Hepatic steatosis induced by nicotine plus Coca-Cola™ is prevented by nicotinamide riboside (NR).

Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR. Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks. Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling. Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.

Implementation of Specialty Tobacco Use Disorder Services in a Community Health Setting: Support for Enhanced Prescription Practices.

OBJECTIVES: Although public efforts to reduce tobacco use have been successful, millions of US adults currently smoke tobacco. Reducing the public health burden of tobacco use disorder (TUD) and eliminating disparities experienced by underresourced communities requires increased accessibility to services. The goal of this study was to assess whether prescriptions for evidence-based medications for tobacco treatment showed steeper growth rates among community health clinics providing specialty TUD services as compared with treatment as usual. METHODS: Clinic-wide data on prescriptions for smoking cessation pharmacotherapy at 18 primary care or mental health community clinics operated by Los Angeles County were retrieved for 4 years of an ongoing implementation trial. Specialty services included behavioral counseling and medications for tobacco treatment. Descriptive statistics characterized prescriptions rates across clinics and time. Analyses compared the slopes of the changes between intervention groups across time for primary care and mental health sites. RESULTS: Within primary care clinics, the most commonly prescribed smoking cessation medications were nicotine patches, nicotine gum, and varenicline. Throughout the trial, all clinics displayed increased rates of prescribing smoking cessation medications. Analytic results supported overall steeper increases in prescription rates for these medications among clinics randomized to specialty services versus treatment as usual within primary care ( P = 0.020) and mental health sites ( P = 0.004). CONCLUSIONS: This work provides support for the effectiveness of community-based implementation interventions that promote prescribing smoking cessation medications with the potential to reduce health disparities among communities at greater risk for TUD and its consequences.

Embedding comprehensive smoking cessation programs into community clinics: study protocol for a cluster-randomized controlled trial.

BACKGROUND: Cigarette smoking among adults in the USA is a leading cause of preventable death worldwide, even though there has been a decline in prevalence since 2005. The addictive nature of nicotine is the chief reason smokers continue to use tobacco. Although the majority of smokers report a desire to quit smoking, a small minority who attempt to quit achieve long-term cessation. Combined, smoking cessation best practices include coordinated medication and behavioral treatments. However, these treatments are not currently adequately delivered to Medi-Cal beneficiaries in the publicly funded patient-centered medical homes (PCMHs) and community mental health clinics operated by Los Angeles County (LAC)-Department of Health Services (LACDHS) and LAC-Department of Mental Health (LACDMH). METHODS: This is a 5-year implementation, cluster-randomized comparative effectiveness trial that will support the implementation of smoking cessation services delivered in LAC-LACDHS-operated outpatient primary care clinics and in LAC-LACDMH-operated community mental health clinics. We will enroll 1000 participants from clinics that will offer smoking cessation services and 200 from clinics that will offer treatment as usual. Participants will be asked to complete assessments at baseline, 3 months, 6 months, and 12 months. The assessments will include self-reports on smoking history, anxiety, stress, quality of life, and participant satisfaction. Participants who are assigned to clinics that provide smoking cessation services will also be asked about the frequency of their participation in the smoking cessation services during the 12-month period. DISCUSSION: This study will evaluate the effectiveness and feasibility of implementing smoking cessation services in outpatient primary care and community mental health clinics. It will also determine if there will be higher rates of smoking cessation in the implementation sites as compared to the sites with treatment as usual. If the implementation proves to be effective, the plan is to sustain these services using a workflow we will develop in the LAC-operated sites. This would lead to ameliorating the significant smoking cessation treatment gaps among those served within the LAC Health Agency departments. TRIAL REGISTRATION: ClinicalTrials.gov NCT04717544 "Embedding comprehensive smoking cessation programs into community clinics." Registered on January 22, 2021.

Metabolic parameters in smokers undergoing smoking reduction.

