Essential Fatty Acids and Osteoarthritis.

OBJECTIVE: Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Although n-3 fatty acids reduce inflammation, different n-3 fatty acids have different effects on inflammation and clinical outcomes, with eicosapentaenoic acid (EPA) having the strongest effect. We examined whether specific essential fatty acid levels affected the development of OA. METHODS: We studied participants from the Multicenter Osteoarthritis Study (MOST) at risk of developing knee OA. As part of MOST, participants were asked repeatedly about knee pain, and knee radiographs and magnetic resonance images (MRIs) were obtained. Using baseline fasting samples, we analyzed serum fatty acids with standard assays. After excluding participants with baseline OA, we defined two sets of cases based on their status through 60 months' follow-up: those developing incident radiographic OA and those developing incident symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage damage and synovitis and worsening knee pain and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of specific n-3 and n-6 fatty acids, adjusting for age, sex, body mass index, education, physical activity, race, baseline pain, smoking, statin use, and depressive symptoms. RESULTS: We studied 363 cases with incident symptomatic knee OA and 295 with incident radiographic knee OA. The mean age was 62 years (59% women). We found no associations of specific n-3 fatty acid levels, including EPA, or of n-6 fatty acid levels with incident OA (eg, for incident symptomatic knee OA, the odds ratio per SD increase in EPA was 1.0 [95% confidence interval 0.87-1.17]). Results for other OA outcomes also failed to suggest a protective effect of specific n-3 fatty acids with OA outcomes. CONCLUSION: We found no association of serum levels of EPA or of other specific n-3 fatty acids or n-6 fatty acids with risk of incident knee OA or other OA outcomes.

Development of a Magnetic Resonance Imaging-Based Definition of Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: Although magnetic resonance imaging (MRI) is the imaging modality of choice for research, there is no widely accepted MRI definition of knee osteoarthritis (OA). We undertook this study to test the performance of different MRI definitions of OA. METHODS: We studied Multicenter Osteoarthritis Study participants with knee symptoms using posteroanterior and lateral knee radiographs and MRIs. Radiographic OA was defined as Kellgren/Lawrence grade ≥2 in the tibiofemoral (TF) and/or patellofemoral (PF) joint. Symptomatic OA was defined using a validated questionnaire. MRI findings of cartilage damage, osteophytes, bone marrow lesions (BMLs), and synovitis were scored using the Whole-Organ MRI Score system. We compared definitions using combinations of MRI features to the validation criteria of prevalent radiographic OA and symptomatic OA. All combinations included cartilage damage score ≥2 (0-6 scale) and osteophyte score ≥2 (0-6 scale); addition of BMLs and synovitis score was also tested. We also evaluated a Delphi panel definition that defined OA differently for the PF and TF joints. For each definition, we calculated sensitivity, specificity, and the area under the curve (AUC). RESULTS: We included 1,185 knees from 1,185 participants (mean age 66 years, 62% female, 89% White). Among the 1,185 knees, 482 knees had radiographic OA, and 524 knees had symptomatic OA. The MRI definitions with a cartilage score ≥2 and osteophyte score ≥2 and definitions which added BMLs or synovitis score ≥1 had the highest sensitivities (95.2% and 94.5%, respectively) for prevalent radiographic OA (AUCs 0.67 and 0.69, respectively), and also had the highest sensitivities for symptomatic OA. The Delphi panel definition had similar performance but was more complex to apply. CONCLUSION: An MRI OA definition requiring cartilage damage and a small osteophyte with or without BMLs or synovitis had the best performance and was simplest for identifying radiographic OA and symptomatic OA.

An overview of the BOIN design and its current extensions for novel early-phase oncology trials.

Bayesian Optimal Interval (BOIN) designs are a class of model-assisted dose-finding designs that can be used in oncology trials to determine the maximum tolerated dose (MTD) of a study drug based on safety or the optimal biological dose (OBD) based on safety and efficacy. BOIN designs provide a complete suite for dose finding in early phase trials, as well as a consistent way to explore different scenarios such as toxicity, efficacy, continuous outcomes, delayed toxicity or efficacy and drug combinations in a unified manner with easy access to software to implement most of these designs. Although built upon Bayesian probability models, BOIN designs are operationally simple in general and have good statistical operating characteristics compared to other dose-finding designs. This review paper describes the original BOIN design and its many extensions, their advantages and limitations, the software used to implement them, and the most suitable situation for use of each of these designs. Published examples of the implementation of BOIN designs are provided in the Appendix.

