Are Semi-Quantitative Clinical Cultures Inadequate? Comparison to Quantitative Analysis of 1053 Bacterial Isolates from 350 Wounds.

Early awareness and management of bacterial burden and biofilm is essential to wound healing. Semi-quantitative analysis of swab or biopsy samples is a relatively simple method for measuring wound microbial load. The accuracy of semi-quantitative culture analysis was compared to 'gold standard' quantitative culture analysis using 428 tissue biopsies from 350 chronic wounds. Semi-quantitative results, obtained by serial dilution of biopsy homogenates streaked onto culture plates divided into 4 quadrants representing occasional, light, moderate, and heavy growth, were compared to total bacterial load quantified as colony-forming units per gram (CFU/g). Light growth, typically considered an insignificant finding, averaged a clinically significant 2.5 × 105 CFU/g (SE = 6.3 × 104 CFU/g). Occasional growth (range: 102-106 CFU/g) and light growth (103-107 CFU/g) corresponded to quantitative values that spanned a 5-log range; moderate and heavy growth corresponded to a range of 4-log and 6-log, respectively, with a high degree of overlap in range of CFU/g per category. Since tissue biopsy and quantitative culture cannot be widely practiced and semi-quantitative analysis is unreliable, other clinically relevant approaches are required to determine wound bioburden and guide best management practices. Fluorescence imaging is a point-of-care technology that offers great potential in this field.

Detection of bacterial fluorescence from in vivo wound biofilms using a point-of-care fluorescence imaging device.

Wound biofilms must be identified to target disruption and bacterial eradication but are challenging to detect with standard clinical assessment. This study tested whether bacterial fluorescence imaging could detect porphyrin-producing bacteria within a biofilm using well-established in vivo models. Mouse wounds were inoculated on Day 0 with planktonic bacteria (n = 39, porphyrin-producing and non-porphyrin-producing species, 107  colony forming units (CFU)/wound) or with polymicrobial biofilms (n = 16, 3 biofilms per mouse, each with 1:1:1 parts Staphylococcus aureus/Escherichia coli/Enterobacter cloacae, 107  CFU/biofilm) that were grown in vitro. Mouse wounds inoculated with biofilm underwent fluorescence imaging up to Day 4 or 5. Wounds were then excised and sent for microbiological analysis. Bacteria-matrix interaction was assessed with scanning electron microscopy (SEM) and histopathology. A total of 48 hours after inoculation with planktonic bacteria or biofilm, red fluorescence was readily detected in wounds; red fluorescence intensified up to Day 4. Red fluorescence from biofilms persisted in excised wound tissue post-wash. SEM and histopathology confirmed bacteria-matrix interaction. This pre-clinical study is the first to demonstrate the fluorescence detection of bacterial biofilm in vivo using a point-of-care wound imaging device. These findings have implications for clinicians targeting biofilm and may facilitate improved visualisation and removal of biofilms.

Evaluation of Inter-pair Differences in Caries among South Indian Monozygotic Twins: A Cross-sectional Study.

INTRODUCTION: Assessment of difference in caries prevalence among twins may help determine the character and the extent of the influence exercised by the environment, as a complement of the genetic constitution. AIM: To investigate the inter-pair differences in caries prevalence among South Indian monozygotic twins in relation to birth weight, birth order, and gender. Possible correlation among other attributes such as breastfeeding, socioeconomic status, oral habits, frequency of brushing, and sweet intake were also assessed. MATERIALS AND METHODS: A sample of 40 monozygotic children between the age group of 6 and 12 was selected. The parents were asked to complete the questionnaire and report with their children. Then dental examinations were carried out and the prevalence of dental caries among the twins were assessed. RESULTS: Among the total samples, 61.5% exhibited caries. Lower birth weight twins showed an increased chance of caries (72.22%), compared to higher birth weight twins (68.18%). Second of the twins had an increased risk of dental caries (70%) compared to the first (60%). 90% of the male twins and 45% of the female twins had caries. The association between dental caries and other variables were also assessed; those who were exclusively breastfed had an increased risk (70%) of caries. Evaluation of socioeconomic status and caries revealed a risk of for the high (65%), middle (62.5%), and lower groups (58.33%). Children without oral habits showed a higher prevalence (73.3%) of caries when compared to those without any habits (50%). It was noticed that the brushing frequency is not related to the severity of caries. The strongest association was noticed between excessive sweet liking and prevalence of dental caries. CONCLUSION: The study revealed difference in caries prevalence among monozygotic twins in relation to birth weight, birth order, and gender. It was found that variations in caries prevalence existed with other attributes also. HOW TO CITE THIS ARTICLE: Zarina R, Kuriakose S, et al. Evaluation of Inter-pair Differences in Caries among South Indian Monozygotic Twins: A Cross-sectional Study. Int J Clin Pediatr Dent 2019;12(4):318-324.

