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We investigated whether baseline sagittal-plane ankle, knee, and hip contribution to the total support moment (TSM) are each associated with baseline-to-2-year tibiofemoral and patellofemoral tissue damage worsening in adults with knee osteoarthritis. Ambulatory lower-limb kinetics were captured and computed. TSM is the sum of ankle, knee, and hip extensor moments at each instant during gait. Ankle, knee, and hip contributions to TSM were computed as joint moments divided by TSM, expressed as percentages. Participants underwent MRI of both knees at baseline and 2 years later. Logistic regression models assessed associations of baseline ankle contribution to TSM with baseline-to-2-year cartilage damage and bone marrow lesion worsening, adjusted for age, sex, BMI, gait speed, disease severity, and pain. We used similar analytic approaches for knee and hip contributions to TSM. Sample included 391 knees from 204 persons (age[SD]: 64[10] years; 76.5% women). Greater ankle contribution may be associated with increased odds of tibiofemoral cartilage damage worsening (OR = 2.38; 95% CI: 1.02-5.57) and decreased odds of patellofemoral bone marrow lesion worsening (OR = 0.14; 95% CI: 0.03-0.73). The ORs for greater knee contribution were in the protective range for tibiofemoral compartment and in the deleterious range for patellofemoral. Greater hip contribution may be associated with increased odds of tibiofemoral worsening (OR = 2.71; 95% CI: 1.17-6.30). Greater ankle contribution to TSM may be associated with baseline-to-2-year tibiofemoral worsening, but patellofemoral tissue preservation. Conversely, greater knee contribution may be associated with patellofemoral worsening, but tibiofemoral preservation. Preliminary findings illustrate potential challenges in developing biomechanical interventions beneficial to both tibiofemoral and patellofemoral compartments.

Information on bronchoalveolar lavage (BAL) in patients with COVID-19 is limited, and clinical correlation has not been reported. This study investigated the key features of BAL fluids from COVID-19 patients and assessed their clinical significance. A total of 320 BAL samples from 83 COVID-19 patients and 70 non-COVID-19 patients (27 patients with other respiratory viral infections) were evaluated, including cell count/differential, morphology, flow cytometric immunophenotyping, and immunohistochemistry. The findings were correlated with clinical outcomes. Compared to non-COVID-19 patients, BAL from COVID-19 patients was characterized by significant lymphocytosis (p

In a multicenter, phase II investigator-initiated trial of sequential pembrolizumab and AVD, nearly two-thirds of patients with untreated unfavorable or advanced stage classic Hodgkin Lymphoma (cHL) achieved PET-defined complete or near complete metabolic responses (CMR) following 3 doses of pembrolizumab monotherapy. Furthermore, all achieved CMR following 2 cycles of AVD chemotherapy and 100% of patients were alive without relapse at the time of initial publication. We now report long-term follow-up, including 3-year OS and planned correlative analyses. Thirty patients received single agent pembrolizumab every 3 weeks x 3, followed by AVD chemotherapy for 4-6 cycles depending on stage and bulk. PET/CT scan was performed after pembrolizumab monotherapy, 2 cycles of AVD, and at the end of therapy. Baseline biopsy samples were analyzed for genomic alterations of chromosome 9p24.1 and PD-1 pathway markers by immunohistochemistry. At a median follow up of 33.1 months (range, 26.0-43.0), PFS and OS remain 100%. All patients had genomic alterations in 9p24.1 and were positive for PD-L1 by immunohistochemistry. There was no relationship between response to single agent pembrolizumumab measured by decline in metabolic tumor volume and 9p24.1 alterations or PD-1 pathway H-scores. With additional follow-up, sequential pembrolizumab and AVD remains highly effective. The high response rates observed at all PD-ligand levels suggest that even low levels of PD ligand expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase II trial (NCT05008224) to confirm these findings is ongoing.

Clinical trials for systemic lupus erythematosus ("lupus") under enroll Black individuals despite higher disease prevalence, morbidity, and mortality among Black compared to White individuals. To begin to address this disparity, we leveraged community-academic partnerships in 2 US cities (Boston and Chicago) to train popular opinion leaders (POLs) to disseminate information about clinical trials in predominantly Black communities.The team of community and academic partners collaboratively developed a 5-module curriculum about clinical trials, barriers, facilitators, and structural racism in research. We enrolled POLs in Boston and Chicago to participate virtually in the curriculum and assessed knowledge gained by comparing pre- and post-test scores. We described the POLs' ability to disseminate information about clinical trials through their communities.We enrolled 19 POLs in Boston and 16 in Chicago; overall, 71% reported a lupus diagnosis, 94% were female, and 80% self-identified as Black or African American. The program was adapted to virtual formats due to the COVID-19 pandemic. POLs demonstrated significant improvement comparing pre/post scores for the conduct of clinical trials and history of racism in clinical research. Fifteen POLs (43%) reported their dissemination of information about clinical trials. Information reached 425 community members in Boston (90% virtually) and 1,887 in Chicago (95% virtually).By leveraging community-academic partnerships, we developed and implemented a curriculum to promote familiarity with clinical trials, leading to information dissemination by POLs in predominantly Black communities that are underrepresented in lupus clinical trials. The program successfully transitioned to a virtual model during the COVID-19 pandemic.

ImportanceTo our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant.ObjectiveTo evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose–positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma.Design, Setting, and ParticipantsA single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT.InterventionsTwo cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment.Main Outcomes and MeasuresThe primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety.ResultsForty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting.Conclusions and RelevanceResults suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant.Trial RegistrationClinicalTrials.gov Identifier: NCT03077828

Objective Lupus is a chronic, autoimmune disease that disproportionately affects African Americans. We adapted the Centers for Disease Control and Prevention’s Popular Opinion Leader model to implement an intervention tailored for African American individuals that leverages an academic-community partnership and community-based social networks to disseminate culturally appropriate lupus education. Methods Academic rheumatologists, social scientists, and researchers in Boston, MA and Chicago, IL partnered with local lupus support groups, community organizations, and churches in neighborhoods with higher proportions of African Americans to develop curriculum and recruit community leaders with and without lupus (Popular Opinion Leaders; POLs). POLs attended four training sessions focused on lupus education, strategies to educate others, and a review of research methods. POLs disseminated information through their social networks and recorded their impact, which was mapped using a geographic information system framework. Results We trained 18 POLs in greater Boston and 19 in greater Chicago: 97% were African American, 97% were female; and the mean age was 57 years. Fifty-nine percent of Boston POLs and 68% of Chicago POLs had lupus. POLs at both sites engaged members of their social networks and communities in conversations about lupus, health disparities, and the importance of care. Boston POLs documented 97 encounters with 547 community members reached. Chicago POLs documented 124 encounters with 4083 community members reached. Conclusions An adapted, community-based POL model can be used to disseminate lupus education and increase awareness in African American communities. Further research is needed to determine the degree to which this may begin to reduce disparities in access to care and outcomes.

Objectives Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. Methods Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. Results 1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%–29 % (derivation) and 2%–23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). Conclusions In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials.

Summary Objective Examine associations of hip abductor strength with (1) cartilage damage worsening in the tibiofemoral and patellofemoral compartments 2 years later, and (2) poor function and disability outcomes 5 years later. Methods Participants had knee osteoarthritis (K/L ≥ 2) in at least one knee. Hip abductor strength was measured using Biodex Dynamometry. Participants underwent 3.0T MRI of both knees at baseline and 2 years later. Baseline-to-2-year cartilage damage progression, defined as any worsening of WORMS cartilage damage score, was assessed at each tibiofemoral and patellofemoral surface. LLFDI (Late-Life Function and Disability Instrument) and Chair-Stand-Rate were recorded at baseline and 5-year follow-up; outcomes analyzed using quintiles. Poor outcomes were defined as remaining in the same low-function quintiles or being in a worse quintile at 5-year follow-up. We analyzed associations of baseline hip abductor strength with cartilage damage worsening and function and disability outcomes using multivariable log-binomial models. Results 275 knees from 164 persons [age = 63.7 (SD = 9.8) years, 79.3% women] comprised the structural outcome sample, and 187 persons [age = 64.2 (9.7), 78.6% women] the function and disability outcomes sample. Greater baseline hip abductor strength was associated with reduced risks of baseline-to-2-year medial patellofemoral and lateral tibiofemoral cartilage damage worsening [adjusted relative risks (RRs) range: 0.80–0.83) and with reduced risks of baseline-to-5-year poor outcomes for Chair-Stand-Rate and LLFDI Basic Lower-Extremity Function and Disability Limitation (adjusted RRs range: 0.91–0.94). Conclusion Findings support a beneficial role of hip abductor strength for disease modification and for function and disability outcomes, and as a potential therapeutic target in managing knee osteoarthritis.

