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PurposeWe evaluated and identified baseline factors associated with change in health related quality of life among patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome.Materials and methodsA total of 191 men and 233 women with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome (collectively referred to as urologic chronic pelvic pain syndrome) were followed for 12 months with bimonthly completion of the Short Form 12 to assess general mental and physical health related quality of life, and with biweekly assessment of condition specific health related quality of life using the Genitourinary Pain Index. A functional clustering algorithm was used to classify participants as improved, stable or worsened for each health related quality of life measure. Ordinal logistic regression was used to determine baseline factors associated with change.ResultsPhysical health related quality of life improved in 22% of the participants, mental health related quality of life improved in 25% and condition specific health related quality of life improved in 47%. Better baseline physical health related quality of life, older age and the presence of nonurological symptoms were associated with lower likelihood of improvement in physical health related quality of life. Better baseline mental health related quality of life, female sex, and greater baseline depression and stress were associated with a lower likelihood of improvement in mental health related quality of life. Better baseline condition specific health related quality of life and more severe baseline urologic chronic pelvic pain syndrome pain symptoms were associated with a lower likelihood of improvement in condition specific health related quality of life.ConclusionsWhile several nonurologic chronic pelvic pain syndrome factors influenced the trajectory of general health related quality of life over time, only condition specific baseline health related quality of life and urologic chronic pelvic pain syndrome symptoms were associated with urologic chronic pelvic pain syndrome specific health related quality of life change. Significant differences in how urologic chronic pelvic pain syndrome impacts various aspects of health related quality of life suggest a multidisciplinary approach to assessment and treatment of these patients.

Objective: People with HIV (PWH) experience excess comorbidities, including neurocognitive disorders, which are linked to inflammation, particularly monocyte-macrophage activation. Smoking contributes to morbidity and mortality in well-treated PWH. We investigated associations between smoking, neurocognitive function, and inflammation in PWH on ART., Design: We used baseline data on cognition and inflammation from a longitudinal study of virologically-suppressed PWH who do and do not smoke., Methods: Participants completed 4 neurocognitive tests (7 measures), with a composite score as the primary measure. Inflammatory markers were plasma sCD14, sCD163, and CCL2/MCP-1; %CD14+ monocytes expressing CD16, CD163, and CCR2; and %CD8+ T cells co-expressing CD38/HLA-DR. Exploratory analyses included a plasma cytokine/chemokine panel, neurofilament light chain (NFL), hsCRP and monocyte transcriptomes by RNAseq., Results: We recruited 58 PWH (26 current smoking [PWH/S], 32 no current smoking [PWH/NS]). Mean composite and individual neurocognitive scores did not differ significantly by smoking status except for the color shape task; PWH/S exhibited worse cognitive flexibility, with adjusted mean times 317.2 (95%CI 1.4, 632.9) msec longer than PWH/NS. PWH/S had higher plasma sCD14 than PWH/NS (median(IQR) 1820(1678, 2105) versus 1551(1284, 1760) ng/ml, p=0.009). Other inflammatory markers were not significantly different between PWH/S and PWH/NS. Monocyte transcriptomes showed several functions, regulators and gene sets that differed by smoking status., Conclusions: sCD14, a marker of monocyte activation, is elevated in PWH who smoke. While neurocognitive measures and other inflammatory markers did not generally differ, these data implicate smoking-related myeloid activation and monocyte gene dysregulation in the HIV/smoking synergy driving HIV-associated comorbidities., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction., Objective: To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism., Methods: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones., Results: Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model-predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone., Conclusion: During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones., (© 2024 American Society of Andrology and European Academy of Andrology.)

Background: Surgical site infections (SSIs) are a common complication in liver transplant (LT) recipients. Lack of pediatric prophylaxis guidelines results in variation in preventative antibiotic regimens., Methods: We performed a retrospective observational study of LT recipients <18 years old using a merged data set that included data from the Pediatric Health Information System and the United Network for Organ Sharing between 2006 and 2017. The exposure was defined as the antibiotic(s) received within 24 hours of LT, with 6 categories, ranging from narrow (category 1: cefazolin), to broad). The primary outcome was presence or absence of SSI in the index admission. Mixed-effects logistic regression compared the effectiveness of each category in preventing SSI, relative to category 1., Results: Of the 2586 LT, 284 (11%) met SSI criteria. The SSI rate was higher in the younger subcohort (16.2%) than in the older (8.6%), necessitating a stratified analysis. Antibiotics from category 5 were most commonly used. In the younger subcohort, the adjusted risk was increased in all categories compared with the reference, most notably in category 3 (odds ratio [OR], 2.58 [95% confidence interval: .69-9.59]) and category 6 (2.76 [.66-11.56]). In the older subcohort, estimated ORs were also increased for each category, most notably in category 4 (2.49 [95% confidence interval: .99-6.27]). None of the ORs suggested benefit from broader-spectrum prophylaxis. Our E-value assessment suggests that it's unlikely there is unmeasured confounding by indication to the degree necessary to revert ORs to protective., Conclusions: There was wide variation in antibiotic prophylaxis. Adjusted analyses did not reveal a protective benefit of broader-spectrum prophylaxis in either subcohort, suggesting that narrower regimens may be adequate., Competing Interests: Potential conflicts of interest. A. J. S. S. reports grants from the National Institutes of Health, Argenx, and Patient-Centered Outcomes Research Institute (PCORI); consulting fees from WilmerHale on behalf of Gilead Sciences; payment for a presentation for NYU's Pathways in Quantitative Aging Research Summer Program; and membership on the External Advisory Board of Florida Atlantic University's Summer Institute in Biostatistics. B. T. F. reports grants from Pfizer, Merck, and Allovir and consulting fees from Astellas. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Drawing from insights from communication science and behavioral economics, the University of Pennsylvania Telehealth Research Center of Excellence (Penn TRACE) is designing and testing telehealth strategies with the potential to transform access to care, care quality, outcomes, health equity, and health-care efficiency across the cancer care continuum, with an emphasis on understanding mechanisms of action. Penn TRACE uses lung cancer care as an exemplar model for telehealth across the care continuum, from screening to treatment to survivorship. We bring together a diverse and interdisciplinary team of international experts and incorporate rapid-cycle approaches and mixed methods evaluation in all center projects. Our initiatives include a pragmatic sequential multiple assignment randomized trial to compare the effectiveness of telehealth strategies to increase shared decision-making for lung cancer screening and 2 pilot projects to test the effectiveness of telehealth to improve cancer care, identify multilevel mechanisms of action, and lay the foundation for future pragmatic trials. Penn TRACE aims to produce new fundamental knowledge and advance telehealth science in cancer care at Penn and nationally., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Point-of-sale food messaging can encourage healthier purchases, but no studies have directly compared multiple interventions in the field., Objective: To examine which of 4 food and beverage messages would increase healthier vending machine purchases., Design, Setting, and Participants: This randomized trial assessed 13 months (February 1, 2019, to February 29, 2020) of vending sales data from 267 machines and 1065 customer purchase assessments from vending machines on government property in Philadelphia, Pennsylvania. Data analysis was performed from March 5, 2020, to November 8, 2022., Interventions: Study interventions were 4 food and beverage messaging systems: (1) beverage tax posters encouraging healthy choices because of the Philadelphia tax on sweetened drinks; (2) green labels for healthy products; (3) traffic light labels: green (healthy), yellow (moderately healthy), or red (unhealthy); or (4) physical activity equivalent labels (minutes of activity to metabolize product calories)., Main Outcomes and Measures: Sales data were analyzed separately for beverages and snacks. The main outcomes analyzed at the transaction level were calories sold and the health status (using traffic light criteria) of each item sold. Additional outcomes were analyzed at the monthly machine level: total units sold, calories sold, and units of each health status sold. The customer purchase assessment outcome was calories purchased per vending trip., Results: Monthly sales data came from 150 beverage and 117 snack vending machines, whereas 1065 customers (558 [52%] male) contributed purchase assessment data. Traffic light labels led to a 30% decrease in the mean monthly number of unhealthy beverages sold (mean ratio [MR], 0.70; 95% CI, 0.55-0.88) compared with beverage tax posters. Physical activity labels led to a 34% (MR, 0.66; 95% CI, 0.51-0.87) reduction in the number of unhealthy beverages sold at the machine level and 35% (MR, 0.65; 95% CI, 0.50-0.86) reduction in mean calories sold. Traffic light labels also led to a 30-calorie reduction (b = -30.46; 95% CI, -49.36 to -11.56) per customer trip in the customer purchase analyses compared to physical activity labels. There were very few significant differences for snack machines., Conclusions and Relevance: In this 13-month randomized trial of 267 vending machines, the traffic light and physical activity labels encouraged healthier beverage purchases, but no change in snack sales, compared with a beverage tax poster. Corporations and governments should consider such labeling approaches to promote healthier beverage choices., Trial Registration: ClinicalTrials.gov Identifier: NCT06260176.

