The primary analysis in a longitudinal randomized controlled trial is sometimes a comparison of arms at a single time point. While a two-sample t-test is often used, missing data are common in ...longitudinal studies and decreases power by reducing sample size. Mixed models for repeated measures (MMRM) can test treatment effects at specific time points, have been shown to give unbiased estimates in certain missing data contexts, and may be more powerful than a two sample t-test.
We conducted a simulation study to compare the performance of a complete-case t-test to a MMRM in terms of power and bias under different missing data mechanisms. Impact of within- and between-person variance, dropout mechanism, and variance-covariance structure were all considered.
While both complete-case t-test and MMRM provided unbiased estimation of treatment differences when data were missing completely at random, MMRM yielded an absolute power gain of up to 12 %. The MMRM provided up to 25 % absolute increased power over the t-test when data were missing at random, as well as unbiased estimation.
Investigators interested in single time point comparisons should use a MMRM with a contrast to gain power and unbiased estimation of treatment effects instead of a complete-case two sample t-test.
When conservative treatments do not work, TKA may be the best option for patients with knee osteoarthritis, although a relatively large proportion of individuals do not have clinically important ...improvement after TKA. Evidence also suggests that women are less likely to benefit from TKA than men, but the reasons are unclear. Widespread pain disproportionately affects women and has been associated with worse outcomes after joint arthroplasty, yet it is unknown if the effect of widespread pain on TKA outcomes differs by patient gender.
(1) Does the association between widespread pain and no clinically important improvement in osteoarthritis-related pain and disability 2 years after TKA differ between men and women? (2) Does the use of pain medications 2 years after TKA differ between those with widespread pain and those without widespread pain before surgery?
Osteoarthritis Initiative (https://nda.nih.gov/oai/) study participants were followed annually from March 2005 until October 2015. Participants who underwent TKA up to the 7-year follow-up visit with pain/disability assessment at the protocol-planned visit before TKA and at the second planned annual visit after surgery were included in the analysis. Among 4796 study participants, 391 had a confirmed TKA, including 315 with pain/disability assessment at the protocol-planned visit before TKA. Overall, 95% of participants (298) had the required follow-up assessment; 5% (17) did not have follow-up data. Widespread pain was defined based on the modified American College of Rheumatology criteria. Symptoms were assessed using the WOMAC pain (range 0 to 20; higher score, more pain) and disability (range 0 to 68; higher score, more disability) scores, and the Knee Injury and Osteoarthritis Outcome Score for pain (range 0 to 100; higher score, less pain). Improvements in pain and disability were classified based on improvement from established clinically important differences (decrease in WOMAC pain ≥ 1.5; decrease in WOMAC disability ≥ 6.0; increase in Knee Injury and Osteoarthritis Outcome Score for pain ≥ 9). At baseline, more women presented with widespread pain than men (45% 84 of 184 versus 32% 36 of 114). Probability and the relative risk (RR) of no clinically important improvement were estimated using a logistic regression analysis in which participants with widespread pain and those without were compared. The analyses were done for men and women separately, then adjusted for depression and baseline outcome scores.
Among women, preoperative widespread pain was associated with an increased risk of no clinically important improvement 2 years after TKA, based on WOMAC pain scores (13.5% versus 4.6%; RR 2.93 95% CI 1.18 to 7.30; p = 0.02) and the Knee Injury and Osteoarthritis Outcome Score for pain (16.5% versus 4.9%; RR 3.39 95% CI 1.34 to 8.59; p = 0.02). Given the lower and upper limits of the confidence intervals, our data are compatible with a broad range of disparate associations between widespread pain and lack of clinically important improvement in WOMAC pain scores (RR 0.77 95% CI 0.22 to 2.70; p = 0.68) and the Knee Injury and Osteoarthritis Outcome Score for pain (RR 1.37 95% CI 0.47 to 4.00; p = 0.57) among men, as well as clinically important improvement in WOMAC disability scores among men (RR 0.72 95% CI 0.20 to 2.55; p = 0.61) and women (RR 1.98 95% CI 0.92 to 4.26; p = 0.08). Participants presenting with widespread pain before TKA were more likely than those without widespread pain to use medication for symptoms of knee osteoarthritis most days for at least 1 month 2 years after TKA (51% 61 of 120 versus 32% 57 of 178; mean difference, 18.8 95% CI 7.3 to 30.1; p < 0.01).
Widespread pain before TKA was associated with an increased risk of no clinically important improvement in knee pain 2 years postoperatively among women. Because of the small number of men with widespread pain in the sample, the results for men were inconclusive. In clinical practice, screening TKA candidates for widespread pain may be useful, and expectations of surgical outcomes may need to be tempered if patients have a concurrent diagnosis of widespread pain. Future studies should include more men with widespread pain and investigate if treatment of widespread pain before or concurrent with TKA surgery may improve surgical outcomes.