Objective Identify distinct trajectories of lack of knee confidence over an 8-year follow-up period and examine baseline factors associated with poor trajectories in persons with or at risk for knee osteoarthritis (OA). Methods The Osteoarthritis Initiative is a prospective cohort study of persons with or at high risk for knee OA. Confidence in the knees was assessed within the Knee Injury and Osteoarthritis Outcome Score instrument querying how much the individual is troubled by lack of confidence in his/her knee(s), rated as not-at-all (0), mildly (1), moderately (2), severely (3), and extremely (4) troubled, reported annually from baseline to 96 months. Lack of knee confidence was defined as a score ≥ 2. We used latent class models to identify subgroups that share similar underlying knee confidence trajectories over an 8-year period, and multivariable multinomial logistic regression models to examine baseline factors associated with poor trajectories. Results Among 4515 participants [mean age 61.2 years (SD 9.2), BMI 28.6 kg/m2 (4.8); 2640 (58.5%) women], four distinct knee confidence trajectories were identified: persistently good (65.6%); declining (9.1%); poor, improving (13.9%); and persistently poor (11.4%). Baseline predictors associated with persistently poor confidence (reference: persistently good) were younger age, male sex, higher BMI, depressive symptoms, more advanced radiographic disease, worse knee pain, weaker knee extensors, history of knee injury and surgery, and reported hip and/or ankle pain. Conclusion Findings suggest the dynamic nature of self-reported knee confidence and addressing modifiable factors (e.g., BMI, knee strength, depressive symptoms, lower limb pain) may improve its long-term course.

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell’s palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Background We used a Popular Opinion Leader (POL) model, which leverages community leaders’ social networks to disseminate health information and change norms in vulnerable communities. We established an academic-community partnerships in Chicago and Boston to increase knowledge about lupus and promote early care-seeking behaviors among African American individuals. We aimed to describe sociodemographic characteristics of Chicago where POLs disseminated lupus-related information and to explore using the Area Deprivation Index (ADI) as a measure of the sociodemographic characteristics (higher ADI, more deprived). Methods Fourteen POLs were recruited from primarily African American, underserved areas to disseminate lupus-related information. POLs recorded encounters throughout their social networks noting the number of individuals contacted and the addresses of venues where educational material was shared. GIS mapping documented the networks, the Healthy Chicago Data (HCD) described the sociodemographic factors and health resources of the POL networks, and GIS addresses linked geocodes with the ADI for these neighborhoods by census block tracks. Results Nine POLs’ social networks were concentrated in four selected predominantly African American communities (Washington Heights, Morgan Park, Englewood and Roseland) located on the Southside of Chicago where health, educational, and financial resources are limited using HCD. 8–17% of individuals living in these areas lacked health insurance, and the percent living below the Federal poverty line and for not completing high school was highest in Englewood (30.8%, 19.7%) and Roseland (27.2%, 13.5%), respectively. Five additional POLs also participated with social networks in other neighborhoods where we could calculate an ADI as shown in the figure 1. The percentage of ADI encounters in Chicago ranged from 9% in ADI 1 to 18% in ADI 10. Conclusions POLs reached communities with varied ADI categories reflecting dissemination from least to most disadvantaged areas. Acknowledgements Funded by DHHS, OMH Grant #1CPIMP171141-01-00.

The Lupus Intervention Fatigue Trial (LIFT) is a prospective, randomized controlled trial to assess the effectiveness of a six-month motivational interviewing intervention program versus an educational control to reduce fatigue in persons with systematic lupus erythematosus (SLE). Participants are randomized using a stratified, 1:1 allocation design to the LIFT intervention or control arm. We plan to enroll 236 participants to achieve the target of 200 persons with six-month follow-up for the primary endpoint. Specific aims of this study are to evaluate the impact of the LIFT intervention on 1) self-reported measures of fatigue and 2) impact on accelerometer-measured physical activity. The primary study outcome is six-month change in fatigue from baseline, assessed by the Fatigue Severity Score (FSS). Additional outcomes include objective measures of physical activity, including non-sedentary behavior and moderate-to-vigorous activity (secondary outcome), and adherence to the LIFT dietary intervention, as assessed by nutrient density (diet quality) and recommended food groups/eating patterns (exploratory outcome) in persons with SLE. Intervention effectiveness will be assessed using an intention-to-treat two-arm comparison of six-month change in FSS, with one interim monitoring analysis. A two-sample independent group t-test will compare the six-month changes in FSS between the study arms. Intervention effect durability will be assessed 12-months after baseline (6 months after completion of the intervention). Enrollment began in June 2019 and is expected to end in June 2023. This study will inform future intervention strategies that promote physical activity and improved diet quality to reduce fatigue in persons with SLE.

Background: Genomic copy number alterations (CNAs) of chromosome 9p24.1 characterize classic Hodgkin lymphoma (cHL) leading to increased expression of programmed cell death ligands -1 and -2 (PD-L1 and PD-L2). Amplifications and high level copy number gains (CNG) have been associated with advanced stage cHL and inferior treatment outcomes with standard chemotherapy. Few studies have assessed 9p24.1 genomic alterations in the frontline setting in the context of PD-1 blockade monotherapy. We conducted a phase 2 clinical trial of sequential pembrolizumab (PEM) x 3 followed by doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy (4-6 cycles) in newly diagnosed cHL. Interim response to single agent PEM was assessed by PET-CT and by decline in metabolic tumor volume (MTV). Herein, we report updates after extended follow-up of patients (median 33.1 months), and results of correlative studies analyzing 9p24.1 CNAs and PD-1 pathway expression. Methods: Pre-treatment diagnostic biopsy specimens were double stained for PD-L1 (E1L3N, XP Cell Signaling) and PAX5, single stained for PD-L2 and pSTAT3, and scored by two expert hematopathologists (QC, LBS) for percentage positive cells and intensity of staining. A modified H score was calculated as the product of staining intensity (0-3) and percentage of positive tumor cells (0-100%), ranging from 0 - 300 was calculated for PD-L1, PD-L2, and pSTAT3. Fluorescence in situ hybridization (FISH) to assess chromosome 9p24.1 CNAs was performed by co-hybridizing PD-L1/PD-L2 probes (target) with the centromeric 9 probe (control). In each case, the percentage and magnitude of 9p24.1 CNAs were evaluated. Four FISH categories were defined based on the target:control ratio and total copy numbers (CNs) of the target per Hodgkin Reed-Sternberg (HRS) cell to include: amplification (ratio≥3), copy number gain (CNGs) (1≤ratio The relationships between PD-1 pathway markers, genomic alterations, and response to single agent PEM by MTV were assessed statistically using Fisher's Exact test, Kruskal-Wallis test, or Spearman's rank correlation as appropriate. PD-L1 H Scores were grouped into terciles of approximately equal size for categorical analysis. Response was defined as a complete metabolic response (CMR), ≥ 90% reduction in MTV (near CMR), or partial response with < 90% reduction by MTV (PR). Kaplan-Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS). Results: Thirty patients were enrolled from September 2017 through August 1, 2019; 28 had tissue available for FISH analysis and 29 for immunohistochemistry. Patient responses to single agent PEM were PMR in 11 (36.7%), near-CMR in 8 (26.7%), and CMR in 11 (36.7%). CMR rate following AVD x 2 was 100%. With the extended follow-up (median 33.1 months, range 26.0-43.0), PFS and OS both remained at 100% (Figures 1a, 1b). Among 28 cases with available FISH analysis, all patients demonstrated genomic alterations in 9p24.1. The highest level alteration was amplification in 14 patients (50%) and copy number gain in 14 (50.0%) Six of 22 examined cases were EBER-positive. Forty-one percent (n=7) of patients with a CMR or near CMR had amplifications in 9p24.1, compared to 64% (n=7) with a PMR following PEM monotherapy (p=0.2). The median PD-L1 H score was 215 (range 20-300). Of 29 patients assessed, 28% had PD-L1 H scores in the first tercile (H-score 1-190), 34% in the second tercile (190-240), and 38% in the third tercile (240-300). There was no association between response to single agent PEM and 9p24.1 alteration, PD-L1, PD-L2 or STAT3 H-scores, % residual disomy, or EBER status (see Figure 1c for PD-L1 results). Conclusions: We found that after extended follow-up, sequential pembrolizumab and AVD chemotherapy remains a highly effective strategy with 100% of patients remaining alive without relapse. The high response rates observed at all PD-L1/PD-L2 levels in this clinical study suggest that even low levels of PD ligand expression may be sufficient for response to PD-1 blockade in previously untreated cHL. We gratefully acknowledge support from Merck & Co. Figure 1 Figure 1. Disclosures Allen: Kyowa Kirin: Consultancy; Secure Bio: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Epizyme: Consultancy. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Karyopharm (Curio Science): Honoraria; Merck: Consultancy, Honoraria, Research Funding.