Informational needs of brain metastases patients and their caregivers.

BACKGROUND: In response to a dearth of formal health information targeted towards patients with brain metastases and their caregivers, a formal informational and supportive care needs assessment was conducted. METHODS: Brain metastases patients and caregivers who attended a clinic focused on the treatment of brain metastases at a tertiary medical center completed a self-report survey to assess informational needs across 6 domains: medical, physical, practical, social, emotional, and spiritual informational needs. Univariate and multivariate analyses of associations between variables was conducted using linear regression models. RESULTS: A total of 109 patients and 77 caregivers participated. Patients and caregivers both prioritized medical and physical informational domains, with a large focus on symptoms and side-effect profiles, significance of brain metastases locations and their implications, available treatment options and their risks and benefits, prognoses and follow-ups if treatment is completed, and end-of-life experiences and supports. One-on-one counseling was preferred by both caregivers and patients for these domains, as well as for practical informational needs; while patients preferred pamphlets to address social, emotional and spiritual informational needs, caregivers preferred one-on-one counseling for the former two domains as well. CONCLUSIONS: Brain metastases patients and their caregivers prioritize medical and physical informational needs, with one-on-one counseling and pamphlets being the most preferred modalities for information provision. Further exploration regarding existing non-validated resources and the development of tailored resources to address the unique needs of these patient and caregiver populations are warranted.

Development of a Professional Certification in Cancer Patient Education.

Patient educators come into the field from diverse professional backgrounds and often lack training in how to teach and develop patient education resources since no formal patient education professional certification program exists. A professional certification program for patient educators would further define the professional scope of practice and reduce variability in performance. The purpose of this study was to (1) determine the level of interest among Canadian cancer patient educators in a patient education professional certification program and (2) determine the competencies to be included in the professional certification program. A 12-item survey was designed by executive members of the Canadian Chapter of the Cancer Patient Education Network. The survey included a list of competencies associated with patient education, and a 4-point Likert scale ranging from "slightly important" to "very important" was used to determine the rank of each competency. The survey was sent to 53 patient educators across Canada. Ninety-two percent of the patient educators are interested in a professional certification program. Patient educators indicated that competencies related to developing patient resources, collaboration, plain language expertise, and health literacy were of most importance. Patient educators support the development of a patient education professional certification program and endorsed the competencies proposed. This information provides the foundation for the creation of a professional certification program for cancer patient educators.

Enhanced amphetamine-induced motor impulsivity and mild attentional impairment in the leptin-deficient rat model of obesity.

Evidence suggests that impulse control deficits contribute to excessive food intake in some individuals with obesity. In addition to its known role in regulating appetite and glucose metabolism, the hormone leptin also directly modulates the activity of central dopamine systems. Although dopamine is involved in regulating impulsivity, the influence of leptin per se on this cognitive domain remains unclear. This study explored the performance of male leptin knockout (KO) and wild type (WT) rats in the 5-Choice Serial Reaction Time task (5CSRTT) of motor impulsivity and visuospatial attention. Behavioural performance was assessed under baseline conditions, following 4 weeks high-fat diet (HFD; 60 kcal%) consumption, and after acute pharmacological challenge with the indirect dopamine agonist, amphetamine. Subjects were also tested for glucose tolerance and insulin sensitivity, and dorsal and ventral striatal tissue was assayed ex vivo for markers of dopaminergic transmission. Obese KO rats learned the 5CSRTT at a slower rate compared to WT rats, in a manner suggestive of mild attentional impairment. However, task performance at baseline and after HFD intake was similar to that of WT controls. HFD intake reduced omissions across all subjects, whereas amphetamine challenge revealed a prominent genotype effect on 5CSRTT performance, with potentiated levels of impulsive responding and faster response times in KO rats compared to WT animals. Effects of amphetamine on other variables were similar between genotypes. Notably, the expression of striatal dopaminergic markers was unchanged in KO rats, and neither chronic food restriction nor HFD intake altered the impairments in glucose or insulin metabolism previously reported in these animals. These data suggest that leptin deficiency enhances impulsive action under conditions of dopaminergic challenge, yet this seems independent of overt changes in the expression of post-synaptic markers of dopamine signalling in striatal regions.

