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.

Novel Framework for Measuring Whole Knee Osteoarthritis Progression Using Magnetic Resonance Imaging.

OBJECTIVE: We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores. METHODS: We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression. RESULTS: Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression. CONCLUSION: Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

Quadriceps Strength After Anterior Cruciate Ligament Reconstruction Compared With Uninjured Matched Controls: A Systematic Review and Meta-analysis.

BACKGROUND: The limb symmetry index may overestimate the recovery of quadriceps muscle strength after anterior cruciate ligament reconstruction. Comparison of individuals who have had anterior cruciate ligament reconstruction with age-, sex-, and activity-matched individuals might be more appropriate to guide rehabilitation interventions. PURPOSE: To compare the quadriceps strength between the injured limb of people with anterior cruciate ligament reconstruction and the limb of an age-, sex-, and activity-matched control group. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: MEDLINE, CINAHL, EMBASE, SCOPUS, and SPORTDiscus were searched between inception and April 2019. Studies were included if they reported the peak quadriceps strength for persons with anterior cruciate ligament reconstruction and age-, sex-, and activity-matched control groups measured using isometric or isokinetic dynamometry. Risk of bias was assessed, and meta-analyses and metaregression (for effect of time since surgery) were performed. RESULTS: A total of 2759 studies were identified and 21 were included for analyses. Quadriceps strength was lower in the limbs with anterior cruciate ligament reconstruction compared with the limb from matched controls within 6 months of anterior cruciate ligament reconstruction (standardized mean difference [SMD], -1.42; 95% CI, -1.62 to -1.23), 6 to 18 months after anterior cruciate ligament reconstruction (SMD, -0.92; 95% CI, -1.18 to -0.66), and >18 to 48 months after anterior cruciate ligament reconstruction (SMD, -0.38; 95% CI, -0.79 to 0.03). Results of the metaregression were significant, with the difference between anterior cruciate ligament reconstruction and matched controls decreasing with time since surgery (P < .001). CONCLUSION: In people with anterior cruciate ligament reconstruction, the injured limb had lower quadriceps strength compared with the limb of age-, sex-, and activity-matched controls up to 4 years after surgery. Clinicians should consider comparison with matched cohorts for return to sports decision making.

Revisiting methods for modeling longitudinal and survival data: Framingham Heart Study.

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

Association of Quadriceps Adiposity With an Increase in Knee Cartilage, Meniscus, or Bone Marrow Lesions Over Three Years.

OBJECTIVE: To evaluate the association of fatty infiltration of the quadriceps and vastus medialis (VM) with an increase in knee cartilage, meniscus, or bone marrow lesions, using magnetic resonance imaging (MRI) in knee osteoarthritis (OA) over 3 years. METHODS: Participants (n = 69) with and without radiographic knee OA underwent MRI at baseline and 3 years later. Chemical shift-based water/fat MRI was used to quantify the intramuscular fat fraction and the lean anatomical cross-sectional area (ACSA) for the VM and entire quadriceps muscles. MRI images of the knee were analyzed using the semiquantitative modified whole-organ MRI score (mWORMS) grading to assess change in lesions in the articular cartilage, meniscus, and bone marrow. Logistic regression was used to assess whether baseline quadriceps and VM fat fraction and lean ACSA were associated with an increase in mWORMS scores. Odds ratios (ORs) were adjusted for age, sex, and body mass index. RESULTS: Overall, of the 69 subjects, 43 (62%) had an increase in cartilage lesions (26 of 43), meniscus lesions (19 of 43), or bone marrow lesions (22 of 43) scores. The quadriceps (OR 2.13 [95% confidence interval (95% CI) 1.09-4.15]) and VM (OR 2.05 [95% CI 1.25-3.36]) fat fraction were both associated with an increase in cartilage, meniscus, or bone marrow lesion scores over 3 years. The association of quadriceps or VM lean ACSA with the outcomes was not significant. CONCLUSION: These longitudinal findings using quantitative MRI methods for assessment of muscle adiposity highlight the role of quadriceps adiposity, specifically in the VM, in knee OA progression. However, studies in larger cohorts are needed to confirm these findings.

Association of Visceral Adiposity With Pain but Not Structural Osteoarthritis.

