Home environment factors associated with child BMI changes during COVID-19 pandemic.

BACKGROUND: The influence of home obesogenic environments, as assessed by the validated Family Nutrition and Physical Activity (FNPA) tool, and child obesity during the COVID pandemic were evaluated using electronic health records in this retrospective cohort study. METHODS: Historical data on BMI and the FNPA screening tool were obtained from annual well-child visits within the Geisinger Health System. The study examined youth ages 2-17 that had a BMI record and an FNPA assessment prior to the pandemic (BMI 3/1/19-2/29/20), 1 BMI record 3 months into the pandemic (6/1/20-12/31/20) and 1 BMI in the second year of the pandemic (1/1/21-12/31/21). Tertiles of obesity risk by FNPA score were examined. Mixed-effects linear regression was used to examine change in BMI slope (kg/m2 per month) pre-pandemic to pandemic using FNPA summary and subscales scores as predictors and adjusting for confounding factors. RESULTS: The analyses included 6,746 children (males: 51.7%, non-Hispanic white: 86.6%, overweight:14.8%, obesity:10.3%, severe obesity: 3.9%; mean(SD) age: 5.7(2.8) years). The rate of BMI change in BMI was greatest from early pandemic compared to pre-pandemic for children in lowest versus highest tertiles of FNPA summary score (0.079 vs. 0.044 kg/m2), FNPA-Eating (0.068 vs. 0.049 kg/m2), and FNPA-Activity (0.078 vs. 0.052 kg/m2). FNPA summary score was significantly associated with change in BMI from the pre-pandemic to early pandemic period (p = 0.014), but not associated with change in BMI during the later pandemic period. CONCLUSIONS: This study provides additional insight into the changes in the rate of BMI change observed among children and adolescents in the United States during the COVID-19 pandemic. The FNPA provides ample opportunity to continue our exploration of the negative impact of the COVID-19 pandemic on the longitudinal growth patterns among children and adolescents.

Childhood Obesity and Early Body Mass Index Gains Associated with COVID-19 in a Large Rural Health System.

OBJECTIVE: To evaluate body mass index (BMI) change among a population of children with a high proportion residing in rural areas across two pandemic time periods. METHODS: Electronic health records were evaluated in a rural health system. INCLUSION CRITERIA: 2-17 years at initial BMI; >2 BMIs during pre-pandemic (January 1, 2018-February 29, 2020); >1 BMI in early pandemic (June 1, 2020-December 31, 2020); and >1 BMI in later pandemic (January 1, 2021-December 31, 2021). Mixed effects linear regression models were used to estimate average monthly rate of change in BMI slope (∆BMI) from pre-pandemic to pandemic and test for effect modification of sex, race/ethnicity, age, BMI, public insurance, and rural address. RESULTS: Among the 40,627 participants, 50.2% were female, 84.6% were non-Hispanic white, 34.9% used public insurance, and 42.5% resided in rural areas. The pre-pandemic proportion of children with overweight, obesity, and severe obesity was 15.6%, 12.8%, and 6.3%, respectively. The ∆BMI nearly doubled during the early pandemic period compared with the pre-pandemic period (0.102 vs 0.055 kg/m2), however, ∆BMI in the later pandemic was lower (0.040 vs 0.055 kg/m2). ∆BMI remained higher in the later pandemic for all race categories compared to Non-Hispanic white. Children with public insurance had higher ∆BMI compared to those with private insurance that remained higher in the later pandemic (0.051 vs 0.035 kg/m2). There was no significant difference between ∆BMI for rural and urban children during pandemic periods. CONCLUSIONS: Despite the decreased ∆BMI among children in the later pandemic, prevalence of obesity and severe obesity remain high. Efforts must continue to be made to limit excess weight gain during childhood and to assess the impact of forces like structural and social factors in both etiology and prevention.

Probing prenatal bisphenol exposures and tissue-specific DNA methylation responses in cord blood, cord tissue, and placenta.

