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Building community-clinical linkages to increase older adult physical activity: The PT-REFER trial protocol and participant baseline characteristics

Contemp Clin Trials Commun

2019 Harris, Jeffrey

Background: Physical activity is important for maintaining older adult health, but a majority of older adults are not meeting recommended physical activity levels. This paper describes the protocol and participant baseline characteristics for a trial (named "PT-REFER") to test an intervention focused on developing community-clinical linkages to increase older adult referrals from physical therapy clinics to an evidence-based group exercise program (Enhance(R)Fitness) (EF) offered by YMCA associations. Methods: We designed a two-arm cluster-randomized controlled trial with YMCA associations. We conducted formative research with YMCA staff and physical therapists to inform intervention format and content. The primary outcome is the number of new participants enrolled in EF over the course of 30 months. We also collect process information on cost and implementation though structured surveys and semi-structured qualitative interviews. Results: The PT-REFER intervention creates a learning collaborative for YMCA associations, which are tasked with implementing a number of capacity- and partnership-building activities over the course of seven months, and participating in monthly group technical assistance calls. We recruited 20 YMCA associations from 13 states. At baseline, the average number of EF sites per association was 3.9 and the monthly average number of new EF participants was 3.7. Conclusions: This study will test an approach to increasing the capacity of YMCAs for conducting outreach to physical therapy clinics, and evaluate the factors that may influence its implementation. As a result, it has the potential to contribute to our understanding of how to develop viable and sustainable community-clinical linkages for older adult health.

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer

Support Care Cancer

2019 Lyman, Gary H, MD, MPH Gary Lyman

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays >/= 7 days, dose reductions >/= 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays >/= 7 days, 50.1% experienced dose reductions >/= 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS >/= 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays >/= 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays >/= 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI >/= 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays >/= 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Plant- and animal-protein diets in relation to sociodemographic drivers, quality, and cost: findings from the Seattle Obesity Study

Am J Clin Nutr

2019 Drewnowski, Adam, PhD Adam Drewnowski

BACKGROUND: Promoting plant-based proteins is at the forefront of many initiatives in public health nutrition. OBJECTIVES: The aim of this study was to characterize the sociodemographic drivers of plant-based protein diet consumption, and to study these in relation to diet quality and cost. METHODS: The Seattle Obesity Study series (SOS I and II) yielded the study sample (n = 1636). Sociodemographic data were obtained by survey self-report. Diet quality and cost came from the Fred Hutchinson Cancer Research Center Food-Frequency Questionnaire linked to retail food prices. The Healthy Eating Index 2010 (HEI-2010) and mean adequacy ratio (MAR) served as measures of diet quality. Linear regressions with robust standard errors examined associations. RESULTS: Total proteins contributed 16.8% of daily dietary energy. The breakdown by animal and plant proteins was 10.9% and 5.9%, respectively. The sociodemographic factors associated with plant-protein consumption were a positive attitude towards healthy eating and higher education but not income. Plant-protein diets were characterized by severalfold increases in nuts and seeds, soy and legumes, but much less meat, poultry, dairy, solid fats, and added sugars. Higher quartiles of plant-based diets were associated with significantly higher HEI-2010 (beta: 13.0 from quartile 1 to quartile 4; 95% CI: 11.8, 14.3) and higher MAR (beta: 6.0; 95% CI: 3.5, 8.5) with minimal impact on diet costs (beta: 0.35; 95% CI: 0.04, 0.67). In contrast, higher quartiles of animal-protein diets were associated with higher diet costs (beta: 1.07; 95% CI: 0.77, 1.36) but lower HEI-2010 (beta: -3.2; 95% CI: -4.5, -1.9). Each additional 3% of energy from plant proteins was associated with an 8.4-unit increase in HEI-2010 (95% CI: 7.6, 9.1) and with a 4.1-unit increase in MAR (95% CI: 2.7, 5.5) with a minimal increase in diet cost (beta: 0.28; 95% CI: 0.06, 0.50). CONCLUSION: Plant-based protein diets may be a cost-effective way to improve diet quality at all levels of income. Future research needs to evaluate the quality of plant-based protein in relation to amino acids and health.

Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease


2019 Wald, Anna, MD, MPH Anna Wald

BACKGROUND: Genital herpes simplex virus (HSV) type 2 is a common persistent infection that frequently reactivates to cause recurrent lesions and recurrent viral shedding which is incompletely controlled by antiviral therapy. GEN-003 is a candidate therapeutic vaccine containing 2 HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant (M2). METHODS: HSV-2 seropositive persons with genital herpes were randomized into three dose cohorts of Gen-003 (60microg antigen/50microgM2, 60microg/75microgM2 or Placebo). Three intramuscular doses 21days apart of GEN-003 or placebo were administered. Participants obtained genital area swabs twice-daily for HSV-2 detection and monitored genital lesions for 12months. The rates of virus shedding and lesion rates before vaccination were compared to 3 defined periods after vaccination; Days 43-71, Month 6 and Month 12. RESULTS: GEN-003 at a dose of 60microg each antigen/50microgM2 reduced HSV shedding immediately after dosing with a rate ratio of 0.58, compared to 0.75 for the GEN-003 60microg/75microgM2 and 1.06 for placebo. Lesion rates, recurrence rates, and duration of recurrences were also reduced. Reactogenicity was higher with the 75microgM2 dose than the 50microgM2 dose, specifically for pain, tenderness, malaise and fatigue. Antibody and cellular immune responses were stimulated by both doses and persisted to 12months. CONCLUSIONS: GEN-003 vaccine manufactured with a scalable process gave results similar to those observed in prior clinical trials. GEN-003 had an acceptable safety profile and stimulated both humoral and cellular immune responses. The 60microg antigen/50microgM2 provided the maximal effect on virologic and clinical measures and warrants further development. (Funded by Genocea; number NCT02515175).

Systemic Interferon-gamma Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial

Cancer Immunol Res

2019 Zhang, Shihong

Interferon-gamma (IFNgamma) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer-testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNgamma treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNgamma. We performed pre- and post-treatment biopsies. IFNgamma changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (p<0.05). Gene expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNgamma used to convert SS and MRCL into "hot" tumors will work in concert with anti-PD1 therapy to provide patient benefit.

Reimbursing Patients for Participation in Cancer Clinical Trials

JAMA Oncol

2019 Unger, Joseph M, PhD, MS Joseph Unger


Evaluating Relationships between Visceral Fat Measures and Adipokines Concentrations among Women with a History of Preeclampsia

Am J Perinatol

2019 Gammill, Hilary S

OBJECTIVE: We sought to evaluate associations between postpartum plasma adipokine concentrations among women with a history of preeclampsia (PE) without severe features (MPE), PE with severe features (SPE), and no PE (NPE). We also investigated relationships between adipokines and computed tomography (CT)-quantified measures of visceral fat (VF) area (VFA) and subcutaneous fat area (SCFA). STUDY DESIGN: We performed a secondary analysis of data collected as part of a previously performed cross-sectional study at our institution. Women with and without a history of PE were recruited in 10 years after delivery. VFA and SCFA measures were performed by CT scan. Anthropometric data and peripheral blood samples from subjects were collected concurrently. RESULTS: Plasma adiponectin concentrations (microg/mL) were significantly lower among MPE (18.5 +/- 7.1) compared with NPE (27.3 +/- 13.8) and SPE (25.7 +/- 9.6). Leptin (p = 0.32) and resistin (p = 0.93) concentrations were similar among the groups. Adiponectin concentrations more closely aligned with VFA (beta = - 0.001, p = 0.03), while resistin concentrations trended toward correlating with SCFA (beta = 0.02, p = 0.05). Leptin was not preferential to VFA or SCFA. CONCLUSION: VF distribution may contribute to the variation in PE phenotype. Adiponectin specifically may be a promising marker representing VFA.

Two-phase, generalized case-control designs for quantitative longitudinal outcomes

Am J Epidemiol

2019 Heagerty, Patrick J, PhD Patrick Heagerty

We propose a general class of two-phase, epidemiological study designs for quantitative, longitudinal data that are useful when phase one longitudinal outcome and covariate data are available, but the exposure (e.g., biomarker) can only be collected on a subset of subjects during phase two. To conduct a design in the class, one first summarizes the longitudinal outcomes by fitting a simple linear regression of the response on a time-varying covariate for each subject. Sampling strata are defined by splitting the estimated regression intercept or slope distributions into distinct (low, medium, and high) regions. Stratified sampling is then conducted from strata defined by the intercepts, slopes, or from a mixture. In general, samples selected with extreme intercept values will yield low variances for time-fixed exposure associations with the outcome and samples enriched with extreme slope values will yield low variances for time-varying exposure associations with the outcome (including interactions with time-varying exposures). We describe ascertainment corrected maximum likelihood and multiple imputation estimation procedures that permit valid and efficient inferences. We embed all methodological developments within the framework of conducting a sub-study that seeks to examine genetic associations with lung function in continuously smoking participants in the Lung Health Study.