Introduction: Approximately 30-35% of patients with classic Hodgkin Lymphoma will prove refractory to frontline therapy or relapse subsequently. Traditional second-line chemotherapy regimens including ifosfamide, carboplatin, and etoposide (ICE) result in complete response rates of ~50%. Achievement of complete metabolic response (CMR) assessed by PET/CT imaging prior to autologous hematopoietic stem cell transplant (AHSCT) predicts favorable progression free survival (PFS) and overall survival (OS). PD-1 blockade is a well-established therapeutic strategy for the treatment of cHL. Pembrolizumab (PEM) is a checkpoint inhibitor targeting PD-1 currently FDA approved as monotherapy in relapsed cHL. We hypothesized that PEM in combination with ICE (PEM-ICE) chemotherapy would be a safe and effective regimen that would yield high CMR rates prior to AHSCT. Methods: This single arm, phase II, multi-institutional clinical trial evaluated the addition of PEM to ICE chemotherapy in AHSCT eligible patients with relapsed and refractory cHL (NCT03077828). The regimen consisted of 21 day cycles of PEM 200 mg IV on day 1 with standard ICE including ifosfamide 5 g/m2 with MESNA as a 24hr continuous infusion on day 2, carboplatin AUC 5 IV (max 800 mg) on day 2, and etoposide 100 mg/m2/day IV on days 1 to 3. Two cycles of PEM-ICE were followed by stem cell mobilization/collection. One cycle of PEM 200 mg IV monotherapy was then administered. Our primary endpoint was the rate of CMR on PET/CT (PET2) imaging defined as a Deauville score of ≤ 3. Images were reviewed centrally. An optional third cycle of PEM-ICE was permitted for patients achieving CMR to allow for appropriate timing of AHSCT. Secondary objectives included clinical outcomes (PFS and OS), safety and tolerability, and transplantation related metrics including ability to collect stem cells and time to engraftment. Results: A total of 42 patients were enrolled with 37 patients evaluable for the primary endpoint. Median age was 34 (19-70) with female predominance (n=27, 64%). 16 patients had primary refractory disease. The CMR rate assessed by PET/CT imaging following 2 cycles of PEM-ICE was 86.5% (95% CI, 71.2-95%), meeting our primary endpoint of improvement over historical outcomes to 70%. The PET2 ORR was 97.3% with 11% PR and 2.7% PD. PET2 scores were Deauville 1 in 45% (n=17), Deauville 2 in 27.0% (n=10), Deauville 3 in 8.1% (n=3), Deauville 4 in 13.5% (n=5), and Deauville 5 in 5.4% (n=2). New areas of PET-positivity in two cases were biopsied showing noncaseating granuloma in one case and EBV but no cHL in another. Five patients received the optional third cycle of PEM-ICE chemotherapy with 35 of the 37 evaluable patients proceeding to AHSCT. Seven patients had radiation as part of the conditioning regimen with an additional 4 patients receiving consolidative radiation following transplant. After a median follow up of 27 months, the median PFS was 26.9 months with survival probability at 24 months of 88.2% (Figure 1). Median OS was not reached with too few events but remained 95.1% at 27 months. The addition of PEM to ICE did not impair stem cell mobilization and all patients successfully collected, with 35 (87%) within 2 apheresis sessions (range 1-7). No patients had engraftment delays or failure. Of the 42 patients, all received at least one dose of PEM and were therefore eligible for toxicity analyses. 34 patients (81%) experienced adverse events (AEs) attributed to PEM and 22 patients (52.3%) had grade 3-4 AEs comprised of cytopenias, elevated AST/ALT, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe AEs attributed to PEM which included anemia, back pain, decreased EF, fever, and thrombocytopenia. There were no significant PEM-related autoimmune events that delayed a patient's treatment on protocol. There were two grade 5 toxicities on the protocol including a patient with cardiac arrest during stem cell collection and a patient with acute respiratory distress syndrome attributed to engraftment syndrome. Both were judged "possibly" related to PEM. Conclusions: Pembrolizumab with ICE chemotherapy is a tolerable and efficacious regimen with high CMR rate as assessed by PET/CT. Despite short follow up, patients had excellent PFS and OS in the post-transplant setting. The results support further investigation of PEM-ICE as second-line treatment for AHSCT eligible patients with relapsed and refractory classical Hodgkin lymphoma. Figure 1 Figure 1. Disclosures Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Allen: Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria; Secure Bio: Consultancy, Honoraria. Karmali: Epizyme: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Genentech: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy. OffLabel Disclosure: new combination of study agent with standard of care chemotherapy regimen

Objective To evaluate if molecular markers of eosinophilia in olfactory-enriched mucosa are associated with olfactory dysfunction. Study Design Cross-sectional study of tissue biopsies from 99 patients, and an additional 30 patients who underwent prospective olfactory testing prior to sinonasal procedures. Methods Tissue biopsies were processed for analysis of inflammatory markers using quantitative real time polymerase chain reaction (qRT-PCR). Ipsilateral olfactory performance was assessed using the Sniffin' Sticks (Burghart, Wedel, Germany) threshold component and the University of Pennsylvania Smell Identification Test (Sensonics, Haddon Heights, NJ). Age-adjusted data was correlated with inflammatory marker expression and clinical measures of obstruction from computed tomography and endoscopy. Results Gene expression of the eosinophil marker CLC (Charcot Leyden crystal protein) was elevated in superior turbinate (ST) tissue in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) compared to ST and inferior turbinate tissue in CRS without nasal polyps (CRSsNP) and control patients (all P < 0.001, respectively). CLC in ST tissue was correlated with IL-5 and eotaxin-1 expression (all P < 0.001; P = 0.65, and 0.49, respectively). CLC expression was strongly correlated with eosinophilic cationic protein levels (P < 0.001; r = −0.76), and ST CLC expression was inversely related to olfactory threshold (P = 0.002, r = −0.57) and discrimination scores (P = 0.05, r = −0.42). In multiple linear regression of CLC gene expression, polyp status, and radiographic and endoscopic findings with olfactory threshold, CLC was the only significantly correlated variable (P < 0.05). Conclusion Markers of eosinophils are elevated in the ST of patients with CRSwNP and correlate with olfactory loss. These findings support the hypothesis that olfactory dysfunction in CRS correlates local eosinophil influx into the olfactory cleft. Level of Evidence NA. Laryngoscope, 2017

