The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies.

Aims: Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Methods: The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.

Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin.

Aims: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Methods: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.

The Effects of College on Weight: Examining the "Freshman 15" Myth and Other Effects of College Over the Life Cycle.

This study examines the effects of college on weight over much of the life cycle. I compare weights for college students with their weights before and after college and with the weights of noncollege peers using data from the National Longitudinal Survey of Youth (NLSY). I also examine the longer-term effects of college measured almost three decades later.

Chronic constipation and co-morbidities: A prospective population-based nested case-control study.

Background: Chronic constipation (CC) is common in the community but surprisingly little is known about relevant gastro-intestinal (GI) and non-GI co-morbidities.

Objective: The purpose of this study was to assess the epidemiology of CC and in particular provide new insights into the co-morbidities linked to this condition.

Methods: In a prospective, population-based nested case-control study, a cohort of randomly selected community residents (n = 8006) were mailed a validated self-report gastrointestinal symptom questionnaire.

The Challenges and Opportunities Associated with Reimbursement for Obesity Pharmacotherapy in the USA.

Obesity has become a serious public health problem that has stimulated primordial and primary prevention efforts, and a triad of management options (lifestyle, pharmacotherapy, and surgical interventions). A growing body of evidence supports the need for a multi-pronged, clinic-based approach that leverages the synergy between pharmaceutical and lifestyle modification. Recent US policy changes-namely, the passage of the Patient Protection and Affordable Care Act coupled with recognition of obesity as a disease by the American Medical Association-suggest that financial incentives and attitudes towards obesity management are changing.

Weighing the Evidence of Common Beliefs in Obesity Research.

Obesity is a topic on which many views are strongly held in the absence of scientific evidence to support those views, and some views are strongly held despite evidence to contradict those views. We refer to the former as "presumptions" and the latter as "myths." Here, we present nine myths and 10 presumptions surrounding the effects of rapid weight loss; setting realistic goals in weight loss therapy; stage of change or readiness to lose weight; physical education classes; breastfeeding; daily self-weighing; genetic contribution to obesity; the "Freshman 15"; food deserts; regularly eating (versus skipping) breakfast; eating close to bedtime; eating more fruits and vegetables; weight cycling (i.

Multidomain patient-reported outcomes of irritable bowel syndrome: exploring person-centered perspectives to better understand symptom severity scores.

Objectives: Patient-reported outcomes assessing multiple gastrointestinal symptoms are central to characterizing the therapeutic benefit of novel agents for irritable bowel syndrome (IBS). Common approaches that sum or average responses across different illness components must be unidimensional and have small unique variances to avoid aggregation bias and misinterpretation of clinical data. This study sought to evaluate the unidimensionality of the IBS Symptom Severity Scale (IBS-SSS) and to explore person-centered cluster analytic methods for characterizing multivariate-based patient profiles.

Seasonal patterns of abdominal pain consultations among adults and children.

Background And Aim: Consultations for chronic abdominal pain are frequent in adults and children. A seasonal pattern of abdominal pain consultations with winter predominance was shown in previous pediatric studies; however, no studies have investigated whether such a pattern exists in adult patients. Understanding the differences in seasonal patterns of abdominal pain consultations among adults and children may indicate that either different mechanisms exist for common chronic pain conditions or triggering factors may vary by age.

Pharmacodynamic analysis of tumour perfusion assessed by 15O-water-PET imaging during treatment with sunitinib malate in patients with advanced malignancies.

Background: We evaluated pharmacodynamic changes in tumour perfusion using positron emission tomography (PET) imaging with 15O-water to assess biological response to sunitinib, a multitargeted tyrosine kinase inhibitor.

Methods: Patients with advanced malignancies received sunitinib 50 mg/day orally, once daily for 4 weeks on treatment, followed by 2 weeks off treatment, in repeated 6-week cycles. Quantitative measurement of tumour perfusion was assessed using 15O-water-PET at baseline and after 2 weeks of treatment.

Factors associated with persistent and nonpersistent chronic constipation, over 20 years.

Background & Aims: The prevalence of chronic constipation (CC) has been reported to be as high as 20% in the general population, but little is known about its natural history. We estimated the natural history of CC and characterized features of persistent CC and nonpersistent CC, compared with individuals without constipation.

Methods: In a prospective cohort study, we analyzed data collected from multiple, validated surveys (minimum of 2) of 2853 randomly selected subjects, over a 20-year period (median, 11.

Patient-reported outcomes for irritable bowel syndrome are associated with patients' severity ratings of gastrointestinal symptoms and psychological factors.

Background & Aims: Patient-reported outcomes (PROs) are used to gauge the benefit of treatments for functional gastrointestinal disorders, including irritable bowel syndrome (IBS). Commonly used end points derived from scales of symptom severity differ in their structure, format, and the extent to which they are based on established psychometric fundamentals. We evaluated the overlap between 2 measures of IBS symptom severity, documented their association with different symptoms (pain, bloating, altered defecation), and identified psychological factors that might bias PRO ratings, by affecting how patients interpret IBS symptom severity.

Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam.

Aims: The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma.

Methods: We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.

Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib.

Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.

Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered.

Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure.

Purpose: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study.

Experimental Design: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis.

Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.

Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.

Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning.

Age, socioeconomic status and obesity growth.

We use panel data from the National Longitudinal Survey of Youth (NLSY) to examine how body weight changes with age for a cohort moving through early adulthood, to investigate how the age-obesity gradient differs with socioeconomic status (SES) and to study channels for these SES disparities. Our results show first that weight increases with age and is inversely related to SES during childhood. Second, the obesity gradient widens over the lifecycle, consistent with research on other health outcomes.

Delayed release dexlansoprazole in the treatment of GERD and erosive esophagitis.

Although proton pump inhibitors (PPI) have a record of remarkable effectiveness and safety in the management of gastroesophageal reflux disease (GERD), several treatment challenges with PPI have emerged. Dexlansoprazole MR is the (R)-enantiomer of lansoprazole contained in a formulation that produces two distinct releases of drug and significantly extends the duration of active plasma concentrations and % time pH > 4 beyond that of conventional single-release PPI. Dexlansoprazole MR can be administered without regard to meals or the timing of meals in most patients.

Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.

Purpose: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.

A gap in our understanding: chronic constipation and its comorbid conditions.

Constipation is one of the most common digestive disorders in the United States; however, the association of this condition with related comorbidities, both gastrointestinal and extraintestinal, is poorly documented. Here, we have reviewed the association of constipation with specific comorbidities. The data suggest that there are considerable clinical consequences associated with constipation.

Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma.

Background: In a randomized, phase 3 trial, sunitinib demonstrated superior efficacy over interferon-alfa as first-line therapy in patients with metastatic clear-cell renal cell carcinoma (RCC). On the basis of outcome data from that trial, the authors developed a nomogram for predicting the probability of 12-month progression-free survival for patients who received sunitinib therapy.

Methods: Three-hundred seventy-five patients who received sunitinib in the phase 3 trial were the subject of the current analysis.

Activity of sunitinib in patients with advanced neuroendocrine tumors.

Purpose: Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3.

Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

Purpose: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC).

Patients And Methods: Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment).

The effects of cigarette costs on BMI and obesity.

About 30% of Americans are currently obese, which is roughly a 100% increase from 25 years ago. Public health officials have consequently become alarmed because recent research indicates that societal costs of obesity now exceed those of cigarette smoking and alcoholism. Cigarette taxes may have exacerbated the prevalence of obesity.