Objective: We assessed the impact of an online intervention using clinician prompts for human papillomavirus (HPV) vaccination with a cluster randomized controlled trial., Methods: The randomized trial occurred July 2021-January 2022 in 48 primary care pediatric practices (24 intervention, 24 control) across the US. We trained clinicians via two online learning modules, plus weekly ''quick tips'' delivered via text or email. The training taught practices to implement a staff prompt to the clinician (e.g., printed reminders placed on the keyboard) plus electronic health record (EHR) prompts (if not already done) at well and acute/chronic visits for initial and subsequent HPV vaccination. We assessed missed opportunities for HPV vaccination using logistic regression models accounting for clustering by practice on an intent to treat basis. Surveys assessed facilitators and barriers to using prompts., Results: During the 6-month intervention, missed opportunities for HPV vaccination increased (worsened) in both intervention and control groups. However, at well child care visits, missed opportunities for the initial HPV vaccine increased by 4.5 (95% CI: -9.0%, -0.1%) percentage points less in intervention versus control practices. Change in missed opportunities for subsequent doses at well child care and non-well child care visits did not differ between trial groups. An end-of trial survey found understaffing as a common challenge., Conclusions: Clinician prompts reduced missed opportunities for HPV vaccination at well child care visits. Understaffing related to the COVID-19 pandemic may have led to worsening missed opportunities for both groups and likely impeded practices in fully implementing changes., Competing Interests: Declaration of Competing Interest Dr. Humiston has the following conflicts of interest: until 9/2022, Dr. Humiston’s employer received grant money for her work sponsored by the Pediatric Infectious Diseases Society (PIDS) Foundation, a not-for-profit organization. PIDS is funded for the project through unrestricted joint educational grants from Sanofi US, Merck & Co., Inc., Pfizer, Inc., GlaxoSmithKline, and Seqirus USA, Inc., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

We pay tribute to Marshall Joffe, PhD, and his substantial contributions to the field of causal inference with focus in biostatistics and epidemiology. By compiling narratives written by us, his colleagues, we not only present highlights of Marshall's research and their significance for causal inference but also offer a portrayal of Marshall's personal accomplishments and character. Our discussion of Marshall's research notably includes (but is not limited to) handling of posttreatment variables such as noncompliance, employing G-estimation for treatment effects on failure-time outcomes, estimating effects of time-varying exposures subject to time-dependent confounding, and developing a causal framework for case-control studies. We also provide a description of some of Marshall's unpublished work, which is accompanied by a bonus anecdote. We discuss future research directions related to Marshall's research. While Marshall's impact in causal inference and the world outside of it cannot be wholly captured by our words, we hope nonetheless to present some of what he has done for our field and what he has meant to us and to his loved ones., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a responsive instrument in psoriatic arthritis (PsA) and whether it differentiates between axial and peripheral disease activity in PsA., Methods: Individuals with PsA initiating therapy in a longitudinal cohort study based in the United States were included. Axial PsA (axPsA), most often also associated with peripheral disease, was defined as fulfillment of the Assessment of Spondyloarthritis international Society axial spondyloarthritis classification criteria or presence of axial disease imaging features. Baseline BASDAI, individual BASDAI items, patient global assessment, patient pain, and Routine Assessment of Patient Index Data 3, and score changes following therapy initiation were descriptively reported. Standardized response means (SRMs) were calculated as the mean change divided by the SD of the change., Results: The mean (SD) baseline BASDAI score at the time of therapy initiation was 5.0 (2.2) among those with axPsA (n = 40) and 4.8 (2.0) among those with peripheral-only disease (n = 79). There was no significant difference in patient-reported outcome scores between the groups. The mean change for BASDAI was similar among axial vs peripheral disease (-0.75 vs -0.83). SRMs were similar across axial vs peripheral disease for BASDAI (-0.37 vs -0.44) and the individual BASDAI items., Conclusion: BASDAI has reasonable responsiveness in PsA but does not differentiate between axPsA and peripheral PsA. (ClinicalTrials.gov: NCT03378336)., (Copyright © 2024 by the Journal of Rheumatology.)

Importance: Despite the frequency of total knee arthroplasty (TKA) and clinical implications of prosthetic joint infections (PJIs), knowledge gaps remain concerning the incidence, microbiological study results, and factors associated with these infections., Objectives: To identify the incidence rates, organisms isolated from microbiological studies, and patient and surgical factors of PJI occurring early, delayed, and late after primary TKA., Design, Setting, and Participants: This cohort study obtained data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse on patients who underwent elective primary TKA in the VA system between October 1, 1999, and September 30, 2019, and had at least 1 year of care in the VA prior to TKA. Patients who met these criteria were included in the overall cohort, and patients with linked Veterans Affairs Surgical Quality Improvement Program (VASQIP) data composed the VASQIP cohort. Data were analyzed between December 9, 2021, and September 18, 2023., Exposures: Primary TKA as well as demographic, clinical, and perioperative factors., Main Outcomes and Measures: Incident hospitalization with early, delayed, or late PJI. Incidence rate (events per 10 000 person-months) was measured in 3 postoperative periods: early (≤3 months), delayed (between >3 and ≤12 months), and late (>12 months). Unadjusted Poisson regression was used to estimate incidence rate ratios (IRRs) with 95% CIs of early and delayed PJI compared with late PJI. The frequency of organisms isolated from synovial or operative tissue culture results of PJIs during each postoperative period was identified. A piecewise exponential parametric survival model was used to estimate IRRs with 95% CIs associated with demographic and clinical factors in each postoperative period., Results: The 79 367 patients (median (IQR) age of 65 (60-71) years) in the overall cohort who underwent primary TKA included 75 274 males (94.8%). A total of 1599 PJIs (2.0%) were identified. The incidence rate of PJI was higher in the early (26.8 [95% CI, 24.8-29.0] events per 10 000 person-months; IRR, 20.7 [95% CI, 18.5-23.1]) and delayed periods (5.4 [95% CI, 4.9-6.0] events per 10 000 person-months; IRR, 4.2 [95% CI, 3.7-4.8]) vs the late postoperative period (1.3 events per 10 000 person-months). Staphylococcus aureus was the most common organism isolated overall (489 [33.2%]); however, gram-negative infections were isolated in 15.4% (86) of early PJIs. In multivariable analyses, hepatitis C virus infection, peripheral artery disease, and autoimmune inflammatory arthritis were associated with PJI across all postoperative periods. Diabetes, chronic kidney disease, and obesity (body mass index of ≥30) were not associated factors. Other period-specific factors were identified., Conclusions and Relevance: This cohort study found that incidence rates of PJIs were higher in the early and delayed vs late post-TKA period; there were differences in microbiological cultures and factors associated with each postoperative period. These findings have implications for postoperative antibiotic use, stratification of PJI risk according to postoperative time, and PJI risk factor modification.