How income and food prices influence global dietary intakes by age and sex: evidence from 164 countries.

BACKGROUND: While income and prices are key drivers of dietary choices, how their influence varies by food category, nation, and demographics is not well established. Based on intake data for 164 countries and 11 food categories, we examined how income and food prices relate to food intake globally, including by world region, age, and sex. METHODS: We used 2010 intake data from the Global Dietary Database, the first database of consumption estimates for major food categories by country, age, and sex. We combined these data with national per capita GDP and food price data. We estimated intake responsiveness to income and prices for each food category, accounting for differences by national income, world region, age, and sex. RESULTS: We identified several differences in intake responsiveness. For example, rising income was estimated to increase milk intake most strongly in Sub-Saharan Africa and fruit intake most strongly among older women globally. Comparing our intake results to previous findings based on expenditure data, we found more goods that exhibited declining intake in response to rising incomes, fewer significant relationships for a number of food categories, particularly for higher income regions, and whereas in prior studies, elasticities mostly decrease with national income, we identified food categories where this was not the case. CONCLUSION: The results of this study show heterogeneous associations among income, prices, and food intakes. Policymakers should consider the price and income elasticities of certain foods, as well as the role of demographics within and across countries, as they address global nutrition and health challenges.

The glucoregulatory actions of leptin.

BACKGROUND: The hormone leptin is an important regulator of metabolic homeostasis, able to inhibit food intake and increase energy expenditure. Leptin can also independently lower blood glucose levels, particularly in hyperglycemic models of leptin or insulin deficiency. Despite significant efforts and relevance to diabetes, the mechanisms by which leptin acts to regulate blood glucose levels are not fully understood. SCOPE OF REVIEW: Here we assess literature relevant to the glucose lowering effects of leptin. Leptin receptors are widely expressed in multiple cell types, and we describe both peripheral and central effects of leptin that may be involved in lowering blood glucose. In addition, we summarize the potential clinical application of leptin in regulating glucose homeostasis. MAJOR CONCLUSIONS: Leptin exerts a plethora of metabolic effects on various tissues including suppressing production of glucagon and corticosterone, increasing glucose uptake, and inhibiting hepatic glucose output. A more in-depth understanding of the mechanisms of the glucose-lowering actions of leptin may reveal new strategies to treat metabolic disorders.

Health care resource use and cost differences by opioid therapy type among chronic noncancer pain patients.

The study assessed 12-month chronic pain (CP)-related health care utilization and costs among chronic noncancer pain (CNCP) patients who initiated various long-term opioid treatments. Treatments included monotherapy with long-acting opioids (mono-LAOs), mono-therapy with short-acting opioids (mono-SAOs), both LAOs and SAOs (combination), and opioid therapy initiated with SAO or LAO and switched to the other class (switch). Using MarketScan® claims databases (2006-2012), we identified CNCP patients with ≥90 days opioid supply after pain diagnosis and continuous enrollment 12 months before pain diagnosis (baseline period) and 12 months after opioid start (post-index period). Outcomes included CP-related health care utilization and costs. Among CNCP patients (n=21,203), the cohort distribution was 74% mono-SAOs, 22% combination, 2% mono-LAOs, and 2% switch. During follow-up, the average daily morphine equivalent dose was highest in mono-LAO patients (96.4 mg) compared with combination patients (89.8 mg), switch patients (64.3 mg), and mono-SAO patients (36.2 mg). After adjusting for baseline differences, the mono-LAO cohort had lower total CP-related costs ($4,933) compared with the mono-SAO ($8,604), switch ($10,470), and combination ($15,190) cohorts (all: P<0.05). Mono-LAO patients had greater CP-related prescription costs but lower medical costs than the other cohorts during the follow-up period, including lower CP-related hospitalizations (1% vs 11%-20%), emergency department visits (4% vs 11%-18%), and diagnostic radiology use (21% vs 54%-61%) (all: P<0.001). Use of pain-related medications and other treatment modalities was also significantly lower in the mono-LAO cohort relative to the other cohorts. CNCP patients using long-term monotherapy with LAOs had the lowest CP-related total health care costs in the 12 months after opioid initiation compared with mono-SAO, switch, or combination patients despite higher opioid daily doses and higher prescription costs. Future research accounting for severity and duration of pain would aid in determining the optimal long-term opioid regimen for CNCP patients.

