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 (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL). RESULTS: Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related. CONCLUSIONS: Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.

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 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. RESULTS: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. CONCLUSIONS: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

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. I find that college freshmen gain substantially less than the 15 pounds rumored to be typical for freshmen. Using difference models, individual-specific fixed-effects models, and instrumental variables models to control for various sources of potential bias, I find that freshman year college attendance is estimated to cause only about a one-pound increase. Supplemental results show that those from lower socioeconomic backgrounds gain more weight during the freshman college year. Longer term, having a college education consistently decreases weight. These negative effects have faded over the last 20 years, and they diminish as respondents approach middle age. These trends are more prevalent for whites and Hispanics than for blacks.

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. CC was defined according to Rome III criteria. Medical records of each case and control were abstracted to identify potential CC comorbidities. RESULTS: Altogether 3831 (48%) subjects returned questionnaires; 307 met criteria for CC. Age-adjusted prevalence in females was 8.7 (95% confidence interval (CI) 7.1-10.3) and 5.1 (3.6-6.7) in males, per 100 persons. CC was not associated with most GI pathology, but the odds for constipation were increased in subjects with anal surgery relative to those without (odds ratio (OR) = 3.3, 95% CI 1.2-9.1). In those with constipation vs those without, neurological diseases including Parkinson's disease (OR = 6.5, 95% CI 2.9-14.4) and multiple sclerosis (OR = 5.5, 95% CI 1.9-15.8) showed significantly increased odds for chronic constipation, adjusting for age and gender. In addition, modestly increased odds for chronic constipation in those with angina (OR = 1.4, 95% CI 1.1-1.9) and myocardial infarction (OR = 1.5, 95% CI 1.0-2.4) were observed. CONCLUSIONS: Neurological and cardiovascular diseases are linked to constipation but in the community constipation is unlikely to account for most lower GI pathology.

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. This paradigm shift has implications for current and future obesity pharmacotherapy. However, barriers to pharmacotherapy utilization include patient and physician perceptions of modest efficacy, historical safety issues, regulatory obstacles, and lack of reimbursement. The shifting attitudes and challenges associated not only with a multi-payer system, but also the lack of clearly defined cross-payer reimbursement strategies, prompted a survey to determine coverage for obesity treatment. Participants indicated that federal/state mandates and growth of quality-driven healthcare initiatives will eventually drive wider pharmacotherapy reimbursement within 1-5 years. There are signs that federal/state programs are already moving towards reimbursement by improving quality measures to track obesity outcomes and reduce costs. Future research on clinical and economic outcomes of combination weight-management programs coupled with innovative approaches (e.g., eHealth) in the real-world setting that demonstrate value to patients, healthcare providers, payers, and employers will help reshape obesity management by reducing barriers and broadening reimbursement coverage for anti-obesity pharmacotherapy.

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.e., yo-yo dieting); snacking; built environment; reducing screen time in childhood obesity; portion size; participation in family mealtime; and drinking water as a means of weight loss. For each of these, we describe the belief and present evidence that the belief is widely held or stated, reasons to support the conjecture that the belief might be true, evidence to directly support or refute the belief, and findings from randomized controlled trials, if available. We conclude with a discussion of the implications of these determinations, conjecture on why so many myths and presumptions exist, and suggestions for limiting the spread of these and other unsubstantiated beliefs about the obesity domain.

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. METHODS: Ninety-eight Rome-diagnosed patients with IBS completed the IBS-SSS and a single, global item of symptom severity (UCLA Symptom Severity Scale) at pretreatment baseline of a clinical trial funded by the National Institutes of Health. k-means cluster analyses were performed on participants' symptom severity scores. RESULTS: The IBS-SSS was not unidimensional. Exploratory cluster analyses revealed four common symptom profiles across five items of the IBS-SSS. One cluster of patients (25%) had elevated scores on pain frequency and bowel dissatisfaction, with less elevated but still high scores on life interference and low pain severity ratings. A second cluster (19%) was characterized by intermediate scores on both pain dimensions but more elevated scores on bowel dissatisfaction. A third cluster (18%) had elevated scores across all IBS-SSS subcomponents. The fourth and the most common cluster (37%) had relatively low scores on all dimensions except bowel dissatisfaction and life interference due to IBS symptoms. CONCLUSIONS: Patient-reported outcome end points and research on IBS more generally relying on multicomponent assessments of symptom severity should take into account the multidimensional structure of symptoms to avoid aggregation bias and to optimize the sensitivity of detecting treatment effects.

