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To address the difficulty in characterizing early mechanical faults in the trip mechanism of circuit breakers, a data mining method based on variational mode decomposition (VMD) and phase space reconstruction (PSR) method was proposed. First, the vibration signal in the trip stage was separated from the whole according to the current features. Then, it was decomposed using the VMD algorithm to obtain the intrinsic mode functions (IMFs) and these sub signals were mapped to high-dimensional phase space based on the PSR algorithm. Then, the features of the attractor trail shape and the recurrence plot matrixes were extracted. In order to judge the fault in the trip mechanism, a fault simulation test was carried out and the characteristic under different faults was analyzed. Based on these samples, a fault identification model is established by support vector machine (SVM) and the effectiveness is verified by other test samples. The accuracy of the SVM model is 98%, which is higher than that of the BPNN and KNN clustering models. This research supplements the existing method for condition evaluation of the trip mechanism and can provide a reference for circuit breaker fault diagnosis.

Background Osteoarthritis (OA) is the most common form of arthritis, causing by multiple factors. It has long been a belief that arthritis pain is influenced by the weather. However, scientific studies have documented inconsistent results. To date, neither systematic review nor meta-analysis of existing findings has comprehensively considered their relations. The present study will critically appraise and synthesize the existing evidence from observational studies that examined the relationship between certain climate conditions and OA. Methods and design: This protocol will be conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. There are no restrictions on the study date or publication status for searches in the Cochrane Library, EMBASE, Web of Science, PubMed, and other relative databases. All eligible observational studies will be included, with weather conditions as effect factors and OA symptom or imaging abnormality as outcomes. Two reviewers will be responsible for data extraction and analysis. Risk of bias and quality appraisal will be performed for the included studies using Newcastle-Ottawa Scale (NOS). Meta-analysis will be conducted using Rev Man V.5.3 with the associations between weather conditions and OA presented by odds ratios (ORs), relative risks (RRs), hazard ratios (HRs) and the 95% confidence intervals (CIs). Results This systematic review and meta-analysis will present the overall association between weather conditions and OA. The association of climate factors influencing OA incidence or progression would be further illustrated in subgroup analysis depending on whether that has been extensively described in the literature. Discussion This study will provide the analysis evidence on the effect of meteorological factors on OA. In an approach of dealing with weather conditions, the results will benefit the daily management of OA.

Full-scale discharge tests of transmission line–tower air gaps are costly and time-consuming, and they cannot exhaustively simulate all the gap configurations in practical engineering. In this paper, a machine learning model established by support vector machine is introduced to predict the switching impulse discharge voltages of the ultra-high-voltage (UHV) AC transmission line–tower air gaps. The three-dimensional finite element models of a UHV cup-type tower and a UHV compact transmission line were established for electric field calculation, and some features were extracted from the hypothetic discharge channel and the shortest path between the bundled conductor and the tower. These features under a given voltage were normalised and input to the SVM model, while the output is two binary values, respectively, representing gap withstanding or breakdown. Trained by experimental data of one type of the UHV transmission line–tower gaps, the SVM model is able to predict the discharge voltages of another gap type. The mean absolute percentage errors of the two engineering gap types, under different gap distances, are 8.31 and 4.86%, respectively, which are acceptable for engineering applications. The results provide a possible way to obtain the discharge voltages of complicated engineering gaps by mathematical calculations.

Air insulation strength relates closely to the electrostatic field distribution of the gap configuration. To achieve insulation prediction on the basis of electric field (EF) simulations, the spatial structure is characterized by a feature set including 38 parameters defined on a straight line between sphere electrodes. A support vector classifier (SVC) with particle swarm optimization (PSO) is used to establish a prediction model, whose input variables are those features. The EF nonuniform coefficient f of each sample gap is calculated and used for training sample selection according to the ranges off values. Trained by only 11-sample data, the PSO-optimized SVC model is employed to predict the power frequency breakdown voltages of 260-sphere gaps with a wide range of structure sizes. The predicted values coincide with the standard data given in IEC 60052 very well, with the same trend and minor relative errors. The MAPEs of the five predictions with different training sets are within 2.0%. The model is also effective to predict the breakdown voltages of Φ9.75-cm sphere-Φ6.5-cm sphere gaps, whose MAPEs are within 2.6%. The results demonstrate the effectiveness of the EF feature set and the generalization ability of the SVC model under the case of limited samples. This paper lays the foundation for estimating the dielectric strength of other air gaps with similar structures.

