Search

The Finkelstein and Schoenfeld (FS) test is a popular generalized pairwise comparison approach to analyze prioritized composite endpoints (eg, components are assessed in order of clinical importance). Power and sample size estimation for the FS test, however, are generally done via simulation studies. This simulation approach can be extremely computationally burdensome, compounded by increasing number of composite endpoints and with increasing sample size. Here we propose an analytical solution to calculate power and sample size for commonly encountered two‐component hierarchical composite endpoints. The power formulas are derived assuming underlying distributions in each of the component outcomes on the population level, which provide a computationally efficient and practical alternative to the standard simulation approach. Monte Carlo simulation results demonstrate that performance of the proposed power formulas are consistent with that of the simulation approach, and have generally desirable objective properties including robustness to mis‐specified distributional assumptions. We demonstrate the application of the proposed formulas by calculating power and sample size for the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial. [ABSTRACT FROM AUTHOR]

Background: The impact of back pain on disability in older women is well-understood, but the influence of back pain on mortality is unclear.Objective: To examine whether back pain was associated with all-cause and cause-specific mortality in older women and mediation of this association by disability.Design: Prospective cohort study.Setting: The Study of Osteoporotic Fractures.Participants: Women aged 65 or older.Measurement: Our primary outcome, time to death, was assessed using all-cause and cause-specific adjusted Cox models. We used a four-category back pain exposure (no back pain, non-persistent, infrequent persistent, or frequent persistent back pain) that combined back pain frequency and persistence across baseline (1986-1988) and first follow-up (1989-1990) interviews. Disability measures (limitations of instrumental activities of daily living [IADL], slow chair stand time, and slow walking speed) from 1991 were considered a priori potential mediators.Results: Of 8321 women (mean age 71.5, SD = 5.1), 4975 (56%) died over a median follow-up of 14.1 years. A higher proportion of women with frequent persistent back pain died (65.8%) than those with no back pain (53.5%). In the fully adjusted model, women with frequent persistent back pain had higher hazard of all-cause (hazard ratio [HR] = 1.24 [95% CI, 1.11-1.39]), cardiovascular (HR = 1.34 [CI, 1.12-1.62]), and cancer (HR = 1.33, [CI 1.03-1.71]) mortality. No association with mortality was observed for other back pain categories. In mediation analyses, IADL limitations explained 47% of the effect of persistent frequent back pain on all-cause mortality, slow chair stand time, and walking speed, explained 27% and 24% (all significant, p < 0.001), respectively.Limitations: Only white women were included.Conclusion: Frequent persistent back pain was associated with increased mortality in older women. Much of this association was mediated by disability. [ABSTRACT FROM AUTHOR]

Objective: To evaluate construct validity and scoring methods of the world health organization--health and work performance questionnaire (HPQ) for people with arthritis. Methods: Construct validity was examined through hypothesis testing using the recommended guidelines of the consensus-based standards for the selection of health measurement instruments (COSMIN). Results: The HPQ using the absolute scoring method showed moderate construct validity as four of the seven hypotheses were met. The HPQ using the relative scoring method had weak construct validity as only one of the seven hypotheses were met. Conclusion: The absolute scoring method for the HPQ is superior in construct validity to the relative scoring method in assessing work performance among people with arthritis and related rheumatic conditions; however, more research is needed to further explore other psychometric properties of the HPQ. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to identify features of the environment associated with community participation of older adults. Method: A systematic review of studies that examined associations between environment and community participation in older adults was conducted. Environmental features were extracted and grouped using the International Classification of Functioning, Disability, and Health’s environmental categories. Meta-analysis of environmental categories was conducted by calculating combined effect size (ES) estimates. Results: Significant, small to moderate, random ESs were found for six of seven environmental categories: neighborliness (ES = 0.52, 95% confidence interval [CI] = [0.18, 0.87]), social support (ES = 0.38, 95% CI = [0.13, 0.62]), land-use diversity (ES = 0.29, 95% CI = [0.16, 0.42]), transportation (ES = 0.29, 95% CI = [0.15, 0.43]), civil protection (e.g., safety; ES = 0.27, 95% CI = [0.0, 0.54]), and street connectivity/walkability (ES = 0.20, 95% CI = [0.15, 0.26]). Discussion: Community initiatives that address specific features of the social environment and street-level environment may increase community participation of older adults. [ABSTRACT FROM AUTHOR]

ObjectiveTo determine the prospective relationship between changes in sugar-sweetened beverage (SSB) intake and central adiposity in older children.DesignDietary intakes of children were obtained by 3 d food records at ages 10 and 13 years. Waist circumference (WC) and weight and height to determine BMI were measured at 10 and 13 years and total body fat mass (TBFM) at 13 years by dual-energy X-ray absorptiometry. Analyses were conducted using multivariable linear regression. Reporting errors were measured and participants were categorized as under-, plausible and over-reporters of dietary intakes.SettingCommunity-based British cohort of children participating in the Avon Longitudinal Study of Parents and Children.ResultsAmong 2455 older children, increased SSB consumption from ages 10 to 13 years was associated with higher WC (standardized β=0·020, P=0·19), BMI (β=0·028, P=0·03) and TBFM (β=0·017, P=0·20) at 13 years. Effects were strengthened among plausible dietary reporters (n 1059): WC (β=0·097, P<0·001), BMI (β=0·074, P<0·001) and TBFM (β=0·065, P=0·003). The association between change in SSB and WC was weakened, but remained statistically significant after accounting for BMI (β=0·042, P=0·02) and TBFM (β=0·048, P=0·01).ConclusionsHigher consumption of SSB from ages 10 to 13 years was associated with a larger WC at age 13 years independent of differences in total adiposity. Accounting for dietary reporting errors strengthened associations. Our findings further support recommendations to limit intakes of SSB to reduce excess weight gain in children and suggest that SSB have an additional deleterious effect on central adiposity. [ABSTRACT FROM AUTHOR]