INTRODUCTION: Few human studies have explored the mechanisms of smoking-induced insulin resistance. Aims: To prospectively examine the metabolic changes of smoking reduction. METHODS: Cigarette smokers (n = 22; ½-2 packs per day) were enrolled in a smoking reduction program (counseling plus bupropion × 8 weeks; Phase I) followed by monitoring only (no counseling or bupropion × 16 weeks; Phase II). We serially measured exhaled carbon monoxide (CO) and urine nicotine metabolites; fat distribution, and metabolic parameters by hyperinsulinemic clamps including hepatic glucose output (HGO) and indirect calorimetry, adjusted for total caloric intake and expenditure. RESULTS: CO and nicotine metabolite levels fell with smoking reduction during Phase I (all p < 0.05), without any further changes through Phase II. Central-to-peripheral fat ratio increased during Phase I, but then fell during Phase II (all p < 0.05). Over 24 weeks, basal HGO fell (p = 0.02); and falling CO and nicotine metabolite levels correlated inversely with changes in glucose oxidation, and directly with changes in weight (all p < 0.05). CONCLUSIONS: Smoking reduction produced a transient worsening of central fat redistribution followed by a more significant improvement; along with other net beneficial metabolic effects.

Effect of a Coordinated Community and Chronic Care Model Team Intervention vs Usual Care on Systolic Blood Pressure in Patients With Stroke or Transient Ischemic Attack: The SUCCEED Randomized Clinical Trial.

Importance: Few stroke survivors meet recommended cardiovascular goals, particularly among racial/ethnic minority populations, such as Black or Hispanic individuals, or socioeconomically disadvantaged populations. Objective: To determine if a chronic care model-based, community health worker (CHW), advanced practice clinician (APC; including nurse practitioners or physician assistants), and physician team intervention improves risk factor control after stroke in a safety-net setting (ie, health care setting where all individuals receive care, regardless of health insurance status or ability to pay). Design, Setting, and Participants: This randomized clinical trial included participants recruited from 5 hospitals serving low-income populations in Los Angeles County, California, as part of the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) clinical trial. Inclusion criteria were age 40 years or older; experience of ischemic or hemorrhagic stroke or transient ischemic attack (TIA) no more than 90 days prior; systolic blood pressure (BP) of 130 mm Hg or greater or 120 to 130 mm Hg with history of hypertension or using hypertensive medications; and English or Spanish language proficiency. The exclusion criterion was inability to consent. Among 887 individuals screened for eligibility, 542 individuals were eligible, and 487 individuals were enrolled and randomized, stratified by stroke type (ischemic or TIA vs hemorrhagic), language (English vs Spanish), and site to usual care vs intervention in a 1:1 fashion. The study was conducted from February 2014 to September 2018, and data were analyzed from October 2018 to November 2020. Interventions: Participants randomized to intervention were offered a multimodal coordinated care intervention, including hypothesized core components (ie, ≥3 APC clinic visits, ≥3 CHW home visits, and Chronic Disease Self-Management Program workshops), and additional telephone visits, protocol-driven risk factor management, culturally and linguistically tailored education materials, and self-management tools. Participants randomized to the control group received usual care, which varied by site but frequently included a free BP monitor, self-management tools, and linguistically tailored information materials. Main Outcomes and Measures: The primary outcome was change in systolic BP at 12 months. Secondary outcomes were non-high density lipoprotein cholesterol, hemoglobin A1c, and C-reactive protein (CRP) levels, body mass index, antithrombotic adherence, physical activity level, diet, and smoking status at 12 months. Potential mediators assessed included access to care, health and stroke literacy, self-efficacy, perceptions of care, and BP monitor use. Results: Among 487 participants included, the mean (SD) age was 57.1 (8.9) years; 317 (65.1%) were men, and 347 participants (71.3%) were Hispanic, 87 participants (18.3%) were Black, and 30 participants (6.3%) were Asian. A total of 246 participants were randomized to usual care, and 241 participants were randomized to the intervention. Mean (SD) systolic BP improved from 143 (17) mm Hg at baseline to 133 (20) mm Hg at 12 months in the intervention group and from 146 (19) mm Hg at baseline to 137 (22) mm Hg at 12 months in the usual care group, with no significant differences in the change between groups. Compared with the control group, participants in the intervention group had greater improvements in self-reported salt intake (difference, 15.4 [95% CI, 4.4 to 26.0]; P = .004) and serum CRP level (difference in log CRP, -0.4 [95% CI, -0.7 to -0.1] mg/dL; P = .003); there were no differences in other secondary outcomes. Although 216 participants (89.6%) in the intervention group received some of the 3 core components, only 35 participants (14.5%) received the intended full dose. Conclusions and Relevance: This randomized clinical trial of a complex multilevel, multimodal intervention did not find vascular risk factor improvements beyond that of usual care; however, further studies may consider testing the SUCCEED intervention with modifications to enhance implementation and participant engagement. Trial Registration: ClinicalTrials.gov Identifier: NCT01763203.

Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial.

BACKGROUND: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). METHODS: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. RESULTS: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25). CONCLUSIONS: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

A Pilot Study of Human Milk to Reduce Intestinal Inflammation After Bone Marrow Transplant.

OBJECTIVE: Human milk administration in the early peritransplant period would lower intestinal inflammation after bone marrow transplant (BMT). MATERIALS AND METHODS: Children 0-5 years undergoing BMT received either a ready-to-feed human milk preparation designed for these children (Prolacta Bioscience, Duarte, CA) or standard formula. Babies breastfeeding at the time of BMT were also enrolled on the human milk arm. Human milk was administered from day -3 until day +14 after BMT. Metagenomic shotgun sequencing and metabolomics of stool, plasma cytokines, and regenerating islet-derived 3α (REG3α) levels were measured at enrollment and day +14. Human leukocyte antigen-DR isotype (HLA-DR), CD38, and CD69 expression on T cells were evaluated at day +21. RESULTS: Forty-six children were enrolled, 32 received human milk (donor milk n = 23, breastfeeding babies n = 9), and 14 were controls who received standard feeds supervised by a BMT dietician. Twenty-four patients received at least 60% of goal human milk and were evaluable. Plasma interleukin (IL)-8 (p = 0.04), IL-10 (p = 0.02), and REG3α (p = 0.03) were decreased in the human milk cohort. Peripheral blood CD69+ CD8+ T cells were higher in controls (p = 0.01). Species abundance of Adenovirus (p = 0.00034), Escherichia coli (p = 0.0017), Cryptosporidium parvum (p = 0.0006), Dialister invisus (p = 0.01), and Pseudomonas aeruginosa (p = 0.05) from stool was higher in controls. Stool alanine, tyrosine, methionine, and the ratio of fecal alanine to choline and phosphocholine were higher in controls (p < 0.05). No difference was observed in stool propionate and butyrate levels as measures of short-chain fatty acids between the two cohorts. CONCLUSIONS: Administration of human milk resulted in decreased markers of intestinal inflammation and could be a valuable adjunct for patients after BMT.

Ticagrelor and the Prevention of Microvascular Complications in Diabetes Patients with Lower Extremity Arterial Disease; Rationale and Design of the Hema-Kinesis Trial.

BACKGROUND: Lower extremity arterial disease (LEAD) occurs more common in patients with diabetes than without diabetes. Microvascular complications of diabetes contribute to higher rates of adverse limb events in patients with LEAD. Blood flow in the macrocirculation and microcirculation is reduced with increasing low-shear and high-shear blood viscosity. We hypothesize that the adenosine enhancing properties of ticagrelor will reduce low-shear blood viscosity and improve microcirculatory flow in the dorsum of the feet of patients with type 2 diabetes. Ticagrelor is a P2Y12 receptor antagonist with evidence of cardiovascular event reduction in patients with acute coronary syndromes and those with a previous myocardial infarction. In a large multicenter trial of patients with symptomatic LEAD and a history of limb revascularization, ticagrelor was no more effective than clopidogrel in reducing cardiovascular disease events; however, this trial was not designed to investigate microvascular complications of diabetes. DESIGN: Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry. If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.