Rivaroxaban With or Without Aspirin in Patients with Heart Failure and Chronic Coronary or Peripheral Artery Disease: The COMPASS Trial


2019 Probstfield, Jeffrey L

BACKGROUND: Patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD) and history of heart failure (HF) are at high risk for major adverse cardiovascular events (MACE). We explored the effects of rivaroxaban with or without aspirin in these patients. METHODS: The COMPASS trial randomized 27,395 participants with chronic CAD or PAD to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg alone. Patients with NYHA class III or IV HF or left ventricular ejection fraction (EF) <30% were excluded. The primary MACE outcome comprised cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome was major bleeding using modified ISTH criteria. Investigators recorded a history of HF and EF at baseline, if available. We examined the effects of rivaroxaban on MACE and major bleeding in patients with or without a history of HF and an EF < or >/=40% at baseline. RESULTS: Of the 5902 participants (22%) with a history of HF, 4971 (84%) had EF recorded at baseline and 12% had EF <40%. Rivaroxaban and aspirin had similar relative MACE reduction compared with aspirin in participants with HF (5.5% versus 7.9%; HR 0.68, 95% CI 0.53-0.86) and those without HF (3.8% vs 4.7%, HR 0.79, 95% CI 0.68-0.93, p for interaction 0.28) but larger absolute risk reduction (ARR) in those with HF (HF ARR 2.4%, NNT=42 no HF ARR 1.0%, NNT=103). The primary MACE outcome was not statistically different between those with EF<40% [HR 0.88, 95% CI 0.55-1.42) and >/=40% (HR 0.81, 95% CI: 0.67-0.98), p for interaction 0.36]. The excess hazard for major bleeding was not different in participants with HF (2.5% vs 1.8%, HR 1.36, 95% CI 0.88-2.09) compared to those without HF (3.3% vs 1.9%, HR 1.79, 95% CI 1.45-2.21, p for interaction 0.26). There were no significant differences in the primary outcomes with rivaroxaban alone. CONCLUSIONS: In patients with chronic CAD or PAD and a history of mild or moderate HF, combination rivaroxaban and aspirin compared with aspirin alone produces similar relative but larger absolute benefits compared with those without HF. CLINICAL TRIAL REGISTRATION: Unique Identifier: NCT01776424 URL:

Massively parallel profiling and predictive modeling of the outcomes of CRISPR/Cas9-mediated double-strand break repair

Nucleic Acids Res

2019 Shendure, Jay A, MD, PhD Jay Shendure

Non-homologous end-joining (NHEJ) plays an important role in double-strand break (DSB) repair of DNA. Recent studies have shown that the error patterns of NHEJ are strongly biased by sequence context, but these studies were based on relatively few templates. To investigate this more thoroughly, we systematically profiled approximately 1.16 million independent mutational events resulting from CRISPR/Cas9-mediated cleavage and NHEJ-mediated DSB repair of 6872 synthetic target sequences, introduced into a human cell line via lentiviral infection. We find that: (i) insertions are dominated by 1 bp events templated by sequence immediately upstream of the cleavage site, (ii) deletions are predominantly associated with microhomology and (iii) targets exhibit variable but reproducible diversity with respect to the number and relative frequency of the mutational outcomes to which they give rise. From these data, we trained a model that uses local sequence context to predict the distribution of mutational outcomes. Exploiting the bias of NHEJ outcomes towards microhomology mediated events, we demonstrate the programming of deletion patterns by introducing microhomology to specific locations in the vicinity of the DSB site. We anticipate that our results will inform investigations of DSB repair mechanisms as well as the design of CRISPR/Cas9 experiments for diverse applications including genome-wide screens, gene therapy, lineage tracing and molecular recording.

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