Evidence of an association between milk intake and childhood adiposity remains inconsistent, with few data available regarding the effects of the amount of dairy fat consumed. This study examined the relation between dairy consumption (total, full, and reduced fat) at age 10 y on risk of excess adiposity at age 13 y in participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2455). Intakes were assessed by 3-d dietary records. Total body fat mass (TBFM) using dual-energy X-ray absorptiometry was examined at 13 y. Outcomes included excess TBFM (top quintile of TBFM), overweight, and change in bodymass index (BMI). The highest vs. lowest quartile of total dairy consumers (g/d) at age 10 y did not have an increased risk of excess TBFM (OR: 0.73; 95% CI: 0.46, 1.16; P-trend = 0.28) or overweight (OR: 0.69; 95% CI: 0.41, 1.15; P = 0.24) at age 13 y. Children in the highest quartile of full-fat dairy intakes vs. those in the lowest quartile had a reduced risk of excess TBFM (OR: 0.64; 95% CI: 0.41, 1.00; P = 0.04) and a suggestion of a reduction in overweight (OR: 0.65; 95%CI: 0.40, 1.06; P = 0.19) at age 13 y. Furthermore, the highest vs. lowest consumers of full-fat products had smaller gains in BMI during follow-up [2.5 kg/m² (95%CI: 2.2, 2.7) vs. 2.8 kg/m² (95%CI: 2.5, 3.0); P < 0.01]. Associations with reduced-fat dairy consumption did not attain statistical significance. In this study, dairy consumption was not related to excess fat accumulation during late childhood. Estimates had wide confidence limits but generally showed inverse relations between dairy intakes and risk of excess adiposity. Additional prospective research is warranted to confirm the effects of dairy intake on obesity in children. [ABSTRACT FROM AUTHOR]

Background: Interaction in clinical trials presents challenges for design and appropriate sample size estimation. Here we considered interaction between treatment assignment and a dichotomous prognostic factor with a continuous outcome. Our objectives were to describe differences in power and sample size requirements across alternative distributions of a prognostic factor and magnitudes of the interaction effect, describe the effect of misspecification of the distribution of the prognostic factor on the power to detect an interaction effect, and discuss and compare three methods of handling the misspecification of the prognostic factor distribution. Methods: We examined the impact of the distribution of the dichotomous prognostic factor on power and sample size for the interaction effect using traditional one-stage sample size calculation. We varied the magnitude of the interaction effect, the distribution of the prognostic factor, and the magnitude and direction of the misspecification of the distribution of the prognostic factor. We compared quota sampling, modified quota sampling, and sample size re-estimation using conditional power as three strategies for ensuring adequate power and type I error in the presence of a misspecification of the prognostic factor distribution. Results: The sample size required to detect an interaction effect with 80% power increases as the distribution of the prognostic factor becomes less balanced. Misspecification such that the actual distribution of the prognostic factor was more skewed than planned led to a decrease in power with the greatest loss in power seen as the distribution of the prognostic factor became less balanced. Quota sampling was able to maintain the empirical power at 80% and the empirical type I error at 5%. The performance of the modified quota sampling procedure was related to the percentage of trials switching the quota sampling scheme. Sample size re-estimation using conditional power was able to improve the empirical power under negative misspecifications (i.e. skewed distributions) but it was not able to reach the target of 80% in all situations. Conclusions: Misspecifying the distribution of a dichotomous prognostic factor can greatly impact power to detect an interaction effect. Modified quota sampling and sample size re-estimation using conditional power improve the power when the distribution of the prognostic factor is misspecified. Quota sampling is simple and can prevent misspecification of the prognostic factor, while maintaining power and type I error. [ABSTRACT FROM AUTHOR]

Objective. To investigate comprehensively the relationships between Behçet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses.Methods. Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I2 and Q-statistics, and modelled using meta-regression.Results. Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical characteristics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant.Conclusion. The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement. [ABSTRACT FROM PUBLISHER]

The article identifies factors that explain heterogeneity in trials of glucosamine. The study found that heterogeneity among trials of glucosamine is larger than would be expected by chance. It also found that effect sizes were consistently higher among trials with industry involvement. Explanations for the difference include different glucosamine preparations, inadequate allocation concealment, and industry bias.

Background: The Dietary Guidelines for Americans 2005 recommends that Americans increase their intake of dairy products. However, some studies have reported that increasing dairy product intake is associated with an increased risk of prostate cancer. We conducted a meta-analysis to examine associations between intakes of calcium and dairy products and the risk of prostate cancer. Methods: We searched Medline for prospective studies published in English-language journals from 1966 through May 2005. We identified 12 publications that used total, advanced, or fatal prostate cancer as end points and reported associations as relative risks (I4Rs) with 95% confidence intervals (CIs) by category of dairy product or calcium intake. Data were extracted using standardized data forms. Random-effects models were used to pool study results and to assess dose-response relationships between dairy product or calcium intakes and the risk of prostate cancer. We conducted sensitivity analyses by changing criteria for inclusion of studies or by using fixed-effects models. All statistical tests were two-sided. Results: Men with the highest intake of dairy products (RR =1.11 195% CI = 1.00 to 1.22], P = .047) and calcium (RR = 1.39 [95% CI = 1.09 to 1.77], P = .018) were more likely to develop prostate cancer than men with the lowest intake. Dose-response analyses suggested that dairy product and calcium intakes were each positively associated with the risk of prostate cancer (Ptrend = .029 and .014, respectively). Sensitivity analyses generally supported these associations, although the statistical significance was attenuated. The pooled relative risks of advanced prostate cancer were 1.33 (95% CI = 1.00 to 1.78; P = .055) for the highest versus lowest intake categories of dairy products and 1.46 (95% CI = 0.65 to 3.25; P>.2) for the highest versus lowest intake categories of calcium. Conclusions: High intake of dairy products and calcium may be associated with an increased risk of prostate cancer, although the increase appears to be small. [ABSTRACT FROM AUTHOR]

A nonparametric maximum likelihood estimator (NPMLE) of the underlying distribution in the presence of truncation, first published in the astronomy literature by Lynden-Bell in 1971, has received considerable attention in the statistics and biostatistics literature. A limitation of this useful estimator is that it relies on the independence of the variable of interest and of the truncation variable. In this paper, a generalization of this estimator is proposed, which expands the applicability of the estimator by allowing for dependence between the variable of interest and the truncation variable in the presence of a covariate. Weak convergence and asymptotic optimality in the Hajek-Beran sense (Beran, R, 1977, Estimating a distribution function. Annals of Statistics, 5, 400-404.) are shown for this generalized estimator process. A related estimator of the joint distribution of the covariate and the variable of interest is introduced, which shares the asymptotic normality and optimality of the previous estimator. Finally, simulation results are used to compare the generalization to the Lynden-Bell estimator in a variety of situations. [ABSTRACT FROM AUTHOR]

Randomized clinical trial (RCT) publications with inappropriate random-sequence generation, lack of allocation concealment, or imperfect blinding yield inflated estimates of effect compared to those in which adequate methods are described. RCTs that do not state methods used yield similar effect estimates, suggesting that inadequate methods were used. We compared RCT publications with investigator reports of actual practice for 40 rheumatology RCTs published in 1997/1998. In RCTs in which these methods were not described in the trial reports and would thus have been characterized as “inadequate,” investigators reported using methods of random-sequence generation and allocation concealment that would be considered adequate in 77.4 and 78.1% of RCTs, respectively. This suggests that, in contrast to previous reports, inadequate random-sequence generation and allocation concealment, per se, may not be a major problem in RCTs. Characterizing RCTs as “good” or “poor” quality based on the published report is likely to be inappropriate. [Copyright &y& Elsevier]

Evaluates the benefit of glucosamine and chronroitin preparations for osteoarthritis (OA) symptoms using meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip OA. Data sources; Study selection; Data extraction; Data synthesis; Conclusions.