Importance: Policymakers and researchers have proposed a variety of interpretative front-of-package food labeling systems, but it remains unclear which is most effective at encouraging people to choose healthier foods and beverages, including among people with less education., Objective: To test the effects of 4 interpretative front-of-package food labeling systems on the healthfulness of beverage and snack selections, overall and by education level., Design, Setting, and Participants: This randomized clinical trial of a national sample of US adults 18 years and older was conducted online from November 16 to December 3, 2022., Intervention: Participants were randomized to view products with 1 of 5 food labeling systems, including control (calorie labels only) or 1 of 4 interpretative labeling systems: green ("choose often") labels added to healthy foods; single traffic light labels added to healthy, moderately healthy, and unhealthy foods; physical activity calorie equivalent labels added to all products; and nutrient warning labels added to products high in calories, sugar, saturated fat, or sodium. All conditions had calorie labels on all products., Main Outcomes and Measures: Participants selected 1 of 16 beverages and 1 of 16 snacks that they wanted to hypothetically purchase. The primary outcomes were calories selected from beverages and from snacks. Secondary outcomes included label reactions and perceptions., Results: A total of 7945 participants completed the experiment and were included in analyses (4078 [51%] female, 3779 [48%] male, and 88 [1%] nonbinary or another gender; mean [SD] age, 47.5 [17.9 years]). Compared with the control arm, exposure to the green (average differential effect [ADE], -34.2; 95% CI, -42.2 to -26.1), traffic light (ADE, -31.5; 95% CI, -39.5 to -23.4), physical activity (ADE, -39.0; 95% CI, -47.0 to -31.1), or nutrient warning labels (ADE, -28.2; 95% CI, -36.2 to -20.2) led participants to select fewer calories from beverages (all P < .001). Similarly, compared with the control label, exposure to the green (ADE, -12.7; 95% CI, -17.3 to -8.2), traffic light (ADE, -13.7; 95% CI, -18.2 to -9.1), physical activity (ADE, -18.5; 95% CI, -23.1 to -13.9), or nutrient warning labels (ADE, -14.2; 95% CI, -18.8 to -9.6) led participants to select fewer calories from snacks (all P < .001). These effects did not differ by education level. The green labels were rated as less stigmatizing than the other interpretative systems but otherwise generally received the least favorable label reactions and perceptions (eg, elicited less attention, were perceived as less trustworthy), while the nutrient warnings and physical activity labels received the most favorable ratings., Conclusions and Relevance: In this randomized clinical trial of front-of-package food labeling systems, all 4 interpretative labeling systems reduced calories selected from beverages and from snacks compared with calorie labels, with no differences by education level., Trial Registration: ClinicalTrials.gov Identifier: NCT05432271.

Purpose: The Coronavirus Disease 2019 pandemic disrupted healthcare, but the impact on vaccination missed opportunities (MOs, vaccine-eligible visits without vaccination) is unknown. We evaluated pandemic-related trends in MOs at adolescent well-care visits for three vaccines: human papillomavirus; quadrivalent meningococcal conjugate; and tetanus, diphtheria, and acellular pertussis (Tdap)., Methods: We analyzed electronic health record data from 24 pediatric primary care practices in 13 states from 1/1/2018 to 12/31/2021. Segmented logistic regression estimated risk differences for MOs during the pandemic relative to prepandemic trends., Results: Among 106,605 well-care visits, we observed decreases in MOs prepandemic followed by an increase in MOs during the pandemic for all three vaccines. Relative to prepandemic, MOs increased for human papillomavirus (+15.9%, 95% confidence interval [CI]: 11.7%, 20.1%), meningococcal conjugate (+9.4%, 95% CI: 5.2%, 13.7%), and tetanus, diphtheria, and acellular pertussis (Tdap) (+ 8.2%, 95% CI: 4.3%, 12.1%)., Discussion: Increases in vaccine MOs during the pandemic equaled or exceeded pre-pandemic decreases. Reducing MOs in adolescent well-care could raise vaccine coverage., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences., Materials and Methods: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity., Results: An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms., Conclusions: A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.