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

Efficacy of Computer-Based Telephone Counseling on Long-Term Adherence to Strength Training in Elderly Patients With Knee Osteoarthritis: A Randomized Trial.

OBJECTIVE: To determine whether the Boston Overcoming Osteoarthritis through Strength Training Telephone-Linked Communication (BOOST-TLC) program, a novel telephone-based, motivational, strength-training exercise-adherence counseling intervention, improved adherence to a strength-training exercise program over 2 years. METHODS: Participants were recruited for this 2-year, single-blind, parallel-arm randomized controlled trial from knee osteoarthritis patient registries, community newspapers, and online websites in Massachusetts. Eligibility criteria included age 50 years or older, painful knee osteoarthritis, and ability to use a telephone. Exclusion criteria included medical conditions precluding exercise, inflammatory arthritis, current regular strength training, planned knee replacement surgery, dementia, inability to follow exercise instructions, and inability to use the TLC system. After participating in a group exercise class, participants were randomized to receiving motivational telephone calls through the BOOST-TLC program for 24 months or the control. Both control and intervention participants received a monthly automated phone message reminder to continue the program. Exercise adherence was ascertained by a single self-report item scored 0-10, where 10 represented complete adherence. Outcomes were evaluated at 6, 12, 18, and 24 months. RESULTS: A total of 104 subjects were randomized, and 89 subjects (44 control, 45 TLC) completed the 24-month follow-up. There was no significant difference in adherence at 24 months between groups (mean for control group 4.01 [95% confidence interval (95% CI) 3.03, 4.99], mean for TLC subjects 3.63 [95% CI 2.70, 4.56]; P = 0.57). CONCLUSION: In those with knee osteoarthritis who had participated in an exercise program, frequent motivational telephone reminders did not increase adherence to strength-training exercise.

Association of Back Pain with All-Cause and Cause-Specific Mortality Among Older Women: a Cohort Study.

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

Changes in Pain Sensitization After Bariatric Surgery.

OBJECTIVE: To evaluate changes in pain (at the knee and elsewhere) and pain sensitization in obese subjects with knee pain who were having bariatric surgery compared with similarly obese individuals who were undergoing medical management. METHODS: This study included a cohort of subjects who were having bariatric surgery and those undergoing medical management. Knee pain severity of the more painful knee (index knee) was assessed at baseline and at 12 months using the Western Ontario and McMaster Universities Osteoarthritis Index. The pressure pain threshold (PPT) was evaluated at the index patella and the right wrist. Low patella PPT may reflect peripheral and/or central sensitization, and low wrist PPT may reflect central sensitization. The mean change in measures of pain and pain sensitization was analyzed in the surgery and medical management groups separately. RESULTS: A total of 45 subjects in the surgery group and 22 in the medical management group completed baseline and follow-up visits. The mean weight loss was 32.7 kg (29.0%) and 4.6 kg (4.1%) in the surgery and medical management groups, respectively. Knee pain decreased only in the surgery group, in which the PPT at the patella improved by 38.5% (P = 0.0007) and at the wrist by 30.9% (P = 0.005). There was no significant change in PPT in the medical management group. CONCLUSION: Persons who underwent bariatric surgery experienced an improvement in pain sensitization, reflected by improvements in PPT. This improvement was observed not only at the patella, but also at the wrist, suggesting that central sensitization improved after bariatric surgery.

Relationship Between Laryngeal Sensory Deficits, Aspiration, and Pneumonia in Patients with Dysphagia.

The laryngeal adductor reflex (LAR) is an airway protective reflex that manifests as a brief vocal fold closure in response to laryngeal stimulation. This study examined if the absence of the LAR in response to touch delivered by a laryngoscope is associated with penetration/aspiration or pneumonia in patients with dysphagia. Inpatients at a teaching hospital with clinical symptoms of dysphagia were recruited upon referral to the otolaryngology clinic for a swallowing evaluation. Otolaryngologists observed the status of secretions and touched each arytenoid with the tip of the laryngoscope. The patients were then asked to swallow 3-5 mL grape gelatin and 3-5 mL colored water. All procedures were video-recorded. Two independent raters noted absence/presence of the LAR and penetration/aspiration of pharyngeal secretions, gelatin, and water on the recorded videos. A diagnosis of pneumonia during the patient's entire hospital stay was determined by a review of the hospital's medical records. Statistical analyses were performed using Fisher's exact test. Sixty-one patients were included. Twenty-one patients (34.5%) did not exhibit the LAR. No association was found between the absent LAR and penetration or aspiration. There was, however, a significant association between an absence of the LAR and pneumonia development. Patients with an absent LAR had 6.8 times the odds of developing pneumonia as compared to those with a present LAR (OR 6.75; 95% CI 1.76-25.96; p < 0.01). Using the LAR as a marker of laryngeal sensory function appears to be valuable for identifying patients at high risk of pneumonia.