Level III, therapeutic study.
Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by ...chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
Putrescine, spermidine, and spermine (i.e., polyamines) are small cationic amines synthesized by cells or acquired from the diet or gut bacteria. Polyamines are required for both normal and ...colorectal cancer (CRC) cell growth.
We investigated the association between dietary polyamines and risk of CRC incidence and mortality.
The study was a prospective analysis in 87,602 postmenopausal women in the Women's Health Initiative Observational Study. Multivariate Cox regression was used to calculate HRs and 95% CIs.
Total dietary polyamine intake (mean ± SD: 289.2 ± 127.4 μmol/d) was not positively associated with CRC in fully adjusted models. Instead, intake ≥179.67 μmol/d was associated with reduced risk of CRC HR (95% CI): 0.82 (0.68, 1.00), 0.81 (0.66, 0.99), 0.91 (0.74, 1.12), and 0.80 (0.62, 1.02) for quintiles 2-5, respectively, compared with quintile 1. Reduced risk was not significant across all quintiles. Polyamines were not significantly associated with CRC-specific mortality in fully adjusted models. When stratified by risk factors for CRC, only body mass index (BMI) and fiber intake significantly modified the association between polyamine intake and CRC. In women with BMI (in kg/m²) ≤25 or fiber consumption above the median, polyamine intake was associated with significantly lower risk of CRC.
No positive association between dietary polyamines and CRC or CRC-specific mortality risk in women was observed. Instead, a protective effect of dietary polyamines was suggested in women with some CRC risk-lowering behaviors in particular. These results are consistent with emerging evidence that exogenous polyamines may be beneficial in colon health and warrant additional study.
Objective
Local‐area cartilage segmentation (LACS) software was developed to segment medial femur (MF) cartilage on magnetic resonance imaging (MRI). Our objectives were 1) to extend LACS to the ...lateral femur (LF), medial tibia (MT), and lateral tibia (LT), 2) to compare LACS to an established manual segmentation method, and 3) to visualize cartilage responsiveness over each cartilage plate.
Methods
Osteoarthritis Initiative participants with symptomatic knee osteoarthritis (OA) were selected, including knees selected at random (n = 40) and knees identified with loss of cartilage based on manual segmentation (Chondrometrics GmbH), an enriched sample of 126 knees. LACS was used to segment cartilage in the MF, LF, MT, and LT on sagittal 3D double‐echo steady‐state MRI scans at baseline and at 2‐year follow‐up. We compared LACS and Chondrometrics average thickness measures by estimating the correlation in each cartilage plate and estimating the standardized response mean (SRM) for 2‐year cartilage change. We illustrated cartilage loss topographically with SRM heatmaps.
Results
The estimated correlation between LACS and Chondrometrics measures was r = 0.91 (95% confidence interval 95% CI 0.86, 0.94) for LF, r = 0.93 (95% CI 0.89, 0.95) for MF, r = 0.97 (95% CI 0.96, 0.98) for LT, and r = 0.87 (95% CI 0.81, 0.91) for MT. Estimated SRMs for LACS and Chondrometrics measures were similar in the random sample, and SRM heatmaps identified subregions of LACS‐measured cartilage loss.
Conclusion
LACS cartilage thickness measurement in the MF and LF and tibia correlated well with established manual segmentation–based measurement, with similar responsiveness to change, among knees with symptomatic knee OA. LACS measurement of cartilage plate topography enables spatiotemporal analysis of cartilage loss in future knee OA studies.
Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis.
The ...Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided.
In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk RR = 1.04, 95% confidence interval CI = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03).
Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.
Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase ...risk of type 2 diabetes (T2D).
The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided.
In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0-85.1 months) and 33.0 months (range = 0.0-82.6 months) were 42.8% and 44.1% (relative risk RR = 1.03, 95% confidence interval CI = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03).
Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.
Objective
We aimed to estimate Coccidioides serologic screening rates before initiation of biologic disease‐modifying antirheumatic drugs including tofacitinib (b/tsDMARDs), conventional synthetic ...disease‐modifying antirheumatic drugs (csDMARDs), and/or noninhaled corticosteroids.
Methods
This retrospective cohort study used 2011 to 2016 US Medicare claims data and included beneficiaries with rheumatic or autoimmune disease residing in regions within Arizona, California, and Texas endemic for Coccidioides spp. with ≥1 prescription for a b/tsDMARD, csDMARD, and/or noninhaled corticosteroid. We estimated prior‐year serologic screening incidence before initiating b/tsDMARDs, csDMARD, and/or noninhaled corticosteroid.