In systemic sclerosis (SSc), pulmonary hypertension remains a significant cause of morbidity and mortality. Although conventionally classified as group 1 pulmonary arterial hypertension, systemic sclerosis-related pulmonary hypertension (SSc-PH) is a heterogeneous disease. The contribution of left-sided cardiac disease in SSc-PH remains poorly understood. How often does left ventricular (LV) dysfunction occur in SSc among patients undergoing right heart catheterization and how does coexistent LV dysfunction with SSc-PH affect all-cause mortality in this patient population? We conducted a retrospective, observational study of 165 patients with SSc who underwent both echocardiography and right heart catheterization. LV dysfunction was identified using LV global longitudinal strain (GLS) on speckle-tracking echocardiography based on a defined threshold of > −18%. SSc-PH was defined by a mean pulmonary artery pressure > 20 mmHg. Among patients with SSc who have undergone right heart catheterization, LV dysfunction occurred in 74.2% with SSc-PH and 51.2% without SSc-PH. The median survival of patients with SSc-PH and LV dysfunction was 67.9 (95% CI, 38.3-102.0) months, with a hazard ratio of 12.64 (95% CI, 1.73-92.60) for all-cause mortality when adjusted for age, sex, SSc disease duration, and FVC compared with patients with SSc without pulmonary hypertension with normal LV function. LV dysfunction is common in SSc-PH. Patients with SSc-PH and LV dysfunction by LV GLS have increased all-cause mortality. This suggests that LV GLS may be helpful in identifying underlying LV dysfunction and in risk assessment of patients with SSc-PH. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives. This study detected secular change in disability and health among persons aged 55 to 70 years, the life period when increases in disability and morbidity begin and retirement occurs. Methods. Cross-sectional comparisons were completed with data from similarly aged members of the original (n = 1760) and offspring (n = 1688) cohorts of the Framingham Heart Study, which represent 2 generations. Analyses were conducted by gender and on chronic disease subgroups by logistic regression. Results. There was substantially less disability in the offspring cohort than in the original cohort. Thirty-six percent of offspring men were disabled vs 52% of original cohort men (P = .001); among women, these proportions were 54% vs 72% (P = .001). Fewer offspring perceived their health as fair or poor and fewer had chronic diseases. Offspring were more physically active and less likely to smoke or consume high amounts of alcohol, but their average weight was greater. The secular decline in disability was strongly evident among individuals with chronic diseases. Conclusions. Our findings depict a secular change toward a less disabled and globally healthier population in the period of life when retirement occurs. (Am J Public Health. 1999;89: 1678-1683) [ABSTRACT FROM AUTHOR]

Use of statistical methods for early stopping of clinical trials allows more efficient and ethical utilization of subjects. In uncommon diseases, where the pool of potential subjects is limited, these methods provide a way to maximize the information gathered from trials. For trials in lupus, methods for early stopping should be more widely utilized. We discuss the ethics, practical aspects, pros and cons, and statistical foundations of some established methods for early stopping, with an emphasis on those that have available implementation in computer software. An example of the design and analysis of a treatment trial in systemic lupus erythematosus with the triangular test method of early stopping is also given. [ABSTRACT FROM AUTHOR]

Simplified drug regimens may improve retention in care for persons with chronic diseases. In April 2013, South Africa adopted a once-daily single-pill human immunodeficiency virus (HIV) treatment regimen as the standard of care, replacing a multiple-pill regimen. Because the regimens had similar biological efficacy, the shift to single-pill therapy offered a real-world test of the impact of simplified drug-delivery mechanisms on patient behavior. Using a quasi-experimental regression discontinuity design, we assessed retention in care among patients starting HIV treatment just before and just after the guideline change. The study included 4,484 patients starting treatment at a large public sector clinic in Johannesburg, South Africa. The share of patients prescribed a single-pill regimen increased by over 40 percentage points between March and April 2013. Initiating treatment after the policy change was associated with 11.7–percentage-points' higher retention at 12 months (95% confidence interval: −2.2, 29.4). Findings were robust to different measures of retention, different bandwidths, and different statistical models. Patients starting treatment early in HIV infection—a key population in the test-and-treat era—experienced the greatest improvements in retention from single-pill regimens. [ABSTRACT FROM AUTHOR]

An editorial is presented on reexamining remission definitions in rheumatoid arthritis while considering the twenty-eight–joint disease activity score, c-reactive protein level, and patient global assessment. Topics include definitions performed best in predicting long-term good function and lack of radiographic progression; and committee endorsed a stringent definition using measures from the validated core set of outcome measures.

