Exploration of individual socioeconomic and health-related characteristics associated with human papillomavirus vaccination initiation and vaccination series completion among adult females: A comprehensive systematic evidence review with meta-analysis.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates among females are lower than the World Health Organization target and vaccination rates specifically among adult females are even much lower. METHODS: We systematically evaluated individual socioeconomic and health-related characteristics associated with HPV vaccination initiation and vaccination series completion among adult females (PROSPERO: CRD42023445721). We performed a literature search on December 14, 2022, and supplemented the search on August 1, 2023. We pooled appropriate multivariable-adjusted results using an inverse variance random-effects model and expressed the results as odds ratios with associated 95 % confidence intervals. A point pooled significantly increased/decreased odds of 30-69 % was regarded to be strongly associated, and ≥ 70 % was very strongly associated. RESULTS: We included 63 cross-sectional studies. There were strongly increased odds of vaccination initiation among White women compared with Black or Asian women, and those with higher education, health insurance, a history of sexually transmitted infection (STI), receipt of influenza vaccination in the preceding year, not married/cohabiting, not smoking, using contraception, and having visited a healthcare provider in the preceding year. We observed very strongly increased odds of vaccination initiation among those younger and having been born in the country of study. Similarly, there were strongly increased odds of completing the vaccination series for the same variables as initiating vaccination, except for higher education, prior STI, smoking and contraception use. Additional variables associated with strongly increased odds of vaccination series completion not seen in initiation were higher annual household income, being lesbian/bisexual, and having a primary care physician. We observed very strongly increased odds of vaccination series completion similar to vaccination initiation but including for White compared with Black women, higher education, and prior cervical cancer screening. CONCLUSIONS: These individual characteristics may be the key to identifying women at increased risk of not being vaccinated against HPV and could inform targeted messaging to drive HPV vaccination.

A Primary Care-Based Weight Navigation Program.

Importance: Evidence-based weight management treatments (WMTs) are underused; strategies are needed to increase WMT use and patients' weight loss. Objective: To evaluate the association of a primary care-based weight navigation program (WNP) with WMT use and weight loss. Design, Setting, and Participants: This cohort study comprised a retrospective evaluation of a quality improvement program conducted from October 1, 2020, to September 30, 2021. Data analysis was performed from August 2, 2022, to March 7, 2024. Adults with obesity and 1 or more weight-related condition from intervention and control sites in a large academic health system in the Midwestern US were propensity matched on sociodemographic and clinical factors. Exposure: WNP, in which American Board of Obesity Medicine-certified primary care physicians offered weight-focused visits and guided patients' selection of preference-sensitive WMTs. Main Outcomes and Measures: Primary outcomes were feasibility measures, including rates of referral to and engagement in the WNP. Secondary outcomes were mean weight loss, percentage of patients achieving 5% or more and 10% or more weight loss, referral to WMTs, and number of antiobesity medication prescriptions at 12 months. Results: Of 264 patients, 181 (68.6%) were female and mean (SD) age was 49.5 (13.0) years; there were no significant differences in demographic characteristics between WNP patients (n = 132) and matched controls (n = 132). Of 1159 WNP-eligible patients, 219 (18.9%) were referred to the WNP and 132 (11.4%) completed a visit. In a difference-in-differences analysis, WNP patients lost 4.9 kg more than matched controls (95% CI, 2.11-7.76; P < .001), had 4.4% greater weight loss (95% CI, 2.2%-6.4%; P < .001), and were more likely to achieve 5% or more weight loss (odds ratio [OR], 2.90; 95% CI, 1.54-5.58); average marginal effects, 21.2%; 95% CI, 8.8%-33.6%) and 10% or more weight loss (OR, 7.19; 95% CI, 2.55-25.9; average marginal effects, 17.4%; 95% CI, 8.7%-26.2%). Patients in the WNP group were referred at higher rates to WMTs, including bariatric surgery (18.9% vs 9.1%; P = .02), a low-calorie meal replacement program (16.7% vs 3.8%; P < .001), and a Mediterranean-style diet and activity program (10.6% vs 1.5%; P = .002). There were no between-group differences in antiobesity medication prescribing. Conclusions and Relevance: The findings of this cohort study suggest that WNP is feasible and associated with greater WMT use and weight loss than matched controls. The WNP warrants evaluation in a large-scale trial.

