Widespread Pain Is Associated with Increased Risk of No Clinical Improvement After TKA in Women.

BACKGROUND: 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. QUESTIONS/PURPOSES: (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? METHODS: 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. RESULTS: 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). CONCLUSIONS: 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 OF EVIDENCE: Level III, therapeutic study.

Single time point comparisons in longitudinal randomized controlled trials: power and bias in the presence of missing data.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sedentary behavior is associated with colorectal adenoma recurrence in men.

PURPOSE: The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence. METHODS: Pooled analyses from two randomized, controlled trials included 1,730 participants who completed the Arizona Activity Frequency Questionnaire at baseline, had a colorectal adenoma removed within 6 months of study registration, and had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior, light-intensity physical activity, and moderate-vigorous physical activity on colorectal adenoma recurrence. RESULTS: No statistically significant trends were found for any activity type and odds of colorectal adenoma recurrence in the pooled population. However, males with the highest levels of sedentary time experienced 47% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.23 (0.88, 1.74), 1.41 (0.99, 2.01), and 1.47 (1.03, 2.11), respectively (p(trend) = 0.03). No similar association was observed for women. CONCLUSIONS: This study suggests that sedentary behavior is associated with a higher risk of colorectal adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway.

Dietary polyamine intake and polyamines measured in urine.

Dietary polyamines have recently been associated with increased risk of pre-malignant colorectal lesions. Because polyamines are synthesized in cells and taken up from dietary sources, development of a biomarker of exposure is challenging. Excess polyamines are primarily excreted in the urine. This pilot study seeks to identify dietary correlates of excreted urinary polyamines as putative biomarkers of exposure. Dietary polyamines/other nutrients were estimated from a food frequency questionnaire (FFQ) and correlated with urinary levels of acetylated polyamines in 36 men using 24-h urine samples. Polyamines, abundant in cheese and citrus, were highly positively correlated with urinary N(8)-acetylspermidine (correlation coefficient; r = 0.37, P = 0.03), but this correlation was attenuated after adjustment for total energy intake (r = 0.07, P = 0.68). Dietary energy intake itself was positively correlated with urinary total acetylated polyamine output (r = .40, P = 0.02). In energy-adjusted analyses, folic acid and folate from food were associated with urinary N(1),N(12)-diacetylspermine (r = 0.34, P = 0.05 and r = -0.39, P = 0.02, respectively). Red meat negatively correlated with total urinary acetylated polyamines (r = -0.42, P = 0.01). Our findings suggest that energy, folate, folic acid, saturated fat, and red meat intake, as opposed to FFQ-estimated dietary polyamines, are correlated with urinary polyamines.

Service Dogs for Veterans and Military Members With Posttraumatic Stress Disorder: A Nonrandomized Controlled Trial.

Importance: Military members and veterans (hereafter, veterans) with posttraumatic stress disorder (PTSD) increasingly seek psychiatric service dogs as a complementary intervention, yet the effectiveness of service dogs is understudied. Objective: To estimate the associations between psychiatric service dog partnership and self-reported and clinician-rated PTSD symptom severity, depression, anxiety, and psychosocial functioning after 3 months of intervention among veterans. Design, Setting, and Participants: This nonrandomized controlled trial used standardized and validated assessment instruments completed by participants and administered by blinded clinicians. Recruitment, eligibility screening, and enrollment were conducted between August 2017 and December 2019. Veterans were recruited using the database of an accredited nonprofit service dog organization with constituents throughout the US. Participants were veterans with a PTSD diagnosis; they were allocated to either the intervention group (n = 81) or control group (n = 75). Outcome assessments were performed at baseline and at the 3-month follow-up. Data analyses were completed in October 2023. Interventions: Participants allocated to the intervention group received a psychiatric service dog for PTSD, whereas those allocated to the control group remained on the waiting list based on the date of application submitted to the service dog organization. Both groups had unrestricted access to usual care. Main Outcomes and Measures: The primary outcomes were PTSD symptom severity, depression, and anxiety after 3 months, and the secondary outcomes were psychosocial functioning, such as quality of life and social health. The self-reported PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was used to measure symptom severity, and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) was used to assess PTSD diagnosis (score range for both instruments: 0-80, with higher scores indicating greater PTSD symptoms). Results: The 156 participants included in the trial had a mean (SD) age of 37.6 (8.3) years and included 117 males (75%), 17 Black or African American individuals (11%), 30 Hispanic individuals (19%), and 117 White individuals (76%). Compared with the control group, the intervention group had significantly lower PTSD symptom severity based on the PTSD Checklist for DSM-5 mean (SD) score (41.9 [16.9] vs 51.7 [16.1]; difference in means, -11.5 [95% CI, -16.2 to -6.6]; P < .001) and the CAPS-5 mean (SD) score (30.2 [10.2] vs 36.9 [10.2]; difference in means, -7.0 [95% CI, -10.8 to -4.5]; P < .001) at 3 months. The intervention group also had significantly lower depression scores (odds ratio [OR], 0.45 [95% CI, 0.23-0.86]; difference in means, -3.3 [95% CI, -6.8 to -0.6]), anxiety (OR, 0.25 [95% CI, 0.13-0.50]; difference in means, -4.4 [95% CI, -6.9 to -2.1]), and most areas of psychosocial functioning (eg, social isolation: OR, 0.34 [95% CI, 0.18-0.64]). Conclusions and Relevance: This nonrandomized controlled trial found that compared with usual care alone, partnership with a trained psychiatric service dog was associated with lower PTSD symptom severity and higher psychosocial functioning in veterans. Psychiatric service dogs may be an effective complementary intervention for military service-related PTSD. Trial Registration: ClinicalTrials.gov ID: NCT03245814.

