Vascular function and skeletal fragility: A study of tonometry, brachial hemodynamics, and bone microarchitecture.

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore, we assessed the association of vascular function, measured by tonometry and brachial hemodynamic testing, with bone density, microarchitecture, and strength, measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in 1391 individuals in the Framingham Heart Study. We hypothesized that decreased vascular function (pulse wave velocity, primary pressure wave, brachial pulse pressure, baseline flow amplitude and brachial flow velocity) contributes to deficits in bone density, microarchitecture and strength, particularly in cortical bone, which is less protected from excessive blood flow pulsatility than the trabecular compartment. We found that individuals with increased carotid-femoral pulse wave velocity had lower cortical volumetric bone mineral density (tibia: -0.21 [-0.26,-0.15] standardized beta [95% confidence interval], radius: -0.20 [-0.26,-0.15]), lower cortical thickness (tibia: -0.09 [-0.15,-0.04], radius: -0.07 [-0.12,-0.01]) and increased cortical porosity (tibia: 0.20 [0.15,0.25], radius: 0.21 [0.15,0.27]). However, these associations did not persist after adjustment for age, sex, height, and weight. These results suggest that vascular dysfunction with aging may not be an etiologic mechanism that contributes to the co-occurrence of osteoporosis and cardiovascular disease in older adults. Further study employing longitudinal measures of HR-pQCT parameters is needed to fully elucidate the link between vascular function and bone health.

Osteoporosis and heart disease are both medical conditions that commonly develop in older age. It is not known whether abnormal functioning of blood vessels contributes to the development of bone fragility with aging. In this study, we investigated the relationship between impaired blood vessel function and bone density and micro-structure in a group of 1391 people enrolled in the Framingham Heart Study. Blood vessel function was measured using specialized tools to assess blood flow and pressure. Bone density and micro-structure were measured using advanced imaging called high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that people with impaired blood vessel function tended to have lower bone density and worse deterioration in bone micro-structure. However, once we statistically controlled for age and sex and other confounders, we did not find any association between blood vessel function and bone measures. Overall, our results showed that older adults with impaired blood vessel function do not exhibit greater deterioration in the skeleton.

Estimating glucocorticoid-related morbidity in lupus nephritis using the glucocorticoid toxicity index.

OBJECTIVE: Lupus nephritis (LN) is often treated with high doses of glucocorticoids (GCs). The glucocorticoid toxicity index (GTI) was developed by expert consensus to quantify GC toxicity. To date, the GTI has not been shown to correlate with GC exposure in patients with LN. METHODS: We performed a retrospective cohort study of patients with biopsy-confirmed LN between 2006 and 2016. Cumulative GC exposure and GTI scores were determined via medical record review. Both the aggregate improvement score (GTI-AIS) and the cumulative worsening score (GTI-CWS) were calculated. We performed linear regression to determine the association between GC exposure and GTI scores at 1 year and 5 years following kidney biopsy. RESULTS: This study included 49 patients with a mean age of 33.3 (SD 9.5) years. Mean GC exposure was 23.0 mg prednisone-equivalents per day through year 1 and 9.9 mg prednisone-equivalents per day through year 5. At 5 years, higher GC exposure was associated with higher GTI-AIS (p < 0.001) and GTI-CWS (p = 0.002), and this association persisted in multivariate analysis adjusting for age, sex, race, induction medication, and nephritis class (p = 0.026 for AIS, p = 0.012 for CWS). At 1 year, GC exposure was not associated with GTI scores (p = 0.70 for AIS; p = 0.58 for CWS). CONCLUSION: In this cohort study, the GTI was associated with cumulative steroid exposure at 5 years after diagnosis. In patients with LN, the GTI may serve as a useful outcome measure in future LN trials evaluating the steroid sparing effect of novel therapies.

Financial Incentives and Health Coaching to Improve Physical Activity Following Total Knee Replacement: A Randomized Controlled Trial.