We devised a scoring system to identify patients with systemic sclerosis (SSc) at risk for pulmonary hypertension (PH) and predict all-cause mortality. Using 7 variables obtained via pulmonary function testing, echocardiography, and computed tomographic chest imaging, we applied the score to a retrospective cohort of 117 patients with SSc. There were 60 (51.3%) who were diagnosed with PH by right heart catheterization. Using a scoring threshold ≥ 0, our decision tool predicted PH with a sensitivity, specificity, and accuracy of 0.87 (95% CI 0.75, 0.94), 0.74 (95% CI 0.60, 0.84), and 0.80 (95% CI 0.72, 0.87), respectively. When adjusted for age at PH diagnosis, sex, and receipt of pulmonary arterial vasodilators, each one-point score increase was associated with an adjusted HR of 1.19 (95% CI 1.05, 1.34) for all-cause mortality. With further validation in external cohorts, our simplified clinical decision tool may better streamline earlier detection of PH in SSc. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) and pain are both made more severe by low‐grade inflammation. This study was undertaken to examine whether visceral fat, a major source of inflammatory cytokines and adipokines, is associated with an increased risk of knee OA or musculoskeletal pain. Methods: Subjects in the Multicenter Osteoarthritis Study cohort, who were age 50–79 years and had or were at high risk of knee OA, underwent whole‐body dual x‐ray absorptiometry (DXA) at baseline. At baseline, 30 months, and 60 months radiographs and magnetic resonance images (MRIs) of the knees were obtained, and patients were asked to score the severity of their knee pain and to identify sites of joint pain using a body homunculus. Baseline DXA scans were used to measure total body fat and visceral and subcutaneous fat in the torso. The association of fat depot size with structural outcomes (incident radiographic OA and cartilage loss and synovitis on MRI) and with pain outcomes (worsening knee pain, number of painful joints, and widespread pain) was assessed. Regression analyses were adjusted for age, sex, race, education level, smoking status, physical activity, body mass index (BMI), and depressive symptoms. Results: Of the 2,961 participants at baseline, 60.7% were women. The mean age was 62.5 years and mean BMI was 30.5 kg/m2. After adjustment for covariates, no fat measures were associated with any structural outcomes. However, total and visceral, but not subcutaneous, fat were positively associated with worsening knee pain (P = 0.0005 for total fat and P = 0.007 for visceral fat) and widespread pain (P = 0.001 for total fat and P = 0.02 for visceral fat), and the amount of visceral fat was associated with the number of painful joints (P = 0.07). Conclusion: Our findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain. [ABSTRACT FROM AUTHOR]

Wang and Chang studied the bias in the estimation of the marginal survival curve of recurrent event data and came up with an unbiased Kaplan–Meier (KM)-like estimator. However, there were no corresponding hypothesis tests to compare Wang and Chang's survival estimates among different groups. In this article, we extended three commonly used rank tests to compare Wang and Chang's KM-like survival estimates. Intra-subject correlation (ISC) issue is handled by using a robust variance estimator. We also studied the empirical power difference between our new method and Jung and Jeong's method which was developed for clustered survival data and explored the relationship between ISC and the power of different rank tests. for this article are available online. [ABSTRACT FROM AUTHOR]

Objective: Studies suggest that parenteral MTX may be more efficacious than the oral form at equivalent doses for the treatment of rheumatoid arthritis. We carried out a meta-analysis to compare the efficacy of oral versus parenteral MTX in RA. Methods: PubMed, Web of Science and Embase were systematically searched from inception to June 8th 2017 and reviewed following PRISMA 2009 guidelines, by two independent reviewers. To be included, trials had to study adults with RA randomized to the same dose of either oral or parenteral MTX. The primary endpoint was ACR20 at 6 months. Intention-to-treat analysis results were used when possible. Data from direct comparisons between oral and parenteral methotrexate quantitatively analyzed using maximum likelihood random effects meta-analysis. Relative treatment effects were generated as an odds ratio [OR] (OR>1 indicated a benefit for parenteral therapy). Results: The search yielded 357 papers or abstracts. After review of titles or abstracts and full text papers, we found 4 that met inclusion criteria with 703 patients randomized. Dose of MTX started at 15mg/week and increased up to 25mg/week. The summary OR for achieving ACR20 using parenteral vs. oral MTX was 3.02 (95% CI 1.41, 6.46), with no significant difference in the risk for all adverse events. Conclusion: Parenteral MTX therapy had significantly higher odds than oral MTX of achieving reduction in disease activity. We propose that parenteral MTX is more effective than weekly oral MTX; its widespread use may lead to better control of disease and a decrease in demand for biologic agents. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether women with surgical menopause have a higher risk of frailty than naturally menopausal women. Design: Prospective cohort study with up to 18 years of follow‐up. Setting: Four U.S clinical centers. Participants: Community‐dwelling white women aged 65 and older (mean 71.2±5.2) enrolled in the Study of Osteoporotic Fractures (N=7,699). Measurements: Surgical menopause was based on participant self‐report of having undergone bilateral oophorectomy before menopause. The outcome was incident frailty, classified as robust, prefrail, frail, or death at 4 follow‐up interviews, conducted 6 to 18 years after baseline. Information on baseline serum total testosterone concentrations was available for 541 participants. Results: At baseline, 12.6% reported surgical menopause. Over the follow‐up period, 22.0% died, and 10.1% were classified as frail, 39.7% as prefrail, and 28.3% as robust. Surgically menopausal women had significantly lower total serum testosterone levels (13.2 ± 7.8 ng/dL) than naturally menopausal women (21.7 ± 14.8 ng/dL) (p=0.000), although they were not at greater risk of frailty (adjusted odds ratio (aOR)=0.94, 95% confidence interval (CI)=0.72–1.22), prefrailty (aOR=0.96, 95% CI=0.80–1.10), or death (aOR=1.17, 95% CI=0.97–1.42) after adjusting for age, body mass index, and number of instrumental activity of daily living impairments. There was no evidence that oral estrogen use modified these associations. Conclusion: In postmenopausal women, surgical menopause was not associated with greater risk for frailty than natural menopause, even in the absence of estrogen therapy. Future prospective studies are needed to investigate hormonal mechanisms involved in development of frailty in older postmenopausal women. J Am Geriatr Soc 66:2172–2177, 2018. [ABSTRACT FROM AUTHOR]

Objective: To assess whether vascular activity seen on 18F‐fluorodeoxyglucose–positron emission tomography (FDG‐PET) scan is associated with angiographic change in large vessel vasculitis (LVV). Methods: Patients with LVV were recruited into a prospective cohort. All patients underwent magnetic resonance angiography or computed tomography angiography and FDG‐PET imaging. Follow‐up imaging using the same imaging modalities was obtained ≥6 months later per a standardized imaging protocol. Arterial damage, defined as stenosis, occlusion, or aneurysm, and corresponding FDG uptake were evaluated in 17 arterial territories. On follow‐up, development of new lesions was recorded, and existing lesions were characterized as improved, worsened, or unchanged. Results: A total of 1,091 arterial territories from 70 patients with LVV (38 patients with Takayasu arteritis, 32 patients with giant cell arteritis) were evaluated. Over a median 1.6 years of follow‐up, new lesions developed only in 8 arterial territories in 5 patients with Takayasu arteritis. Arterial lesions improved in 16 territories and worsened in 6 territories. Most arterial territories that did not have vascular activity on FDG‐PET scan at baseline had no angiographic change over the follow‐up period (787 [99%] of 793). Few territories with baseline FDG‐PET activity had angiographic change over time (24 [8%] of 298), but of the territories that developed angiographic change, 80% had FDG‐PET activity at baseline. Within the same patient, an arterial territory with baseline FDG‐PET activity had significantly increased risk for angiographic change compared to a paired arterial territory without FDG‐PET activity (odds ratio 19.49 [95% confidence interval 2.44–156.02]; P < 0.01). Concomitant edema and wall thickening further increased risk for angiographic change. Conclusion: Development of angiographic change was infrequent in this cohort of patients with LVV. A lack of baseline FDG‐PET activity was strongly associated with stable angiographic disease. In cases of angiographic progression, change was preceded by the presence of FDG‐PET activity. [ABSTRACT FROM AUTHOR]