Coccidioides Serologic Screening Practices in Individuals With Rheumatic and Autoimmune Diseases.

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.

Risk of Coccidioidomycosis Infection Among Individuals Using Biologic Response Modifiers, Corticosteroids, and Oral Small Molecules.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

One-year risk for advanced colorectal neoplasia: U.S. versus U.K. risk-stratification guidelines.

BACKGROUND: Guidelines from the United Kingdom and the United States on risk stratification after polypectomy differ, as do recommended surveillance intervals. OBJECTIVE: To compare risk for advanced colorectal neoplasia at 1-year colonoscopy among patients cross-classified by U.S. and U.K. surveillance guidelines. DESIGN: Pooled analysis of 4 prospective studies between 1984 and 1998. SETTING: Academic and private clinics in the United States. PATIENTS: 3226 postpolypectomy patients with 6- to 18-month follow-up colonoscopy. MEASUREMENTS: Rates of advanced neoplasia (an adenoma ≥1 cm, high-grade dysplasia, >25% villous architecture, or invasive cancer) at 1 year, compared across U.S. and U.K. risk categories. RESULTS: Advanced neoplasia was detected 1 year after polypectomy in 3.8% (95% CI, 2.7% to 4.9%) of lower-risk patients and 11.2% (CI, 9.8% to 12.6%) of higher-risk patients by U.S. criteria. According to U.K. criteria, 4.4% (CI, 3.3% to 5.4%) of low-risk patients, 9.9% (CI, 8.3% to 11.5%) of intermediate-risk patients, and 18.7% (CI, 14.8% to 22.5%) of high-risk patients presented with advanced neoplasia; U.K. high-risk patients comprised 12.1% of all patients. All U.S. lower-risk patients were low-risk by U.K. criteria; however, more patients were classified as low-risk, because the U.K. guidelines do not consider histologic features. Higher-risk U.S. patients were distributed across the 3 U.K. categories. Among all patients with advanced neoplasia, 26.3% were reclassified by the U.K. criteria to a higher-risk category and 7.0% to a lower-risk category, with a net 19.0% benefiting from detection 2 years earlier. Overall, substitution of U.K. for U.S. guidelines resulted in an estimated 0.03 additional colonoscopy every 5 years per patient. LIMITATIONS: Patients were enrolled 15 to 20 years ago, and quality measures for colonoscopy were unavailable. Patients lacking follow-up colonoscopy or with surveillance colonoscopy after 6 to 18 months and those with cancer or insufficient baseline adenoma characteristics were excluded (2076 of 5302). CONCLUSION: Application of the U.K. guidelines in the United States could identify a subset of high-risk patients who may warrant a 1-year clearing colonoscopy without substantially increasing rates of colonoscopy. PRIMARY FUNDING SOURCE: European Union Public Health Programme.