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. The aim of the study was to investigate whether a seasonal variation in abdominal pain consultation patterns exists among adults and children. METHODS: The number of outpatient consultations among children (5-17 years) and adults (18 years or older) with a diagnosis of abdominal pain of nonspecified origin (International Classification of Diseases-9 code 789.0) from May 2000 to December 2008 was identified in an administrative claims database. The primary outcome measure was the rate of abdominal pain consultations (total number of abdominal pain consultations/total number of distinct patients by month×1000) by season in children and adults. Seasons were defined as follows: winter (December-February), spring (March-May), summer (June-August), and fall (September-November). A trend test was conducted to determine the degree of linearity in the patterns between the 2 groups. Among children, subanalyses by age 5 to 11 years and 12 to 17 years and sex were conducted. RESULTS: A total of 172.4 million distinct patients (13.4% children, 87.6% adults) were identified in the database between May 2000 and December 2008. During the same time period, 15.6 million patient consultations for abdominal pain were identified (10.1% children, 89.9% adults). Children demonstrated a seasonal pattern in abdominal pain consultations, which best fit a quadratic regression curve, with consultations less common during the summer months. Abdominal pain consultations in adults were linear with no seasonal predominance. The trend in seasonal variation of abdominal pain consultations among children stratified by age and sex remained consistent with the overall child population. CONCLUSIONS: Abdominal pain consultations in children are less common during summer months, whereas no evidence of seasonal pattern of consultation was found in adults. Factors involved in the pathogenesis of abdominal pain in adults and children may differ.

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. At least one reference tumour lesion was included in the fields of view and assessed at both time points. Patients also underwent 18 F-fluorodeoxyglucose (FDG)-PET imaging at baseline and after 2 and 4 weeks of treatment. Radiological response of the reference tumour lesion and overall radiological response were assessed at week 12. Serum pharmacokinetic and biomarker analyses were also performed. RESULTS: Data were available for seven patients. Compared with baseline, all patients experienced a decrease in reference tumour blood flow ranging from 20 % to 85 % and also a reduction in the FDG standard uptake value ranging from 29 % to 67 %. Six patients experienced a partial metabolic response based on FDG-PET criteria. Four patients had stable disease defined by radiological response (Response Evaluation Criteria in Solid Tumors) lasting between 4 and 12 cycles. An association between perfusion change and clinical benefit, and biomarker levels including vascular endothelial growth factor was observed. CONCLUSION: Administering sunitinib to patients with advanced malignancies is associated with early biological responses, including decreased blood flow in secondary tumour deposits.

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, 11.6 years). Based on responses, subjects were characterized as having persistent CC, nonpersistent CC, or no constipation. We assessed the association between constipation status and potential risk factors using logistic regression models, adjusting for age and sex. RESULTS: Of the respondents, 84 had persistent CC (3%), 605 had nonpersistent CC (21%), and 2164 had no symptoms of constipation (76%). High scores from the somatic symptom checklist (odds ratio [OR] = 2.1; 95% confidence interval [CI], 1.3-3.4) and frequent doctor visits (OR = 2.0; 95% CI, 1.0-3.8) were significantly associated with persistent CC, compared with subjects with no constipation symptoms. The only factor that differed was increased use of laxatives or fiber among subjects with persistent CC (OR = 3.0; 95% CI, 1.9-4.9). CONCLUSIONS: The prevalence of constipation might be exaggerated-the proportion of the population with persistent CC is low (3%). Patients with persistent and nonpersistent CC have similar clinical characteristics, although individuals with persistent CC use more laxatives or fiber. CC therefore appears and disappears among certain patients, but we do not have enough information to identify these individuals in advance.