Restoration of Lepr in ß cells of Lepr null mice does not prevent hyperinsulinemia and hyperglycemia.

OBJECTIVE: The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing ß cells of the pancreas. Previous studies assessing the role of leptin receptors in ß cells used Cre-loxP to disrupt the leptin receptor gene (Lepr) in ß cells, but variable results were obtained. Furthermore, recombination of Lepr was observed in the hypothalamus or exocrine pancreas, in addition to the ß cells, and Lepr in non-ß cells may have compensated for the loss of Lepr in ß cells, thus making it difficult to assess the direct effects of Lepr in ß cells. To determine the significance of Lepr exclusively in ß cells, we chose to selectively restore Lepr in ß cells of Lepr null mice (LeprloxTB/loxTB). MATERIALS AND METHODS: We used a mouse model in which endogenous expression of Lepr was disrupted by a loxP-flanked transcription blocker (LeprloxTB/loxTB), but was restored by Cre recombinase knocked into the Ins1 gene, which is specifically expressed in ß cells (Ins1Cre). We bred LeprloxTB/loxTB and Ins1Cre mice to generate LeprloxTB/loxTB and LeprloxTB/loxTBIns1Cre mice, as well as Leprwt/wt and Leprwt/wtIns1Cre littermate mice. Male and female mice were weighed weekly between 6 and 11 weeks of age and fasting blood glucose was measured during this time. Oral glucose was administered to mice aged 7-12 weeks to assess glucose tolerance and insulin secretion. Relative ß and α cell area and islet size were also assessed by immunostaining and analysis of pancreas sections of 12-14 week old mice. RESULTS: Male and female LeprloxTB/loxTB mice, lacking whole-body expression of Lepr, had a phenotype similar to db/db mice characterized by obesity, hyperinsulinemia, glucose intolerance, and impaired glucose stimulated insulin secretion. Despite restoring Lepr in ß cells of LeprloxTB/loxTB mice, fasting insulin levels, blood glucose levels and body weight were comparable between LeprloxTB/loxTBIns1Cre mice and LeprloxTB/loxTB littermates. Furthermore, glucose tolerance and insulin secretion in male and female LeprloxTB/loxTBIns1Cre mice were similar to that observed in LeprloxTB/loxTB mice. Analysis of pancreatic insulin positive area revealed that restoration of Lepr in ß cells of LeprloxTB/loxTB mice did not prevent hyperplasia of insulin positive cells nor did it rescue Glut-2 expression. CONCLUSION: Collectively, these data suggest that direct action of leptin on ß cells is insufficient to restore normal insulin secretion and glucose tolerance in mice without leptin receptor signaling elsewhere.

Costs of Diagnostic Assessment for Lung Cancer: A Medicare Claims Analysis.

PURPOSE: To assess the diagnostic costs leading up to a lung cancer diagnosis in patients with abnormal computed tomography (CT) scans. PATIENTS AND METHODS: A retrospective cohort study using the 5% Medicare claims data (January 1, 2009, to December 31, 2011) was conducted. Patients aged 65 to 74 years with an abnormal chest CT scan were identified. Index was defined as the date of the abnormal chest CT scan. Outcomes assessed over a 12-month follow-up after index included lung cancer diagnosis rate and the use and associated costs of follow-up diagnostic tests up to diagnosis of lung cancer. RESULTS: Of 8979 patients identified with an abnormal chest CT scan (mean age, 69.3 ± 2.9 years), 13.9% were diagnosed with lung cancer over 12 months. Chest x-rays were the most common diagnostic test. Of the 19% who underwent a biopsy, 43.6% were not diagnosed with lung cancer during follow-up. The average total diagnostic assessment cost per patient was higher for those with versus without lung cancer ($7567 vs. $3558). Among patients not diagnosed with lung cancer, the median diagnostic cost per patient for those with versus without biopsy was ∼ 28 times higher. Adverse events significantly increased the average cost per biopsy (approximately 4-fold). CONCLUSION: Total lung cancer diagnostic cost was $38.3M in the defined study sample, of which 43.1% was accounted for by biopsied patients without a lung cancer diagnosis. Additional risk stratification is required to decrease unnecessary biopsy referrals and costs. Further, adverse events significantly increased costs.

Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice.