Beyond Necrotizing Enterocolitis: Other Clinical Advantages of an Exclusive Human Milk Diet.

OBJECTIVE: Articles previously published by Sullivan et al. and Cristofalo et al. were reanalyzed using the proportion of cow milk-based nutrition received to determine whether that affected clinical outcomes during hospitalization for infants birth weight 500-1250 g. Abrams et al. showed in the same cohort incidences of necrotizing enterocolitis (NEC), NEC requiring surgery and sepsis increased proportionally to the amount of dietary cow milk. METHODS: The data from the two studies conducted under essentially the same protocol were combined yielding a cohort of 260 infants receiving a diet ranging from 0% to 100% cow milk. Data analysis utilized negative binomial regression which mitigates differences between subjects in terms of their time on study by incorporating that number into the statistical model. The percent of cow milk-based nutrition was the only predictor investigated. RESULTS: For all outcomes the larger the amount of cow's milk in the diet the greater the number of days of that intervention required. A trend toward statistical significance was seen for ventilator days; however, only parenteral nutrition (PN) days and days to full feeds achieved statistical significance. CONCLUSIONS: Incorporation of any cow milk-based nutrition into the diet of extremely premature infants correlates with more days on PN and a longer time to achieve full feeds. There was a nonstatistically significant trend toward increased ventilator days. These represent additional clinical consequences of the use of any cow milk-based protein in feeding EP infants.

α7-Nicotinic Acetylcholine Receptor Agonist Ameliorates Nicotine Plus High-Fat Diet-Induced Hepatic Steatosis in Male Mice by Inhibiting Oxidative Stress and Stimulating AMPK Signaling.

α7-Nicotinic acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers.

Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

IMPORTANCE: Gene transfer has rarely been tested in randomized clinical trials. OBJECTIVE: To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization. INTERVENTIONS: Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo. MAIN OUTCOMES AND MEASURES: Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5). RESULTS: Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P = .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak -dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10). CONCLUSIONS AND RELEVANCE: AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00787059.

Premature Infants 750-1,250 g Birth Weight Supplemented with a Novel Human Milk-Derived Cream Are Discharged Sooner.

OBJECTIVE: Infants may benefit from early nutritional intervention to decrease hospital stay. To evaluate the effects of adding a human milk (HM)-derived cream (Cream) product to a standard feeding regimen in preterm infants. MATERIALS AND METHODS: In a prospective multicenter randomized study, infants with birth weights 750-1,250 g were assigned to a Control or Cream group. The Control group received a standard feeding regimen consisting of mother's own milk or donor HM with donor HM-derived fortifier. The Cream group received the standard feeding regimen along with an additional HM-derived cream supplement when the HM they received was <20 kcal/oz. Primary outcomes of this secondary analysis included comorbidities, length of stay (LOS), and postmenstrual age (PMA) at discharge. RESULTS: We enrolled 75 infants (Control n = 37, Cream n = 38) with gestational age 27.7 ± 1.8 weeks and birth weight 973 ± 145 g (mean ± SD). After adjusting for gestational age, birth weight, and presence of bronchopulmonary dysplasia (BPD), the Cream group had a decreased PMA at discharge (39.9 ± 4.8 versus 38.2 ± 2.7 weeks, p = 0.03) and LOS (86 ± 39 versus 74 ± 22 days, p = 0.05). For 21 infants with BPD, these values trended toward significance for PMA at discharge (44.2 ± 6.1 versus 41.3 ± 2.7 weeks, p = 0.08) and LOS (121 ± 49 versus 104 ± 23 days, p = 0.08). CONCLUSIONS: Very preterm infants who received an HM-derived cream supplement were discharged earlier. Infants with BPD may have benefited the most.

Beyond Necrotizing Enterocolitis Prevention: Improving Outcomes with an Exclusive Human Milk-Based Diet.