Weight Loss Treatment and Longitudinal Weight Change Among Primary Care Patients With Obesity.

Importance: Among individuals with obesity, 5% or greater weight loss can improve health. Weight management treatments (WMT) include nutrition counseling, very low-calorie meal replacement (MR), antiobesity medications (AOM), and bariatric surgery; however, little is known about how these WMT are associated with weight change among individual patients and populations. Objective: To characterize weight status and WMT use among primary care patients and assess associations between WMT and weight trajectories. Design, Setting, and Participants: Retrospective, population-based cohort study of primary care patients from 1 academic health system in Michigan between October 2015 and March 2020 using cross-sectional analysis to compare obesity prevalence and WMT utilization. For patients with obesity and WMT exposure or matched controls, a multistate Markov model assessing associations between WMT and longitudinal weight status trajectories was used. Data were analyzed from October 2021 to October 2023. Exposures: Cross-sectional exposure was year: 2017 or 2019. Trajectory analysis exposures were WMT: nutrition counseling, MR, AOM, and bariatric surgery. Main Outcomes and Measures: Cross-sectional analysis compared mean body mass index (BMI), obesity prevalence, and, among patients with obesity, prospective WMT use. The trajectory analysis examined longitudinal weight status using thresholds of ±5% and 10% of baseline weight with primary outcomes being the 1-year probabilities of 5% or greater weight loss for each WMT. Results: Adult patients (146 959 participants) consisted of 83 636 female participants (56.9%); 8940 (6.1%) were Asian, 14 560 (9.9%) were Black, and 116 664 (79.4%) were White. Patients had a mean (SD) age of 49.6 (17.7) years and mean (SD) BMI of 29.2 (7.2). Among 138 682 patients, prevalence of obesity increased from 39.2% in 2017 to 40.7% in 2019; WMT use among patients with obesity increased from 5.3% to 7.1% (difference: 1.7%; 95% CI, 1.3%-2.2%). In a multistate model (10 180 patients; 33 549 patient-years), the 1-year probability of 5% or greater weight loss without WMT exposure was 15.6% (95% CI, 14.3%-16.5%) at reference covariates. In contrast, the probability of 5% or greater weight loss was more likely with year-long exposures to any WMT (nutrition counseling: 23.1%; 95% CI, 21.3%-25.1%; MR: 54.6%; 95% CI, 46.5%-61.2%; AOM: 27.8%; 95% CI, 25.0%-30.5%; bariatric surgery: 93.0%; 95% CI, 89.7%-95.0%). Conclusions and Relevance: In this cohort study of primary-care patients with obesity, all WMT increased the patient-level probability of achieving 5% or greater weight loss, but current rates of utilization are low and insufficient to reduce weight at the population level.

Does mainstream BRCA testing affect surgical decision-making in newly-diagnosed breast cancer patients?

BACKGROUND: Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making. METHODS: Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively. RESULTS: 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38-57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy. CONCLUSION: Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk.

Testing a very low-carbohydrate adaption of the Diabetes Prevention Program among adults with prediabetes: study protocol for the Lifestyle Education about prediabetes (LEAP) trial.