OBJECTIVE: Most persons who undergo total knee replacement (TKR) do not increase their physical activity following surgery. We assessed whether financial incentives and health coaching would improve physical activity in persons undergoing TKR. METHODS: We designed a factorial randomized controlled trial among persons undergoing TKR for osteoarthritis. Subjects underwent normal perioperative procedures, including postoperative physical therapy, and were assigned to 1 of 4 arms: attention control, telephonic health coaching (THC), financial incentives (FI), or THC + FI. We objectively measured step counts and minutes of physical activity using a commercial accelerometer (Fitbit Zip) and compared the changes from pre-TKR to 6 months post-TKR across the 4 study arms. RESULTS: Of the 202 randomized subjects, 150 (74%) provided both pre-TKR and 6 months post-TKR accelerometer data. Among completers, the mean ± SE daily step count at 6 months ranged from 5,619 ± 381 in the THC arm to 7,152 ± 407 in the THC + FI arm (adjusting for baseline values). Daily step count 6 months post-TKR increased by 680 (95% confidence interval [95% CI] -94, 1,454) in the control arm, 274 (95% CI -473, 1,021) in the THC arm, 826 (95% CI 89, 1,563) in the FI arm, and 1,808 (95% CI 1,010, 2,606) in the THC + FI arm. Weekly physical activity increased by mean ± SE 14 ± 10, 14 ± 10, 16 ± 10, and 39 ± 11 minutes in the control, THC, FI, and THC + FI arms, respectively. CONCLUSION: A dual THC + FI intervention led to substantial improvements in step count and physical activity following TKR.

Implementation of a workplace intervention using financial rewards to promote adherence to physical activity guidelines: a feasibility study.

BACKGROUND: We designed and implemented the Brigham and Women's Wellness Initiative (B-Well), a single-arm study to examine the feasibility of a workplace program that used individual and team-based financial incentives to increase physical activity among sedentary hospital employees. METHODS: We enrolled sedentary, non-clinician employees of a tertiary medical center who self-reported low physical activity. Eligible participants formed or joined teams of three members and wore Fitbit Flex activity monitors for two pre-intervention weeks followed by 24 weeks during which they could earn monetary rewards. Participants were rewarded for increasing their moderate-to-vigorous physical activity (MVPA) by 10% from the previous week or for meeting the Centers for Disease Control and Prevention (CDC) physical activity guidelines (150 min of MVPA per week). Our primary outcome was the proportion of participants meeting weekly MVPA goals and CDC physical activity guidelines. Secondary outcomes included Fitbit-wear adherence and factors associated with meeting CDC guidelines more consistently. RESULTS: B-Well included 292 hospital employees. Participants had a mean age of 38 years (SD 11), 83% were female, 38% were obese, and 62% were non-Hispanic White. Sixty-three percent of participants wore the Fitbit ≥4 days per week for ≥20 weeks. Two-thirds were satisfied with the B-Well program, with 79% indicating that they would participate again. Eighty-six percent met either their personal weekly goal or CDC physical activity guidelines for at least 6 out of 24 weeks, and 52% met their goals or CDC physical activity guidelines for at least 12 weeks. African Americans, non-obese subjects, and those with lower impulsivity scores reached CDC guidelines more consistently. CONCLUSIONS: Our data suggest that a financial incentives-based workplace wellness program can increase MVPA among sedentary employees. These results should be reproduced in a randomized controlled trial. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02850094 . Registered July 27, 2016 [retrospectively registered].

Effect of Obesity on Pain and Functional Recovery Following Total Knee Arthroplasty.