The early-gestational fetal epigenome establishes the landscape for fetal development and is susceptible to disruption via environmental stressors including chemical exposures. Research has explored how cell- and tissue-type-specific epigenomic signatures contribute to human disease, but how the epigenome in each tissue comparatively responds to environmental exposures is largely unknown. This pilot study compared DNA methylation in four previously identified genes across matched cord blood (CB), cord tissue (CT), and placental (PL) samples from 28 mother-infant pairs in tthe Michigan Mother Infant Pairs study; evaluated association between prenatal exposure to bisphenols (BPA, BPF, and BPS) and DNA methylation (DNAm) by tissue type; compared epigenome-wide DNAm of CB and PL; and explored associations between prenatal bisphenol exposures and epigenome-wide DNAm in PL. Bisphenol concentrations were quantified in first-trimester maternal urine. DNAm was assessed at four genes via pyrosequencing in three tissues; epigenome-wide DNAm analysis via Infinium MethylationEPIC array was completed on CB and PL. Candidate gene analysis revealed tissue-specific differences across all genes. In adjusted linear regression, BPA and BPF were associated with DNAm across candidate genes in PL but not CB and CT. Epigenome-wide comparison of matched CB and PL DNAm revealed tissue-specific differences at most CpG sites and modest associations between maternal first-trimester bisphenol exposures and PL but not CB DNAm. These data endorse inclusion of a variety of tissues in prenatal exposure studies. Overlapping and divergent responses in CB, CT, and PL demonstrate their utility in combination to capture a fuller picture of the epigenetic effect of developmental exposures.

Comparing enhancements to well-child visits in the prevention of obesity: ENCIRCLE cluster-randomized controlled trial.

BACKGROUND: Obesity disproportionally impacts rural, lower-income children in the United States. Primary care providers are well-positioned to engage parents in early obesity prevention, yet there is a lack of evidence regarding the most effective care delivery models. The ENCIRCLE study, a pragmatic cluster-randomized controlled trial, will respond to this gap by testing the comparative effectiveness of standard care well-child visits (WCV) versus two enhancements: adding a patient-reported outcome (PRO) measure (PRO WCV) and PRO WCV plus Food Care (telehealth coaching and a grocery store tour). METHODS: A total of 2,025 parents and their preschool-aged children (20-60 months of age) will be recruited from 24 Geisinger primary care clinics, where providers are randomized to the standard WCV, PRO WCV, or PRO WCV plus Food Care intervention arms. The PRO WCV includes the standard WCV plus collection of the PRO-the Family Nutrition and Physical Activity (FNPA) risk assessment-from parents. Parents complete the PRO in the patient-portal or in the clinic (own device, tablet, or kiosk), receive real-time feedback, and select priority topics to discuss with the provider. These results are integrated into the child's electronic health record to inform personalized preventive counseling by providers. PRO WCV plus Food Care includes referrals to community health professionals who deliver evidence-based obesity prevention and food resource management interventions via telehealth following the WCV. The primary study outcome is change in child body mass index z-score (BMIz), based on the World Health Organization growth standards, 12 months post-baseline WCV. Additional outcomes include percent of children with overweight and obesity, raw BMI, BMI50, BMIz extended, parent involvement in counseling, health behaviors, food resource management, and implementation process measures. DISCUSSION: Study findings will inform health care systems' choices about effective care delivery models to prevent childhood obesity among a high-risk population. Additionally, dissemination will be informed by an evaluation of mediating, moderating, and implementation factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT04406441); Registered May 28, 2020.

Patient-reported outcome measures can advance population health, but is access to instruments and use equitable?