BACKGROUND: The Center for Disease Control and Prevention's National Diabetes Prevention Program (NDPP) aims to help individuals with prediabetes avoid progression to type 2 diabetes mellitus (T2DM) through weight loss. Specifically, the NDPP teaches individuals to follow a low-fat, calorie-restricted diet and to engage in regular physical activity to achieve ≥ 5% body weight loss. Most NDPP participants, however, do not achieve this weight loss goal, and glycemic control remains largely unchanged. One promising opportunity to augment the NDPP's weight loss and glycemic effectiveness may be to teach participants to follow a very low-carbohydrate diet (VLCD), which can directly reduce post-prandial glycemia and facilitate weight loss by reducing circulating insulin and enabling lipolysis. To date, there have been no high-quality, randomized controlled trials to test whether a VLCD can prevent progression to T2DM among individuals with prediabetes. The aim of this study is to test the effectiveness of a VLCD version the NDPP (VLC-NDPP) versus the standard NDPP. We hypothesize the VLC-NDPP will demonstrate greater improvements in weight loss and glycemic control. METHODS: We propose to conduct a 12-month, 1:1, randomized controlled trial that will assign 300 adults with overweight or obesity and prediabetes to either the NDPP or VLC-NDPP. The primary outcome will be glycemic control as measured by change in hemoglobin A1c (HbA1c) from baseline to 12 months. Secondary outcomes will include percent body weight change and changes in glycemic variability, inflammatory markers, lipids, and interim HbA1c. We will evaluate progression to T2DM and initiation of anti-hyperglycemic agents. We will conduct qualitative interviews among a purposive sample of participants to explore barriers to and facilitators of dietary adherence. The principal quantitative analysis will be intent-to-treat using hierarchical linear mixed effects models to assess differences over time. DISCUSSION: The NDPP is the dominant public health strategy for T2DM prevention. Changing the program's dietary advice to include a carbohydrate-restricted eating pattern as an alternative option may enhance the program's effectiveness. If the VLC-NDPP shows promise, this trial would be a precursor to a multi-site trial with incident T2DM as the primary outcome. TRIAL REGISTRATION: NCT05235425. Registered February 11, 2022.

Impact of a Pilot Structured Mobile Technology Based Lifestyle Intervention for Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Lifestyle modification is the main treatment for nonalcoholic fatty liver disease (NAFLD), but remains challenging to implement. The aim of this pilot was to assess the acceptability and feasibility of a mobile-technology based lifestyle program for NAFLD patients. METHODS: We enrolled adult patients with NAFLD in a 6-month mobile-technology based program where participants received a FitBit with weekly tailored step count goals and nutritional assessments. Anthropometrics, hepatic and metabolic parameters, Fibroscan, physical function and activity, and health-related quality of life measures were obtained at enrollment and month 6. Semi-structured exit interviews were conducted to assess patient's experience with the program. RESULTS: 40 (63%) eligible patients were enrolled. Median age was 52.5 with 53% males, 93% whites, 43% with diabetes and median BMI 33.9. On baseline Fibroscan, 59% had F0-2 fibrosis and 70% had moderate-severe steatosis. 33 patients completed the study. Median percentage of days with valid FitBit data collection was 91. 4 patients increased and maintained, 19 maintained, and 8 increased but subsequently returned to baseline weekly step count. 59% of patients reported Fitbit was easy to use and 66% felt step count feedback motivated them to increase their activity. Roughly 50% of patients had reduction in weight, triglycerides and Fibroscan liver stiffness, and 75% had improvement in controlled attenuation parameter and physical function. CONCLUSIONS: A 6-month mobile-technology based pilot lifestyle intervention was feasible and acceptable to NAFLD patients. The program promoted physical activity and was associated with improvement in clinical parameters in some patients.

ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

Availability of Sexually Transmitted Infection Screening and Expedited Partner Therapy at Federally Qualified Health Centers in Michigan.

Via secret shopper study, we assessed: (1) availability of sexually transmitted infection (STI) screening; (2) provision of expedited partner therapy; and (3) wait times for new patient STI screening appointments at Michigan federally qualified health centers. Of the 147 clinics with STI screening availability, 10.2% (15) confirmed expedited partner therapy provision.

Mixed methods pilot study of a low-carbohydrate diabetes prevention programme among adults with pre-diabetes in the USA.