Smoking paradox in the development of psoriatic arthritis among patients with psoriasis: a population-based study.

OBJECTIVES: Smoking is associated with an increased risk of psoriatic arthritis (PsA) in the general population, but not among patients with psoriasis. We sought to clarify the possible methodological mechanisms behind this paradox. METHODS: Using 1995-2015 data from The Health Improvement Network, we performed survival analysis to examine the association between smoking and incident PsA in the general population and among patients with psoriasis. We clarified the paradox using mediation analysis and conducted bias sensitivity analyses to evaluate the potential impact of index event bias and quantify its magnitude from uncontrolled/unmeasured confounders. RESULTS: Of 6.65 million subjects without PsA at baseline, 225 213 participants had psoriasis and 7057 developed incident PsA. Smoking was associated with an increased risk of PsA in the general population (HR 1.27; 95% CI 1.19 to 1.36), but with a decreased risk among patients with psoriasis (HR 0.91; 95% CI 0.84 to 0.99). Mediation analysis showed that the effect of smoking on the risk of PsA was mediated almost entirely through its effect on psoriasis. Bias-sensitivity analyses indicated that even when the relation of uncontrolled confounders to either smoking or PsA was modest (both HRs=~1.5), it could reverse the biased effect of smoking among patients with psoriasis (HR=0.9). CONCLUSIONS: In this large cohort representative of the UK general population, smoking was positively associated with PsA risk in the general population, but negatively associated among patients with psoriasis. Conditioning on a causal intermediate variable (psoriasis) may even reverse the association between smoking and PsA, potentially explaining the smoking paradox for the risk of PsA among patients with psoriasis.

Variability of the Pressure Measurements Exerted by the Tip of Laryngoscope During Laryngeal Sensory Testing: A Clinical Demonstration.

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

Identification of Transthyretin Cardiac Amyloidosis Using Serum Retinol-Binding Protein 4 and a Clinical Prediction Model.

Importance: Transthyretin cardiac amyloidosis (ATTR) is an underrecognized cause of heart failure (HF) in older individuals, owing in part to difficulty in diagnosis. ATTR can result from substitution of valine for isoleucine at codon 122 of the transthyretin (TTR) gene (V122I), present in 3.43% of African American individuals. Objective: To examine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Design, Setting, and Participants: In this combined prospective and retrospective cohort study performed at a tertiary care referral center, 50 African American patients 60 years or older with nonamyloid HF and cardiac wall thickening prospectively genotyped from September 1, 2014, through December 31, 2015, and a comparator cohort of 25 patients with biopsy-proven ATTR V122I amyloidosis recruited from September 1, 2009, through November 31, 2014, comprised the development cohort. Twenty-seven African American patients and 9 patients with ATTR V122I amyloidosis comprised the validation cohort. Main Outcomes and Measures: Circulating RBP4, TTR, B-type natriuretic peptide (BNP), and troponin I (TnI) concentrations and electrocardiographic, echocardiographic, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Results: Age, sex, and BNP and TnI concentrations were similar between the 25 patients with ATTR V122I amyloidosis (mean [SD] age, 72.2 [7.4] years; 18 male [72%]) and the 50 controls (mean [SD] age, 69.2 [5.7] years; 31 male [62%]). Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared with nonamyloid controls (31.5 vs 49.4 µg/mL, P < .001), and the difference persisted after controlling for potential confounding variables. Left ventricular ejection fraction was lower in patients with ATTR V122I amyloidosis (mean [SD], 40% [14%] vs 57% [14%], P < .001), whereas interventricular septal diameter was higher (mean [SD], 16 [3] vs 14 [2] mm, P < .001). The ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (area under the curve [AUC] = 0.78; 95% CI, 0.67-0.88). A clinical prediction algorithm composed of RBP4, TTR, left ventricular ejection fraction, interventricular septal diameter, mean limb lead QRS voltage, and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC = 0.97; 95% CI, 0.93-1.00), whereas a 4-parameter model, including RBP4 concentration, retained excellent discrimination (AUC = 0.92; 95% CI, 0.86-0.99). The models maintained excellent discrimination in the validation cohort. Conclusions and Relevance: A prediction model using circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloidosis from nonamyloid HF in a case-matched cohort. This clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly African American patients with HF.