Patient reported outcome measures (PROM) can engage patients and clinicians to improve health outcomes. Their population health impact may be limited by systematic barriers inhibiting access to completion. In this analysis we evaluated the association between individual parent/child characteristics and clinic factors with parental completion of a locally developed PROM, the Early Healthy Lifestyles (EHL) questionnaire. Participants included parent-child dyads who presented at 14 pediatric clinics for regularly scheduled well-child visits (WCV) prior to age 26 months. EHL items include feeding practices, diet, play time, screen exposure, and sleep. Completion was categorized at patient- (i.e., parent-child dyad) and clinic-levels. Parents completed the 15-item EHL in the patient portal before arrival or in the clinic; ninety-three percent of EHL questionnaires were completed in the clinic vs. 7% in the patient portal. High-completers completed EHL for half of WCVs; low-completers completed at least once; and non-completers never completed. Clinics were classified by EHL adoption level (% high completion): High-adoption: >50%; Moderate-adoption: 10%-50%; and Low-adoption: <10%. Individual-level factors had negligible impact on EHL completion within moderate/low EHL adoption sites; high-adoption sites were used to evaluate infant and maternal factors in association with EHL completion using hierarchical logistic regression. Noncompletion of EHL was significantly associated (p < 0.05) with infant use of public insurance (OR = 1.92 [1.42, 2.59]), >1 clinic site for WCV (OR = 1.83 [1.34, 2.50]), non-White birth mother (OR = 1.78 [1.28, 2.47]), and body weight <2,500 grams or gestational age <34 weeks (OR = 1.74 [1.05, 2.90]). The number of WCVs, a proxy for clinic size, was evaluated but was not associated with completion. Findings indicate potential disparities between populations exposed to, completing, and benefitting from these tools.

A Description of Breast Models Used to Teach Clinical Skills.

Background: Health care trainees lack opportunities to practice breast assessment and clinical skills with patients, making breast models significant for hands-on training. Insufficient training leads to low competence across practitioners in breast health areas of practice, including clinical lactation. The aim of this review was to describe types of breast models used to teach clinical skills of the breast across breast health areas. The secondary aims were to describe education interventions that included each model and identify whether multiple skin tones were available in models. Methods: Authors conducted a scoping review to identify which types of breast models are used to teach clinical skills across breast health areas of practice and determine gaps in literature regarding how clinical lactation skills are taught. The literature search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, MedLine, and ProQuest. Inclusion criteria were students/professionals engaging in breast model simulation. Eighteen studies were reviewed. Authors extracted data on participants, breast health area, breast model, intervention, evaluation, general outcomes, skin tone, and research design. Results: The most common skill area was clinical breast exam (n = 7), while least was breastfeeding education (n = 1). Most models were commercial (n = 12). Zero studies described skin tone. Generally, breast model simulations were correlated with increased clinical skills and confidence regardless of model used. Conclusions: Despite demonstrated gain of skills, this review reveals inconsistent use of breast models and evaluation, exclusion of diverse skin tones, and lack of breast models reported to teach clinical lactation skills.

An Application of Kane's Validity Framework to Evaluate Formative and Summative Assessment Instruments for Telesimulations in Clinical Lactation.

INTRODUCTION: Health professional learners have limited exposure to breastfeeding patients from diverse backgrounds in clinical rotations. Instead, simulation-based training is used for lactation skills training. There are no validated or standardized simulations and assessment rubrics for lactation. In this pilot, breastfeeding telesimulations with standardized patients (SPs) wearing a high-fidelity breast model matching their skin tone were developed. The validity of Formative and Summative Assessment Rubrics (FAR, SAR) were assessed following Kane's validity framework. The objective was to provide initial evidence for the validity of the FAR and SAR as constructs of competence in lactation support at the entry to practice or practice level. METHODS: Three breastfeeding case scenarios, FAR, and SAR were developed and evaluated with clinical lactation specialists (evaluators, n = 17) and SPs. The FAR was used in practice telesimulations where SPs' (n = 14) performance and telesimulation feasibility were assessed. The FAR was updated in preparation for a pilot study where medical students (n = 13) completed the 3 telesimulations. In the pilot, the updated FAR was used by SPs (n = 6) to assess medical students' performance of clinical skills. After the pilot, rubrics were updated after focus groups with SPs and discussions with evaluators. Evaluators (n = 3) graded students' posttelesimulation documentations using the SAR. Cronbach ɑ level and the intraclass correlation coefficient were assessed iteratively to collect evidence for the scoring, generalizability, and extrapolation of the FAR and SAR according to Kane's framework. RESULTS: The FAR and SAR were found to have acceptable internal consistency and moderate to high interrater reliability (intraclass correlation coefficient, 0.55-0.94), which provided evidence for scoring and generalizability of the instruments. Evaluators agreed that SPs' performances were realistic (5.6/6), and SPs' feedback was organized (5.5/6) and helpful (5.6/6), which provided evidence for extrapolation. CONCLUSIONS: Initial evidence for validity of scoring, generalization, and extrapolation FAR and SAR (according to Kane's framework) in assessing health professional learner's performance of clinical lactation skills has been presented. These results from a pilot study suggest that the FAR and SAR are reliable instruments for assessing learners' clinical performance in a breastfeeding-focused telesimulation where the SP wears a high-fidelity breast model matching their skin tone. Additional studies will be required to collect evidence according to all 4 categories of Kane's framework for the validity of the FAR and SAR.