OBJECTIVE: Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lepob/ob) develop hyperinsulinemia prior to onset of obesity and glucose intolerance. Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis in Lepob/ob mice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction in Lepob/ob mice on circulating insulin, body composition, and glucose homeostasis. METHODS: Leptin expressing (Lepwt/wt) mice lacking 3 insulin alleles were crossed with Lepob/ob mice to generate Lepob/ob and Lepwt/wt littermates lacking 1 (Ins1+/+;Ins2+/-), 2 (Ins1+/+;Ins2-/-) or 3 (Ins1+/-;Ins2-/-) insulin alleles. Animals were assessed for body weight gain, body composition, glucose homeostasis, and islet morphology. RESULTS: We found that in young Lepob/ob mice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75-95% and attenuated body weight gain by 50-90% compared to Ins1+/+;Ins2+/-;Lepob/ob mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1+/+;Ins2-/-;Lepob/ob and Ins1+/-;Ins2-/-;Lepob/ob mice, respectively. Loss of 2 or 3 insulin alleles in young Lepob/ob mice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles in Lepwt/wt mice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance. CONCLUSION: Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lepob/ob mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.

Single- versus multiple-tablet HIV regimens: adherence and hospitalization risks.

OBJECTIVES: To evaluate the impact of antiretroviral therapy as a single-tablet regimen (STR) and multiple-tablet regimen (MTR) on outcomes in human immunodeficiency virus (HIV)/AIDS patients using electronic health records from the Veterans Healthcare Administration (VHA). STUDY DESIGN: Retrospective cohort. METHODS: This study evaluated VHA patients to whom HIV medications were dispensed as STRs or MTRs during the study period (January 1, 2006, to July 30, 2012). Patients were followed from the index date (ie, start of regimen) until treatment discontinuation, end of study period, last date of healthcare-related activity, or death. Differences in outcomes of hospitalization, adherence defined as a medication possession ratio of ≥ 95%, and undetectable viral load were evaluated using a Cox-proportional hazard and logistic model controlling for covariates measured during a 6-month baseline period. RESULTS: A total of 15,602 patients (6191 STR and 9411 MTR) met all study criteria. The study sample was, on average, aged 52 years with similar CD4 counts (mean ± SD: 432.2 ± 282.8 vs 419.3 ± 280.9; P = .287), but a significantly lower proportion of STR versus MTR patients had an undetectable viral load at baseline (42% vs 46%; P < .001). After controlling for baseline covariates, the STR cohort had twice the odds of being adherent (odds ratio [OR], 1.98; P < .001), 31% had a significantly lower hazard of having a hospitalization (hazard ratio, 0.69; P < .001), and 21% had higher odds of having an undetectable viral load during follow-up (OR, 1.21; P < .001). CONCLUSIONS: STR is associated with higher adherence rates, decreased hospitalizations, and more patients with an undetectable viral load in VHA patients with HIV/AIDS.

Hypoglycemia Incidence Rates and Associated Health Care Costs in Patients with Type 2 Diabetes Mellitus Treated with Second-Line Linagliptin or Sulfonylurea After Metformin Monotherapy.