Background: Chromosome 9p24.1/PD-L1/PD-L2 genomic copy number alterations (CNAs) including amplifications and copy number gains (CNGs) are predominant features of classic Hodgkin lymphoma (cHL) and lead to overexpression of the programmed death-1 (PD-1) ligands 1 and 2 (PD-L1 and PD-L2). Amplifications and high level CNGs have been associated with advanced stage cHL and inferior treatment outcomes with standard chemotherapy. There are few studies that correlate 9p24.1/PD-L1/PD-L2 amplifications or CNGs with response to PD-1 blockade monotherapy in the frontline setting. We conducted a phase 2 clinical trial of sequential pembrolizumab (PEM) x 3 followed by doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy (4-6 cycles) for newly diagnosed cHL. Interim response to single agent PEM was assessed by PET-CT and by decline in metabolic tumor volume (MTV). Herein, we report the results of correlative studies analyzing 9p24.1 CNAs, PD-1 pathway expression and response to PD-1 blockade. Methods: Pre-treatment diagnostic biopsy specimens were double stained for PD-L1 (E1L3N, XP Cell Signaling) and PAX5, single stained for PD-L2 and pSTAT3, and scored by two expert hematopathologists (QC, LBS) for percentage positive cells and intensity of staining. A modified H score was calculated as the product of staining intensity (0-3) and percentage of positive tumor cells (0-100%), ranging from 0 - 300. Fluorescence in situ hybridization to assess (FISH) chromosome 9p24.1 CNAs was performed by co-hybridizing PD-L1/PD-L2 probes (target) with the centromeric 9 probe (control). In each case, the percentage and magnitude of 9p24.1 CNAs were evaluated. Four FISH categories were defined based on the target: control ratio and the total copy numbers (CNs) of the target per Hodgkin Reed-Sternberg (HRS) cell to include: amplification (ratio≥3, CNs≥ 6), copy number gain (CNGs) (1≤ratio Results: Thirty patients were enrolled from September 2017, through August 1, 2019; 28 had tissue available for FISH analysis and 29 for immunohistochemistry. Response to single agent PEM was PR in 11 (36.7%), near-CMR in 8 (26.7%), and CMR in 11 (36.7%). CMR rate following AVD x 2 was 100%. All patients in this analysis had genomic alterations, although 5 patients did not reach the cut off of 10%. The highest level alteration was amplification in 11 patients (36.7%), copy gain in 7 (23.3%), polysomy in 5 (16.7%) and disomy in 5 (16.7%) (Table 1). The average 9p24.1 copy number per HRS cell was 3.1 (range 2-8.1). Six of 22 examined cases were EBER-positive. There was no evidence of a statistical relationship between response to single agent PEM and 9p24.1 alteration, PD-L1, PD-L2 or STAT3 H-scores, or EBER status. We found PD-L1 H Score tercile differed statistically by FISH category (P=.024, Fisher's Exact Test). Notably, there were no patients with amplification in the lowest tercile. More compelling, we found a positive association between PD-L1 H Score and average 9p24.1 locus copy number (Spearman's ρ=.36, P=.063, Fig 1a) and a negative association between PD-L1 H Score and percent disomic cells (Spearman's ρ= -0.21, P=0.29, Fig 1b) although the statistical significance of these results was limited by the small sample size. Conclusions: Our data is consistent with prior reports indicating a positive association between 9p24.1 genetic alterations and PD-L1 expression. The high response rates observed at all PD ligand levels seen in this clinical study suggests that even low levels of PD ligand expression may be sufficient for response to PD-1 blockade in previously untreated cHL. Disclosures Allen: Bayer:Consultancy, Other;Imbrium:Consultancy, Other;Research to Practice:Speakers Bureau;Clinical Care Options:Speakers Bureau;Curio Sciences:Honoraria.Evens:Merck:Consultancy, Honoraria, Research Funding;Pharmacyclics:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;MorphoSys:Consultancy, Honoraria;Research To Practice:Honoraria, Speakers Bureau;Abbvie:Consultancy, Honoraria;Mylteni:Consultancy, Honoraria;Seattle Genetics:Consultancy, Honoraria, Research Funding;Epizyme:Consultancy, Honoraria, Research Funding.Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics:Research Funding;Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda:Consultancy.Pro:Verastem Oncology:Research Funding.Karmali:Takeda:Research Funding;BeiGene:Speakers Bureau;BMS/Celgene/Juno:Honoraria, Other, Research Funding, Speakers Bureau;Karyopharm:Honoraria;AstraZeneca:Speakers Bureau;Gilead/Kite:Honoraria, Other, Research Funding, Speakers Bureau.Gordon:Zylem Biosciences:Patents & Royalties: Patents, No Royalties.Winter:Amgen:Consultancy;Epizyme:Other: DSMB;Norvartis:Consultancy, Other: DSMB;CVS/Caremark:Consultancy;Ariad/Takeda:Consultancy;Delta Fly Pharma:Consultancy;Merck:Membership on an entity's Board of Directors or advisory committees, Other: advisory board;Karyopharm:Membership on an entity's Board of Directors or advisory committees, Other: advisory board.

Background The Popular Opinion Leader (POL) model was developed by the Centers of Disease Control to train community leaders to increase awareness in their social networks about health-related issues that disproportionately affect vulnerable populations. We established an academic-community partnership in Chicago and Boston and used a POL model to increase knowledge about lupus and to promote early care-seeking behaviors among African American individuals. With the knowledge that where a person lives directly influences his/her health, one of our goals was to understand the sociodemographic characteristics of the Chicago communities where the POLs disseminated lupus-related information. Methods Ten POLs were identified and participated in four two-hour session educational training program. All POLs were female, the mean age was 59% and 100% were African American. Over the course of 6 months, the POLs tracked their encounters throughout their social networks by recording addresses of venues where educational information was disseminated and the number of individuals contacted. Data were entered into the Geographic Information System to evaluate the reach of their networks. We utilized the Healthy Chicago Database to describe the sociodemographic factors and some of the health resources of the Chicago neighborhoods identified by the POLs social networks. Results The 10 POLs social networks were concentrated in four selected communities (Washington Heights, Morgan Park, Englewood and Roseland). These neighborhoods are located on the Southside of Chicago where health, educational, and financial resources are limited. All four communities were predominantly African-American, range 54.6%–96.1%. Individuals living in these neighborhoods with no health insurance ranged from 8.4%–17.2%, in Morgan Park and Englewood, respectively. Individual poverty was highest in Englewood (30.8%) and Roseland (27.2%) compared with approximately 18% in the other two neighborhoods. The percentage of individuals who did not complete high school was highest in Englewood (19.7%) and Englewood (13.5%) compared with approximately 10% in the other two areas. Conclusions Engagement of local community members through POL conversations tapped into neighborhoods that demonstrated concerning sociodemographic features such as individual poverty, lack of health insurance, and lack of education through high school. Since the POLs had strong social networks prior to recruitment, they selected these communities to facilitate dissemination of lupus awareness education where resources may be limited. This illustrates the importance of POL engagement with community stakeholders who can use this information to work towards reducing health disparities in lupus in communities with limited resources. Funding Source(s): DHHS, Office of Minority Health

BACKGROUND Cardiovascular disease (CVD) risk prediction tools are often applied to populations beyond those in which they were designed when validated tools for specific subpopulations are unavailable. METHODS Using data from 2283 human immunodeficiency virus (HIV)-infected adults aged ≥18 years, who were active in the HIV Outpatient Study (HOPS), we assessed performance of 3 commonly used CVD prediction models developed for general populations: Framingham general cardiovascular Risk Score (FRS), American College of Cardiology/American Heart Association Pooled Cohort equations (PCEs), and Systematic COronary Risk Evaluation (SCORE) high-risk equation, and 1 model developed in HIV-infected persons: the Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study equation. C-statistics assessed model discrimination and the ratio of expected to observed events (E/O) and Hosmer-Lemeshow χ2 P value assessed calibration. RESULTS From January 2002 through September 2013, 195 (8.5%) HOPS participants experienced an incident CVD event in 15 056 person-years. The FRS demonstrated moderate discrimination and was well calibrated (C-statistic: 0.66, E/O: 1.01, P = .89). The PCE and D:A:D risk equations demonstrated good discrimination but were less well calibrated (C-statistics: 0.71 and 0.72 and E/O: 0.88 and 0.80, respectively; P < .001 for both), whereas SCORE performed poorly (C-statistic: 0.59, E/O: 1.72; P = .48). CONCLUSIONS Only the FRS accurately estimated risk of CVD events, while PCE and D:A:D underestimated risk. Although these models could potentially be used to rank US HIV-infected individuals at higher or lower risk for CVD, the models may fail to identify substantial numbers of HIV-infected persons with elevated CVD risk who could potentially benefit from additional medical treatment.