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.

Relationship of Patellofemoral Osteoarthritis to Changes in Performance-based Physical Function Over 7 Years: The Multicenter Osteoarthritis Study.

OBJECTIVE: To determine the relationship of patellofemoral osteoarthritis (PFOA) to changes in performance-based function over 7 years. METHODS: There were 2666 participants (62.2 ± 8.0 yrs, BMI 30.6 ± 5.9 kg/m2, 60% female) from the Multicenter Osteoarthritis Study with knee radiographs at baseline who completed repeated chair stands and a 20-meter walk test (20MWT) at baseline, 2.5, 5, and 7 years. Generalized linear models assessed the relation of radiographic PFOA and radiographic PFOA with frequent knee pain to longitudinal changes in performance-based function. Analyses were adjusted for age, sex, BMI, tibiofemoral OA, and injury/surgery. RESULTS: Linear models demonstrated a significant group-by-time interaction for the repeated chair stands (P = 0.04) and the 20MWT (P < 0.0001). Those with radiographic PFOA took 1.01 seconds longer on the repeated chair stands (P = 0.02) and 1.69 seconds longer on the 20MWT (P < 0.0001) at 7 years compared with baseline. When examining the relation of radiographic PFOA with frequent knee pain to performance-based function, there was a significant group-by-time interaction for repeated chair stands (P = 0.05) and the 20MWT (P < 0.0001). Those with radiographic PFOA with frequent knee pain increased their time on the repeated chair stands by 1.12 seconds (P = 0.04) and on the 20MWT by 1.91 seconds (P < 0.0001) over 7 years. CONCLUSION: Individuals with radiographic PFOA and those with radiographic PFOA with frequent knee pain have worsening of performance-based function over time. This knowledge may present opportunities to plan for early treatment strategies for PFOA to limit functional decline over time.

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.

Association of Bariatric Surgery With Vascular Outcomes.

Importance: Bariatric surgical weight loss is associated with reduced cardiovascular mortality; however, the mechanisms underlying this association are incompletely understood. Objectives: To identify variables associated with vascular remodeling after bariatric surgery and to examine how sex, race, and metabolic status are associated with microvascular and macrovascular outcomes. Design, Setting, and Participants: This population-based longitudinal cohort included 307 individuals who underwent bariatric surgery. Participants were enrolled in the bariatric weight loss program at Boston Medical Center, a large, multi-ethnic urban hospital, with presurgical and postsurgical assessments. Data were collected from December 11, 2001 to August 27, 2019. Data were analyzed in September 2019. Exposure: Bariatric surgery. Main Outcomes and Measures: Flow-mediated dilation (FMD) and reactive hyperemia (RH) (as measures of macrovascular and microvascular function, respectively) and clinical variables were measured preoperatively at baseline and at least once postoperatively within 12 months of the bariatric intervention. Results: A total of 307 participants with obesity (mean [SD] age, 42 [12] years; 246 [80%] women; 199 [65%] White; mean [SD] body mass index, 46 [8]) were enrolled in this study. Bariatric surgery was associated with significant weight loss and improved macrovascular and microvascular function across subgroups of sex, race, and traditional metabolic syndrome (mean [SD] pre- vs postsurgery weight: 126 [25] kg vs 104 [25] kg; P < .001; mean [SD] pre- vs postsurgery FMD: 9.1% [5.3] vs 10.2% [5.1]; P < .001; mean [SD] pre- vs postsurgery RH: 764% [400] vs 923% [412]; P < .001). Factors associated with change in vascular phenotype correlated most strongly with adiposity markers and several metabolic variables depending on vascular territory (eg, association of weight change with change in RH: estimate, -3.2; 95% CI, -4.7 to -1.8; association of hemoglobin A1c with change in FMD: estimate, -0.5; 95% CI, -0.95 to -0.05). While changes in macrovascular function among individuals with metabolically healthy obesity were not observed, the addition of biomarker assessment using high-sensitivity C-reactive protein plasma levels greater than 2 mg/dL identified participants with seemingly metabolically healthy obesity who had low-grade inflammation and achieved microvascular benefit from weight loss surgery. Conclusions and Relevance: The findings of this study suggest that bariatric intervention is associated with weight loss and favorable remodeling of the vasculature among a wide range of individuals with cardiovascular risk. Moreover, differences in arterial responses to weight loss surgery by metabolic status were identified, underscoring heterogeneity in physiological responses to adiposity change and potential activation of distinct pathological pathways in clinical subgroups. As such, individuals with metabolically healthy obesity represent a mixed population that may benefit from more refined phenotypic classification.