Objective: To test the hypothesis that a feedback-based intervention would reduce human papillomavirus (HPV) vaccine missed opportunities., Methods: In a longitudinal cluster randomized controlled trial of 48 pediatric primary care practices, we allocated half the practices to receive a sequential, multicomponent intervention phased over consecutive periods. In a prior trial (period 1), communication skills training reduced missed opportunities for the initial HPV vaccine dose at well visits but not at acute/chronic visits. The current trial (period 2) evaluated the added value of performance feedback to clinicians after communication training. Performance feedback consisted of an introductory training module, weekly electronic "Quick Tips," and 3 individualized performance feedback reports to clinicians. We fit logistic regression models for the primary outcome of HPV vaccination missed opportunities using generalized estimating equations with independence working correlation, accounting for clustering at the practice level., Results: Performance feedback resulted in a 3.4 (95% confidence interval [CI]: -6.8, 0.0) percentage point greater reduction in missed HPV vaccine opportunities for the intervention versus control group during acute/chronic visits for subsequent HPV vaccinations (dose 2 or 3). However, during well visits for HPV vaccination dose #1, intervention practices increased missed opportunities (worsened) by 4.2 (95% CI: 1.0, 7.4) percentage points more than control practices, reducing the prior period 1 improvements and blunting the overall effect of performance feedback. We did not observe differences for the other visit/dose categories., Conclusions: Performance feedback improved HPV vaccination for one subset of visits (acute/chronic, subsequent HPV vaccinations due), but not for well visits., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Sexual dysfunction (SD), including erectile (ED) and ejaculatory dysfunction, is associated with diminished quality of life (QoL) in men with UCPPS (chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and/or interstitial cystitis/bladder pain syndrome (IC/BPS))., Aim: We sought to compare SD among male patients with UCPPS, other chronic pain conditions (positive controls, PC), and healthy controls (HC) without chronic pain, and to evaluate the association of comorbidities, psychosocial factors, and urologic factors of SD in all 3 groups., Methods: Baseline data from male UCPPS participants, PC (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and HC enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping Study were included in the analysis. Sexual function was assessed using the International Index of Erectile Function-Erectile Function Domain (IIEFEF) and Ejaculatory Function Scale (EFS). Male ED was defined as a composite IIEF-EF score <21. Higher EFS score indicated worse sexual dysfunction; no threshold to define SD was identified for the EFS. Multivariable logistic and linear regression was used to investigate associations of comorbidities, psychosocial factors, and urologic factors with ED and ejaculatory, respectively., Outcomes: Comorbidities, genital pain, and psychosocial factors are associated with SD across the study population and male patients with UCPPS had a high prevalence of ED and greater ejaculatory dysfunction., Results: There were 191 males with UCPPS; 44 PC; and 182 HC. Males with UCPPS had worse SD compared to PC and HC including lower mean IIEF-EF scores, greater degree of ejaculatory dysfunction, and lower quality of sexual relationships. Among all 3 cohorts, depression, stress, and pain were associated with ED in univariable and multivariable analysis, as was diabetes mellitus. Pain in the genitalia, severity of urinary symptoms, depression, stress, and history of childhood sexual trauma were associated with ejaculatory dysfunction in univariable and multivariable analysis., Clinical Implications: A multidisciplinary approach that addresses the identified risk factors for SD may improve overall QoL in males with UCPPS., Strengths and Limitations: Our study is strengthened by its use of validated, patient-reported questionnaires and inclusion of healthy and positive controls. Our understanding of the role of IC in this study is limited because only 1 patient in the study had IC/BPS as a sole diagnosis., Conclusions: When compared to healthy controls and patients with other chronic pain conditions, males with UCPPS experience higher degrees of SD, including erectile and ejaculatory dysfunction. Loh-Doyle JC, Stephens-Shields AJ, Rolston R, et al. Predictors of Male Sexual Dysfunction in Urologic Chronic Pelvic Pain Syndrome (UCPPS), Other Chronic Pain Syndromes, and Healthy Controls in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. J Sex Med 2022;19:1804-1812., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The Lung Allocation Score (LAS) is used in the U.S. to prioritize lung transplant candidates. Selection bias, induced by dependent censoring of waitlisted candidates and prediction of posttransplant survival among surviving, transplanted patients only, is only partially addressed by the LAS. Recently, a modified LAS (mLAS) was designed to mitigate such bias. Here, we estimate the clinical impact of replacing the LAS with the mLAS., Methods: We considered lung transplant candidates waitlisted during 2016 and 2017. LAS and mLAS scores were computed for each registrant at each observed organ offer date; individuals were ranked accordingly. Patient characteristics associated with better priority under the mLAS were investigated via logistic regression and generalized linear mixed models. We also determined whether differences in rank were explained more by changes in predicted pre- or posttransplant survival. Simulations examined how 1-year waitlist, posttransplant, and overall survival might change under the mLAS., Results: Diagnosis group, 6-minute walk distance, continuous mechanical ventilation, functional status, and age demonstrated the highest impact on differential allocation. Differences in rank were explained more by changes in predicted pretransplant survival than changes in predicted posttransplant survival, suggesting that selection bias has more impact on estimates of waitlist urgency. Simulations suggest that for every 1000 waitlisted individuals, 12.8 (interquartile range: 5.2-24.3) fewer waitlist deaths per year would occur under the mLAS, without compromising posttransplant and overall survival., Conclusions: Implementing a mLAS that mitigates selection bias into clinical practice can lead to important differences in allocation and possibly modest improvement in waitlist survival., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: Oral cancer is the sixth most common cancer worldwide and is the seventh most common in Botswana. Lack of improvement in oral cancer survival despite the availability of multiple treatment options may be due to the high prevalence of advanced stage at presentation. We identified risk factors for presenting with oral cancer at an advanced stage to facilitate interventions to reduce mortality from oral cancers., Methods: A retrospective cohort analysis was conducted among individuals with biopsy-confirmed oral cancer at Princess Marina Hospital in Gaborone, Botswana, between 2010 and 2020. Data collected included age at diagnosis, sex, place of residence, HIV status, oral cancer stage, and oral subsite. Multivariable analyses were controlled for age, sex, district of residence, and oral subsite., Results: Of the 218 records analyzed, 79% were male, 58% were HIV-positive, the median age was 56 years (interquartile range: 47-63), and 67% presented with advanced-stage disease. Cancers from hidden oral sites were more likely to present at an advanced stage with an adjusted odds ratio (OR) of 2.98 (95% CI, 1.29 to 6.89; P = .01). Residence in socioeconomically disadvantaged districts was associated with higher likelihood (OR, 2.36; 95% CI, 1.28 to 4.39; P = .01) of advanced stage presentation compared with other districts. HIV infection was not associated with risk of advanced lesion presentation (OR, 1; 95% CI, 0.61 to 1.61; P = .97)., Conclusion: Hidden oral cancer sites and residence in districts with limited access to care were risk factors for advanced oral cancer at the time of diagnosis in Botswana. These findings support a need to increase efforts to improve access to care and increase oral cancer awareness to decrease the burden of advanced oral cancer.

Background: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported., Objective: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia., Design: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505)., Setting: 46 U.S. and Canadian hospitals., Participants: Patients aged 50 years or older undergoing hip fracture surgery., Intervention: Spinal or general anesthesia., Measurements: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care., Results: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups., Limitation: Missing outcome data and multiple outcomes assessed., Conclusion: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia., Primary Funding Source: Patient-Centered Outcomes Research Institute .

Context: Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol., Objective: To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism., Methods: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests., Result: Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone., Conclusion: Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Propensity score methods are increasingly used as a tool to control for confounding bias in pharmacoepidemiologic studies. The propensity score is a dimension reducing balancing score, creating treatment and reference groups that have comparable distributions of measured covariates. The purpose of this methods review is to provide an overview of the use of propensity score methods, including a summary of important data assumptions, various applications of the propensity score, and how to evaluate covariate balance. This article is intended for pharmacists and researchers who wish to receive an introduction to propensity score methods and be able to engage in high-level discussions on application and reporting., Competing Interests: Potential Conflicts of Interest: CEL is an Executive Committee Member of the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training. The Center receives funding from Pfizer and Sanofi to support trainee education. CEL recently received honoraria from the American College of Clinical Pharmacy Foundation and University of Florida, unrelated to the topic of this paper. CEL is a Special Government Employee of the US Food and Drug Administration and currently consults for the Reagan-Udall Foundation for the FDA.

Smoking burdens are greatest among underserved patients. Lung cancer screening (LCS) reduces mortality among individuals at risk for smoking-associated lung cancer. Although LCS programs must offer smoking cessation support, the interventions that best promote cessation among underserved patients in this setting are unknown. This stakeholder-engaged, pragmatic randomized clinical trial will compare the effectiveness of four interventions promoting smoking cessation among underserved patients referred for LCS. By using an additive study design, all four arms provide standard "ask-advise-refer" care. Arm 2 adds free or subsidized pharmacologic cessation aids, arm 3 adds financial incentives up to $600 for cessation, and arm 4 adds a mobile device-delivered episodic future thinking tool to promote attention to long-term health goals. We hypothesize that smoking abstinence rates will be higher with the addition of each intervention when compared with arm 1. We will enroll 3,200 adults with LCS orders at four U.S. health systems. Eligible patients include those who smoke at least one cigarette daily and self-identify as a member of an underserved group (i.e., is Black or Latinx, is a rural resident, completed a high school education or less, and/or has a household income <200% of the federal poverty line). The primary outcome is biochemically confirmed smoking abstinence sustained through 6 months. Secondary outcomes include abstinence sustained through 12 months, other smoking-related clinical outcomes, and patient-reported outcomes. This pragmatic randomized clinical trial will identify the most effective smoking cessation strategies that LCS programs can implement to reduce smoking burdens affecting underserved populations. Clinical trial registered with clinicaltrials.gov (NCT04798664). Date of registration: March 12, 2021. Date of trial launch: May 17, 2021.