OBJECTIVES: (1) To estimate weight change from a low-carbohydrate diabetes prevention programme (LC-DPP) and (2) to evaluate the feasibility and acceptability of an LC-DPP. RESEARCH DESIGN: Single-arm, mixed methods (ie, integration of quantitative and qualitative data) pilot study. SETTING: Primary care clinic within a large academic medical centre in the USA. PARTICIPANTS: Adults with pre-diabetes and Body Mass Index of ≥25 kg/m2. INTERVENTION: We adapted the Centers for Disease Control and Prevention's National Diabetes Prevention Program (NDPP)-an evidence-based, low-fat dietary intervention-to teach participants to follow a very low-carbohydrate diet (VLCD). Participants attended 23 group-based classes over 1 year. OUTCOME MEASURES: Primary outcome measures were (1) weight change and (2) percentage of participants who achieved ≥5% wt loss. Secondary outcome measures included intervention feasibility and acceptability (eg, attendance and qualitative interview feedback). RESULTS: Our enrolment target was 22. One person dropped out before a baseline weight was obtained; data from 21 individuals were analysed. Mean weight loss in kilogram was 4.3 (SD 4.8) at 6 months and 4.9 (SD 5.8) at 12 months. Mean per cent body weight changes were 4.5 (SD 5.0) at 6 months and 5.2 (SD 6.0) at 12 months; 8/21 individuals (38%) achieved ≥5% wt loss at 12 months. Mean attendance was 10.3/16 weekly sessions and 3.4/7 biweekly or monthly sessions. Among interviewees (n=14), three factors facilitated VLCD adherence: (1) enjoyment of low-carbohydrate foods, (2) diminished hunger and cravings and (3) health benefits beyond weight loss. Three factors hindered VLCD adherence: (1) enjoyment of high-carbohydrate foods, (2) lack of social support and (3) difficulty preplanning meals. CONCLUSIONS: An LC-DPP is feasible, acceptable and may be an effective option to help individuals with pre-diabetes to lose weight. Data from this pilot will be used to plan a fully powered randomised controlled trial of weight loss among NDPP versus LC-DPP participants. TRIAL REGISTRATION NUMBER: NCT03258918.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

Characterizing Employees' Preferences for Incentives for Healthy Behaviors: Examples to Improve Interest in Wellness Programs.

Background. Many employers now incentivize employees to engage in wellness programs, yet few studies have examined differences in preferences for incentivizing participation in healthy behaviors and wellness programs. Method. We surveyed 2,436 employees of a large university about their preferences for incentivizing participation in different types of healthy behaviors and then used multivariable logistic regression to estimate associations between employees' socioeconomic and demographic characteristics and their preferences for incentives for engaging in healthy behaviors. Results. Compared with nonunion members, union members had higher odds of wanting an incentive for eating healthily (adjusted odds ratio [AOR] = 1.60, 95% [CI; 1.21, 2.12]), managing weight (AOR = 1.53, 95% CI [1.14, 2.06]), avoiding drinking too much alcohol (AOR = 1.41, 95% CI [1.11, 1.78]), quitting tobacco (AOR = 1.37, 95% CI [1.06, 1.77]), managing stress (AOR = 1.37, 95% CI [1.08, 1.75]), and managing back pain (AOR = 1.64, 95% CI [1.28, 2.10]). Compared with staff, faculty employees reported higher odds for wanting an incentive for reducing alcohol intake (AOR = 1.34, 95% CI [1.00, 1.78]) and quitting tobacco (AOR = 1.43, 95% CI [1.04, 1.96]). Women had lower odds than men (AOR = 0.80, 95% CI [0.64, 0.99]) of wanting an incentive for managing back pain. Conclusions. Preferences for incentives to engage in different types of healthy behaviors differed by employees' socioeconomic and demographic characteristics. Organizations may consider using survey data on employee preferences for incentives to more effectively engage higher risk populations in wellness programs.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Mind the gap: results of a multispecialty survey on coordination of care for peri-procedural anticoagulation.

To understand how physicians from various specialties perceive coordination of care when managing peri-procedural anticoagulation. Cross-sectional survey of cardiologists, gastroenterologists, and primary care physicians (PCPs) in an integrated health system (N = 251). The survey began with a vignette of a patient with atrial fibrillation co-managed by his PCP, cardiologist, and an anticoagulation clinic who must hold warfarin for a colonoscopy. Respondents' experiences and opinions around responsibilities and institutional support for managing peri-procedural anticoagulation were elicited using multiple choice questions. We examined differences in responses across specialties using Chi square analysis. The response rate was 51% (n = 127). 52% were PCPs, 28% cardiologists, and 21% gastroenterologists. Nearly half (47.2%) of respondents believed that the cardiologist should be primarily responsible for managing peri-procedural anticoagulation, while fewer identified the PCP (25.2%), anticoagulation clinic (21.3%), or gastroenterologist (6.3%; p = 0.09). Respondents across specialties had significantly different approaches to deciding how to manage the clinical case presented (p < 0.001). Most cardiologists (60.0%) would decide whether to offer bridging without consulting with other providers or clinical resources, while most PCPs would decide after consulting clinical resources (57.6%). Gastroenterologists would most often (46.2%) defer the decision to another provider. A majority of all three specialties agreed that their institution could do more to help manage peri-procedural anticoagulation, and there was broad support (88.1%) for anticoagulation clinics' managing all aspects of peri-procedural anticoagulation. Providers across specialties agree that their institution could do more to help manage peri-procedural anticoagulation, and overwhelmingly support anticoagulation clinics' taking responsibility.