Reliability and Validity of Single Axial Slice vs. Multiple Slice Quantitative Measurement of the Volume of Effusion-Synovitis on 3T Knee MRI in Knees with Osteoarthritis.

Effusion-synovitis (ES) is recognized as a component of osteoarthritis, creating a need for rapid methods to assess ES on MRI. We describe the development and reliability of an efficient single-slice semi-automated quantitative approach to measure ES. We used two samples from the Osteoarthritis Initiative (OAI): 50 randomly selected OAI participants with radiographic osteoarthritis (i.e., Kellgren-Lawrence (KL) grade 2 or 3) and a subset from the Foundation for the National Institutes of Health Osteoarthritis Biomarker study. An experienced musculoskeletal radiologist trained four non-expert readers to use custom semi-automated software to measure ES on a single axial slice and then read scans blinded to prior assessments. The estimated intraclass correlation coefficient (ICC) for intra-reader reliability of the single-slice ES method in the KL 2-3 sample was 0.96 (95% CI: 0.93, 0.97), and for inter-reader reliability, the ICC was 0.90 (95% CI: 0.87, 0.95). The intra-reader mean absolute difference (MAD) was 35 mm3 (95% CI: 28, 44), and the inter-reader MAD was 61 mm3 (95% CI: 48, 76). Our single-slice quantitative knee ES measurement offers a reliable, valid, and efficient surrogate for multi-slice quantitative and semi-quantitative assessment.

Cartilage Topography Assessment With Local-Area Cartilage Segmentation for Knee Magnetic Resonance Imaging.

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.

Primary care physician compliance with colorectal cancer screening guidelines.

OBJECTIVE: To assess self-reported compliance to colorectal cancer (CRC) screening guidelines among primary care physicians (PCPs) and to assess physician and practice characteristics associated with reported compliance. METHODS: Survey data from 984 PCPs in Arizona were used. Self-reported CRC screening practices, recommendations, and compliance with guidelines were assessed. Physician and practice characteristics associated with guideline compliance were also evaluated. RESULTS: While 77.5% of physicians reported using national screening guidelines, only 51.7% reported recommendations consistent with the guidelines. Younger physicians were significantly more likely to report compliance with screening guidelines (OR = 1.50, 95% CI = 1.07-2.10) as were female clinicians (OR = 1.46, 95% CI = 1.11-1.92). Physicians practicing in solo (OR = 0.33, 95% CI = 0.19-0.58), group (OR = 0.36, 95% CI = 0.21-0.62), or community health centers (OR = 0.37, 95% CI = 0.17-0.81) were significantly less likely to report following guidelines as compared to those in academic practice. Guideline compliance was higher for fecal occult blood test (FOBT) (65.0%) than colonoscopy (56.7%); overuse of screening for these modalities was reported among 34.4% of physicians. CONCLUSIONS: PCPs are not adequately following CRC screening guidelines. Further studies are needed to clarify the reasons for this lack of compliance, especially as guidelines become more complex.

Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study.

A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.

Components of metabolic syndrome and metachronous colorectal neoplasia.

BACKGROUND: The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese. METHODS: We assessed the relation between metachronous neoplasia and the components of metabolic syndrome (MetS) as defined by the National Cholesterol Education Program's Adult Treatment Panel III in 2,392 participants of two previously conducted chemoprevention trials. Waist circumference, fasting plasma glucose, trigylcerides, high-density lipoprotein, and systolic and diastolic blood pressure were measured at baseline. RESULTS: MetS classification was associated with increased odds of metachronous neoplasia among women [odds ratio (OR), 1.37; 95% confidence interval (95% CI), 1.01-1.85] but not among men (OR, 0.99; 95% CI, 0.81-1.21). High waist circumference in men (OR, 1.41; 95% CI, 1.15-1.72) and women (OR, 1.41; 95% CI, 1.05-1.90) and elevated fasting glucose in women (OR, 1.46; 95% CI, 1.09-1.96), as defined by Adult Treatment Panel III cutpoints, were associated with increased odds, whereas none of the other criteria were independently associated with metachronous neoplasia. When each trait was evaluated using quartiles, elevated glucose among women and large waist circumference among men were significantly associated with metachronous lesions. Exploratory analysis of waist circumference and fasting glucose suggested an interaction, where only the combination of large waist circumference and elevated glucose conferred significant increased odds of metachronous neoplasia among both men (OR, 1.36; 95% CI, 1.04-1.78; P(interaction) = 0.08) and women (OR, 1.83; 95% CI, 1.26-2.67; P(interaction) = 0.12). CONCLUSIONS: These results suggest that, of the specific components of MetS, those that capture impaired glucose uptake increased the odds of metachronous neoplasia.