Critical review of oncology clinical trial design under non-proportional hazards.

In trials of novel immuno-oncology drugs, the proportional hazards (PH) assumption often does not hold for the primary time-to-event (TTE) efficacy endpoint, likely due to the unique mechanism of action of these drugs. In practice, when it is anticipated that PH may not hold for the TTE endpoint with respect to treatment, the sample size is often still calculated under the PH assumption, and the hazard ratio (HR) from the Cox model is still reported as the primary measure of the treatment effect. Sensitivity analyses of the TTE data using methods that are suitable under non-proportional hazards (non-PH) are commonly pre-planned. In cases where a substantial deviation from the PH assumption is likely, we suggest designing the trial, calculating the sample size and analyzing the data, using a suitable method that accounts for non-PH, after gaining alignment with regulatory authorities. In this comprehensive review article, we describe methods to design a randomized oncology trial, calculate the sample size, analyze the trial data and obtain summary measures of the treatment effect in the presence of non-PH. For each method, we provide examples of its use from the recent oncology trials literature. We also summarize in the Appendix some methods to conduct sensitivity analyses for overall survival (OS) when patients in a randomized trial switch or cross-over to the other treatment arm after disease progression on the initial treatment arm, and obtain an adjusted or weighted HR for OS in the presence of cross-over. This is an example of the treatment itself changing at a specific point in time - this cross-over may lead to a non-PH pattern of diminishing treatment effect.

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.

2D (2 Dimensional) TEQR design for Determining the optimal Dose for safety and efficacy.

Designs, such as the Eff-Tox, OBD (optimal biological dose), STEIN (simple efficacy toxicity interval), and TEPI (toxicity efficacy probability interval) designs, have been proposed to determine the optimal dose of a new oncology drug using both efficacy and toxicity. The goal of these designs is to select the optimal drug dose for further phase trials more accurately than dose finding designs that only consider toxicity, such as the 3 + 3, TEQR (toxicity equivalence range), mTPI (modified toxicity probability interval), and EWOC (escalation with overdose control) designs. We propose a new frequentist design for optimal dose selection, the 2D TEQR design, that is easier to understand and simpler to implement than the TEPI, Eff-Tox, STEIN and OBD designs, as it is based on the empirical or observed toxicity and efficacy rates and does not require specialized computations. We compare the performance of this new design with those of the TEPI, STEIN, Eff-Tox and OBD Isotonic designs. Although for the same sample size and cohort size, the frequentist 2D TEQR design is less accurate than the Bayesian TEPI design and also the STEIN design in selecting the optimal dose, the accuracy of optimal dose selection of the 2D TEQR design can be increased, in many cases, with a moderate increase in cohort size. The 2D TEQR design is as accurate as or more accurate than the Eff-Tox design in optimal dose selection, and better than the OBD Isotonic design, unless there is a clear peak in the true response rates, in which case the OBD Isotonic design performs better than the other designs.

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.

Extensions of the mTPI and TEQR designs to include non-monotone efficacy in addition to toxicity for optimal dose determination for early phase immunotherapy oncology trials.

With the emergence of immunotherapy and other novel therapies, the traditional assumption that the efficacy of the study drug increases monotonically with dose levels is not always true. Therefore, dose-finding methods evaluating only toxicity data may not be adequate. In this paper, we have first compared the Modified Toxicity Probability Interval (mTPI) and Toxicity Equivalence Range (TEQR) dose-finding oncology designs for safety with identical stopping rules; we have then extended both designs to include efficacy in addition to safety - we determine the optimal dose for safety and efficacy using these designs by applying isotonic regression to the observed toxicity and efficacy rates, once the early phase trial is completed. We consider multiple types of underlying dose response curves, i.e., monotonically increasing, plateau, or umbrella-shaped. We conduct simulation studies to investigate the operating characteristics of the two proposed designs and compare them to existing designs. We found that the extended mTPI design selects the optimal dose for safety and efficacy more accurately than the other designs for most of the scenarios considered.

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.