Objective Fatigue is a common symptom in systemic lupus erythematosus (SLE), and engaging in physical activity may reduce fatigue. We aimed to characterize relationships between fatigue, other health status measures assessed with the Patient Reported Outcomes Measurement Information System (PROMIS) instruments, and accelerometer-based physical activity measurements in patients with SLE. The internal consistency of each PROMIS measure in our SLE sample was also evaluated. Methods This cross-sectional study analyzed 123 adults with SLE. The primary fatigue outcome was Fatigue Severity Scale score. Secondary outcomes were PROMIS standardized T-scores in seven health status domains. Accelerometers were worn for seven days, and mean daily minutes of light, moderate/vigorous, and bouted (10 minutes) moderate/vigorous physical activity were estimated. Cronbach’s alpha was determined for each PROMIS measure to assess internal consistency. Relationships between Fatigue Severity Scale, PROMIS, and physical activity were summarized with Spearman partial correlation coefficients ( r), adjusted for average daily accelerometer wear time. Results Mean Fatigue Severity Scale score (4.3, SD 1.6) was consistent with clinically relevant levels of fatigue. Greater daily and bouted moderate/vigorous physical activity minutes correlated with lower Mean Fatigue Severity Scale score ( r = −0.20, p = 0.03 and r = −0.30, p = 0.0007, respectively). For PROMIS, bouted moderate/vigorous physical activity minutes correlated with less fatigue ( r = −0.20, p = 0.03). PROMIS internal consistency was excellent, with Cronbach’s alpha > 0.90 for each domain. Mean PROMIS T-scores for fatigue, pain interference, anxiety, sleep disturbance, sleep-related impairment, and physical function were worse than reported for the general US population. More moderate/vigorous physical activity minutes were associated with less pain interference ( r = −0.22, p = 0.01). Both light physical activity and moderate/vigorous physical activity minutes correlated with better physical function ( r = 0.19, p = 0.04 and r = 0.25, p = 0.006, respectively). Conclusion More time spent in moderate/vigorous physical activity was associated with less fatigue (Fatigue Severity Scale and PROMIS), less pain interference, and better physical function (PROMIS). PROMIS had excellent internal consistency in our SLE sample, and six of seven PROMIS measures indicated poorer average health status in SLE patients compared with the general US population.

This cohort study evaluates long-term levels of physical activity and inactivity among adults with or likely to develop knee osteoarthritis., Key Points Question Are long-term strenuous physical activity and extensive sitting each associated with risk for developing radiographic knee osteoarthritis in individuals at high risk for the disease? Findings In this cohort study of 1194 persons at high risk for but without radiographic evidence of knee osteoarthritis who were followed up for up to 10 years, long-term participation in strenuous physical activities was not associated with risk of incident radiographic knee osteoarthritis. Persistent extensive sitting was not associated with either elevated or reduced risk. Meaning These findings suggest that older adults at high risk for knee osteoarthritis may safely engage in strenuous physical activities at a moderate level to improve their general health., Importance Persons with knee symptoms recognize the health benefits of engaging in physical activity, but uncertainty persists about whether regular strenuous physical activity or exercise can accelerate tissue damage. A sedentary lifestyle of inactivity or underloading may also be associated with deleterious joint health. Objective To establish whether long-term strenuous physical activity participation and extensive sitting behavior are each associated with increased risk of developing radiographic knee osteoarthritis (KOA) in individuals at high risk for the disease. Design, Setting, and Participants This cohort study analyzed data from the Osteoarthritis Initiative, a prospective longitudinal cohort study of men and women with or at an increased risk of developing symptomatic, radiographic KOA. Community-dwelling adults were recruited from 4 US sites (Baltimore, Maryland; Columbus, Ohio; Pittsburgh, Pennsylvania; and Pawtucket, Rhode Island) and were followed up for up to 10 years. Individuals were included if they had a baseline Kellgren and Lawrence grade of 0 in both knees and completed a PASE (Physical Activity Scale for the Elderly) questionnaire at baseline and at least 2 follow-up visits over an 8-year interval. Data analyses were conducted from May 2018 to November 2018. Exposures Baseline to 8-year trajectories of strenuous physical activity participation and extensive sitting behavior were identified using group-based trajectory models. Main Outcomes and Measures Incident radiographic KOA, defined as Kellgren and Lawrence grade 2 or higher in either knee by the 10-year follow-up visit. Results A total of 1194 participants were included in the sample (697 women [58.4%]), with a baseline mean (SD) age of 58.4 (8.9) years and mean body mass index (BMI) of 26.8 (4.5). Four distinct trajectories of weekly hours spent in strenuous physical activities and 3 distinct trajectories of extensive sitting were identified. Long-term engagement in low-to-moderate physical activities (adjusted odds ratio [OR], 0.69; 95% CI, 0.48-1.01) or any strenuous physical activities (adjusted OR, 0.75; 95% CI, 0.53-1.07) was not associated with 10-year incident radiographic KOA. Persistent extensive sitting was not associated with incident KOA. Despite relatively mild symptoms and high function in this early-stage sample, 594 participants (49.7%) did not engage in any strenuous physical activities (ie, 0 h/wk) across 8 years, and 507 (42.5%) engaged in persistent moderate-to-high frequency of extensive sitting. Older age, higher BMI, more severe knee pain, non–college graduate educational level, weaker quadriceps, and depression were each associated with a persistent lack of engagement in strenuous physical activities. Conclusions and Relevance Results from this study appeared to show no association between long-term strenuous physical activity participation and incident radiographic KOA. The findings raise the possibility of a protective association between incident KOA and a low-to-moderate level of strenuous physical activities.

Background In 1988, 1 of 3 women (W) and heterosexual men living with human immunodeficiency virus (HIV) reported wanting children, but little is known about parenting desires of men who have sex with men (MSM) living with HIV. We examined parenting desires among persons initiating antiretroviral therapy (ART). Methods Of 1809 participants in the AIDS Clinical Trials Group (ACTG) Study 5257, 1425 W aged ≤45 years or men completed questionnaires about parenting desires at baseline and 96 weeks after initiating ART. Self-reported desires for children in the future (yes/unsure vs no) and associations between baseline sociodemographics and parenting desires at 96 weeks were examined using multivariable logistic regression, overall and within subgroups. Results The 1425 participants were as follows: 36% white, 39% black, 22% Hispanic; median age 36 (interquartile range, 28–44); 70% MSM, 13% men reported sex only with W (MSW), 17% W. At baseline, 42% may want children in the future (42% MSM, 37% MSW, 43% W); at 96 weeks, 41% may want children (41% MSM, 37% MSW, 43% W). At follow-up, approximately 10% of responses changed in each direction. In multivariable analyses, education greater than high school, Conclusions Approximately 40% of MSM, W, and MSW with HIV may want children, both at baseline and 96 weeks after ART initiation. These results highlight the need to regularly assess parenting goals, provide access to comprehensive reproductive services, and address prevention of vertical and heterosexual HIV transmission.