Background: Interaction in clinical trials presents challenges for design and appropriate sample size estimation. Here we considered interaction between treatment assignment and a dichotomous prognostic factor with a continuous outcome. Our objectives were to describe differences in power and sample size requirements across alternative distributions of a prognostic factor and magnitudes of the interaction effect, describe the effect of misspecification of the distribution of the prognostic factor on the power to detect an interaction effect, and discuss and compare three methods of handling the misspecification of the prognostic factor distribution.Methods: We examined the impact of the distribution of the dichotomous prognostic factor on power and sample size for the interaction effect using traditional one-stage sample size calculation. We varied the magnitude of the interaction effect, the distribution of the prognostic factor, and the magnitude and direction of the misspecification of the distribution of the prognostic factor. We compared quota sampling, modified quota sampling, and sample size re-estimation using conditional power as three strategies for ensuring adequate power and type I error in the presence of a misspecification of the prognostic factor distribution.Results: The sample size required to detect an interaction effect with 80% power increases as the distribution of the prognostic factor becomes less balanced. Misspecification such that the actual distribution of the prognostic factor was more skewed than planned led to a decrease in power with the greatest loss in power seen as the distribution of the prognostic factor became less balanced. Quota sampling was able to maintain the empirical power at 80% and the empirical type I error at 5%. The performance of the modified quota sampling procedure was related to the percentage of trials switching the quota sampling scheme. Sample size re-estimation using conditional power was able to improve the empirical power under negative misspecifications (i.e. skewed distributions) but it was not able to reach the target of 80% in all situations.Conclusions: Misspecifying the distribution of a dichotomous prognostic factor can greatly impact power to detect an interaction effect. Modified quota sampling and sample size re-estimation using conditional power improve the power when the distribution of the prognostic factor is misspecified. Quota sampling is simple and can prevent misspecification of the prognostic factor, while maintaining power and type I error. [ABSTRACT FROM AUTHOR]

Patients with systemic sclerosis complicated by both pulmonary hypertension (SSc- PH) and interstitial lung disease (SSc-PH-ILD) have poor prognosis compared to those with SSc-PH or SSc-ILD alone. Little is known of how ILD severity affects outcomes in those with SSc-PH, or how PH severity affects outcomes in thosewith SSc-ILD. Herein, we aimed to delineate clinical features of patients with SSc-PH and SSc-ILD and determine to what degree PH and ILD severity contribute to mortality in patients with SSc. We conducted parallel retrospective studies in cohorts of patients with SSc-PH and SSc-ILD. We categorized ILD severity by pulmonary function testing and PH severity by cardiopulmonary hemodynamics. Our primary outcome was all-cause mortality from time of PH or ILD diagnosis for the SSc-PH and SSc-ILD cohorts, respectively. We calculated adjusted risks of time to all-cause mortality using Cox proportional hazards models. In patients with SSc- PH, severe ILD (HR: 3.54; 95% CI: 1.05, 11.99) was associated with increased hazards for all-cause mortality. By contrast, mild and moderate ILD were not associated with increased mortality risk. In patients with SSc-ILD, both moderate (HR: 2.65; 95% CI: 1.12, 6.31) and severe PH (HR: 6.60; 95% CI: 2.98, 14.61) were associated with increased hazards for all-cause mortality, while mild PH was not. Through our parallel study design, the risk of all-cause mortality increases as severity of concomitant ILD or PH worsens. Therapies that target slowing disease progression earlier in the disease course may be beneficial. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning the use of Arthritis Foundation's Fibromyalgia Self-Help Course.

Objective. We investigated the effect of gender on the clinical Adamantiades–Behçet’s disease (ABD) phenotype with data from the German ABD registry and a meta-analysis from a systematic literature review.Methods. Using the German ABD registry data, we compared 36 clinical variables by gender (with women as the reference category) and investigated potential effect modification by HLA-B5 or ethnic background. The registry data were combined with those from a literature search to calculate pooled relative risks (RRs) for variables with data from ≥10 relevant datasets.Results. The German ABD registry provided information for 747 subjects (58.1% males) and the systematic literature review identified another 52 datasets informing on 16 variables. Both analyses consistently revealed the association of male gender with ocular involvement (RR 1.28 and 1.34 from the ABD registry and meta-analysis, respectively), folliculitis (RR 1.30 and 1.26), papulopustular lesions (RR 1.23 and 1.25), vascular involvement (RR 2.31 and 2.27), superficial (RR 2.96 and 1.63) and deep venous thromboses (RR 2.56 and 2.16) and female gender with genital ulcers (RR 0.78 and 0.92) and joint involvement (RR 0.79 and 0.89). The ABD registry data additionally showed male gender associated with heart involvement (RR 10.60), whereas the meta-analyses revealed male gender associated with the pathergy test (RR 1.14) and female gender associated with erythema nodosum (RR 0.86). HLA-B5 and Turkish or German origin did not affect the observed associations.Conclusion. These analyses support gender-associated clinical variations in ABD and in particular a clinically meaningful risk of cardiovascular involvement for men. [ABSTRACT FROM PUBLISHER]

Simulation studies provide an important statistical tool in evaluating survival methods, requiring an appropriate data-generating process to simulate data for an underlying statistical model. Many studies with time-to-event outcomes use the Cox proportional hazard model. While methods for simulating such data with time-invariant predictors have been described, methods for simulating data with time-varying covariates are sorely needed. Here, we describe an approach for generating data for the Cox proportional hazard model with time-varying covariates when event times follow an Exponential or Weibull distribution. For each distribution, we derive a closed-form expression to generate survival times and link the time-varying covariates with the hazard function. We consider a continuous time-varying covariate measured at regular intervals over time, as well as time-invariant covariates, in generating time-to-event data under a number of scenarios. Our results suggest this method can lead to simulation studies with reliable and robust estimation of the association parameter in Cox-Weibull and Cox-Exponential models. [ABSTRACT FROM AUTHOR]