Risk of renal cell carcinoma following exposure to metalworking fluids among autoworkers.

OBJECTIVES: Metalworking fluids (MWF), used to cool and lubricate metal in occupational settings, are linked to several cancers but data on kidney cancer are limited. We examine how MWF influence the rate of renal cell carcinoma (RCC) in a large prospective study. METHODS: A cohort of Michigan autoworkers consisting of 33 421 individuals was followed from 1985 to 2009. The cohort was linked to the Michigan Cancer Registry to identify new cases of RCC. We analysed RCC in relation to cumulative exposure to each specific type of MWF (straight, soluble and synthetic) and all 3 types pooled into a single MWF variable, with a 15-year lag. Cox proportional hazards regression with splines were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for age, gender, race, calendar year, year hired, time since hire, plant and other MWF types. RESULTS: There were 135 incident cases. A linear increase in the log-HR was observed for RCC with increasing cumulative exposure to each MWF type and total MWF exposure. At the mean of total MWF exposure (18.80 mg/m(3)-year), the estimated HR was 1.11 (95% CI 1.04 to 1.19). CONCLUSIONS: Our results provide evidence for a dose-dependent association between MWF exposure and RCC. The influence of components of oil-based and water-based MWF needs further examination.

History of uterine leiomyoma and risk of endometrial cancer in black women.

BACKGROUND: Previous studies have found an association between uterine leiomyomata (UL) and uterine malignancies. This relation has not been studied in black women, who are disproportionately affected by UL. METHODS: We investigated prospectively the association between self-reported physician-diagnosed UL and endometrial cancer in the Black Women's Health Study. During 1995-2013, 47,267 participants with intact uteri completed biennial health questionnaires. Reports of endometrial cancer were confirmed by pathology data from medical records and cancer registries. Cox regression was used to derive incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: There were 300 incident endometrial cancer cases during 689,546 person-years of follow-up. In multivariable models, UL history was associated with a 42% greater incidence of endometrial cancer compared with no such history (95% CI 1.12-1.80). IRRs for cancer diagnosed 0-2, 3-9, and ≥10 years after UL diagnosis were 3.20 (95% CI 2.06-4.98), 0.95 (95% CI 0.60-1.52), and 1.35 (95% CI 1.03-1.77), respectively. Stronger overall associations between UL history and endometrial cancer were observed for later stages at cancer diagnosis (IRR = 2.25, 95% CI 1.09-4.63) and type II/III cancers (IRR = 3.13, 95% CI 1.64-5.99). CONCLUSIONS: In this large cohort of black women, a history of UL was positively associated with endometrial cancer, particularly type II/III tumors. The strongest association was observed for cancer diagnosed within 2 years of UL diagnosis, a finding that might be explained by greater surveillance of women with UL or misdiagnosis of cancer as UL. However, an association was also observed for cancer reported ≥10 years after UL diagnosis.

Comparative analysis of the growth and biological activity of a respiratory and atheroma isolate of Chlamydia pneumoniae reveals strain-dependent differences in inflammatory activity and innate immune evasion.