Background: The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied., Methods: We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days., Results: A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30)., Conclusions: Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia. (Funded by the Patient-Centered Outcomes Research Institute; REGAIN ClinicalTrials.gov number, NCT02507505.)., (Copyright © 2021 Massachusetts Medical Society.)

A key factor in designing randomized clinical trials is the sample size required to achieve a particular level of power to detect the benefit of a treatment. Sample size calculations depend upon the expected benefits of a treatment (effect size), the accuracy of measurement of the primary outcome, and the level of power specified by the investigators. In this study, we show that radiomic models, which leverage complex brain MRI patterns and machine learning, can be utilized in clinical trials with protocols that incorporate baseline MR imaging to significantly increase statistical power to detect treatment effects. Akin to the historical control paradigm, we propose to utilize a radiomic prediction model to generate a pseudo-control sample for each individual in the trial of interest. Because the variability of expected outcome across patients can mask our ability to detect treatment effects, we can increase the power to detect a treatment effect in a clinical trial by reducing that variability through using radiomic predictors as surrogates. We illustrate this method with simulations based on data from two cohorts in different neurologic diseases, Alzheimer's disease and glioblastoma multiforme. We present sample size requirements across a range of effect sizes using conventional analysis and models that include a radiomic predictor. For our Alzheimer's disease cohort, at an effect size of 0.35, total sample size requirements for 80% power declined from 246 to 212 for the endpoint cognitive decline. For our glioblastoma multiforme cohort, at an effect size of 1.65 with the endpoint survival time, total sample size requirements declined from 128 to 74. This methodology can decrease the required sample sizes by as much as 50%, depending on the strength of the radiomic predictor. The power of this method grows with increased accuracy of radiomic prediction, and furthermore, this method is most helpful when treatment effect sizes are small. Neuroimaging biomarkers are a powerful and increasingly common suite of tools that are, in many cases, highly predictive of disease outcomes. Here, we explore the possibility of using MRI-based radiomic biomarkers for the purpose of improving statistical power in clinical trials in the contexts of brain cancer and prodromal Alzheimer's disease. These methods can be applied to a broad range of neurologic diseases using a broad range of predictors of outcome to make clinical trials more efficient., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Incentivizing research participation is controversial and variably regulated because of uncertainty regarding whether financial incentives serve as undue inducements by diminishing peoples' sensitivity to research risks or unjust inducements by preferentially increasing enrollment among underserved individuals., Objective: To determine whether incentives improve enrollment in real randomized clinical trials (RCTs) or serve as undue or unjust inducements., Design, Setting, and Participants: Two RCTs of incentives that were embedded in 2 parent RCTs, 1 comparing smoking cessation interventions (conducted at smoking cessation clinics in 2 health systems) and 1 evaluating an ambulation intervention (conducted across wards of the Hospital of the University of Pennsylvania) included all persons eligible for the parent trials who did not have prior knowledge of the incentives trials. Recruitment occurred from September 2017 to August 2019 for the smoking trial and January 2018 through May 2019 for the ambulation trial; data were analyzed from January 2020 to July 2020., Interventions: Patients were randomly assigned to incentives of $0, $200, or $500 for participating in the smoking cessation trial and $0, $100, or $300 for the ambulation trial., Main Outcomes and Measures: The primary outcome of each incentive trial was the proportion of people assigned to each recruitment strategy that consented to participate. Each trial was powered to test the hypotheses that incentives served neither as undue inducements (based on the interaction between incentive size and perceived research risk, as measured using a 10-point scale, on the primary outcome), nor unjust inducements (based on the interaction between incentive size and participants' self-reported income). Noninferiority methods were used to test whether the data were compatible with these 2 effects of incentives and superiority methods to compare the primary and other secondary outcomes., Results: There were a total of 654 participants (327 women [50.0%]; mean [SD] age, 50.6 [12.1] years; 394 Black/African American [60.2%], 214 White [32.7%], and 24 multiracial individuals [3.7%]) in the smoking trial, and 642 participants (364 women [56.7%]; mean [SD] age, 46.7 [15.6] years; 224 Black/African American [34.9%], 335 White [52.2%], and 5 multiracial individuals [0.8%]) in the ambulation trial. Incentives significantly increased consent rates among those in the smoking trial in 47 of 216 (21.8%), 78 of 217 (35.9%), and 104 of 221 (47.1%) in the $0, $200, and $500 groups, respectively (adjusted odds ratio [aOR] for each increase in incentive, 1.70; 95% CI, 1.34-2.17; P < .001). Incentives did not increase consent among those in the ambulation trial: 98 of 216 (45.4%), 102 of 212 (48.1%), and 92 of 214 (43.0%) in the $0, $100, and $300 groups, respectively (aOR, 0.88; 95% CI, 0.64-1.22; P = .45). In neither trial was there evidence of undue or unjust inducement (upper confidence limits of ORs for undue inducement, 1.15 and 0.99; P < .001 showing noninferiority; upper confidence limits of ORs for unjust inducement, 1.21 and 1.26; P = .01 and P < .001, respectively). There were no significant effects of incentive size on the secondary outcomes in either trial, including time spent reviewing the risk sections of consent forms, perceived research risks, trial understanding, perceived coercion, or therapeutic misconceptions., Conclusions and Relevance: In these 2 randomized clinical trials, financial incentives increased trial enrollment in 1 of 2 trials and did not produce undue or unjust inducement or other unintended consequences in either trial., Trial Registration: ClinicalTrials.gov Identifier: NCT02697799.

Background/aims: Design of clinical trials requires careful decision-making across several dimensions, including endpoints, eligibility criteria, and subgroup enrichment. Clinical trial simulation can be an informative tool in trial design, providing empirical evidence by which to evaluate and compare the results of hypothetical trials with varying designs. We introduce a novel simulation-based approach using observational data to inform the design of a future pragmatic trial., Methods: We utilize propensity score-adjusted models to simulate hypothetical trials under alternative endpoints and enrollment criteria. We apply our approach to the design of pragmatic trials in psoriatic arthritis, using observational data embedded within the Tight Control of Inflammation in Early Psoriatic Arthritis study to simulate hypothetical open-label trials comparing treatment with tumor necrosis factor-α inhibitors to methotrexate. We first validate our simulations of a trial with traditional enrollment criteria and endpoints against a recently published trial. Next, we compare simulated treatment effects in patient populations defined by traditional and broadened enrollment criteria, where the latter is consistent with a future pragmatic trial. In each trial, we also consider five candidate primary endpoints., Results: Our results highlight how changes in the enrolled population and primary endpoints may qualitatively alter study findings and the ability to detect heterogeneous treatment effects between clinical subgroups. For treatments of interest in the study of psoriatic arthritis, broadened enrollment criteria led to diluted estimated treatment effects. Endpoints with greater responsiveness to treatment compared with a traditionally used endpoint were identified. These considerations, among others, are important for designing a future pragmatic trial aimed at having high external validity with relevance for real-world clinical practice., Conclusion: Observational data may be leveraged to inform design decisions in pragmatic trials. Our approach may be generalized to the study of other conditions where existing trial data are limited or do not generalize well to real-world clinical practice, but where observational data are available.