Comparative analyses of the characteristics of persons living with HIV infection (PLWH) in the United States (US) captured in surveillance and other observational databases are few. To explore potential joint data use to guide HIV treatment and prevention in the US, we examined three CDC-funded data sources in 2012: the HIV Outpatient Study (HOPS), a multisite longitudinal cohort; the Medical Monitoring Project (MMP), a probability sample of PLWH receiving medical care; and the National HIV Surveillance System (NHSS), a surveillance system of all PLWH. Overall, data from 1,697 HOPS, 4,901 MMP, and 865,102 NHSS PLWH were analyzed. Compared with the MMP population, HOPS participants were more likely to be older, non-Hispanic/Latino white, not using injection drugs, insured, diagnosed with HIV before 2009, prescribed antiretroviral therapy, and to have most recent CD4+ T-lymphocyte cell count ≥500 cells/mm3 and most recent viral load test

Purpose Inpatient palliative care consultation (IPCC) may help address barriers that limit the use of hospice and the receipt of symptom-focused care for racial/ethnic minorities, yet little is known about disparities in the rates of IPCC. We evaluated the association between race/ethnicity and rates of IPCC for patients with advanced cancer. Patients and Methods Patients with metastatic cancer who were hospitalized between January 1, 2009, and December 31, 2010, at an urban academic medical center participated in the study. Patient-level multivariable logistic regression was used to evaluate the association between race/ethnicity and IPCC. Results A total of 6,288 patients (69% non-Hispanic white, 19% African American, and 6% Hispanic) were eligible. Of these patients, 16% of whites, 22% of African Americans, and 20% of Hispanics had an IPCC (overall P < .001). Compared with whites, African Americans had a greater likelihood of receiving an IPCC (odds ratio, 1.21; 95% CI, 1.01 to 1.44), even after adjusting for insurance, hospitalizations, marital status, and illness severity. Among patients who received an IPCC, African Americans had a higher median number of days from IPCC to death compared with whites (25 v 17 days; P = .006), and were more likely than Hispanics (59% v 41%; P = .006), but not whites, to be referred to hospice. Conclusion Inpatient settings may neutralize some racial/ethnic differences in access to hospice and palliative care services; however, irrespective of race/ethnicity, rates of IPCC remain low and occur close to death. Additional research is needed to identify interventions to improve access to palliative care in the hospital for all patients with advanced cancer.

The National HIV/AIDS Strategy emphasizes virologic suppression (VS) to reduce HIV incidence in the United States. We assessed temporal trends of and disparities in time to combination antiretroviral therapy (cART) initiation and HIV VS in a large demographically diverse cohort of HIV-infected patients.We included antiretroviral-naive HIV Outpatient Study participants from 2000 to 2013 enrolled within 6 months of their HIV diagnosis who attended ≥2 HIV care-related visits.We evaluated time from HIV diagnosis to first use of cART, time from HIV diagnosis to VS, and time from first use of cART to VS. Kaplan-Meier time-to-event curves and Cox proportional hazards models were used to assess temporal trends and correlates of initiating cART and achieving HIV VS (500 copies per milliliter).Among 1156 HIV Outpatient Study patients [median age, 37 years; 43.2% non-Hispanic/Latino black (NHB), 14.1% Hispanic/Latino], estimated median times from HIV diagnosis to cART initiation and from HIV diagnosis to VS both shortened by40% during the 13.5-year study period, reaching, respectively, 2.5 and 5.4 months. In multivariable analyses, NHB patients (as compared with non-Hispanic/Latino white) and those who had injected drugs (as compared with those who did not) initiated cART in a less timely fashion. After adjusting for CD4 cell count and viral load at cART initiation, NHB patients and those aged30 years (compared with ≥40 years) had lower rates of VS.Despite improvements in HIV treatment over time, patients who were NHB, younger, or used injection drugs had less favorable outcomes.

Objective Manifestations of instability in knee osteoarthritis (OA) include low overall knee confidence, low confidence that the knees will not buckle, buckling, and excessive motion during gait. Confidence and buckling may particularly influence activity choices, contributing to events leading to disability. Buckling is more likely to affect advanced than basic functional tasks. In this prospective longitudinal study, we tested the hypothesis that overall knee confidence, buckling confidence, buckling, and frontal plane motion during gait are associated with advanced 2-year function outcomes in persons with knee OA. Methods Persons with knee OA were queried about overall knee confidence (higher score = worse confidence), buckling confidence, and knee buckling, and underwent quantitative gait analysis to quantify varus–valgus excursion and angular velocity. Physical function was assessed using the Late-Life Function and Disability Instrument Basic and Advanced Lower Extremity Domain scores. Logistic regression was used to evaluate the relationship between baseline instability measures and baseline-to-2-year function outcome, adjusting for potential confounders. Results The sample was comprised of 212 persons (mean age 64.6 years, 76.9% women). Buckling was significantly associated with poor advanced function outcome (adjusted odds ratio [OR] 2.08, 95% confidence interval [95% CI] 1.03–4.20) but not basic function outcome. Overall knee confidence was significantly associated with advanced outcome (adjusted OR 1.65, 95% CI 1.01–2.70), while associations between buckling confidence and both outcomes approached significance. Neither varus–valgus excursion nor angular velocity during gait was associated with either outcome. Conclusion Knee buckling and low knee confidence were each associated with poor 2-year advanced function outcomes. Current treatment does not address these modifiable factors; interventions to address them may improve outcome in knee OA.

Summary Objective Test the hypothesis that greater baseline peak external knee adduction moment (KAM), KAM impulse, and peak external knee flexion moment (KFM) during the stance phase of gait are associated with baseline-to-2-year medial tibiofemoral cartilage damage and bone marrow lesion progression, and cartilage thickness loss. Methods Participants all had knee OA in at least one knee. Baseline peak KAM, KAM impulse, and peak KFM (normalized to body weight and height) were captured and computed using a motion analysis system and six force plates. Participants underwent MRI of both knees at baseline and 2 years later. To assess the association between baseline moments and baseline-to-2-year semiquantitative cartilage damage and bone marrow lesion progression and quantitative cartilage thickness loss, we used logistic and linear regressions with generalized estimating equations (GEE), adjusting for gait speed, age, gender, disease severity, knee pain severity, and medication use. Results The sample consisted of 391 knees (204 persons): mean age 64.2 years (SD 10.0); BMI 28.4 kg/m 2 (5.7); 156 (76.5%) women. Greater baseline peak KAM and KAM impulse were each associated with worsening of medial bone marrow lesions, but not cartilage damage. Higher baseline KAM impulse was associated with 2-year medial cartilage thickness loss assessed both as % loss and as a threshold of loss, whereas peak KAM was related only to % loss. There was no relationship between baseline peak KFM and any medial disease progression outcome measures. Conclusion Findings support targeting KAM parameters in an effort to delay medial OA disease progression.

BackgroundMonitoring antiretroviral drug resistance can inform treatment recommendations; however, there are few such data from US patients before they initiate ART.MethodsWe analysed data from HIV Outpatient Study (HOPS) participants from nine US HIV clinics who were diagnosed with HIV infection during 1999–2011. Using the IAS-USA December 2010 guidelines, we assessed the frequency of major drug resistance mutations (mDRMs) related to antiretroviral agents in viral isolates from patients who underwent commercial genotypic testing (GT) for resistance before initiating ART. We employed general linear regression models to assess factors associated with having undergone GT, and then factors associated with having mDRM.ResultsAmong 1531 eligible patients, 758 (49.5%) underwent GT before first ART, increasing from 15.5% in 1999–2002 to 75.9% in 2009–11 (P 5.0 log10 copies/mL and those with a first HOPS visit in 2006 or later were significantly (P ConclusionsDuring 1999–2011, GT use among antiretroviral-naive patients became more common, but a quarter of patients in recent years remained untested. The frequency of mDRMs remained stable over time at about 15%.

Objective Most estimates of physical activity (PA) patterns in systemic lupus erythematosus (SLE) are based on subjective self-report measures prone to error. The aims of this study were to obtain objective measurements of PA using an accelerometer and estimates of energy expenditure based on the self-reported International Physical Activity Questionnaire (IPAQ), and to describe their relationship.