Maternal and neonatal one-carbon metabolites and the epigenome-wide infant response.

Maternal prenatal status, as encapsulated by that to which a mother is exposed through diet and environment, is a key determinant of offspring health and disease. Alterations in DNA methylation (DNAm) may be a mechanism through which suboptimal prenatal conditions confer disease risk later in life. One-carbon metabolism (OCM) is critical to both fetal development and in supplying methyl donors needed for DNAm. Plasma concentrations of one-carbon metabolites across maternal first trimester (M1), maternal term (M3), and infant cord blood (CB) at birth were tested for association with DNAm patterns in CB from the Michigan Mother and Infant Pairs (MMIP) pregnancy cohort. The Illumina Infinium MethylationEPIC BeadChip was used to quantitatively evaluate DNAm across the epigenome. Global and single-site DNAm and metabolite models were adjusted for infant sex, estimated cell type proportions, and batch as covariates. Change in mean metabolite concentration across pregnancy (M1 to M3) was significantly different for S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), betaine, and choline. Both M1 SAH and CB SAH were significantly associated with the global distribution of DNAm in CB, with indications of a shift toward less methylation. M3 SAH and CB SAH also displayed significant associations with locus-specific DNAm in infant CB (FDR<0.05). Our findings underscore the role of maternal one-carbon metabolites in shifting the global DNAm pattern in CB and emphasizes the need to closely evaluate how dietary status influences cellular methylation potential and ultimately offspring health.

Gestational exposure to high fat diets and bisphenol A alters metabolic outcomes in dams and offspring, but produces hepatic steatosis only in dams.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Perinatal development is a critical window for altered, lifelong health trajectory, and evidence supports the role of perinatal programming in chronic metabolic diseases. To examine the impact of diet and bisphenol A (BPA) on the developmental trajectory of NAFLD in offspring, we exposed dams from pre-gestation through lactation to a human-relevant dose of oral BPA coupled with intake of high fat Western or Mediterranean-style diets. We assessed hepatic steatosis by quantifying hepatic triglycerides (TGs) and metabolic health by measuring body weight, relative organ weights, and serum hormone levels in dams and offspring at postnatal day 10 (PND10) and 10-months of age. In dams, consumption of the Western or Mediterranean diet increased hepatic TGs 1.7-2.4-fold, independent of BPA intake. Among offspring, both perinatal diet and BPA exposure had a greater impact on metabolic outcomes than on hepatic steatosis. At PND10, serum leptin levels were elevated 2.6-4.8-fold in pups exposed to the Mediterranean diet, with a trend for sex-specific effects on body and organ weights. At 10-months, sex-specific increases in organ weight and hormone levels were observed in mice perinatally exposed to Western + BPA or Mediterranean + BPA. These findings suggest lifestage-specific interaction of perinatal exposures to experimental diets and BPA on offspring metabolic health without effects on NAFLD later in life. Importantly, alterations in dam phenotype by diet and BPA exposure appear to impact offspring health trajectory, emphasizing the need to define dam diet in assessing effects of environmental exposures on offspring health.