Physical activity as a determinant of fecal bile acid levels.

Physical activity is protective against colon cancer, whereas colonic bile acid exposure is a suspected risk factor. Although likely related, the association between physical activity and bile acid levels has not been well-studied. Furthermore, the effect of triglycerides, which are known to modify bile acid levels, on this relationship has not been investigated. We conducted a cross-sectional analysis of baseline fecal bile acid levels for 735 colorectal adenoma formers obtained from participants in a phase III ursodeoxycholic acid chemoprevention trial. Compared with the lowest quartile of recreational physical activity duration, the highest quartile was associated with a 17% lower fecal bile acid concentration, adjusted for age, sex, dietary fiber intake, and body mass index (P = 0.042). Furthermore, consistent with a previously established relationship between serum triglyceride levels and bile acid metabolism, we stratified by triglyceride level and observed a 34% lower fecal bile acid concentration (highest versus lowest quartiles of physical activity) in individuals with low triglycerides (<136 mg/dL; P = 0.002). In contrast, no association between physical activity and fecal bile acid concentration was observed for subjects with high triglycerides (> or =136 mg/dL). Our results suggest that the biological mechanism responsible for the protective effect of physical activity on the incidence of colon cancer may be partially mediated by decreasing colonic bile acid exposure. However, this effect may be limited to individuals with lower triglyceride levels.

Plasma insulin-like growth factor I is inversely associated with colorectal adenoma recurrence: a novel hypothesis.

The insulin-like growth factor I (IGF-I) axis has been proposed to be a significant factor in the development of certain cancers, including colorectal. However, results from epidemiologic studies suggest modest effects on colorectal cancer risk. Using cross-sectional and prospective study designs within the same cohort of men who had at least one adenoma at baseline, we investigated whether plasma IGF-I, IGF-I binding protein 1, and IGF-I binding protein 3 were associated with colorectal adenoma characteristics at baseline and whether their levels were related to odds for adenoma recurrence. Plasma levels of each marker were measured at baseline in 299 male participants in the Wheat Bran Fiber Trial, who were followed prospectively for recurrence of their adenomatous lesions. In cross-sectional analyses, plasma IGF-I was significantly positively associated with the presence of adenomas with any villous features (P = 0.04). In contrast, IGF-I levels were inversely associated with odds of colorectal adenoma recurrence, with adjusted odds ratios (95% confidence interval) of 0.55 (0.29-1.01) and 0.49 (0.26-0.91) for the second and third tertiles of IGF-I, respectively, compared with the first tertile (P(trend) = 0.02). The inverse association was stronger for advanced adenoma recurrence (P(trend) = 0.02) than for nonadvanced recurrence (P(trend) = 0.10). These results suggest that, once an adenoma is removed, higher IGF-I levels reduce the odds of the formation of new lesions in the colorectum.

Race, sex, and risk factors in radiographic worsening of knee osteoarthritis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner.

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.

Benign breast biopsy diagnosis and subsequent risk of breast cancer.

BACKGROUND: We examine benign breast biopsy diagnoses as reported by community pathologists in New Mexico and investigate associations with future breast cancer development. METHODS: Using data collected between 1992 and 2000 by the New Mexico Mammography Project and cancer data through 2003 from the New Mexico Tumor Registry, we calculated breast cancer rates following 14,602 benign breast biopsies for women ages 30 to 89 years. For comparison, we also calculated the breast cancer rate following 215,283 normal screening mammograms. Hazard ratios (HR) are presented. RESULTS: We identified 480 subsequent breast cancer diagnoses among 14,602 women with benign breast biopsies and 4,402 breast cancer diagnoses among 215,283 women with mammograms assigned a "negative" or "benign finding" assessment. Histologic diagnoses in absence of atypia had an age-adjusted HR of 1.95 [95% confidence interval (95% CI), 1.77-2.15]. Among low-risk histologic diagnoses, the strongest associations with subsequent breast cancer development included adenosis, apocrine metaplasia, calcifications, and ductal hyperplasia. Fibroadenoma, inflammation, and cysts did not exhibit an association with breast cancer development. Women with low-risk diagnoses and breast tissue characterized as fatty or with scattered densities had a HR of 2.09 (95% CI, 1.68-2.60), whereas women with low-risk histologic diagnoses and dense breasts had a HR of 3.36 (95% CI, 2.83-3.99). CONCLUSIONS: The observed breast cancer occurrence contributes to evidence of increased risk following benign biopsy. The risk associated with histologic diagnoses in absence of atypia was twice the risk experienced by women with normal mammogram evaluations and may be modified by breast density.