Background: The lung allocation system in the U.S. prioritizes lung transplant candidates based on estimated pre- and post-transplant survival via the Lung Allocation Scores (LAS). However, these models do not account for selection bias, which results from individuals being removed from the waitlist due to receipt of transplant, as well as transplanted individuals necessarily having survived long enough to receive a transplant. Such selection biases lead to inaccurate predictions., Methods: We used a weighted estimation strategy to account for selection bias in the pre- and post-transplant models used to calculate the LAS. We then created a modified LAS using these weights, and compared its performance to that of the existing LAS via time-dependent receiver operating characteristic (ROC) curves, calibration curves, and Bland-Altman plots., Results: The modified LAS exhibited better discrimination and calibration than the existing LAS, and led to changes in patient prioritization., Conclusions: Our approach to addressing selection bias is intuitive and can be applied to any organ allocation system that prioritizes patients based on estimated pre- and post-transplant survival. This work is especially relevant to current efforts to ensure more equitable distribution of organs., (© 2021. The Author(s).)

Importance: Missed opportunities for human papillomavirus (HPV) vaccination during pediatric health care visits are common., Objectives: To evaluate the effect of online communication training for clinicians on missed opportunities for HPV vaccination rates overall and at well-child care (WCC) visits and visits for acute or chronic illness (hereafter referred to as acute or chronic visits) and on adolescent HPV vaccination rates., Design, Setting, and Participants: From December 26, 2018, to July 30, 2019, a longitudinal cluster randomized clinical trial allocated practices to communication training vs standard of care in staggered 6-month periods. A total of 48 primary care pediatric practices in 19 states were recruited from the American Academy of Pediatrics Pediatric Research in Office Settings network. Participants were clinicians in intervention practices. Outcomes were evaluated for all 11- to 17-year-old adolescents attending 24 intervention practices (188 clinicians) and 24 control practices (177 clinicians). Analyses were as randomized and performed on an intent-to-treat basis, accounting for clustering by practice., Interventions: Three sequential online educational modules were developed to help participating clinicians communicate with parents about the HPV vaccine. Weekly text messages were sent to participating clinicians to reinforce learning. Statisticians were blinded to group assignment., Main Outcomes and Measures: Main outcomes were missed opportunities for HPV vaccination overall and for HPV vaccine initiation and subsequent doses at WCC and acute or chronic visits (visit-level outcome). Secondary outcomes were HPV vaccination rates (person-level outcome). Outcomes were compared during the intervention vs baseline., Results: Altogether, 122 of 188 clinicians in intervention practices participated; of these, 120, 119, and 116 clinicians completed training modules 1, 2, and 3, respectively. During the intervention period, 29 206 adolescents (14 664 girls [50.2%]; mean [SD] age, 14.2 [2.0] years) made 15 888 WCC and 28 123 acute or chronic visits to intervention practices; 33 914 adolescents (17 069 girls [50.3%]; mean [SD] age, 14.2 [2.0] years) made 17 910 WCC and 35 281 acute or chronic visits to control practices. Intervention practices reduced missed opportunities overall by 2.4 percentage points (-2.4%; 95% CI, -3.5% to -1.2%) more than controls. Intervention practices reduced missed opportunities for vaccine initiation during WCC visits by 6.8 percentage points (-6.8%; 95% CI, -9.7% to -3.9%) more than controls. The intervention had no effect on missed opportunities for subsequent doses of the HPV vaccine or at acute or chronic visits. Adolescents in intervention practices had a 3.4-percentage point (95% CI, 0.6%-6.2%) greater improvement in HPV vaccine initiation compared with adolescents in control practices., Conclusions and Relevance: This scalable, online communication training increased HPV vaccination, particularly HPV vaccine initiation at WCC visits. Results support dissemination of this intervention., Trial Registration: ClinicalTrials.gov Identifier: NCT03599557.

Aim: The purpose of this study was to determine the extent of agreement between adherence measures obtained using two technological interventions, electronic monitoring (EM) and a smartphone application (App)., Background: Clinicians, patients, and researchers depend on valid measurements of medication adherence to inform the delivery of preemptive care when needed. Technology is routinely used for monitoring medication adherence in both clinical practice and research, yet there is a dearth of research comparing novel App based approaches to traditional approaches used for assessing medication adherence., Methods: Adherence rates were captured on both the EM and the App for 3697 daily observations from 44 participants with acute coronary syndrome over 90 days immediately following discharge from acute care. For EM, adherence was measured using EM equipped pill bottles. For the App, adherence was measured by having participants upload daily photos to the App prior to taking their daily aspirin. Agreement was assessed using a Bland-Altman analysis., Results: The mean adherence rate was higher on the App, 92%, than the EM, 78% (p < 0.001). The mean difference in adherence rates between these methods was 14% (95% Confidence Interval: -23%, -5%)., Conclusions: These findings illustrate a lack of agreement between technological interventions used for measuring adherence in cardiovascular patient populations, with higher adherence rates observed with the App compared to EM. These findings are salient given the increased reliance on telehealth due to the ongoing COVID-19 pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The implementation of evidence-based practices in critical care faces specific challenges, including intense time pressure and patient acuity. These challenges result in evidence-to-practice gaps that diminish the impact of proven-effective interventions for patients requiring intensive care unit support. Research is needed to understand and address implementation determinants in critical care settings., Methods: The Handoffs and Transitions in Critical Care-Understanding Scalability (HATRICC-US) study is a Type 2 hybrid effectiveness-implementation trial of standardized operating room (OR) to intensive care unit (ICU) handoffs. This mixed methods study will use a stepped wedge design with randomized roll out to test the effectiveness of a customized protocol for structuring communication between clinicians in the OR and the ICU. The study will be conducted in twelve ICUs (10 adult, 2 pediatric) based in five United States academic health systems. Contextual inquiry incorporating implementation science, systems engineering, and human factors engineering approaches will guide both protocol customization and identification of protocol implementation determinants. Implementation mapping will be used to select appropriate implementation strategies for each setting. Human-centered design will be used to create a digital toolkit for dissemination of study findings. The primary implementation outcome will be fidelity to the customized handoff protocol (unit of analysis: handoff). The primary effectiveness outcome will be a composite measure of new-onset organ failure cases (unit of analysis: ICU)., Discussion: The HATRICC-US study will customize, implement, and evaluate standardized procedures for OR to ICU handoffs in a heterogenous group of United States academic medical center intensive care units. Findings from this study have the potential to improve postsurgical communication, decrease adverse clinical outcomes, and inform the implementation of other evidence-based practices in critical care settings., Trial Registration: ClinicalTrials.gov identifier: NCT04571749 . Date of registration: October 1, 2020.