Summary Objective Among high risk individuals, whether knee lesions in tissues involved in osteoarthritis (OA) can improve prediction of knee OA is unclear. We hypothesized that models predicting (1) incident osteophytes and (2) incident osteophytes and joint space narrowing can be improved by including symptoms or function, and further improved by lesion status. Design In Osteoarthritis Initiative (OAI) participants with normal knee X-rays, we assessed cartilage damage, bone marrow lesions (BMLs), and menisci. Cox proportional hazards models were used to develop risk prediction models for risk of each outcome. Nested models (increasingly larger baseline covariable sets) were compared using likelihood ratio tests and Schwarz Bayesian Information Criterion (SBC). Model discrimination used receiver operating characteristic (ROC) curves and area under the curve (AUC). Results In 841 participants [age 59.6, body mass index (BMI) 26.7, 55.9% women] over up to 7 years follow-up, each larger set improved prediction (+hand OA, injury, surgery, activities; +symptoms/function). Prediction was further improved by including cartilage damage both compartments, BMLs both compartments, meniscal tear, meniscal extrusion, sum of lesion types, number of subregions with cartilage damage, number of subregions with BMLs, and (concurrently) subregion number with cartilage damage, subregion number with BMLs, and meniscal tear. AUCs were ≥0.80 for both outcomes for number of subregions with cartilage damage and the combined model. Conclusions Among persons at higher risk for knee OA with normal X-rays, MRI tissue lesions improved prediction of mild as well as moderate disease. These findings support that disease onset is likely occurring during the "high-risk" period and encourage a reorientation of approach.

BACKGROUND: Physical activity ameliorates fatigue in systemic lupus erythematosus (SLE) patients by an unknown mechanism. Adipokines, which are influenced by adiposity and physical activity, may be associated with patient-reported fatigue. OBJECTIVE: We describe cross-sectional associations between adipokines and fatigue, physical activity, and SLE disease activity. METHODS: We measured adipokines, self-reported fatigue, and objective physical activity in 129 SLE patients. Fatigue was assessed with the Fatigue Severity Scale (FSS) and Patient Reported Outcomes Measurement Information System(®) (PROMIS(®)) Fatigue score. Disease activity was measured with the Safety of Estrogens in Systemic Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI). Participants wore an accelerometer for 7 days to measure physical activity. Leptin, adiponectin, and resistin were measured in stored serum with a Luminex bead-based assay. Multivariable regression models assessed relationships between fatigue and adipokines, and Spearman correlation coefficients summarized associations between adipokines, physical activity, and SELENA-SLEDAI. RESULTS: Median adipokine levels were: leptin 30.5 ng/ml (Interquartile Range 14.0, 56.6), adiponectin 11.6 µg/ml (7.2, 16.8) and resistin 1.4 ng/ml (1.0, 2.2). Associations between adipokines and FSS or PROMIS Fatigue were not significant. Body mass index (BMI) ≥30 kg/m(2) was associated with FSS and PROMIS Fatigue in regression analyses (p

Objective. Few strategies to improve pain outcome in knee osteoarthritis (OA) exist in part because how best to evaluate pain over the long term is unclear. Our objectives were to determine the frequency of a good pain experience outcome based on previously formulated OA pain stages and test the hypothesis that less depression and pain catastrophizing and greater self-efficacy and social support are each associated with greater likelihood of a good outcome. Methods. Study participants, all with knee OA, reported pain stage at baseline and 2 years. Baseline assessments utilized the Geriatric Depression Scale, Pain Catastrophizing Scale, Arthritis Self-Efficacy Scale, and Medical Outcomes Study social support survey. Using pain experience stages, good outcome was defined as persistence in or movement to no pain or stage 1 (predictable pain, known trigger) at 2 years. A multivariable logistic regression model was developed to identify independent predictors of a good outcome. Results. Of 212 participants, 136 (64%) had a good pain outcome and 76 (36%) a poor pain outcome. In multivariable analysis, higher self-efficacy was associated with a significantly higher likelihood of good outcome (adjusted odds ratio [OR] 1.14 [95% confidence interval (95% CI) 1.04 –1.24]); higher pain catastrophizing was associated with a significantly lower likelihood of good outcome (adjusted OR 0.88 [95% CI 0.83– 0.94]). Conclusion. This stage-based measure provides a meaningful and interpretable means to assess pain outcome in knee OA. The odds of a good 2-year outcome in knee OA were lower in persons with greater pain catastrophizing and higher in persons with greater self-efficacy. Targeting these factors may help to improve pain outcome in knee OA.

Objective Little is known about early knee osteoarthritis (OA). The significance of lesions on magnetic resonance imaging (MRI) in older persons without radiographic OA is unclear. Our objectives were to determine the extent of tissue pathology by MRI and evaluate its significance by testing the following hypotheses: cartilage damage, bone marrow lesions, and meniscal damage are associated with prevalent frequent knee symptoms and incident persistent symptoms; bone marrow lesions and meniscal damage are associated with incident tibiofemoral (TF) cartilage damage; and bone marrow lesions are associated with incident patellofemoral (PF) cartilage damage. Methods In a cohort study of 849 Osteoarthritis Initiative (OAI) participants who had a bilateral Kellgren/Lawrence (K/L) score of 0, we assessed cartilage damage, bone marrow lesions, and meniscal damage using the MRI OA Knee Score, as well as prevalent frequent knee symptoms, incident persistent symptoms, and incident cartilage damage. Multiple logistic regression (one knee per person) was used to evaluate associations between MRI lesions and each of these outcomes. Results Of the participants evaluated, 76% had cartilage damage, 61% had bone marrow lesions, 21% had meniscal tears, and 14% had meniscal extrusion. Cartilage damage (any; TF and PF), bone marrow lesions (any; TF and PF), meniscal extrusion, and body mass index (BMI) were associated with prevalent frequent symptoms. Cartilage damage (isolated PF; TF and PF), bone marrow lesions (any; isolated PF; TF and PF), meniscal tears, and BMI were associated with incident persistent symptoms. Hand OA, but no individual lesion type, was associated with incident TF cartilage damage, and bone marrow lesions (any; any PF) with incident PF damage. Having more lesion types was associated with a greater risk of outcomes. Conclusion MRI-detected lesions are not incidental and may represent early disease in persons at increased risk of knee OA.

SummaryObjectiveVarus thrust visualized during walking is associated with a greater medial knee load and an increased risk of medial knee osteoarthritis (OA) progression. Little is known about how varus thrust presence determined by visual observation relates to quantitative gait kinematic data. We hypothesized that varus thrust presence is associated with greater knee frontal plane dynamic movement during the stance phase of gait.MethodsParticipants had knee OA in at least one knee. Trained examiners assessed participants for varus thrust presence during ambulation. Frontal plane knee motion during ambulation was captured using external passive reflective markers and an 8-camera motion analysis system. To examine the cross-sectional relationship between varus thrust and frontal plane knee motion, we used multivariable regression models with the quantitative motion measures as dependent variables and varus thrust (present/absent) as predictor; models were adjusted for age, gender, body mass index (BMI), gait speed, and knee static alignment.Results236 persons [mean BMI: 28.5 kg/m2 (standard deviation (SD) 5.5), mean age: 64.9 years (SD 10.4), 75.8% women] contributing 440 knees comprised the study sample. 82 knees (18.6%) had definite varus thrust. Knees with varus thrust had greater peak varus angle and greater peak varus angular velocity during stance than knees without varus thrust (mean differences 0.90° and 6.65°/s, respectively). These patterns remained significant after adjusting for age, gender, BMI, gait speed, and knee static alignment.ConclusionVisualized varus thrust during walking was associated with a greater peak knee varus angular velocity and a greater peak knee varus angle during stance phase of gait.

Background There are few recent studies of incident hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected patients in the United States. Methods We studied HIV Outpatient Study (HOPS) participants seen in 9 HIV-specialty clinics who had ≥1 clinical encounter during 2000–2013 and ≥2 HCV-related tests, the first of which was a negative HCV antibody test (Ab). Hepatitis C virus incident cases were identified by first positive HCV Ab, viral load, or genotype. We assessed rates of incident HCV overall, by calendar intervals, and by demographic and HIV risk strata, and we explored risk factors for incident HCV using Cox proportional hazards models. Results The 1941 eligible patients (median age 40 years, 23% female, 61% men who had sex with men [MSM], and 3% persons who injected drugs [PWID]) experienced 102 (5.3%) incident HCV infections for an overall incidence of 1.07 (95% confidence interval [CI], 0.87–1.30) per 100 person-years (py). Hepatitis C virus incidence decreased from 1.83 in 2000–2003 to 0.88 in 2011–2013 (P = .024), with decreases observed (P < .05) among PWID and heterosexuals, but not among MSM. Overall, MSM comprised 59% of incident cases, and PWID were at most risk for incident HCV infection (adjusted hazard ratio [aHR] for PWID = 4.62 and 95% CI = 2.11–10.13; for MSM, aHR = 1.48 and 95% CI = 0.86–2.55 compared with heterosexuals). Conclusions Among HIV-infected patients in care during 2000–2013, incidence of HCV infection exceeded 1 case per 100 py. Our findings support recommendations for annual HCV screenings for HIV-infected persons, including persons with only MSM risk, to enable HCV diagnosis and treatment for coinfected individuals.