OBJECTIVE: The aim of this study was to compare outcomes of infants pre and post initiation of a feeding protocol providing an exclusive human milk-based diet (HUM). MATERIALS AND METHODS: In a multicenter retrospective cohort study, infants with a birth weight <1,250 g who received a bovine-based diet (BOV) of mother's own milk fortified with bovine fortifier and/or preterm formula were compared to infants who received a newly introduced HUM feeding protocol. Infants were excluded if they had major congenital anomalies or died in the first 12 hours of life. Data were collected 2-3 years prior to and after introduction of an exclusive HUM diet. Primary outcomes were necrotizing enterocolitis (NEC) and mortality. Secondary outcomes included late-onset sepsis, retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD). RESULTS: A total of 1,587 infants were included from four centers in Texas, Illinois, Florida, and California. There were no differences in baseline demographics or growth of infants. The HUM group had significantly lower incidence of proven NEC (16.7% versus 6.9%, p < 0.00001), mortality (17.2% versus 13.6%, p = 0.04), late-onset sepsis (30.3% versus 19.0%, p < 0.00001), ROP (9% versus 5.2%, p = 0.003), and BPD (56.3% versus 47.7%, p = 0.0015) compared with the BOV group. CONCLUSIONS: Extremely premature infants who received an exclusive HUM diet had a significantly lower incidence of NEC and mortality. The HUM group also had a reduction in late-onset sepsis, BPD, and ROP. This multicenter study further emphasizes the many benefits of an exclusive HUM diet, and demonstrates multiple improved outcomes after implementation of such a feeding protocol.

Safety of a Four-factor Prothrombin Complex Concentrate Versus Plasma for Vitamin K Antagonist Reversal: An Integrated Analysis of Two Phase IIIb Clinical Trials.

OBJECTIVES: Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS: This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. RESULTS: The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS: These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.

Community screening for pre-diabetes and diabetes using HbA1c levels in high-risk African Americans and Latinos.

OBJECTIVE: To evaluate community screening using HbA1c levels in high risk African Americans and Latinos in those not known to have diabetes. DESIGN: HbA1c levels were measured in 1542 African Americans and Latinos aged > or = 40 years with one or more of the following risk factors: family history in first degree relatives, waist circumference > or = 40 inches in males or > or = 35 inches in females, and hypertension, either treatment for or a measured BP of > or = 140/ 90 mm Hg. Oral glucose tolerance tests (OGTT) were offered to those meeting the HbA1c criterion for pre-diabetes. SETTING: Churches, community health fares, senior citizen sites. PARTICIPANTS: People without known diabetes. MAIN OUTCOME MEASURES: Proportion of people meeting the HbA1c criteria for prediabetes (5.8-6.4%) and diabetes (> or = 6.5%). RESULTS: 32% had one, 50% had two and 18% had three risk factors. By HbA1c criteria, 40% had pre-diabetes and 25% had diabetes. Increased waist circumference was the most common risk factor followed by a positive family history, and lastly, hypertension. Each individual risk factor was significantly (P < .001) and progressively more common as glycemia increased. Each additional risk factor increased the odds of pre-diabetes or diabetes by 2- to 4-fold. In individuals with pre-diabetes who underwent an OGTT, 59% were normal, 35% had pre-diabetes and only 6% had diabetes. CONCLUSIONS: Community screening of high risk African Americans and Latinos with HbA1c levels identifies a large proportion of people with pre-diabetes and diabetes. Those identified with pre-diabetes are unlikely to meet the OGTT criteria for diabetes.

Cost effectiveness analysis of a next generation risk assessment score for cardiovascular disease.