Purpose: We sought to determine the time-lagged, bidirectional relationships among clinical variables of pelvic pain, urinary symptoms, negative mood, nonpelvic pain and quality of life in men and women with urological chronic pelvic pain syndrome, incorporating interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: A total of 204 female and 166 male patients were assessed up to 24 times over a 48-week period on the 5 primary outcomes. A lagged autoregressive analysis was applied to determine the directional relationship of one variable to another 2 weeks later, beyond that of the concurrent relationships at each time point and autocorrelations and trends over time., Results: The results show clear evidence for a bidirectional positive relationship between changes in pelvic pain severity and urinary symptom severity. Increases in either variable predicted significant increases in the other 2 weeks later, beyond that explained by their concurrent relationship at each time point. Pelvic pain and to a lesser degree urinary frequency also showed similar bidirectional relationships with negative mood and decreased quality of life. Interestingly, neither pelvic pain or urinary symptom severity showed lagged relationships with nonpelvic pain severity., Conclusions: Results document for the first time specific short-term positive feedback between pelvic pain and urinary symptoms, and between symptoms of urological chronic pelvic pain syndrome, mood and quality of life. The feedforward aspects of these relationships can facilitate a downward spiral of increased symptoms and worsening psychosocial function, and suggest the need for multifaceted treatments and assessment to address this possibility in individual patients.

Background/objectives: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men., Design: Longitudinal, multisite placebo-controlled trial., Setting/participants: Men enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study., Results: Mean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10., Conclusion: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function., (© 2020 The American Geriatrics Society.)

Context: Testosterone treatment of hypogonadal men improves their hemoglobin, but the mechanism is not understood., Objective: To investigate possible mechanisms by which testosterone stimulates erythropoiesis in hypogonadal older men with unexplained or iron-deficiency anemia., Design: The Anemia Trial of The Testosterone Trials, a placebo-controlled study in older, hypogonadal men., Setting: Twelve academic medical centers., Participants: A total of 95 hypogonadal men (testosterone < 275 ng/mL) ≥65 years with anemia (hemoglobin < 12.7 g/dL). They were classified as having unexplained (n = 58) or iron deficiency anemia (n = 37)., Intervention: Testosterone or placebo gel for 1 year., Main Outcome Measures: Markers of iron metabolism during the first 3 months of treatment., Results: Testosterone replacement significantly (P < 0.001) increased hemoglobin in the 58 men who had unexplained anemia (adjusted mean difference 0.58 g/dL; 95% confidence interval, 0.31-0.85). Testosterone replacement tended to increase hemoglobin in the 37 men who had iron deficiency (0.38 g/dL; -0.19, 0.95), but the response was more variable and not statistically significant (P = 0.19). In men with unexplained anemia, testosterone replacement suppressed hepcidin (-8.2 ng/mL; -13.7, -2.7; P = 0.004) and ferritin (-19.6 µg/L; -32.8, -6.3; P = 0.004), but in men with iron deficiency, testosterone replacement did not. The decrease in hepcidin was moderately correlated with the increase in hemoglobin in the men with unexplained anemia (correlation coefficient -0.35, P = 0.01) but not in those with iron deficiency anemia (correlation coefficient -0.07, P = 0.73)., Conclusions: Testosterone replacement of older hypogonadal men with unexplained anemia stimulates erythropoiesis associated with increased iron mobilization. This effect appears to be attenuated by iron deficiency., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The 2012 implementation of the Patient Protection and Affordable Care Act (ACA) contraceptive coverage mandate removed financial barriers to contraception access for many insured women. Since that time, increases in sexually transmitted disease (STD) rates have been noted, particularly among Black adolescent and young adult women aged 15 to 24 years. It is unclear whether changes in dual-method contraception use (simultaneous use of nonbarrier contraceptive methods and condoms) are associated with the increase in STD rates. A repeated cross-sectional analysis was conducted among adolescent and young adult women to compare pre-ACA data from the 2006-2010 cohort and post-ACA data from the 2013-2015 cohort of the National Survey for Family Growth. A significant decrease in short-acting reversible contraception use (SARC; 78.2% vs. 67.5%; p  <   .01) and a significant increase in long-acting reversible contraception use (LARC; 8.9% vs. 21.8%; p  <   .01) were found, but no significant change in dual-method contraception use was found among pre- versus post-ACA SARC users and SARC nonusers (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 0.64-5.46, p  =   .25), LARC users and LARC nonusers (adjusted odds ratio [AOR]: 1.62, 95% CI: 0.42-6.18, p  =   .48), or White and Black women (AOR: 1.45, 95% CI: 0.66-3.18, p  =   .35). There was no direct association between changes in contraception use and decreased condom use and therefore no indirect association between changes in contraception use and increased STD rates. Health care providers should continue promoting consistent condom use. Additional research is needed to understand recent increases in STD rates among Black women in the post-ACA era.

The question of whether some cases of interstitial cystitis may have an infectious etiology has been debated for some time. Previous studies have looked for the presence of certain specific viruses, but generally did not use the types of sensitive and unbiased approaches that are currently available. As part of the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, we examined urine specimens from interstitial cystitis patients who provided specimens over time and also reported various symptoms at the time of urine collection. We first performed next-generation sequencing to look for the presence of viruses in urines, and detected two human polyomaviruses that are known to be excreted into urine, BKPyV and JCPyV. We were especially interested in BKPyV because it is a known cause of another bladder disease, hemorrhagic cystitis, in bone marrow transplant recipients. Further analysis of individual samples indicates a trend toward higher excretion of polyomaviruses in patients experiencing increased symptoms.

Aims: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments., Methods: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol., Results: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing., Conclusions: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions., (© 2020 Wiley Periodicals LLC.)

Introduction: Little is known about missed opportunities (MOs) for HPV vaccination during primary care visits at which influenza vaccination is delivered., Methods: We extracted electronic health records for HPV vaccine-eligible 11-to-17-year-olds. We assessed the proportion of visits during which an influenza vaccine was given and an HPV vaccine was due, but not given (i.e., MOs)., Results: Of 56,135 eligible visits, 57.5% represented MOs for HPV vaccination. MOs were more common at visits where an initial versus subsequent HPV vaccine dose was due (68.6% vs. 31.3%) and for acute/chronic and nurse-only visits compared to preventive visits (74.0% and 80.2% vs. 36.7%). In a multivariable model, MOs were more likely for the initial HPV dose and for non-preventive visits, but did not vary by patient sex/age., Conclusions: HPV vaccine MOs were common during visits where influenza vaccine was administered. Increasing simultaneous administration of HPV and influenza vaccines could increase HPV vaccine coverage., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Fiks had an independent research grant from Pfizer. He did not receive salary support, but the grant supported his research team. Dr. Fiks is the co-inventor of the Care Assistant decision and workflow support software. He has earned no income and no licensing agreement exists for the intervention. In the past year, Dr. Humiston has been a consultant to Sanofi Pasteur, which manufactures vaccines, although not HPV vaccine. No other disclosures were reported.]., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Limited research suggests commonalities between urological chronic pelvic pain syndromes (UCPPS) and other nonurological chronic overlapping pain conditions (COPCs) including fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. The goal of this case-control study was to examine similarities and differences between UCPPS and these other COPCs., Materials and Methods: As part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research (MAPP) Network, we examined 1039 individuals with UCPPS (n=424), nonurological COPCs (n=200), and healthy controls (HCs; n=415). Validated standardized measures were used to assess urological symptoms, nonurological pain symptoms, and psychosocial symptoms and traits., Results: Participants with UCPPS had more urological symptoms than nonurological COPCs or HCs (P<0.001); nonurological COPC group also had significantly worse urological symptoms than HCs (P<0.001). Participants with nonurological COPCs reported more widespread pain than those with UCPPS (P<0.001), yet both groups had similarly increased symptoms of anxiety, depression, negative affect, perceived stress, neuroticism, and lower levels of extraversion than HCs (P<0.001). Participants with UCPPS with and without COPCs reported more catastrophizing than those with nonurological COPCs (P<0.001)., Discussion: Findings are consistent with the hypothesis of common underlying biopsychosocial mechanisms and can guide the comprehensive assessment and treatment of these conditions regardless of the primary site of pain or diagnosis. Heightened catastrophizing in UCPPS should be examined to inform psychosocial interventions and improve patient care.

