Role of Left Ventricular Dysfunction in Systemic Sclerosis-Related Pulmonary Hypertension.

BACKGROUND: 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. RESEARCH QUESTION: 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? STUDY DESIGN AND METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

A Clinical Decision Tool for Risk Stratifying Patients with Systemic Sclerosis-Related Pulmonary Hypertension.

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.

Hip Abductor Weakness and Its Association With New or Worsened Knee Pain: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: Hip abductors, important for controlling pelvic and femoral orientation during gait, may affect knee pain. Our objective was to evaluate the relation of hip abductor strength to worsened or new-onset frequent knee pain. Given previously noted associations of knee extensor strength with osteoarthritis in women, we performed sex-specific analyses. METHODS: We used data from the Multicenter Osteoarthritis study. Hip abductor and knee extensor strength was measured. Knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire and a question about frequent knee pain at baseline (144-month visit), and 8, 16, and 24 months thereafter. Knee pain outcomes were worsened knee pain (2-point increase in WOMAC pain) and incident frequent knee pain (answering yes to the frequent knee pain question among those without frequent knee pain at baseline). Leg-specific analyses tested hip abductor strength as a risk factor for worsened and new frequent knee pain, adjusting for potential covariates. Additionally, we stratified by knee extensor strength (high versus low). RESULTS: Among women, compared to the highest quartile of hip abductor strength, the lowest quartile had 1.7 (95% confidence interval [95% CI] 1.1-2.6) times the odds of worsened knee pain; significant associations were limited to women with high knee extensor strength (odds ratio 2.0 [95% CI 1.1-3.5]). We found no relation of abductor strength to worsening knee pain in men or with incident frequent knee pain in men or women. CONCLUSION: Hip abductor weakness was associated with worsening knee pain in women with strong knee extensors, but not with incident frequent knee pain in men or women. Knee extensor strength may be necessary, but not sufficient, to prevent pain worsening.

Natural Walking Intensity in Persons With Parkinson Disease.

BACKGROUND AND PURPOSE: Few persons with Parkinson disease (PD) appear to engage in moderate-intensity walking associated with disease-modifying health benefits. How much time is spent walking at lower, yet still potentially beneficial, intensities is poorly understood. The purpose of this exploratory, observational study was to describe natural walking intensity in ambulatory persons with PD. METHODS: Accelerometer-derived real-world walking data were collected for more than 7 days at baseline from 82 participants enrolled in a PD clinical trial. Walking intensity was defined according to the number of steps in each active minute (1-19, 20-39, 40-59, 60-79, 80-99, or ≥100 steps). Daily minutes of walking and duration of the longest sustained walking bout were calculated at each intensity. Number of sustained 10 to 19, 20 to 29, and 30-minute bouts and greater at any intensity also were calculated. Values were analyzed in the context of physical activity guidelines. RESULTS: Most daily walking occurred at lower intensities (157.3 ± 58.1 min of 1-19 steps; 81.3 ± 32.6 min of 20-39 steps; 38.2 ± 21.3 min of 40-59 steps; 15.1 ± 11.5 min of 60-79 steps; 7.4 ± 7.0 min of 80-99 steps; 7.3 ± 9.6 min of ≥100 steps). The longest daily sustained walking bout occurred at the lowest intensity level (15.9 ± 5.2 min of 1-19 steps). Few bouts lasting 20 minutes and greater occurred at any intensity. DISCUSSION AND CONCLUSIONS: Despite relatively high daily step counts, participants tended to walk at remarkably low intensity, in bouts of generally short duration, with relatively few instances of sustained walking. The findings reinforced the need for health promotion interventions designed specifically to increase walking intensity.Video Abstract available for more insight from authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A426 ).

Reliability of Wearable Sensors for Assessing Gait and Chair Stand Function at Home in People With Knee Osteoarthritis.

OBJECTIVE: To assess the reliability of wearable sensors for at-home assessment of walking and chair stand activities in people with knee osteoarthritis (OA). METHODS: Baseline data from participants with knee OA (n = 20) enrolled in a clinical trial of an exercise intervention were used. Participants completed an in-person laboratory visit and a video conference-enabled at-home visit. In both visits, participants performed walking and chair stand tasks while fitted with 3 inertial sensors. During the at-home visit, participants self-donned the sensors and completed 2 sets of acquisitions separated by a 15-minute break, when they removed and redonned the sensors. Participants completed a survey on their experience with the at-home visit. During the laboratory visit, researchers placed the sensors on the participants. Spatiotemporal metrics of walking gait and chair stand duration were extracted from the sensor data. We used intraclass correlation coefficients (ICCs) and the Bland-Altman plot for statistical analyses. RESULTS: For test-retest reliability during the at-home visit, all ICCs were good to excellent (0.85-0.95). For agreement between at-home and laboratory visits, ICCs were moderate to good (0.59-0.87). Systematic differences were noted between at-home and laboratory data due to faster task speed during the laboratory visits. Participants reported a favorable experience during the at-home visit. CONCLUSION: Our method of estimating spatiotemporal gait measures and chair stand duration function remotely was reliable, feasible, and acceptable in people with knee OA. Wearable sensors could be used to remotely assess walking and chair stand in participant's natural environments in future studies.

Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

PURPOSE: Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. METHODS: We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization. RESULTS: Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). CONCLUSION: In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

Association of 18 F-Fluorodeoxyglucose-Positron Emission Tomography Activity With Angiographic Progression of Disease in Large Vessel Vasculitis.

OBJECTIVE: To assess whether vascular activity seen on 18 F-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.

A Multimodal Prediction Model for Diagnosing Pulmonary Hypertension in Systemic Sclerosis.

OBJECTIVE: Diagnosis of pulmonary hypertension (PH) in systemic sclerosis (SSc) requires an invasive right heart catheterization (RHC), often based on an elevated estimated pulmonary artery systolic pressure on screening echocardiography. However, because of the poor specificity of echocardiography, a greater number of patients undergo RHC than necessary, exposing patients to potentially avoidable complication risks. The development of improved prediction models for PH in SSc may inform decision-making for RHC in these patients. METHODS: We conducted a retrospective study of 130 patients with SSc; 66 (50.8%) were diagnosed with PH by RHC. We used data from pulmonary function testing, electrocardiography, echocardiography, and computed tomography to identify and compare the performance characteristics of 3 models predicting the presence of PH: 1) random forest, 2) classification and regression tree, and 3) logistic regression. For each model, we generated receiver operating curves and calculated sensitivity and specificity. We internally validated models using a train-test split of the data. RESULTS: The random forest model performed best with an area under the curve of 0.92 (95% confidence interval [95% CI] 0.83-1.00), sensitivity of 0.95 (95% CI 0.75-1.00), and specificity of 0.80 (95% CI 0.56-0.94). The 2 most important variables in our random forest model were pulmonary artery diameter on chest computed tomography and diffusing capacity for carbon monoxide on pulmonary function testing. CONCLUSIONS: In patients with SSc, a random forest model can aid in the detection of PH with high sensitivity and specificity and may allow for better patient selection for RHC, thereby minimizing patient risk.

Relation of Temporal Asymmetry During Walking to Two-Year Knee Pain Outcomes in Those With Mild-to-Moderate Unilateral Knee Pain: An Exploratory Analysis From the Multicenter Osteoarthritis Study.

OBJECTIVE: We aimed to explore the cross-sectional relation of unilateral knee pain severity and temporal asymmetry during walking and to determine relations of temporal asymmetry during walking to 2-year changes in ipsilateral and contralateral knee pain in those with mild-to-moderate unilateral knee pain. METHODS: The Multicenter Osteoarthritis Study is a prospective cohort study of adults with or at risk for knee osteoarthritis. The current study included participants with unilateral knee pain. Gait was assessed during self-selected and fast walking at baseline. Knee pain was assessed at baseline and 2 years. We calculated limb symmetry indices (LSIs; nonpainful limb/painful limb × 100) for stance, single-limb support time, and double-limb support time, then examined their relations to unilateral knee pain severity, incident contralateral knee pain, and persistent ipsilateral knee pain. RESULTS: Unilateral knee pain severity was not associated with temporal asymmetry during self-selected or fast walking. At 2 years, 17.1% of participants had incident contralateral knee pain and 51.4% had persistent ipsilateral knee pain. For self-selected walking, greater LSIs (i.e., longer time on the nonpainful limb) for stance and single-limb support time were associated with decreased odds of incident contralateral knee pain. Measures of temporal asymmetry were not associated with persistent ipsilateral knee pain, except for single-limb support time during fast walking. CONCLUSION: For those with unilateral knee pain, temporal asymmetry during walking is not associated with pain severity. However, select measures of stance and single-limb support time during self-selected and fast walking relate to longitudinal knee pain outcomes.

Clinical characteristics and outcomes in pulmonary manifestations of systemic sclerosis: Contribution from pulmonary hypertension and interstitial lung disease severity.

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 those with 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.

Prediction models for the risk of total knee replacement: development and validation using data from multicentre cohort studies.