Association Between Patient Satisfaction and Short-Term Outcomes After Major Cancer Surgery.

OBJECTIVE: The aim of this study was to investigate whether patient satisfaction, as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, is associated with short-term outcomes after major cancer surgery. MATERIALS AND METHODS: We first used national Medicare claims to identify patients who underwent a major extirpative cancer surgery from 2011 to 2013. Next, we used Hospital Compare data to assign the HCAHPS score to the hospital where the patient underwent surgery. We then performed univariate statistical analyses and fit multilevel logistic regression models to evaluate the relationship between excellent patient satisfaction and short-term cancer surgery outcomes for all surgery types combined and then by each individual surgery type. RESULTS: We identified 373,692 patients who underwent major cancer surgery for one of nine cancers at 2617 hospitals. In both unadjusted and adjusted analyses, hospitals with higher proportions of patients reporting excellent satisfaction had lower complication rates (p < 0.001), readmissions (p < 0.001), mortality (p < 0.001), and prolonged length of stay (p < 0.001) than hospitals with lower proportions of satisfied patients, but with modest differences. This finding held true broadly across individual cancer types for complications, mortality, and prolonged length of stay, but less so for readmissions. CONCLUSIONS: Hospital-wide excellent patient satisfaction scores are associated with short-term outcomes after major cancer surgery overall, but are modest in magnitude.

Predictability of anthropomorphic measurements in implant selection for breast reconstruction: a retrospective cohort study.

BACKGROUND: Preoperative implant planning for breast reconstruction is often at risk of being changed perioperatively. This study examined which factors are associated with a change of implant selection. METHODS: Women who had unilateral two-stage breast reconstruction between 2002 and 2007 were studied. Inclusion criteria were photographic evidence of preoperative skin markings indicating breast dimensions and a selected implant model. Multivariable logistic regression was used to identify variables associated with a changed selection. RESULTS: Among the 496 women studied, 308 preoperative implant choices (62.1%) were changed during surgery. A change in plan was significantly associated with symmetrization surgery involving contralateral reduction mammaplasty (OR = 1.92; 95% CI, 1.12 to 3.29) and contralateral mastopexy (OR = 2.26; 95% CI, 1.29 to 3.96), but not with BMI. The required implant width changed more than 0.5 cm in 70 cases (14.1%) while height changed more than 0.5 cm in 215 cases (43.2%). The likelihood of a change was high for large preoperative widths (OR = 9.66 for 15.5 cm) and small preoperative heights (OR = 2.97 for 10.5 cm). At a mean follow-up of 16.6 months, patient satisfaction was good or average in 92.1% of cases and 5.9% of implants had been replaced with another model, indicating that the perioperative implant selection was usually appropriate. CONCLUSIONS: This study documents the frequency with which implant choices, despite accurate preoperative planning, are changed perioperatively as a result of relatively small differences in anthropomorphic measurements. Perioperative recalculation of breast dimensions may have an advantage in terms of patient reoperation rates. Changes in width were less frequent than changes in height and projection. Contralateral surgery, large width, and small height were the most influential factors. Level of Evidence: Level IV, risk / prognostic study.

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

Integrating Physical Activity in Primary Care Practice.