Results
During 2012 to 2016, 4,331 beneficiaries filled 64,049 prescriptions for b/tsDMARDs, csDMARDs, and noninhaled corticosteroids. Arizona's estimated screening rate was 20.1% (95% confidence interval 95% CI 14.5–25.7) in the year before prescription initiation for b/tsDMARDs, 8.1% (95% CI 6.5–9.7) before csDMARDs, and 6.9% (95% CI: 5.6–8.2) before corticosteroids. Screening rates for b/tsDMARDs (2.8%, 95% CI 0.0–6.7), csDMARDs (1.0%, 95% CI 0.0–2.0), and corticosteroids (0.8%, 95% CI: 0.4–1.1) were negligible in California and undetected in Texas. Adjusted screening rate before prescription for b/tsDMARDs in Arizona increased from 14.5% (95% CI 7.5–21.5) in 2012 to 26.7% (95% CI 17.6–35.8) in 2016. Rheumatologists prescribing b/tsDMARDs in Arizona screened more than other providers (20.9% 95% CI 13.9–27.9 vs 12.9% 95% CI 5.9–20.0).
Conclusion
Coccidioides serologic screening rates among Medicare beneficiaries with rheumatic/autoimmune diseases on b/tsDMARDs, csDMARDs, and noninhaled corticosteroids was low in Coccidioides spp.–US endemic regions between 2012 and 2016. Alignment of screening recommendations and clinical practice is needed.
The study objective was to examine associations between the use of biologic response modifiers (BRMs), corticosteroids, and oral small molecules (OSMs) and subsequent coccidioidomycosis infection ...risk among US Medicare beneficiaries with rheumatic or autoimmune diseases.
This retrospective cohort study used US 2011 to 2016 Medicare claims data. We identified geographic areas with endemic coccidioidomycosis (≥25 cases per 10,000 beneficiaries). Among beneficiaries having any rheumatic/autoimmune diseases, we identified those initiating BRMs, corticosteroids, and OSMs. Based on refill days supplied, we created time-varying exposure variables for BRMs, corticosteroids, and OSMs with a 90-day lag period after drug cessation. We examined BRMs, corticosteroids, and OSMs and subsequent coccidioidomycosis infection risk using multivariable Cox proportional hazard regression.
Among 135,237 beneficiaries (mean age: 67.8 years; White race: 83.1%; Black race: 3.6%), 5,065 had rheumatic or autoimmune diseases, of which 107 individuals were diagnosed with coccidioidomycosis during the study period (6.1 per 1,000 person-years). Increased risk of coccidioidomycosis was observed among beneficiaries prescribed any BRMs (17.7 per 1,000 person-years; adjusted hazard ratio aHR 3.94; 95% confidence interval CI 1.18-13.16), followed by individuals treated with only corticosteroids (12.2 per 1,000 person-years; aHR 2.29; 95% CI 1.05-5.03) compared to those treated with only OSMs (4.2 per 1,000 person-years). The rate of those treated with only OSMs was the same as that of beneficiaries without these medications.
Incidence of coccidioidomycosis was low among 2011 to 2016 Medicare beneficiaries with rheumatic or autoimmune diseases. BRM and corticosteroid users may have higher risks of coccidioidomycosis compared to nonusers, warranting consideration of screening for patients on BRMs and corticosteroids in coccidioidomycosis endemic areas.
Characterize radiographic worsening in knee osteoarthritis (KOA) by race and sex over 4 years and evaluate the role of established risk factors in observed race/sex differences.
Whites (WHs) (694 ...males and 929 females) and African-Americans (AAs) (92 males and 167 females) at risk for radiographic KOA were eligible. Cox shared frailty models were used to estimate race and sex group differences in radiographic worsening, defined by Kellgren-Lawrence (K-L) and OARSI joint space narrowing (JSN). Mixed effect models for repeated measures were used to estimate race- and sex-specific mean medial and lateral fixed joint space width (fJSW) over 4 years of follow-up, as well as annual loss of fJSW.
Risk of OARSI medial JSN grade worsening was higher among AA males than WH females HR = 2.28, (95% CI: 1.14–4.57), though adjustment for KOA risk factors attenuated the association. Compared to WH females, WH males had lower risk of K-L grade worsening adjusted HR = 0.75 (95% CI: 0.58–0.96).
Mean baseline medial fJSW (mm) was 6.49 in WH and AA males, 5.42 in WH females, and 5.41 in AA females. Annual change in mean medial fJSW was greater in AA males (−0.19mm/year) than in other subgroups (−0.09 WH males, −0.07 WH females, −0.10 AA females, p < 0.0001). Compared to WHs, AAs had less lateral fJSW at baseline and throughout follow-up.
Compared to WHs and AA females, AA males experienced higher risk of medial joint space loss. Controlling for established risk factors attenuated associations between race/sex and disease worsening, suggesting that risk factors such as obesity, history of knee injury, and bony finger joint enlargements largely explain race/sex variations in rates of KOA development and progression.
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