Background: Back pain is the most common cause of disability worldwide. While disability generally is associated with greater mortality, the association between back pain and mortality is unclear. Our objective was to examine whether back pain is associated with increased mortality risk and whether this association varies by age, sex, and back pain severity. Methods: A systematic search of published literature was conducted using PubMed, Web of Science, and Embase databases from inception through March 2019. We included English-language prospective cohort studies evaluating the association of back pain with all-cause mortality with follow-up periods >5 years. Three reviewers independently screened studies, abstracted data, and appraised risk of bias using the Quality in Prognosis Studies (QUIPS) tool. A random-effects meta-analysis estimated combined odds ratios (OR) and 95% confidence intervals (CI), using the most adjusted model from each study. Potential effect modification by a priori hypothesized factors (age, sex, and back pain severity) was evaluated with meta-regression and stratified estimates. Results: We identified eleven studies with 81,337 participants. Follow-up periods ranged from 5 to 23 years. The presence of any back pain, compared to none, was not associated with an increase in mortality (OR, 1.06; 95% CI, 0.97 to 1.16). However, back pain was associated with mortality in studies of women (OR, 1.22; 95% CI, 1.02 to 1.46) and among adults with more severe back pain (OR, 1.26; 95% CI, 1.14 to 1.40). Conclusion: Back pain was associated with a modest increase in all-cause mortality among women and those with more severe back pain. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence supporting the hypothesized environment–disability link. The objectives of this study were to (a) identify the prevalence of community mobility barriers and transportation facilitators and (b) examine whether barriers and facilitators were associated with disability among older adults with functional limitations. Methods. Four hundred and thirty-five participants aged 65+ years old with functional limitations were recruited from the Multicenter Osteoarthritis Study, a prospective study of community-dwelling adults with or at risk of developing symptomatic knee osteoarthritis. Presence of community barriers and facilitators was ascertained by the Home and Community Environment survey. Two domains of disability, (a) daily activity limitation (DAL) and (b) daily activity frequency (DAF), were assessed with the Late-Life Disability Instrument. Covariates included age, gender, education, race, comorbidity, body mass index, knee pain, and functional limitation. Multivariable logistic regression was used to examine adjusted associations of community factors with presence of DAL and DAF. Results. Approximately one third of the participants lived in a community with high mobility barriers and low transportation facilitators. High mobility barriers was associated with greater odds of DAL (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.2–3.1) after adjusting for covariates, and high transportation facilitators was associated with lower odds of DAL (OR = 0.5, 95% CI 0.3–0.8) but not with DAF in adjusted models. Conclusion. People with functional limitations who live in communities that were more restrictive felt more limited in doing daily activities but did not perform these daily activities any less frequently. [ABSTRACT FROM PUBLISHER]

The article examines the item selection and weighting in the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG). The BVAS/WG data from the Wegener's Granulomatosis Etanercept Trial and linear regression with generalized estimating equations were used. Calculated in the study were the scoring frequencies of the 34 predefined items an other items that were added by the clinicians. It suggests possibilities to improve the item selection and weighting of the BVAS/WG.

Job retention services are recommended for people with chronic diseases based on their high risk for work disability. This randomized trial tested the effectiveness of a job retention intervention in a sample of employed persons with rheumatic diseases at risk for work disability. One hundred and twenty-two experimental participants received the job retention intervention, and 120 controls received written materials. Employment status was assessed at 6-month intervals up to 48 months after enrollment. Main outcomes were time to job loss and satisfaction with the experimental and control interventions. The log-rank test was used to detect a difference between the groups in time to job loss. Between-group differences in satisfaction scores were analyzed using Wilcoxon tests. Job loss was delayed in experimental participants compared with controls, p = 0.03. Satisfaction scores for the job retention intervention were substantially higher than those for the written materials, p < 0.0001. Job retention intervention has the potential to reduce the high rates of chronic disease--associated job loss. [ABSTRACT FROM AUTHOR]

Background Self-management programs have been widely reported to help patients manage symptoms and contain utilization of health care resources for several chronic conditions, but to date no systematic review across multiple chronic diseases has been reported. We evaluated the efficacy of patient self-management educational programs for chronic diseases and critically reviewed their methodology. Methods We searched MEDLINE and HealthSTAR for the period January 1, 1964, through January 31, 1999, then hand searched the reference section of each article for other relevant publications. We included studies if a self-management education intervention for a chronic disease was reported, a concurrent control group was included, and clinical outcomes were evaluated. Two authors reviewed each study and extracted the data on clinical outcomes. Results We included 71 trials of self-management education. Trial methods varied substantially and were suboptimal. Diabetic patients involved with self-management education programs demonstrated reductions in glycosylated hemoglobin levels (summary effect size, 0.45; 95% confidence interval [CI], 0.17-0.74); diabetic patients had improvement in systolic blood pressure (summary effect size, 0.20; 95% CI, 0.01-0.39); and asthmatic patients experienced fewer attacks (log rate ratio, 0.59; 95% CI, 0.35-0.83). Although we found a trend toward a small benefit, arthritis self-management education programs were not associated with statistically significant effects. Evidence of publication bias existed. Conclusions Self-management education programs resulted in small to moderate effects for selected chronic diseases. In light of evidence of publication bias, further trials that adhere to a standard methodology would help clarify whether self-management education is worthwhile. [ABSTRACT FROM AUTHOR]

Many people with arthritis become work disabled, but little is known about (a) the types of work barriers they experience and (b) their use of job accommodations. Our objectives were to describe work barriers and use of accommodations and to examine factors associated with accommodation use in persons with arthritis at risk for work disability. Barrier assessment was conducted using the Work Experience Survey. Factors associated with accommodation use were analyzed by logistic regression. The overwhelming majority of the 121 participants (98%) reported having one or more barriers, and 68% reported 10 or more barriers; 38% used an accommodation. Greater functional limitations and self-efficacy for accommodation request were each associated with accommodation use. Even though these employed persons with arthritis faced multiple barriers at work, only a small number used any form of job accommodation. [ABSTRACT FROM AUTHOR]