The hybrid high-voltage direct current (HVDC) breaker combines mechanical and power electronics switching that enables it to interrupt power flows within a few milliseconds. Mechanical switch is a key component of hybrid HVDC breaker and has a number of serially connected interrupter units which ideally would divide the voltage equally. The static voltage distribution characteristics and voltage sharing design of a multi-break mechanical switch were discussed in this study. A finite-element model was developed to study the static voltage distribution characteristics and capacitance parameters of multi-break mechanical switch (which actually consists of resistance and capacitance parameters under direct current) as a preliminary study. Comparisons were made under the simulation of vertical and U-shaped arrangement forms. The results indicate that the static voltage distribution of the high-voltage terminal is at least more than 65%, whereas the severe non-uniform voltage distribution can be well improved by means of the method proposed in this study.

Electrostatic field distribution has a decisive influence on the strength of air insulation. To predict air-gap breakdown voltages according to electric field calculation results, a set of electrostatic field features is defined on the shortest interelectrode path of the rod–plane gap. These features are taken as the input parameters of a machine learning model established by support vector regression (SVR), thus to describe their relationships with the output breakdown voltage. Trained by small-sample data randomly selected according to the distribution ranges of the electric field non-uniform coefficient, the SVR model is applied to predict the breakdown voltages of rod–plane gaps with the rod diameter of 20, 25 and 30 mm, and the gap distance ranging from 1 to 9 cm. The predicted results agree well with the experimental data, while the mean absolute percentage errors of the six predictions are within 2.5%. Furthermore, the Φ27 mm rod–plane gap breakdown voltages are also predicted, and the results fall in the range between those of Φ25 and Φ30 mm rod–plane gaps, which conform to the actual law. The results validate the validity of the electrostatic field features and the generalisation performance of the SVR model.

Background Patients with knee osteoarthritis (KOA) often complain about clinical symptoms affected by weather-related factors. The purpose of the present study was to use cross-sectional analysis to determine whether weather sensitivity was associated with clinical symptoms, as well as structure abnormalities, in KOA patients.Methods Data from 80 participants were obtained from the Feng Hans Shi Effects on OA (FHS) study, an OA cohort study initiated in China in 2015. The weather sensitivity of each participant was determined by a self-reported questionnaire. The following measurements were used to assess clinical and biological outcomes: a visual analog scale (VAS) for pain; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); and blood levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1(IL-1). Structural changes identified via magnetic resonance imaging (MRI) were also evaluated. Independent sample t-tests, chi-square tests, Fisher’s exact tests, Cochran-Armitage tests for linear trends, and binary linear regression were used to evaluate the clinical characteristics, biomarkers, WOMAC, and Whole-Organ Magnetic Resonance Imaging Score (WORMS) of weather-sensitive KOA patients and non-weather-sensitive KOA patients.Results Most of the KOA participants (57.5%) perceived the weather as affecting their knee-joint clinical symptoms. Through logistic regression analysis, the presence of weather sensitivity was found to increase the risk of KOA participants reporting higher levels of WOMAC pain scores [OR = 3.3 (95% CI: 1.1, 9.9), P > 0.032], functional scores [OR = 5.5 (95% CI: 1.8,16.8), P > 0.003], total scores [OR = 3.3 (95% CI: 1.1, 10.2), P = 0.034], WORMS cartilage scores [OR = 3.1 (95% CI: 1.1, 8.5), P < 0.027], and marrow abnormality scores [OR = 3.0 (95% CI: 1.1, 8.1), P > 0.029].Conclusions Weather-sensitive KOA patients were prone to show more serious clinical symptoms and structural abnormalities in their knee joints. Therefore, the existence of weather sensitivity may accelerate the progress of KOA.