Background: Few prognostic prediction models for total knee replacement are available, and the role of radiographic findings in predicting its use remains unclear. We aimed to develop and validate predictive models for total knee replacement and to assess whether adding radiographic findings improves predictive performance. Methods: We identified participants with recent knee pain (in the past 3 months) in the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI). The baseline visits of MOST were initiated in 2003 and of OAI were initiated in 2004. We developed two predictive models for the risk of total knee replacement within 60 months of follow-up by fitting Cox proportional hazard models among participants in MOST. The first model included sociodemographic and anthropometric factors, medical history, and clinical measures (referred to as the clinical model). The second model added radiographic findings into the predictive model (the radiographic model). We evaluated each model's discrimination and calibration performance and assessed the incremental value of radiographic findings using both category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We tuned the models and externally validated them among participants in OAI. Findings: We included 2658 participants from MOST (mean age 62·4 years [SD 8·1], 1646 [61·9%] women) in the training dataset and 4060 participants from OAI (mean age 60·9 years [9·1], 2379 [58·6%] women) in the validation dataset. 290 (10·9%) participants in the training dataset and 174 (4·3%) in the validation dataset had total knee replacement. The retained predictive variables included in the clinical model were age, sex, race, history of knee arthroscopy, frequent knee pain, current use of analgesics, current use of glucosamine, body-mass index, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, and the most predictive factors were age, race, and WOMAC pain score. The retained predictive variables in the radiographic model were age, sex, race, frequent knee pain, current use of analgesics, WOMAC pain score, and Kellgren-Lawrence grade, and the most predictive factors were Kellgren-Lawrence grade, race, and age. The C-statistic was 0·79 (95% CI 0·76-0·81) for the clinical model and 0·87 (0·85-0·99) for the radiographic model in the training dataset. The calibration slope was 0·95 (95% CI 0·86-1·05) and 0·96 (0·87-1·04), respectively. Adding radiograph findings significantly improved predictive performance with an NRI of 0·43 (95% CI 0·38-0·50) and IDI of 0·14 (95% CI: 0·10-0·18). Both models, with tuned coefficients, showed a good predictive performance among participants in the validation dataset. Interpretation: The risk of total knee replacement can be predicted based on common risk factors with good discrimination and calibration. Additionally, adding radiographic findings of knee osteoarthritis into the model substantially improves its predictive performance. Funding: National Natural Science Foundation of China, National Key Research and Development Program, and Beijing Municipal Science & Technology Commission.

Calculating power for the Finkelstein and Schoenfeld test statistic for a composite endpoint with two components.

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.

A comparison of statistical methods to predict the residual lifetime risk.

Lifetime risk measures the cumulative risk for developing a disease over one's lifespan. Modeling the lifetime risk must account for left truncation, the competing risk of death, and inference at a fixed age. In addition, statistical methods to predict the lifetime risk should account for covariate-outcome associations that change with age. In this paper, we review and compare statistical methods to predict the lifetime risk. We first consider a generalized linear model for the lifetime risk using pseudo-observations of the Aalen-Johansen estimator at a fixed age, allowing for left truncation. We also consider modeling the subdistribution hazard with Fine-Gray and Royston-Parmar flexible parametric models in left truncated data with time-covariate interactions, and using these models to predict lifetime risk. In simulation studies, we found the pseudo-observation approach had the least bias, particularly in settings with crossing or converging cumulative incidence curves. We illustrate our method by modeling the lifetime risk of atrial fibrillation in the Framingham Heart Study. We provide technical guidance to replicate all analyses in R.

One Pill, Once a Day: Simplified Treatment Regimens and Retention in HIV Care.

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.

Impact of COVID-19 Pandemic on Physical Activity, Pain, Mood, and Sleep in Adults with Knee Osteoarthritis.

Objective: To examine changes in physical activity, sleep, pain and mood in people with knee osteoarthritis (OA) during the ongoing COVID-19 pandemic by leveraging an ongoing randomized clinical trial (RCT). Methods: Participants enrolled in a 12-month parallel two-arm RCT (NCT03064139) interrupted by the COVID-19 pandemic wore an activity monitor (Fitbit Charge 3) and filled out custom weekly surveys rating knee pain, mood, and sleep as part of the study. Data from 30 weeks of the parent study were used for this analysis. Daily step count and sleep duration were extracted from activity monitor data, and participants self-reported knee pain, positive mood, and negative mood via surveys. Metrics were averaged within each participant and then across all participants for pre-pandemic, stay-at-home, and reopening periods, reflecting the phased re-opening in the state of Massachusetts. Results: Data from 28 participants showed small changes with inconclusive clinical significance during the stay-at-home and reopening periods compared to pre-pandemic for all outcomes. Summary statistics suggested substantial variability across participants with some participants showing persistent declines in physical activity during the observation period. Conclusion: Effects of the COVID-19 pandemic on physical activity, sleep, pain, and mood were variable across individuals with OA. Specific reasons for this variability could not be determined. Identifying factors that could affect individuals with knee OA who may exhibit reduced physical activity and/or worse symptoms during major lifestyle changes (such as the ongoing pandemic) is important for providing targeted healthcare services and management advice towards those that could benefit from it the most.