The Efficacy of Hybrid Telesimulation with Standardized Patients in Teaching Medical Students Clinical Lactation Skills: A Pilot Study.

Introduction: Medical students lack competencies in clinical lactation. We determined the effect of hybrid telesimulation with a standardized patient (SP) on medical students' clinical performance in lactation support. We assessed students' engagement and satisfaction with the experience. Materials and Methods: Undergraduate medical students (n = 13) completed (1) preparatory case scenarios with multiple-choice questions and (2) three telesimulations with SPs wearing a high-fidelity breast model. Students had the option to complete the Encounter Documentation. SPs used the Formative Assessment Rubric (FAR) to evaluate students' interpersonal skills and clinical lactation experts used the Summative Assessment Rubric to evaluate documentation skills. Investigators collected satisfaction data from a focus group and written evaluation. Dunn's multiple comparison and Freidman tests were used to measure differences in FAR scores between cases and telesimulations. Qualitative data were analyzed using thematic analysis. Results: Most students (70%) attempted case questions multiple times and scores improved (p < 0.0001) between attempts. FAR scores suggest students were prepared for telesimulations (5.5/6-pt Likert) and interpersonal skills were appropriate (5.4/6), with no differences by case (p = 0.11). FAR scores increased between telesimulation 1-2 (+24.5/114, p = 0.002) and 2-3 (+17.5/114, p = 0.014). Students were satisfied with the experience and would recommend it to classmates (both 4.6/6). Thematic analysis revealed feedback regarding interpersonal skills was helpful. Conclusions: Medical students must develop skills to support breastfeeding in virtual settings. Telesimulation can be incorporated into existing curricula to support clinical lactation competencies.

Maternal lipodome across pregnancy is associated with the neonatal DNA methylome.

Aim: To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes. Materials & methods: Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups. Results: M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth. Conclusion: The maternal lipidome may be influential in establishing the infant epigenome.

Cultural Competency Training and Evaluation Methods Across Dietetics Education: A Narrative Review.

Developing cultural competence among credentialed nutrition and dietetics practitioners is critical to move toward eliminating disparities in health care. Despite emphasis put forth on culturally competent care by credentialed nutrition and dietetics practitioners, the types, methods, and outcomes of cultural competency training are lacking or inconsistent. In this narrative review, we evaluated studies detailing cultural competency training for content, modes of delivery, and learner outcomes. Main inclusion criteria were students in dietetics or credentialed nutrition and dietetics practitioners engaging in an educational intervention. Exclusion criteria were studies published before 2000 and not published in the English language. Ten studies were reviewed from four health science databases. Our aims were to quantify the literature on cultural competence training in dietetics education and describe the interventions to identify gaps within the field; thus, a quality assessment tool was not utilized. Data were extracted on learner type, number of participants, curriculum content, intervention type, learning outcomes, and outcome evaluation tool. Most studies employed interprofessional education (n=7) and/or service learning (n=6) as interventions types. Quantitative evaluation of learners in the studies reviewed indicated increased knowledge and skill (statistically significant; n=2), whereas qualitative evaluation of learners indicated themes, including curriculum satisfaction, gains in competence, and comfort working with diverse people. Methods of evaluation and delivery were inconsistent, making it difficult to draw larger conclusions about cultural competency training in dietetics. Cultural competence creates opportunities for growth and development of health professionals to serve diverse communities and work environments; future work should include standardizing evaluations of training, specifically to include both qualitative and quantitative methods.

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood.

Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring's risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism.