To evaluate the clinical efficacy and safety of external application of Traditional Chinese Medicine (EATCM) on acute gouty arthritis (AGA).Six electronic data bases were retrieved from their inception to march 2017. 15 randomized controlled clinical trials (RCTs) were included. The quality of the literatures was assessed according to Cochrane review criteria by using RevMan5.3 software; and related data was counted using Stata14.0 software.There was no significant difference in C-reactiveprotein (CRP) between experimental intervention group and control group [(WMD = 1.093, 95% CI (－2.514, 4.701); P = 0.553)]. In terms of overall efficacy, the EATCM's treatment group was significantly superior to control group [(OR = 3.692; 95% CI (2.408, 5.661); P0.001)]. The EATCM was better than western medicine treatments or other interventions in reducing the adverse reactions [(OR = 0.135; 95% CI (0.067, 0.274); P0.001)]. All these funnel plots showed unlikelihood of publishing bias. But due to excessive heterogeneity, the statistical results of serum uric acid and visual analogue scale and CRP between the two groups became uncertain.The results indicate that EATCM may have greater overall efficacy with fewer adverse drug reactions, although the evidence is weak owing to the low methodological quality and the small number of the included trials.

With the construction of 200 kV flexible DC power grid, 200 kV DC circuit breakers have been demanded. The fast mechanical switch, which is an important component in the hybrid DC circuit breaker, usually adopts multi-break structure to meet the requirements of breaking time and effective opening stroke. For a 200 kV double-break fast mechanical switch, the voltage characteristics in the breaking process were analyzed firstly. Then, the distributed capacitances' parameters were calculated by the finite element method. Finally, the voltage-sharing components' parameters were simulated by using PSCAD/EMTDC. It is suggested that the voltage-sharing capacitors' value be selected from 260 pF to 300 pF, 200 Ω for the current limiting resistor, and 200 MΩ for the voltage-sharing resistor. The research can provide a reference for the voltage-sharing design of mechanical switches in non-arc hybrid DC circuit breakers.

Discharge voltage prediction of practical air gaps in transmission projects is a long-sought goal and also a great challenge in high-voltage (HV) engineering. An approach combined electric field simulation, feature extraction and machine learning algorithm is presented in this study to predict the switching impulse discharge voltages of extra-HV (EHV) and ultra-HV (UHV) transmission lines-tower air gaps. Some features extracted from the electrostatic field distribution are used to characterise the air-gap configuration and taken as input parameters of a prediction model established by a support vector classifier (SVC). Three kinds of actual gap configurations in EHV and UHV transmission lines are taken as test samples to validate the validity of the SVC model. Trained by experimental data of rod-plane gaps and one of the engineering gap configurations, this model is able to predict the discharge voltages of the other two conductor-tower gaps with acceptable accuracy. The mean absolute percentage errors of the three prediction results are 6.84, 4.19 and 3.46%. This research demonstrates the feasibility of discharge voltage prediction for complicated engineering gaps, which is useful to reduce the costly full-scale tests and helpful to guide the external insulation design.

The electric field calculations cannot effectively guide the insulation design of high voltage equipment since the insulation strengths of dielectrics cannot be predicted according to the electromagnetic analysis. In this paper, some features related to the electric field distribution such as the electric field strength, electric field gradient, path length, and the electric field integral are defined and extracted from finite element calculations of air gaps. The electric field features are taken as the input parameters of a grey correlative model established by support vector machine (SVM), so as to establish the multi-dimensional nonlinear relationships between these features and the discharge voltage of an air gap. The grid search (GS) method was used to search the optimal parameters of the SVM. This model was applied to predict the 50% discharge voltages of large sphere-plane air gaps in UHVDC valve halls. The predicted results were obtained after multiple iterative calculations, using the golden section search method. Compared to experimental data, the relative errors of the predicted results are within an acceptable range in view of engineering applications, which indicates the validity of the proposed method. This paper achieves the discharge voltage of air gaps by numerical computations instead of costly experiments.