Background: Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. More importantly, time-dependent survival models that include the raw longitudinal measurements may lead to biased results. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for the longitudinal data and a survival model is applied to the event outcome.Methods: In this paper we compare joint maximum likelihood methods, a two-step approach and a time dependent covariate method that link longitudinal data to survival data with emphasis on using longitudinal measures to predict survival. We apply a Bayesian semi-parametric joint method and maximum likelihood joint method that maximizes the joint likelihood of the time-to-event and longitudinal measures. We also implement the Two-Step approach, which estimates random effects separately, and a classic Time Dependent Covariate Model. We use simulation studies to assess bias, accuracy, and coverage probabilities for the estimates of the link parameter that connects the longitudinal measures to survival times.Results: Simulation results demonstrate that the Two-Step approach performed best at estimating the link parameter when variability in the longitudinal measure is low but is somewhat biased downwards when the variability is high. Bayesian semi-parametric and maximum likelihood joint methods yield higher link parameter estimates with low and high variability in the longitudinal measure. The Time Dependent Covariate method resulted in consistent underestimation of the link parameter. We illustrate these methods using data from the Framingham Heart Study in which lipid measurements and Myocardial Infarction data were collected over a period of 26 years.Conclusions: Traditional methods for modeling longitudinal and survival data, such as the time dependent covariate method, that use the observed longitudinal data, tend to provide downwardly biased estimates. The two-step approach and joint models provide better estimates, although a comparison of these methods may depend on the underlying residual variance. [ABSTRACT FROM AUTHOR]

The Theil-Sen estimator of the slope parameter in simple linear regression is extended to data with both the response and the covariate subject to censoring. Based on inverting a suitable version of Kendall's r statistic, this estimator requires weak assumptions and is simple to compute, and a simple estimate of its asymptotic variance is obtained. A second extension of the Theil-Sen estimator, based on a direct estimation of the median of pairwise slopes, is given. These estimators are compared numerically with versions of Schmitt's estimator and applied to two data sets from the recent astronomical literature. [ABSTRACT FROM AUTHOR]

Background: Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a "connected behavioral approach" that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology.Methods/design: The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity.Discussion: We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018.Trial Registration: ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original. [ABSTRACT FROM AUTHOR]

Estimating the precision of a single proportion via a 100(1-α)% confidence interval in the presence of clustered data is an important statistical problem. It is necessary to account for possible over-dispersion, for instance, in animal-based teratology studies with within-litter correlation, epidemiological studies that involve clustered sampling, and clinical trial designs with multiple measurements per subject. Several asymptotic confidence interval methods have been developed, which have been found to have inadequate coverage of the true proportion for small-to-moderate sample sizes. In addition, many of the best-performing of these intervals have not been directly compared with regard to the operational characteristics of coverage probability and empirical length. This study uses Monte Carlo simulations to calculate coverage probabilities and empirical lengths of five existing confidence intervals for clustered data across various true correlations, true probabilities of interest, and sample sizes. In addition, we introduce a new score-based confidence interval method, which we find to have better coverage than existing intervals for small sample sizes under a wide range of scenarios. [ABSTRACT FROM AUTHOR]

In observational studies with censored data, exposure-outcome associations are commonly measured with adjusted hazard ratios from multivariable Cox proportional hazards models. The difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. We derive the adjusted RMST by integrating an adjusted Kaplan-Meier estimator with inverse probability weighting (IPW). The adjusted difference in RMSTs is the area between the two IPW-adjusted survival functions. In a Monte Carlo-type simulation study, we demonstrate that the proposed estimator performs as well as two regression-based approaches: the ANCOVA-type method of Tian et al and the pseudo-observation method of Andersen et al. We illustrate the methods by reexamining the association between total cholesterol and the 10-year risk of coronary heart disease in the Framingham Heart Study. [ABSTRACT FROM AUTHOR]

Background. Surveys of Behcet's disease (BD) have shown substantial geographic variations in prevalence, but some of these differences may result from methodological inconsistencies. This meta-analysis explored the effect of geographic location and study methodology on the prevalence of BD. Methods. We systematically searched the literature in electronic databases and by handsearching to identify population-based prevalence surveys of BD. Studies were eligible if they provided an original population-based prevalence estimate for BD with the number of prevalent cases identified in the study area. Pooled prevalence proportions across all studies were computed by using random effects models based on a Poisson normal distribution. Pre-defined subgroup analyses and meta-regression were used to investigate the effect of covariates on the prevalence proportions. Results. We included 45 reports published from 1974 to 2015 and covering worldwide areas. The pooled estimates of prevalence proportions (expressed as cases/100 000 inhabitants) were 10.3 (95% CI 6.1, 17.7) for all studies and 119.8 (59.8, 239.9) for Turkey, 31.8 (12.9, 78.4) for the Middle East, 4.5 (2.2, 9.4) for Asia and 3.3 (2.1, 5.2) for Europe. Subgroup analyses showed a strikingly greater prevalence for studies with a sample survey design than a census design [82.5 (95% CI 47.3, 143.9) vs 3.6 (2.6, 5.1)]. Metaregression identified study design as an independent covariate significantly affecting BD prevalence proportions. Conclusions. Differences in BD prevalence proportions likely reflect a combination of true geographic variation and methodological artefacts. In particular, use of a sample or census study design may strongly affect the estimated prevalence. [ABSTRACT FROM AUTHOR]

Purpose: Clinicians often test laryngeal sensation by touching the laryngeal mucosa with the tip of a flexible laryngoscope. However, the pressure applied to the larynx by using this touch method is unknown, and the expected responses elicited by this method are uncertain. The variability in pressure delivered by clinicians using the touch method was investigated, and the subject responses to the touches were also reported. Methods: A fiberoptic pressure sensor passed through the working channel of a laryngoscope, with its tip positioned at the distal port of the channel. Two examiners each tested 8 healthy adults. Each examiner touched the mucosa covering the left arytenoid 3 times. The sensor recorded the pressure exerted by each touch. An investigator noted subject responses to the touches. From the recorded videos, the absence or presence of the laryngeal adductor reflex in response to touch was judged. Results: Pressure values obtained for 46 of the 48 possible samples ranged from 17.9 mmHg to the measurement ceiling of 350.0 mmHg. The most frequently observed response was positive subject report followed by the laryngeal adductor reflex. Conclusion: Pressure applied to the larynx by using the touch method was highly variable, indicating potential diagnostic inaccuracy in determining laryngeal sensory function. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether drinking thin liquids with safety strategies increases the risk for pneumonia as compared with thickened liquids in patients who have demonstrated aspiration of thin liquids. Data sources: Seven electronic databases, one clinical register, and three conference archives were searched. No language or publication date restrictions were imposed. Reference lists were scanned and authors and experts in the field were contacted. Review methods: A blind review was performed by two reviewers for published or unpublished randomized controlled trials and prospective non-randomized trials comparing the incidence of pneumonia with intake of thin liquids plus safety strategies vs. thickened liquids in adult patients who aspirated on thin liquids. The data were extracted from included studies. Odds ratios (OR) for pneumonia were calculated from the extracted data. Risk of bias was also assessed with the included published trials. Results: Seven studies out of 2465 studies including 650 patients met the inclusion criteria. All of the seven studies excluded patients with more than one known risk factor for pneumonia. Six studies compared thin water protocols to thickened liquids for pneumonia prevention. A meta-analysis was done on the six studies, showing no significant difference for pneumonia risk (OR = 0.82; 95% CI = 0.05–13.42; p = 0.89). Conclusions: There was no significant difference in the risk of pneumonia in aspirating patients who took thin liquids with safety strategies compared with those who took thickened liquids only. This result, however, is generalizable only for patients with low risk of pneumonia. [ABSTRACT FROM AUTHOR]