BACKGROUND: While obesity may be a risk factor for complications following total knee arthroplasty, data remain sparse on the impact of the degree of obesity on patient-reported outcomes following this procedure. Our objective was to determine the extent to which obesity level affects the trajectory of recovery as well as patient-reported pain, function, and satisfaction with surgery following total knee arthroplasty. METHODS: We followed a cohort of patients who underwent total knee arthroplasty at 1 of 4 medical centers. Patients were ≥40 years of age with a primary diagnosis of osteoarthritis. We stratified patients into 5 groups according to the World Health Organization classification of body mass index (BMI). We assessed the association between BMI group and pain and function over the time intervals of 0 to 3, 3 to 6, and 6 to 24 months using a piecewise linear model. We also assessed the association between BMI group and patient-reported outcomes at 24 months. Multivariable models adjusted for age, sex, race, diabetes, musculoskeletal functional limitations index, pain medication use, and study site. RESULTS: Of the 633 participants included in our analysis, 19% were normal weight (BMI of <25 kg/m), 32% were overweight (BMI of 25 to 29.9 kg/m), 27% were class-I obese (BMI of 30 to 34.9 kg/m), 12% were class-II obese (BMI of 35 to 39.9 kg/m), and 9% were class-III obese (BMI of ≥40 kg/m). Study participants with a higher BMI had worse preoperative WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain and function scores and had greater improvement from baseline to 3 months. The mean change in pain and function from 3 to 6 and from 6 to 24 months was similar across all BMI groups. At 24 months, participants in all BMI groups had similar levels of pain, function, and satisfaction. CONCLUSIONS: Because of the differential trajectory of recovery in the first 3 months following total knee arthroplasty, the participants in the higher BMI groups were able to attain absolute pain and function scores similar to those in the nonobese and class-I obese groups. These data can help surgeons discuss expectations of pain relief and functional improvement with total knee arthroplasty candidates with higher BMI. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The quality-of-life burden of knee osteoarthritis in New Zealand adults: A model-based evaluation.

BACKGROUND: Knee osteoarthritis is a leading global cause of health-related quality of life loss. The aim of this project was to quantify health losses arising from knee osteoarthritis in New Zealand (NZ) in terms of quality-adjusted life years (QALYs) lost. METHODS: The Osteoarthritis Policy Model (OAPol), a validated Monte Carlo computer simulation model, was used to estimate QALYs lost due to knee osteoarthritis in the NZ adult population aged 40-84 over their lifetimes from the base year of 2006 until death. Data were from the NZ Health Survey, NZ Burden of Diseases, NZ Census, and relevant literature. QALYs were derived from NZ EQ-5D value set 2. Sensitivity to health state valuation, disease and pain prevalence were assessed in secondary analyses. RESULTS: Based on NZ EQ-5D health state valuations, mean health losses due to knee osteoarthritis over people's lifetimes in NZ are 3.44 QALYs per person, corresponding to 467,240 QALYs across the adult population. Average estimated per person QALY losses are higher for non-Maori females (3.55) than Maori females (3.38), and higher for non-Maori males (3.34) than Maori males (2.60). The proportion of QALYs lost out of the total quality-adjusted life expectancy for those without knee osteoarthritis is similar across all subgroups, ranging from 20 to 23 percent. CONCLUSIONS: At both the individual and population levels, knee osteoarthritis is responsible for large lifetime QALY losses. QALY losses are higher for females than males due to greater prevalence of knee osteoarthritis and higher life expectancy, and lower for Maori than non-Maori due to lower life expectancy. Large health gains are potentially realisable from public health and policy measures aimed at decreasing incidence, progression, pain, and disability of osteoarthritis.

Association between activity limitations and pain in patients scheduled for total knee arthroplasty.

BACKGROUND: Historically, persons scheduled for total knee arthroplasty (TKA) have reported severe pain with low demand activities such as walking, but recent data suggests that TKA recipients may have less preoperative pain. Little is known about people who elect TKA with low levels of preoperative pain. To better understand current TKA utilization, we evaluated the association between preoperative pain and difficulty performing high demand activities, such as kneeling and squatting, among TKA recipients. METHODS: We used baseline data from a randomized control trial designed to improve physical activity following TKA. Prior to TKA, participants were categorized according to Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain scores: Low (0-25), Medium (26-40), and High (41-100). Within each group, limitations in both low demand and high demand activities were assessed. RESULTS: The sample consisted of 202 persons with a mean age of 65 (SD 8) years; 21 %, 34 %, and 45 % were categorized in the Low, Medium, and High Pain groups, respectively. Of the Low Pain group, 60 % reported at least one of the following functional limitations: limited flexion, limp, limited walking distance, and limitations in work or housework. While only 12 % of the Low Pain group reported at least moderate pain with walking on a flat surface, nearly all endorsed at least moderate difficulty with squatting and kneeling. CONCLUSIONS: A substantial number of persons scheduled for TKA report Low WOMAC Pain (≤25) prior to surgery. Persons with Low WOMAC Pain scheduled for TKA frequently report substantial difficulty with high demand activities such as kneeling and squatting. Studies of TKA appropriateness and effectiveness for patients with low WOMAC Pain should include measures of these activities. TRIAL REGISTRATION: Identifier NCT01970631 ; Registered 23 October 2013.