Falls in late postmenopausal women with osteopenia usually cause fractures with severe consequences. This 36-month randomized, double-blind and placebo-controlled trial with a 10-year observational follow-up study aimed to investigate the long-term effect of herbal formula Bushen Yijing Fang (BSYJF) on fall risk in the late postmenopausal women with osteopenia. 140 late postmenopausal women (Femoral neck T-score, −2.5~−2 SD) were recruited and randomized to orally receive calcium carbonate 300 mg daily with either BSYJF or placebo for 36 months. The effect was further investigated for another 10-year follow-up. During the 36-month administration, there were 12 falls in BSYJF group and 28 falls in placebo group, respectively, indicating 64% lower risk of falls (RR 0.36 [95% CI, 0.18 to 0.71]; P = 0.004) in BSYJF group. During the 10-year follow-up, 36% lower fall risk (RR 0.64 [95% CI, 0.46 to 0.89]; P = 0.009) was observed in BSYJF group. No significant difference was found in safety profile between two groups. Thirty-six-month administration of BSYJF reduced fall risk with an increase in bone mass, and its latent effect on fall risk was continually observed in the 10-year follow-up in late postmenopausal women with osteopenia. This clinical trial was registered at Chinese clinical trial registry (ChiCTR-IOR-16008942).

The distribution of electric field (EF) has a strong correlation with air insulation strength. In order to obtain air gap breakdown voltage (BV) through simulating calculation instead of experimental measurement, various parameters related to the electrostatic field distribution are used to characterize the sphere gap structure, which are defined on the shortest path between two sphere electrodes. These features of different sphere gaps are extracted from EF simulation results and input to a support vector machine (SVM) model optimized by the grid search algorithm, so as to establish their correlations with the output BVs. The golden section search method is used to predict the BV iteratively. Taking 9 sphere gaps, with the diameter in the range of 15 to 50 cm, as training samples, the SVM model is employed for BV prediction of 107 quasi-uniform sphere gaps with different diameters ranging from 75 to 150 cm and gap distances from 2 to 75 cm. For the predicted results, the average relative error is only 0.97% compared with the test values presented in IEC 60052. The results demonstrate the effectiveness of the EF features and the prediction model. This research offers a reference for air gap BV calculation by numerical approaches.

The hybrid high voltage direct current (HVDC) breaker is a key equipment of the DC grid. The high speed mechanical switch is a key component of the hybrid HVDC breaker and has a number of serially connected switch units. The serially connected units should divide the voltage uniformly. The static voltage distributions and distributed capacitances of a 500 kV hybrid HVDC breaker mechanical switch are studied in this paper. A three dimensional finite element model, considering the actual dimension parameters of six 110 kV high speed mechanical units in serially vertical arrangement, is established to study the static voltage distribution characteristics and capacitance parameters of a 500 kV multi-break high-speed mechanical switch, with six 110 kV high speed mechanical switches in serially vertical arrangement. The calculated results indicate that, under vertical arrangement, from the point of capacitive voltage distribution, the static voltage distributions of the six mechanical switch units are non-uniform, and the high voltage unit is more than 75% of the whole voltage.

The aim of this study was to investigate the role of the mitogen-activated protein kinase kinase-extracellular signal-regulated kinases 1/2 (MEK-ERK1/2) signaling pathway in chondrocyte differentiation and cartilage tissue construction in vitro. Chondrocytes were stimulated with rat serum (RS) and fetal bovine serum (FBS), and chondrocyte phenotypes were investigated microscopically. Chondrocyte proliferation was analyzed using fluorescence activated cell sorting (FACS) and the CCK8 method. Protein and mRNA expressions were assessed by western blot and RT-qPCR. Constructed cartilage tissues were examined by Safranin O-Fast Green FCF staining and immunofluorescence. In contrast to FBS, RS induced rapid dedifferentiation of chondrocytes and decreased type II collagen expression and proteoglycan synthesis. ERK1/2 and type I collagen expression increased during dedifferentiation and decreased during redifferentiation. Increased MEK-ERK1/2 pathway activity resulted in chondrocyte dedifferentiation, and inhibition of ERK1/2 by the inhibitor PD0325901 reversed dedifferentiation and led to redifferentiation. These data suggest strongly that inhibition of MEK-ERK1/2 activation prevents chondrocyte dedifferentiation and fibrocartilage formation.