Importance: Synovitis is common and is associated with progression of structural characteristics of knee osteoarthritis. Intra-articular corticosteroids could reduce cartilage damage associated with synovitis but might have adverse effects on cartilage and periarticular bone.Objective: To determine the effects of intra-articular injection of 40 mg of triamcinolone acetonide every 3 months on progression of cartilage loss and knee pain.Design, Setting, and Participants: Two-year, randomized, placebo-controlled, double-blind trial of intra-articular triamcinolone vs saline for symptomatic knee osteoarthritis with ultrasonic features of synovitis in 140 patients. Mixed-effects regression models with a random intercept were used to analyze the longitudinal repeated outcome measures. Patients fulfilling the American College of Rheumatology criteria for symptomatic knee osteoarthritis, Kellgren-Lawrence grades 2 or 3, were enrolled at Tufts Medical Center beginning February 11, 2013; all patients completed the study by January 1, 2015.Interventions: Intra-articular triamcinolone (n = 70) or saline (n = 70) every 12 weeks for 2 years.Main Outcomes and Measures: Annual knee magnetic resonance imaging for quantitative evaluation of cartilage volume (minimal clinically important difference not yet defined), and Western Ontario and McMaster Universities Osteoarthritis index collected every 3 months (Likert pain subscale range, 0 [no pain] to 20 [extreme pain]; minimal clinically important improvement, 3.94).Results: Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of -0.21 mm vs -0.10 mm (between-group difference, -0.11 mm; 95% CI, -0.20 to -0.03 mm); and no significant difference in pain (-1.2 vs -1.9; between-group difference, -0.6; 95% CI, -1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels (between-group difference, -0.2%; 95% CI, -0.5% to -0.007%).Conclusions and Relevance: Among patients with symptomatic knee osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline, resulted in significantly greater cartilage volume loss and no significant difference in knee pain. These findings do not support this treatment for patients with symptomatic knee osteoarthritis.Trial Registration: ClinicalTrials.gov Identifier: NCT01230424. [ABSTRACT FROM AUTHOR]

Background: Typical survival studies follow individuals to an event and measure explanatory variables for that event, sometimes repeatedly over the course of follow up. The Cox regression model has been used widely in the analyses of time to diagnosis or death from disease. The associations between the survival outcome and time dependent measures may be biased unless they are modeled appropriately. Methods: In this paper we explore the Time Dependent Cox Regression Model (TDCM), which quantifies the effect of repeated measures of covariates in the analysis of time to event data. This model is commonly used in biomedical research but sometimes does not explicitly adjust for the times at which time dependent explanatory variables are measured. This approach can yield different estimates of association compared to a model that adjusts for these times. In order to address the question of how different these estimates are from a statistical perspective, we compare the TDCM to Pooled Logistic Regression (PLR) and Cross Sectional Pooling (CSP), considering models that adjust and do not adjust for time in PLR and CSP. Results: In a series of simulations we found that time adjusted CSP provided identical results to the TDCM while the PLR showed larger parameter estimates compared to the time adjusted CSP and the TDCM in scenarios with high event rates. We also observed upwardly biased estimates in the unadjusted CSP and unadjusted PLR methods. The time adjusted PLR had a positive bias in the time dependent Age effect with reduced bias when the event rate is low. The PLR methods showed a negative bias in the Sex effect, a subject level covariate, when compared to the other methods. The Cox models yielded reliable estimates for the Sex effect in all scenarios considered. Conclusions: We conclude that survival analyses that explicitly account in the statistical model for the times at which time dependent covariates are measured provide more reliable estimates compared to unadjusted analyses. We present results from the Framingham Heart Study in which lipid measurements and myocardial infarction data events were collected over a period of 26 years. [ABSTRACT FROM AUTHOR]

Background: Experimental studies suggest that visceral adiposity and adipose tissue dysfunction play a central role in obesity-related cardiometabolic complications. Impaired angiogenesis in fat has been implicated in the development of adipose tissue hypoxia, capillary rarefaction, inflammation, and metabolic dysregulation, but pathophysiological mechanisms remain unknown. In this study, we examined the role of a novel antiangiogenic isoform of vascular endothelial growth factor-A (VEGF-A), VEGF-A165b, in human obesity.Methods and Results: We biopsied paired subcutaneous and visceral adipose tissue in 40 obese subjects (body mass index, 45±8 kg/m(2); age, 45±11 years) during bariatric surgery and characterized depot-specific adipose tissue angiogenic capacity using an established ex vivo assay. Visceral adipose tissue exhibited significantly blunted angiogenic growth compared with subcutaneous fat (P<0.001) that was associated with marked tissue upregulation of VEGF-A165b (P=0.004). The extent of VEGF-A165b expression correlated negatively with angiogenic growth (r=-0.6, P=0.006). Although recombinant VEGF-A165b significantly impaired angiogenesis, targeted inhibition of VEGF-A165b with neutralizing antibody stimulated fat pad neovascularization and restored VEGF receptor activation. Blood levels of VEGF-A165b were significantly higher in obese subjects compared with lean control subjects (P=0.02), and surgical weight loss induced a marked decline in serumVEGF-A165b (P=0.003).Conclusions: We demonstrate that impaired adipose tissue angiogenesis is associated with overexpression of a novel antiangiogenic factor, VEGF-A165b, that may play a pathogenic role in human adiposopathy. Moreover, systemic upregulation of VEGF-A165b in circulating blood may have wider-ranging implications beyond the adipose milieu. VEGF-A165b may represent a novel area of investigation to gain further understanding of mechanisms that modulate the cardiometabolic consequences of obesity. [ABSTRACT FROM AUTHOR]