Context: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated., Design: Double-blinded, placebo-controlled trial., Setting: Twelve US academic medical centers., Participants: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded., Interventions: Testosterone or placebo gel for 12 months., Main Outcomes: Percentile changes in PSA during testosterone treatment of 12 months., Results: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8., Conclusions: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL., (Copyright © 2019 Endocrine Society.)

Objectives: As ICUs are increasingly a site of end-of-life care, many have adopted end-of-life care resources. We sought to determine the association of such resources with outcomes of ICU patients., Design: Retrospective cohort study., Setting: Pennsylvania ICUs., Patients: Medicare fee-for-service beneficiaries., Interventions: Availability of any of one hospital-based resource (palliative care consultants) or four ICU-based resources (protocol for withdrawal of life-sustaining therapy, triggers for automated palliative care consultation, protocol for family meetings, and palliative care clinicians embedded in ICU rounds)., Measurements and Main Results: In mixed-effects regression analyses, admission to a hospital with end-of-life resources was not associated with mortality, length of stay, or treatment intensity (mechanical ventilation, hemodialysis, tracheostomy, gastrostomy, artificial nutrition, or cardiopulmonary resuscitation); however, it was associated with a higher likelihood of discharge to hospice (odds ratio, 1.58; 95% CI, 1.11-2.24), an effect that was driven by ICU-based resources (odds ratio, 1.37; 95% CI, 1.04-1.81) rather than hospital-based resources (odds ratio, 1.19; 95% CI, 0.83-1.71). Instrumental variable analysis using differential distance (defined as the additional travel distance beyond the hospital closest to a patient's home needed to reach a hospital with end-of-life resources) demonstrated that among those for whom differential distance would influence receipt of end-of-life resources, admission to a hospital with such resources was not associated with any outcome., Conclusions: ICU-based end-of-life care resources do not appear to change mortality but are associated with increased hospice utilization. Given that this finding was not confirmed by the instrumental variable analysis, future studies should attempt to verify this finding, and identify specific resources or processes of care that impact the care of ICU patients at the end of life.

Background: A recent study of older men participating in the Testosterone Trials (TTrials) defined a clinically meaningful change in the Psychosexual Daily Questionnaire (PDQ) question 4 in hypogonadal men age ≥65 years. This study defines clinically meaningful change in the same population for sexual desire assessed by PDQ question 1., Aim: To determine a clinically meaningful change in the answers to question 1 of the PDQ in hypogonadal older men., Methods: Participants in the Sexual Function Trial of the TTrials were randomly divided into a training and test set. Anchor-based methods, including regression analysis, receiver operating characteristic curves, and empirical cumulative distribution functions, were used to determine a clinically meaningful change on question 1 in the training set, and the selected threshold was evaluated in the test set for an effect of testosterone treatment., Results: A clinically meaningful increase in question 1 of the PDQ was determined to be ≥0.7 points., Clinical Implications: Question 1 of the PDQ can be used to assess sexual desire in response to testosterone treatment., Strengths & Limitations: Data were obtained from a single large study of older hypogonadal men., Conclusion: Clinically meaningful improvement of sexual desire is a change of ≥0.7 in the score of question 1 of the PDQ. Stephens-Shields AJ, Wang C, Preston P, et al. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials. J Sex Med 2019;16:951-953., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level ( p = 0.726 species level, p = 0.222 genus level). IC/BPS participants urine trended to an overabundance of Lactobacillus gasseri ( p = 0.09) detected but had a lower prevalence of Corynebacterium compared with control participants ( p = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than Lactobacillus gasseri and Corynebacterium ( p = 0.08 and p = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.

Introduction: The most common and conceptually sound ethical concerns with financial incentives for research participation are that they may (1) represent undue inducements by blunting peoples' perceptions of research risks, thereby preventing fully informed consent; or (2) represent unjust inducements by encouraging enrollment preferentially among the poor. Neither of these concerns has been shown to manifest in studies testing the effects of incentives on decisions to participate in hypothetical randomized clinical trials (RCTs), but neither has been assessed in real RCTs., Methods and Analyses: We are conducting randomized trials of real incentives embedded within two parent RCTs. In each of two trials conducted in parallel, we are randomizing 576 participants to one of three incentive groups. Following preliminary determination of patients' eligibility in the parent RCT, we assess patients' research attitudes, demographic characteristics, perceived research risks, time spent reviewing consent documents, ability to distinguish research from patient care, and comprehension of key trial features. These quantitative assessments will be supplemented by semi-structured interviews for a selected group of participants that more deeply explore patients' motivations for trial participation. The trials are each designed to have adequate power to rule out undue and unjust inducement. We are also exploring potential benefits of incentives, including possible increased attention to research risks and cost-effectiveness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors., Methods: The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617., Findings: The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall)., Interpretation: Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations., Funding: US National Institute on Aging and AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS)., Purpose: We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation., Methods: For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being., Results: ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year., Conclusions: These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS., Clinical Trial Registration: NCT01098279.

Background: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function., Aim: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains., Methods: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set., Outcomes: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials., Results: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men., Clinical Implications: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T., Strengths & Limitations: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity., Conclusion: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009., (Copyright © 2018. Published by Elsevier Inc.)

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.

In patients with chronic kidney disease (CKD), clinical interest often centers on determining treatments and exposures that are causally related to renal progression. Analyses of longitudinal clinical data in this population are often complicated by clinical competing events, such as end-stage renal disease (ESRD) and death, and time-dependent confounding, where patient factors that are predictive of later exposures and outcomes are affected by past exposures. We developed multistate marginal structural models (MS-MSMs) to assess the effect of time-varying systolic blood pressure on disease progression in subjects with CKD. The multistate nature of the model allows us to jointly model disease progression characterized by changes in the estimated glomerular filtration rate (eGFR), the onset of ESRD, and death, and thereby avoid unnatural assumptions of death and ESRD as noninformative censoring events for subsequent changes in eGFR. We model the causal effect of systolic blood pressure on the probability of transitioning into 1 of 6 disease states given the current state. We use inverse probability weights with stabilization to account for potential time-varying confounders, including past eGFR, total protein, serum creatinine, and hemoglobin. We apply the model to data from the Chronic Renal Insufficiency Cohort Study, a multisite observational study of patients with CKD., (Copyright © 2017 John Wiley & Sons, Ltd.)