Knee osteoarthritis (KOA) is the most common form of arthritis, leading to pain disability in seniors and increased health care utilization. Manual therapy is one widely used physical treatment for KOA.To evaluate the effectiveness and adverse events (AEs) of manual therapy compared to other treatments for relieving pain, stiffness, and physical dysfunction in patients with KOA.A systematic review and meta-analysis of manual therapy for KOA.We searched PubMed, EMBASE, the Cochrane Library, and Chinese databases for relevant randomized controlled trials (RCTs) of manual therapy for patients with KOA from the inception to October 2015 without language restrictions. RCTs compared manual therapy to the placebo or other interventional control with an appropriate description of randomization. Two reviewers independently conducted the search results identification, data extraction, and methodological quality assessment. The methodological quality was assessed by PEDro scale. Pooled data was expressed as standard mean difference (SMD), with 95% confident intervals (CIs) in a random effects model. The meta-analysis of manual therapy for KOA on pain, stiffness, and physical function were conducted.Fourteen studies involving 841 KOA participants compared to other treatments were included. The methodological quality of most included RCTs was poor. The mean PEDro scale score was 6.6. The meta-analyses results showed that manual therapy had statistically significant effects on relieving pain (standardized mean difference, SMD = -0.61, 95% CI -0.95 to -0.28, P = 76%), stiffness (SMD = -0.58, 95% CI -0.95 to -0.21, P = 81%), improving physical function (SMD = -0.49, 95% CI -0.76 to -0.22, P = 65%), and total score (SMD = -0.56, 95% CI -0.78 to -0.35, P = 50%). But in the subgroups, manual therapy did not show significant improvements on stiffness and physical function when treatment duration was less than 4 weeks. And the long-term information for manual therapy was insufficient.The limitations of this systematic review include the paucity of literature and inevitable heterogeneity between included studies.The preliminary evidence from our study suggests that manual therapy might be effective and safe for improving pain, stiffness, and physical function in KOA patients and could be treated as complementary and alternative options. However, the evidence may be limited by potential bias and poor methodological quality of included studies. High-quality RCTs with long-term follow-up are warranted to confirm our findings.Key words: Knee osteoarthritis, manual therapy, systematic review.

Objective. The aim of this study is to systematically evaluate the evidence whether traditional Chinese herbal patches (TCHPs) for osteoarthritis (OA) are effective and safe and analyze their medication patterns.Methods. A systematic literature search was performed using all the possible Medical Subject Headings (MeSH) and keywords from January 1979 to July 2013. Both randomized controlled trials (RCTs) and observational studies were included. Estimated effects were analyzed using mean difference (MD) or relative risk (RR) with 95% confidence intervals (CI) and meta-analysis.Results. 86 kinds of TCHPs were identified. RCTs and controlled clinical trials (CCTs) which were mostly of low quality favored TCHPs for local pain and dysfunction relief. TCHPs, compared with diclofenac ointment, had significant effects on global effectiveness rate (RR = 0.50; 95% CI (0.29, 0.87)). Components of formulae were mainly based on the compounds “Xiao Huo Luo Dan” (Minor collateral-freeing pill) and “Du Huo Ji Sheng Tang” (Angelicae PubescentisandLoranthidecoction). Ten kinds of adverse events (AEs), mainly consisting of itching and/or local skin rashes, were identified after 3-4 weeks of follow-up.Conclusions. TCHPs have certain evidence in improving global effectiveness rate for OA; however, more rigorous studies are warranted to support their use.

Background: Knee osteoarthritis (KOA) is the most common form of arthritis, leading to pain disability in seniors and increased health care utilization. Acupotomy has been widely used to treat KOA. But its efficiency has not been scientifically and methodically evaluated. The aim of this study is to evaluate the efficacy and safety of acupotomy for the treatment of patients with KOA. Methods: Relevant studies will be searched from the databases of PubMed, EMBASE, Cochrane Library, China Knowledge Resource Integrated Database, Weipu Database for Chinese Technical Periodicals, SinoMed, and Wanfang Database from their inception to June 10, 2019. Two researchers will independently select studies, collect data, and assess the methodology quality by the Cochrane risk of bias tool. Results: The systematic review will provide high-quality evidence to assess the efficacy and safety of acupotomy for KOA by pain, stiffness, and dysfunction of knee joint, and quality of life, as well as adverse events. Conclusion: The systematic review will provide evidence to assess the effectiveness and safety of acupotomy therapy for KOA patients. PROSPERO registration number: PROSPERO CRD42019132082