PURPOSE OF REVIEW: The genetic material of every organism exists within the context of regulatory networks that govern gene expression-collectively called the epigenome. Animal models and human birth cohort studies have revealed key developmental periods that are important for epigenetic programming and vulnerable to environmental insults. Thus, epigenetics represent a potential mechanism through which sexually dimorphic effects of early-life exposures such as endocrine-disrupting chemicals (EDCs) manifest. RECENT FINDINGS: Several animal studies, and to a lesser extent human studies, have evaluated life-course sexually dimorphic health effects following developmental toxicant exposures; many fewer studies, however, have evaluated epigenetics as a mechanism mediating developmental exposures and later outcomes. To evaluate epigenetic reprogramming as a mechanistic link of sexually dimorphic early-life EDCs exposures, the following criteria should be met: (1) well-characterized exposure paradigm that includes relevant windows for developmental epigenetic reprogramming; (2) evaluation of sex-specific exposure-related epigenetic change; and (3) observation of a sexually dimorphic phenotype in either childhood, adolescence, or adulthood.

Metabolomics of Diabetes in Pregnancy.

PURPOSE OF REVIEW: The purpose of this review is to describe ways in which metabolomics may enhance understanding of gestational diabetes mellitus (GDM) etiology and refine current diagnostic criteria. RECENT FINDINGS: Current clinical recommendations suggest screening for GDM between 24 and 28 of gestational weeks using an oral glucose tolerance test. Despite this consensus, there are discrepancies regarding the exact criteria for GDM diagnosis. Further, emerging evidence has unveiled heterogeneous physiological pathways underlying GDM-specifically, GDM with defective insulin secretion vs. sensitivity-that have important implications for disease diagnosis and management. The objectives of this review are threefold. First, we seek to provide a brief summary of current knowledge regarding GDM pathophysiology. Next, we describe the potential role of metabolomics to refine and improve the prediction, screening, and diagnosis of GDM. Finally, we propose ways in which metabolomics may eventually impact clinical care and risk assessment for GDM and its comorbidities.

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44.

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22.

BACKGROUND: Despite the known benefit of intensive statin therapy for reducing future cardiovascular events, its effectiveness in women has been questioned by some. METHODS AND RESULTS: In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, 911 (21.9%) women and 3251 (78.1%) men were randomized to intensive statin (atorvastatin 80 mg) versus standard therapy (pravastatin 40 mg) therapy for a median duration of 2.1 years. The primary end point was death, myocardial infarction, unstable angina; revascularization (occurring after 30 days); or stroke. Safety end points included elevations in liver function tests, creatine kinase, and myalgias/myositis. Women had a reduction in low-density lipoprotein (LDL) of 42.8% from baseline at 30 days (to a median of 60 mg/dL) in the intensive therapy arm, with 88.8% reaching the LDL goal of <100 mg/dL and 65.0% of <70 mg/dL, compared with a 16.8% reduction in LDL (to a median of 88 mg/dL) in the standard therapy arm. Women receiving intensive statin therapy had a significant 25% relative reduction over standard dose (hazard ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04) for the primary composite end point compared with a 14% reduction for men (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.04; P-interaction, 0.38). No differences were observed between sexes for safety (all P-interaction ≥0.11). CONCLUSIONS: This trial provides evidence that both women and men derived benefit from intensive statin therapy after acute coronary syndrome, and thus, sex should not be a factor in determining who should be treated with intensive statin therapy.

Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48).

BACKGROUND: Vitamin K antagonists have been the standard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism. Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments. Edoxaban is a selective and direct factor Xa inhibitor that may provide effective, safe, and more convenient anticoagulation. STUDY DESIGN: ENGAGE AF-TIMI 48 is a phase 3, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized to edoxaban high exposure (60 mg daily, adjusted for drug clearance), edoxaban low exposure (30 mg daily, adjusted for drug clearance), or warfarin titrated to an international normalized ratio of 2.0 to 3.0. The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure. Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban. Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS(2) score ≥2. Randomization is stratified by CHADS(2) score and anticipated drug exposure. The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism. The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding. Recruitment began in November 2008. The expected median follow-up is 24 months. CONCLUSIONS: ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation.

Patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial.

AIMS: Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We hypothesized that early inhibition of renin-angiotensin-aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo. METHODS AND RESULTS: AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function