Relationship Between Knee Pain and Patient Preferences for Joint Replacement: Health Care Access Matters.

OBJECTIVE: To determine if severity of osteoarthritis-related knee pain is associated with a willingness to undergo total knee replacement (TKR) and whether this association is confounded or modified by components of socioeconomic status and health care coverage. METHODS: Cross-sectional analysis was conducted among 3,530 Osteoarthritis Initiative study participants. Logistic regression models were used to assess the effect of knee pain severity (where 0 = none, 1-3 = mild, 4-7 = moderate, and 8-10 = severe) on willingness to undergo TKR. Stratified analyses were conducted to evaluate whether socioeconomic status and health care coverage modify the effect of knee pain severity on willingness. RESULTS: Participants with severe knee pain, compared to participants without pain, were less willing to undergo TKR (odds ratio [OR] 0.73, 95% confidence interval [95% CI] 0.57-0.93). This association was attenuated when adjusted for age, sex, comorbidity, depression, health insurance coverage, prescription medicine coverage, health care source, education, income, employment, race, and marital status (adjusted OR 0.92, 95% CI 0.68-1.24). The odds of willingness to undergo TKR were significantly lower in those with the highest level of pain, compared to those without pain, among participants without health insurance (adjusted OR 0.08, 95% CI 0.01-0.56), but not among those with health insurance (adjusted OR 1.03, 95% CI 0.73-1.38), when adjusted for demographic, clinical, health care access, and socioeconomic factors (P = 0.015). However, <5% of participants were without health insurance. CONCLUSION: Among participants without health insurance, severe knee pain was paradoxically associated with less willingness to undergo TKR. Policies that improve access to quality health care may affect patient preferences and increase utilization of TKR surgery among vulnerable populations.

Patient preferences for total knee replacement surgery: Relationship to clinical outcomes and stability of patient preferences over 2 years.

OBJECTIVE: Evaluate the relationship between patient preferences for total knee replacement (TKR) with receipt of TKR, and assess participant characteristics that may influence change in willingness to undergo TKR. METHODS: Structured interviews of knee osteoarthritis (OA) patients were conducted. Logistic regression models were conducted to assess the association between baseline willingness and eventual receipt of TKR, adjusted for sociodemographic and clinical variables. Mixed models for repeated measures were used to estimate the effects of sex, race, social support, Δ WOMAC, and orthopedic consult on change in willingness. RESULTS: A total of 589 participants were willing, and 215 participants were unwilling to undergo TKR. Willing participants, compared to others, were more often White (69.4% vs. 48.4%), with more than a high school education (60.8% vs. 47.0%) and employed (39.1% vs. 26.5%). At follow-up, the odds of having TKR were twice as high among those who were willing to have the procedure at baseline, but this was no longer significant when adjusted for demographic variables (adjusted OR = 1.82, 95% CI: 0.89-3.69). Willingness to undergo TKR declined over 2 years. Among those who were willing to undergo TKR at baseline but did not obtain one, only 66.5% were still willing at the 2-year follow-up. This decline was less among those who had a greater increase (>median) in WOMAC disability (adjusted Δ = -0.34, 95% CI: -0.47 to -0.20) than those who had minimal change in their WOMAC disability (p = 0.08). The decline in willingness was also less among those who had seen an orthopedic surgeon (adjusted Δ = -0.32, 95% CI: -0.46 to -0.17) than those who did not (p = 0.05). CONCLUSIONS: Preference for TKR was consistent with TKR surgery utilization, but not after controlling for patient demographic characteristics. Willingness to undergo TKR declined over time, but this decrease was mitigated by worsening OA-related disability and by consultation with an orthopedic surgeon.