BACKGROUND: Chlamydia pneumoniae is a common human pathogen that is associated with upper and lower respiratory tract infections. It has also been suggested that C. pneumoniae infection can trigger or promote a number of chronic inflammatory conditions, including asthma and atherosclerosis. Several strains of C. pneumoniae have been isolated from humans and animals, and sequence data demonstrates marked genetic conservation, leaving unanswered the question as to why chronic inflammatory conditions may occur following some respiratory-acquired infections. METHODS: C. pneumoniae strains AR39 and AO3 were used in vitro to infect murine bone marrow derived macrophages and L929 fibroblasts, or in vivo to infect C57BL/6 mice via the intranasal route. RESULTS: We undertook a comparative study of a respiratory isolate, AR39, and an atheroma isolate, AO3, to determine if bacterial growth and host responses to infection varied between these two strains. We observed differential growth depending on the host cell type and the growth temperature; however both strains were capable of forming plaques in vitro. The host response to the respiratory isolate was found to be more inflammatory both in vitro, in terms of inflammatory cytokine induction, and in vivo, as measured by clinical response and lung inflammatory markers using a mouse model of respiratory infection. CONCLUSIONS: Our data demonstrates that a subset of C. pneumoniae strains is capable of evading host innate immune defenses during the acute respiratory infection. Further studies on the genetic basis for these differences on both the host and pathogen side could enhance our understanding how C. pneumoniae contributes to the development chronic inflammation at local and distant sites.

Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity.

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

Insulin status and vascular responses to weight loss in obesity.

OBJECTIVES: The aim of this study was to determine whether the effects of weight loss on arterial function are differentially modified by insulin status. BACKGROUND: Clinical studies suggest that plasma insulin levels may predict the extent of cardiovascular benefit achieved with weight loss in obese individuals, but mechanisms are currently unknown. METHODS: We prospectively followed 208 overweight or obese patients (body mass index [BMI] ≥25 kg/m(2)) receiving medical/dietary (48%) or bariatric surgical (52%) weight-loss treatment during a median period of 11.7 months (interquartile range: 4.6 to 13 months). We measured plasma metabolic parameters and vascular endothelial function using ultrasound at baseline and following weight-loss intervention and stratified analyses by median plasma insulin levels. RESULTS: Patients age 45 ± 1 years, with BMI 45 ± 9 kg/m(2), experienced 14 ± 14% weight loss during the study period. In individuals with higher baseline plasma insulin levels (above median >12 µIU/ml; n = 99), ≥10% weight loss (compared with <10%) significantly improved brachial artery macrovascular flow-mediated vasodilation and microvascular reactive hyperemia (p < 0.05 for all). By contrast, vascular function did not change significantly in the lower insulin group (≤12 µIU/ml; n = 109) despite a similar degree of weight loss. In analyses using a 5% weight loss cut point, only microvascular responses improved in the higher insulin group (p = 0.02). CONCLUSIONS: Insulin status is an important determinant of the positive effect of weight reduction on vascular function with hyperinsulinemic patients deriving the greatest benefit. Integrated improvement in both microvascular and macrovascular function was associated with ≥10% weight loss. Reversal of insulin resistance and endothelial dysfunction may represent key therapeutic targets for cardiovascular risk reduction in obesity.

Evidence of a paradoxical relationship between endotoxin and lung cancer after accounting for left truncation in a study of Chinese female textile workers.

INTRODUCTION: Occupational exposure to endotoxin, found in Gram-negative bacteria in organic material, has been associated predominantly with a reduced risk of lung cancer among workers. An inverse exposure-response gradient among women textile workers in Shanghai, China, has been reported previously. In this case-cohort study, we investigated the influence of left truncation, which can itself induce a downward trend, on the observed association. METHODS: Subjects were enrolled between 1989 and 1991 and followed until 1998. The data were left-truncated as all subjects were hired before baseline. An analysis was performed with 3038 subcohort members and 602 cases of incident lung cancer. To evaluate left truncation, we compared lung cancer rates in those hired longer ago with those hired more recently among unexposed subjects. Cox proportional hazards modelling was used to estimate incident rate ratios (IRRs) and 95% CIs. RESULTS: Among those who were never exposed to workplace endotoxin, we compared lung cancer rates in those hired >35 years before enrolment with workers hired ≤35 years before enrolment and observed a reduced risk in the former group, IRR=0.74, 95% CI (0.51 to 1.07). After accounting for this downward bias from left truncation, the reduced risk associated with endotoxin remained among those hired ≤50 years before enrolment. In contrast, there was suggestion of an increased risk of lung cancer among those hired >50 years ago. CONCLUSIONS: After examination of left truncation bias, an inverse dose-response between endotoxin and lung cancer remained for all subjects except those hired longest ago.