Background/Aims: Bone marrow-derived mesenchymal stem cells (MSCs) are responsible for new bone formation during adulthood. Accumulating evidences showed that Osthole promotes the osteogenic differentiation in primary osteoblasts. The aim of this study was to investigate whether Osthole exhibits a potential to stimulate the osteogenic differentiation of MSCs and the underlying mechanism. Methods: MSCs were treated with a gradient concentration of Osthole (6.25 µM, 12.5 µM, and 25 µM). Cell proliferation was assessed by western blotting with the proliferating cell nuclear antigen (PCNA) and Cyclin D1 antibodies, fluorescence activated cell sorting (FACS), and cell counting kit 8 (CCK8). MSCs were cultured in osteogenesis-induced medium for one or two weeks. The osteogenic differentiation of MSCs was estimated by Alkaline Phosphatase (ALP) staining, Alizarin red staining, Calcium influx, and quantitative PCR (qPCR). The underlying mechanism of Osthole-induced osteogenesis was further evaluated by western blotting with antibodies in Wnt/β-catenin, PI3K/Akt, BMPs/smad1/5/8, and MAPK signaling pathways. Results: Osthole inhibited proliferation of rat MSCs in a dose-dependent manner. Osthole suppressed osteogenic differentiation of rat MSCs by down-regulating the activities of Wnt/β-catenin and Erk1/2-MAPK signaling. Conclusions: Osthole inhibits the proliferation and osteogenic differentiation of rat MSCs, which might be mediated through blocking the Wnt/β-catenin and Erk1/2-MAPK signaling pathways.

Background/Aims: Cartilage destruction is thought to be the major mediator of osteoarthritis. Recent studies suggest that inhibition of subchrondral bone loss by anti-osteoporosis (OP) drug can protect cartilige erosion. Osthole, as a promising agent for treating osteoporosis, may show potential in treating osteoarthritis. The purpose of this study was to investigate whether Osthole affects the proliferation and catabolism of rat chondrocytes, and the degeneration of cartilage explants. Methods: Rat chondrocytes were treated with Osthole (0 μM, 6.25 μM, 12.5 μM, and 25 μM) with or without IL1-β (10ng/ml) for 24 hours. The expression levels of type II collagen and MMP13 were detected by western Blot. Marker genes for chondrocytes (A-can and Sox9), matrix metalloproteinases (MMPs), aggrecanases (ADAMTS5) and genes implicated in extracellular matrix catabolism were evaluated by qPCR. Cell proliferation was assessed by measuring proliferating cell nuclear antigen (PCNA) expression and fluorescence activated cell sorter. Wnt7b/β-catenin signaling was also investigated. Cartilage explants from two-week old SD rats were cultured with IL-1β, Osthole and Osthole plus IL-1β for four days and glycosaminoglycan (GAG) synthesis was assessed with toluidine blue staining and Safranine O/Fast Green FCF staining, collagen type II expression was detected by immunofuorescence. Results: Osthole reduced expression of chondrocyte markers and increased expression of MMP13, ADAMTS5 and MMP9 in a dose-dependent manner. Catabolic gene expression levels were further improved by Osthole plus IL-1β. Osthole inhibited chondrocyte proliferation. GAG synthesis and type II collagen were decreased in both the IL-1β groups and the Osthole groups, and significantly reduced by Osthole plus IL-1β. Conclusions: Our data suggested that Osthole increases the catabolism of rat chondrocytes and cartilage explants, this effect might be mediated through inhibiting Wnt7b/β-catenin pathway.

Objective. To assess the short-term efficacy and safety of two kinds of Traditional Chinese herbal patches, Fufang Nanxing Zhitong Gao (FNZG) and Shangshi Jietong Gao (SJG), for painful knee osteoarthritis (OA).Methods. Patients were randomly enrolled in a double-blind, placebo-controlled study to receive FNZG (n=60), SJG (n=60), or placebo patch (n=30) for 7 days. Outcome measures included visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Traditional Chinese Medicine Syndrome Questionnaire (TCMSQ) subscale.Results. Although there was no significant difference among, three groups in short-term pain management, patients receiving FNZG got significant improvement in symptom of fear of coldness as compared with placebo patch (P=0.029). The most common local adverse events of rash, itching, erythema, and slightly damaged skin were observed in 7% of participants.Conclusions. FNZG may be a useful treatment for symptom of knee OA and merits long-term study in broader populations.