Configuration-dependent Presentation of Multivalent IL-15:IL-15Rα Enhances the Antigen-specific T Cell Response and Anti-tumor Immunity.

Here we report a "configuration-dependent" mechanism of action for IL-15:IL-15Rα (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15:IL-15Rα molecules are presented to target cells significantly affects its function as a vaccine adjuvant. Although the cellular mechanism of IL-15 trans-presentation via IL-15Rα and its importance for IL-15 function have been described, the full effect of the IL-15:IL-15Rα configuration on responding cells is not yet known. We found that trans-presenting IL-15:IL-15Rα in a multivalent fashion on the surface of antigen-encapsulating nanoparticles enhanced the ability of nanoparticle-treated dendritic cells (DCs) to stimulate antigen-specific CD8(+) T cell responses. Localization of multivalent IL-15:IL-15Rα and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15:IL-15Rα-coated nanoparticles displayed higher levels of functional IL-15 on the cell surface, implicating a mechanism for nanoparticle-mediated transfer of IL-15 to the DC surface. Using artificial antigen-presenting cells to highlight the effect of IL-15 configuration on DCs, we showed that artificial antigen-presenting cells presenting IL-15:IL-15Rα increased the sensitivity and magnitude of the T cell response, whereas IL-2 enhanced the T cell response only when delivered in a paracrine fashion. Therefore, the mode of cytokine presentation (configuration) is important for optimal immune responses. We tested the effect of configuration dependence in an aggressive model of murine melanoma and demonstrated significantly delayed tumor progression induced by IL-15:IL-15Rα-coated nanoparticles in comparison with monovalent IL-15:IL-15Rα. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15:IL-15Rα-coated nanoparticles for antigen delivery.

Postoperative Care Navigation for Total Knee Arthroplasty Patients: A Randomized Controlled Trial.

OBJECTIVE: To establish the efficacy of motivational interviewing-based postoperative care navigation in improving functional status after total knee arthroplasty (TKA) and to identify subgroups likely to benefit from the intervention. METHODS: We conducted a parallel randomized controlled trial in TKA recipients with 2 arms: postoperative care with frequent followup by a care navigator or usual care. The primary outcome was the difference between the arms in Western Ontario and McMaster Universities Osteoarthritis Index function score change, over 6 months postsurgery. We performed a preplanned subgroup analysis of differential efficacy by obesity and exploratory subgroup analyses on sex and pain catastrophizing. RESULTS: We enrolled 308 subjects undergoing TKA for osteoarthritis. Mean ± SD preoperative function score was 41 ± 17 (0-100 scale, where 100 = worst function). At 6 months, subjects in the navigation arm improved by mean ± SD 30 ± 16 points compared to 27 ± 18 points in the usual-care arm (P = 0.148). Participants with moderate to high levels of pain catastrophizing were unlikely to benefit from navigation compared to those with lower levels of pain catastrophizing (P = 0.013 for interaction). CONCLUSION: Subjects assigned to the navigation intervention did not demonstrate greater functional improvement compared to those in the control group. The negative overall result could be explained by the large effect on functional improvement of TKA itself compared to the smaller, additional benefit from care navigation, as well as by potential differential effects for subjects with moderate to high degrees of pain catastrophizing. Greater focus on developing programs for reducing pain catastrophizing could lead to better functional outcomes following TKA.