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. METHODS: Ninety-eight patients diagnosed with IBS, based on Rome III criteria, completed the multicomponent IBS Symptom Severity Scale and the single-item, UCLA Symptom Severity Scale. Data were collected on pain, bloating, and bowel habits, as well as somatization, sensitivity to arousal symptoms (anxiety sensitivity), and a negative thinking style called pain catastrophizing. RESULTS: The 2 global scales were correlated with one another (r = 0.56); each scale was associated most strongly with variation in abdominal pain. Data were consistent with a model in which pain catastrophizing and somatization influenced 1 or more of patients' judgments of pain, bloating, and/or bowel habits, which then affected the PROs. CONCLUSIONS: Depending on their structure and format, PROs can have different levels of sensitivity to core IBS symptoms and be influenced by psychological and somatic complaints that are beyond the aim of therapy and labeling claim. PROs that rely on patients' perspectives to index symptom severity can be improved by consideration of psychometric principles that influence self-report.

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 0.025 mg kg(-1) with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS: Ten healthy volunteers aged 21-26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 +/- 13 l h(-1)[95% confidence interval 48, 66] to 36 +/- 9.8 l h(-1) (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration-time curve (mean difference 22 microg h(-1) l(-1), P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS: Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.

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. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread. RESULTS: Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT(c)F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT(c)F changes correlated with exposure, but not T(max). Maximum mean time-matched, placebo-adjusted QT(c)F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT(c)F >500 ms. Concomitant granisetron produced no significant QT(c)F prolongation. Sunitinib-related adverse events were as previously described. CONCLUSIONS: Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer.

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. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. RESULTS: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease > or =6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. CONCLUSION: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.

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. RESULTS: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40). CONCLUSIONS: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings.

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. Third, a substantial portion of the "effect" of early life conditions operates through race/ethnicity and the translation of advantaged family backgrounds during childhood into higher levels of subsequent education. By contrast, little of the SES gap appears to propagate through household composition, family income or health behaviors. Fourth, adult SES has independent effects after controlling for childhood status.

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. Ultimately, realization of the disease risks associated with chronic constipation may provide the impetus needed to direct new research, and shift attention on the part of patients and practitioners to methods for preventing significant and potentially costly comorbid medical problems.

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. In 1964, the US Surgeon General issued its first report relating smoking and health, and since that time, federal and state governments have increased cigarette taxes in a successful effort to reduce cigarette smoking. However, because cigarette smoking and obesity seem inversely related, cigarette taxes may have simultaneously increased obesity. This paper examines the effects of cigarette costs on BMI and obesity and finds that they have significant positive effects. This paper attempts to reconcile conflicting evidence in the literature by controlling more carefully for correlation with state-specific time trends using panel data. Results indicate that the net benefit to society of increasing cigarette taxes may not be as large as previously thought, though this research in no way concludes that they should be decreased to prompt weight loss.

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. Dexlansoprazole MR 60 mg demonstrated similar efficacy for healing of erosive esophagitis at 8 weeks compared with lansoprazole 30 mg, and dexlansoprazole MR 30 mg was superior to placebo for maintenance of healed erosive esophagitis at 6 months with 99% of nights and 96% of days heartburn-free over 6 months in patients taking dexlansoprazole MR 30 mg. Superior relief of heartburn occurred in patients taking dexlansoprazole MR 30 mg (55% heartburn-free 24-hour periods) vs placebo (14%) for symptomatic nonerosive GERD. The safety profile of dexlansoprazole MR is similar to that of lansoprazole. The extended pharmacodynamic effects, added convenience, and efficacy and safety of dexlansoprazole MR offer a novel approach to gastric pH control in patients with acid-related disorders.