Health disparities research among gay and bisexual men has focused primarily on risk and deficits. However, a focus on resiliencies within this population may greatly benefit health promotion. We describe a pattern of resilience (internalized homophobia (IHP) resolution) over the life-course and its associations with current health outcomes. 1,541 gay and bisexual men from the Multi-Center AIDS Cohort study, an ongoing prospective study of the natural and treated histories of HIV, completed a survey about life-course events thought to be related to health. The majority of men resolved IHP over time independent of demographics. Men who resolved IHP had significantly higher odds of positive health outcomes compared to those who did not. These results provide evidence of resilience among participants that is associated with positive health outcomes. Understanding resiliencies and incorporating them into interventions may help to promote health and well-being among gay and bisexual men.

Background Certain sociodemographic subgroups of HIV-infected patients may experience more chronic disease than others due to behavioural risk factors, advanced HIV disease or complications from extended use of combination antiretroviral therapy (cART), but recent comparative data are limited. Methods We studied HIV-infected adult patients in care during 2006–2010 who had been prescribed ≥6 months of cART. We analysed the prevalence of selected key chronic conditions and polymorbidity (having 2 or more out of 10 key conditions) by gender and race/ethnicity. Results Of the 3,166 HIV-infected patients (median age 47 years, CD4+ T-cell count 496 cells/mm3, duration of cART use 6.8 years), 21% were female, 57% were non-Hispanic White and over half were current or former tobacco smokers. The five most frequent conditions among women (median age 45 years) were dyslipidaemia (67.3%), hypertension (57.4%), obesity (31.7%), viral hepatitis B or C coinfection (29.0%) and low high-density lipoprotein cholesterol (HDLc; 27.3%). The five most frequent conditions in men (median age 47 years) were dyslipidaemia (81.2%), hypertension (54.4%), low HDLc (41.1%), elevated triglycerides (32.3%) and elevated non-HDLc (26.8%). In multivariable analyses, Hispanic patients had higher prevalence of obesity and diabetes than White patients; Black patients had higher prevalence of obesity and hypertension but lower rates of lipid abnormalities. Of all patients, 73.7% of women and 66.8% of men had polymorbidity, with no evidence of disparities by race/ethnicity. Conclusions Among contemporary cART-treated HIV-infected adults, chronic conditions and polymorbidity were common, underscoring the importance of chronic disease prevention and management among ageing HIV-infected patients.

Objective Knee sagittal dynamic joint stiffness (DJS) describes the biomechanical interaction between change in external knee flexion moment and flexion angular excursion during gait. In theory, greater DJS may particularly stress the patellofemoral (PF) compartment and thereby contribute to PF osteoarthritis (OA) worsening. We hypothesized that greater baseline knee sagittal DJS is associated with PF cartilage damage worsening 2 years later. Methods Participants all had OA in at least one knee. Knee kinematics and kinetics during gait were recorded using motion capture systems and force plates. Knee sagittal DJS was computed as the slope of the linear regression line for knee flexion moments vs angles during the loading response phase. Knee magnetic resonance imaging (MRI) scans were obtained at baseline and 2 years later. We assessed the association between baseline DJS and baseline-to-2-year PF cartilage damage worsening using logistic regression with generalized estimating equations (GEE). Results Our sample had 391 knees (204 persons): mean age 64.2 years (SD 10.0); body mass index (BMI) 28.4 kg/m2 (5.7); 76.5% women. Baseline knee sagittal DJS was associated with baseline-to-2-year cartilage damage worsening in the lateral (OR = 5.35, 95% CI: 2.37-12.05) and any PF (OR = 2.99, 95% CI: 1.27-7.04) compartment. Individual components of baseline DJS (i.e., change in knee moment or angle) were not associated with subsequent PF disease worsening. Conclusion Capturing the concomitant effect of knee kinetics and kinematics during gait, knee sagittal DJS is a potentially modifiable risk factor for PF disease worsening.

Objective We evaluated whether African Americans in the Osteoarthritis Initiative (OAI) have a greater risk (versus whites) of poor 4-year function outcome within strata defined by sex, body mass index (BMI), and waist circumference. Methods Using Western Ontario and McMaster Universities Osteoarthritis Index function, 20-meter walk, and chair stand performance, poor outcome was defined as moving into a worse function group or remaining in the 2 worst groups over 4 years. Logistic regression was used to evaluate the relationship between racial group and outcome within each stratum, adjusting for age, education, and income, and then further adjusting for BMI, comorbidity, depressive symptoms, physical activity, knee pain, and osteoarthritis (OA) severity. Results In 3,695 persons with or at higher risk for knee OA, higher BMI and large waist circumference were each associated with poor outcome. Among women with high BMI and among women with large waist circumference, African Americans were at greater risk for poor outcome by every measure, adjusting for age, education, and income. From fully adjusted models, potential explanatory factors included income, comorbidity, depressive symptoms, pain, and disease severity. Findings were less consistent for men, emerging only for the 20-meter walk or chair stand outcomes, and potentially explained by age and knee pain. Conclusion Among OAI women with excess body weight, African Americans are at greater risk than whites for poor 4-year outcome. Modifiable factors that may help to explain these findings in the OAI include comorbidity, depressive symptoms, and knee pain. Targeting such factors, while supporting weight loss, may help to lessen the outcome disparity between African American and white women.

This study analyzed data from a large prospective epidemiologic cohort study among men who have sex with men (MSM), the Multicenter AIDS Cohort Study, to assess syndemic relationships among black MSM in the cohort (N = 301). We hypothesized that multiple interconnections among psychosocial health conditions would be found among these men, defining syndemic conditions. Constituents of syndemic conditions measured included reported depression symptoms, sexual compulsiveness, substance use, intimate partner violence (IPV), and stress. We found significant evidence of syndemics among these black men: depression symptoms were independently associated with sexual compulsiveness (odds ratios [OR]: 1.88, 95% CI = 1.1, 3.3) and stress (OR: 2.67, 95% CI = 1.5, 4.7); sexual compulsiveness was independently associated with stress (OR: 2.04, 95% CI = 1.2, 3.5); substance misuse was independently associated with IPV (OR: 2.57, 95% CI = 1.4, 4.8); stress independently was associated with depression symptoms (OR: 2.67, 95% CI = 1.5, 4.7), sexual compulsiveness (OR: 2.04, 95% CI = 1.2, 3.5) and IPV (OR: 2.84, 95% CI = 1.6, 4.9). Moreover, men who reported higher numbers of syndemic constituents (three or more conditions) reportedly engaged in more unprotected anal intercourse compared to men who had two or fewer health conditions (OR: 3.46, 95% CI = 1.4-8.3). Findings support the concept of syndemics in black MSM and suggest that syndemic theory may help explain complexities that sustain HIV-related sexual transmission behaviors in this group.

BACKGROUND Analgesic use is common but remains poorly described among human immunodeficiency virus (HIV)-infected persons in the highly active antiretroviral therapy era. METHODS We studied HIV Outpatient Study participants during 1996 to 2008. We used Cox proportional hazards regression to assess variables associated with initiation of prolonged analgesia (≥90 consecutive days of analgesics); logistic regression to explore variables associated with initiation of prolonged opioid analgesia among those taking any prolonged analgesia; and linear regression to determine temporal trends in prolonged analgesia. RESULTS Among 4180 patients, 931 (22%) initiated prolonged analgesia. Factors independently associated (P