OBJECTIVES: The goal of this study is to determine the cost-effectiveness of MIRISK VP, a next generation coronary heart disease risk assessment score, in correctly reclassifying and appropriately treating asymptomatic, intermediate risk patients. STUDY DESIGN: A Markov model was employed with simulated subjects based on the Multi-Ethnic Study of Atherosclerosis (MESA). This study evaluated three treatment strategies: (i) practice at MESA enrollment, (ii) current guidelines, and (iii) MIRISK VP in MESA. METHODS: The model assessed patient healthcare costs and outcomes, expressed in terms of life years and quality-adjusted life years (QALYs), over the lifetime of the cohort from the provider and payer perspective. A total of 50,000 hypothetical individuals were used in the model. A sensitivity analysis was conducted (based on the various input parameters) for the entire cohort and also for individuals aged 65 and older. RESULTS: Guiding treatment with MIRISK VP leads to the highest net monetary benefits when compared to the 'Practice at MESA Enrollment' or to the 'Current Guidelines' strategies. MIRISK VP resulted in a lower mortality rate from any CHD event and a modest increase in QALY of 0.12-0.17 years compared to the other two approaches. LIMITATIONS: This study has limitations of not comparing performance against strategies other than the FRS, the results are simulated as with all models, the model does not incorporate indirect healthcare costs, and the impact of patient or physician behaviors on outcomes were not taken into account. CONCLUSIONS: MIRISK VP has the potential to improve patient outcomes compared to the alternative strategies. It is marginally more costly than both the 'Practice at MESA Enrollment' and the 'Current Guidelines' strategies, but it provides increased effectiveness, which leads to positive net monetary benefits over either strategy.

Alterations in phosphorylated CREB expression in different brain regions following short- and long-term morphine exposure: relationship to food intake.

BACKGROUND: Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. METHODS: Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. RESULTS: We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. CONCLUSION: The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight.

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Effect of nicotine on body composition in mice.

Nicotine induces weight loss in both humans and rodents consuming a regular diet; however, the effect of nicotine on body weight and fat composition in rodents consuming a high-fat diet (HFD) has not been well studied. Thus, this study examined the effect of nicotine vs saline on body weight and fat composition in mice fed with either an HFD (62% of kcal from fat) or a standard normal chow diet (NCD) for 7 weeks. Nicotine dose dependently reduced body weight gain in mice that consumed both diets, but this effect was significantly greater in mice on the HFD. Caloric intake was decreased in nicotine-treated mice. Estimates of energy intake suggested that decreased caloric intake accounted for all the reduced weight gain in mice on an NCD and 66% of the reduced weight gain on an HFD. Computed tomography analysis for fat distribution demonstrated that nicotine was effective in reducing abdominal fat in mice that consumed the HFD, with nicotine treatment leading to lower visceral fat. The effect of nicotine on weight loss in mice on an HFD was completely blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, but only partially blocked by the α4ß2 nAChR partial agonist/antagonist, varenicline. We conclude that nicotine is effective in preventing HFD-induced weight gain and abdominal fat accumulation.

Targeting primary care referrals to smoking cessation clinics does not improve quit rates: implementing evidence-based interventions into practice.

OBJECTIVE: To evaluate the impact of a locally adapted evidence-based quality improvement (EBQI) approach to implementation of smoking cessation guidelines into routine practice. DATA SOURCES/STUDY SETTING: We used patient questionnaires, practice surveys, and administrative data in Veterans Health Administration (VA) primary care practices across five southwestern states. STUDY DESIGN: In a group-randomized trial of 18 VA facilities, matched on size and academic affiliation, we evaluated intervention practices' abilities to implement evidence-based smoking cessation care following structured evidence review, local priority setting, quality improvement plan development, practice facilitation, expert feedback, and monitoring. Control practices received mailed guidelines and VA audit-feedback reports as usual care. DATA COLLECTION: To represent the population of primary care-based smokers, we randomly sampled and screened 36,445 patients to identify and enroll eligible smokers at baseline (n=1,941) and follow-up at 12 months (n=1,080). We used computer-assisted telephone interviewing to collect smoking behavior, nicotine dependence, readiness to change, health status, and patient sociodemographics. We used practice surveys to measure structure and process changes, and administrative data to assess population utilization patterns. PRINCIPAL FINDINGS: Intervention practices adopted multifaceted EBQI plans, but had difficulty implementing them, ultimately focusing on smoking cessation clinic referral strategies. While attendance rates increased (p<.0001), we found no intervention effect on smoking cessation. CONCLUSIONS: EBQI stimulated practices to increase smoking cessation clinic referrals and try other less evidence-based interventions that did not translate into improved quit rates at a population level.