Based on a collaborative symposium in 2014 hosted by the Society of Behavioral Medicine (SBM) and the American College of Sports Medicine (ACSM), this paper presents a model for physical activity counseling for primary care physicians (PCPs). Most US adults do not meet national recommendations for physical activity levels. Socioecological factors drive differences in physical activity levels by geography, sex, age, and racial/ethnic group. The recent Patient Protection and Affordable Care Act incentivizes PCPs to offer patients physical activity counseling. However, PCPs have reported socioecological barriers to physical activity counseling and also patient barriers to physical activity, spanning from the individual to the environmental (eg, lack of safe spaces for physical activity), policy (eg, reimbursement policies), and organizational (eg, electronic medical record protocols, worksite norms/policies) levels. The aims of this paper are to: 1) discuss barriers to PCP counseling for physical activity; 2) provide evidence-based strategies and techniques to help PCPs address these counseling barriers; and 3) suggest practical steps for PCPs to counsel patients on physical activity using strategies and supports from policy, the primary care team, and other support networks.

Implementation of a prediabetes identification algorithm for overweight and obese Veterans.

Type 2 diabetes prevention is an important national goal for the Veteran Health Administration (VHA): one in four Veterans has diabetes. We implemented a prediabetes identification algorithm to estimate prediabetes prevalence among overweight and obese Veterans at Department of Veterans Affairs (VA) medical centers (VAMCs) in preparation for the launch of a pragmatic study of Diabetes Prevention Program (DPP) delivery to Veterans with prediabetes. This project was embedded within the VA DPP Clinical Demonstration Project conducted in 2012 to 2015. Veterans who attended orientation sessions for an established VHA weight-loss program (MOVE!) were recruited from VAMCs with geographically and racially diverse populations using existing referral processes. Each site implemented and adapted the prediabetes identification algorithm to best fit their local clinical context. Sites relied on an existing referral process in which a prediabetes identification algorithm was implemented in parallel with existing clinical flow; this approach limited the number of overweight and obese Veterans who were assessed and screened. We evaluated 1,830 patients through chart reviews, interviews, and/or laboratory tests. In this cohort, our estimated prevalence rates for normal glycemic status, prediabetes, and diabetes were 29% (n = 530), 28% (n = 504), and 43% (n = 796), respectively. Implementation of targeted prediabetes identification programs requires careful consideration of how prediabetes assessment and screening will occur.

Physical activity and sedentary behavior measured objectively and subjectively in overweight and obese adults with schizophrenia or schizoaffective disorders.

OBJECTIVE: Describe objective and subjective physical activity levels and time spent being sedentary in adults with schizophrenia or schizoaffective disorders (SZO/SA). METHOD: Baseline physical activity and sedentary behaviors were assessed among 46 overweight and obese community-dwelling adults (aged 18-70 years; BMI > 27 kg/m(2)) diagnosed with SZO/SA by DSM-IV-TR, with mild symptom severity (Positive and Negative Syndrome Scale score < 90) who were interested in losing weight and participated in the Weight Assessment and Intervention in Schizophrenia Treatment (WAIST) study from 2004 to 2008. Objective physical activity levels, measured using actigraphs, in WAIST were compared to a nationally representative sample of users (n = 46) and nonusers (n = 46) of mental health service (MHS) from the National Health and Nutrition Examination Survey (NHANES 2003-2004) matched by sex, BMI, and age. RESULTS: On average, adults with SZO/SA wore actigraphs more than 15 h/d for 7 days averaging 151,000 counts/d. The majority of monitoring time (81%) was classified as sedentary (approximately 13 h/d). Moderate/vigorous and light physical activity accounted for only 2% (19 min/d) and 17% (157 min/d) of monitoring time/d, respectively. Primary source of activity was household activities (409 ± 438 min/wk). Fifty-three percent reported walking for transportation or leisure. Adults with SZO/SA were significantly less active (176 min/d) and more sedentary (756 min/d) than NHANES users of MHS (293 and 640 min/d, respectively) and nonusers of MHS (338 and 552 min/d, respectively) (P < .01). CONCLUSIONS: Overweight and obese adults with SZO/SA were extremely sedentary; engaged in unstructured, intermittent, low-intensity physical activity; and significantly less active than NHANES users and nonusers of MHS. This sedentary lifestyle is significantly lower than those of other inactive US populations, is costly for the individual and community, and highlights the need for physical activity promotion and interventions in this high risk population.