrolled and 78 patients (8.5%) were admitted to the ICU, and 71 patients (7.8%) died during the clinical process. Multivariate logistic regression showed that only the BUN/Albumin ratio was a significant predictor of inhospital mortality and ICU admission.ConclusionAmong dehydration markers the BUN/Albumin ratio is a simple and useful tool for predicting the outcomes of patients visiting the ED. 相似文献
47.
《BONE》2016
The association between vitamin D status and diabetes risk is inconsistent among observational studies, and most of the available studies have been with women. In the present study we investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and incident type 2 diabetes (T2D) in older men (≥ 65 years old) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study enrolled from March 2000 to April 2002.Baseline 25(OH)D levels were available in 1939 subjects without prevalent T2D. Clinical information, body mass index (BMI) and other factors related to T2D were assessed at the baseline visit. Incident diabetes, defined by self-report and medication use, was determined over an average follow-up of 6.4 years. At baseline, participants were, on average, 73.3 (± 5.7) years old, had a mean BMI in the overweight range (27.2 kg/m2 ± 3.6) and had total serum 25(OH)D of 26.1 ng/ml (± 8.3). Incident diabetes was diagnosed in 139 subjects. Cox regression analysis showed a trend toward a protective effect of higher 25(OH)D levels with a lower risk of T2D (HR 0.87, 95% CI: 0.73–1.04 per 1 SD increase of 25(OH)D). After adjusted for BMI and other potential confounders, the relationship between 25(OH)D levels and incident diabetes was further attenuated (HR 1.03, 95% CI 0.85–1.25). No significant difference in the incidence of diabetes emerged after analyzing study subjects according to baseline 25(OH)D quartiles.In conclusion, 25(OH)D levels were not associated with incident T2D in older men. 相似文献
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49.
《Clinical therapeutics》2021,43(7):1253-1264.e5
PurposeDaratumumab is a standard-of-care treatment for newly diagnosed multiple myeloma (NDMM). According to the ALCYONE trial, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) provides significantly longer overall survival and progression-free survival than bortezomib, melphalan, and prednisone (VMP) in patients with NDMM. However, considering the high price of daratumumab, it is necessary to conduct further research on its efficacy and cost. This study evaluated the cost-effectiveness, from the US payer perspective, of D-VMP vs VMP in the first-line setting for patients with NDMM who are not eligible for autologous stem cell transplantation.MethodsA Markov model was developed to estimate the lifetime cost and effectiveness of VMP with or without daratumumab as the first-line therapy for patients with NDMM. Univariable sensitivity analysis and probabilistic sensitivity analysis were performed to address the model robustness and uncertainty. Expected value of perfect information analysis was conducted to explore the uncertainty of decision-making and future costs.FindingsD-VMP provides an additional 2.417 quality-adjusted life years (QALYs), at a cost of $30,893 per QALY. Sensitivity analysis revealed that the transition probability of progression-free survival in D-VMP strategy, the price of daratumumab, and body weight of the patient influenced the model results most strongly. Probabilistic sensitivity analysis showed that D-VMP versus VMP has a 90.8% probability of being cost-effective at the $150,000/QALY willingness-to-pay (WTP) threshold. The population expected value of perfect information was $2150 million at a WTP threshold of $50,000/QALY and $1481 million at $100,000/QALY.ImplicationsIn this study, D-VMP was estimated to be cost-effective compared with VMP for patients with NDMM at a WTP threshold of $150,000/QALY. 相似文献
50.
《Ultrasound in medicine & biology》2019,45(7):1708-1720
Prosthetic mechanical valves are the elective choice in mitral valve (MV) replacement, because of their reliability and easiness of implantation. However, these prostheses can suffer from complications, the major one being prosthetic mitral valve thrombosis (PMVT). In these cases, transthoracic doppler echocardiogram (TDE) is the standard diagnostic workup for diagnosis of valve malfunction. The American Society of Echocardiography (ASE) indicates the possible TDE-derived indexes, which can help in identifying insurgence of MV replacement complications. Unfortunately, in some cases, it is not possible to detect PMVT based on these criteria. In these cases, we speak of Doppler silent thrombosis and only more accurate and invasive analyses, such as fluoroscopy, allow for a correct diagnosis. In this work, computational fluid dynamic models were implemented to simulate valve fluid dynamics in different clinical scenarios in order to improve the reliability of PMVT diagnosis based on TDE. In detail, seven mechanical valve configurations, associated to different potential thrombotic conditions (symmetric and asymmetric stenosis), were designed and tested using five pathologic transmitral velocity profile, extracted from real TDE images; to obtain the flow rate profiles, each TDE velocity profile was scaled to yield a mean flow rate (MFR) of 4, 5 and 6 L/min, respectively. As a result, 105 (7 × 5 × 3) synthetic cases, accounting for different velocity profiles, MFRs and valve configurations, were simulated. TDE-derived indexes were calculated according to the ASE guidelines that were extracted. Advanced statistical methods were applied to propose a new diagnostic algorithm for detecting PMVT. Our results showed that there isn't any significant difference between symmetric and asymmetric stenosis, probe location and flow rate waveform and confirmed that the single modality diagnostic is not able to predict thrombosis in a relevant number of cases, referable to mild and mild-severe stenosis cases. To overcome the problem, a novel multi-parametric discrete score based on the designed diagnostic algorithm was attained and tested; the percentage of stenosis (POS) was predicted with an accuracy rate of 90.5%. Even more interestingly, the error rate of 9.5% is related to four false positive cases corresponding to mild stenosis (POS = 15%) which were erroneously classified as mild-severe stenosis. No false negatives were obtained. Our results suggest that a reliable estimation must take into account the mean flow rate as well as the transmitral velocity profile in order to provide a correct diagnosis. 相似文献