BACKGROUND: Hypoglycemia poses a significant clinical and economic burden to patients with type 2 diabetes mellitus (T2DM). Minimizing the risk of hypoglycemia is an important component when managing patients with T2DM. Understanding hypoglycemia rates and the associated economic consequences can help to inform health care decision makers. OBJECTIVE: To assess hypoglycemia incidence rates and associated costs in patients who initiated second-line treatment with the antidiabetic agents linagliptin or a sulfonylurea (SU) after metformin. METHODS: A large U.S. administrative claims database was used to identify patients with T2DM (during the identification period July 2011-October 2013) who initiated linagliptin or a SU after metformin use. The date of the first prescription for linagliptin or a SU during the identification period was designated as the index date. Linagliptin users were matched to SU users based on demographic and clinical characteristics identified within a 12-month period before the index date using propensity scores (1:3 ratio, caliper: ±0.001). Rates and costs (2013 U.S. dollars) of hypoglycemia resulting in any health care resource use were quantified during a variable follow-up period (i.e., end of the study, end of the 12-month follow-up, treatment regimen change, or disenrollment, whichever came first). Hypoglycemia rates per 100 person-years were compared using univariate Poisson regression, and hazard of hypoglycemia was obtained from multivariate Cox proportional hazards regression. Mean monthly hypoglycemia-related costs, all-cause costs, and T2DM-related costs were computed for patients with hypoglycemia and compared using t-tests. RESULTS: Propensity-score matching resulted in a sample of 11,536 patients (linagliptin = 2,884; SU = 8,652) with a mean age of 56 years and 59% male. The rate of hypoglycemia (per 100 person-years) was lower in the linagliptin than the SU user groups (2.51 vs. 3.63; P= 0.049). Linagliptin users had a 33% lower risk of hypoglycemia compared with SU users (HR = 0.67; 95% CI = 0.47-0.97; P= 0.031). Among patients who had hypoglycemia, linagliptin users showed numerically lower mean monthly hypoglycemia-related costs compared with SU users ($300 vs. $890; P= 0.092), which was primarily driven by differences in hypoglycemia-related costs in the hospital setting. A similar theme was observed with monthly all-cause costs (linagliptin users, $1,971 vs. SU users, $3,758; P= 0.092). CONCLUSIONS: Linagliptin use was associated with a lower incidence rate of hypoglycemia compared with SU use in patients initiating second-line therapy after metformin monotherapy. Among patients who experienced hypoglycemia, linagliptin users appeared to have lower monthly hypoglycemia-related and all-cause costs than SU users. Careful consideration of newer treatment alternatives may be prudent for optimal T2DM management, especially with regard to hypoglycemia. DISCLOSURES: Funding for the research study and resultant publication was provided by Boehringer Ingelheim. Shetty is an employee of Boehringer Ingelheim. Cai was an employee of Boehringer Ingelheim at the time of the study. Raju and D'Souza are employees of Xcenda, which received research funding from Boehringer Ingelheim for the conduct of this study and for the preparation of this manuscript. All authors contributed to concept and study design. Raju took the lead in data analysis, along with D'Souza, and all authors contributed equally to data interpretation. The manuscript was written by Raju, D'Souza, Cai, and Shetty and revised primarily by Raju, along with Shetty and D'Souza.

Long-term, calorie-restricted intake of a high-fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling - two markers of addiction vulnerability.

High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high-fat or high-sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats' performance in the five-choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high-fat diet (HFD) were more impulsive, whereas the high-sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2 R), cAMP response element-binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2 R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high-fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions - findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge-eating disorder.

Impact of COPD Exacerbation Frequency on Costs for a Managed Care Population.

BACKGROUND: There is scarce information on chronic obstructive pulmonary disease (COPD) outcomes and costs for patients with differing levels of COPD exacerbations. OBJECTIVE: To examine COPD-related and all-cause health care resource use and costs in subsequent years for frequently and infrequently exacerbating COPD patients. METHODS: Patients with a diagnosis of COPD (ICD-9-CM codes 491.xx, 492.xx, and 496.xx) were identified (1 hospitalization or 1 emergency department visit or at least 2 outpatient visits) using administrative claims data in 2007. Patients were classified in 2008 as frequent (at least 2 exacerbations/year), infrequent (1 exacerbation/year) and nonexacerbators. Outcomes were computed during a subsequent 2-year period (2009 and 2010). Average per person estimates and total sample-level estimates were calculated. A logistic regression model estimated the predictors of having 2 or more exacerbations per year during the follow-up period. RESULTS: 61,750 COPD patients met the study criteria (mean age 67 years). Of these, 6% (n = 3,852) were frequent exacerbators; 14% were infrequent exacerbators (n = 8,416); and 80% were nonexacerbators (n = 49,482). At baseline, average all-cause health care costs per patient for frequent exacerbators were highest followed by infrequent and nonexacerbators ($12,837, $10,480, and $7,756, respectively). On average, 60% of frequent and 40% of infrequent exacerbators had at least 1 exacerbation per year in follow-up. Average annual per patient COPD-related costs for frequent exacerbators ($3,565 in 2009 and $3,528 in 2010) were more than 3 times (P less than 0.05) and infrequent exacerbators ($2,264 in 2009 and $2,265 in 2010) were more than 2 times (P less than 0.05) higher compared with nonexacerbators ($1,007 in 2009 and $1,027 in 2010). On a total sample-level, infrequent exacerbators were similar if not more burdensome compared with frequent exacerbators in the proportion accounted by these cohorts for total COPD-related costs (23% vs. 18%, respectively) and total number of COPD exacerbations per year (26% vs. 26%). Compared with nonexacerbators, infrequent exacerbators were 3 times (OR = 2.8, P less than 0.001) significantly more likely to have 2 or more exacerbations per year in follow-up, and frequent exacerbators were 7 times (OR = 6.76, P less than 0.001) significantly more likely to have 2 or more exacerbations per year in follow-up. CONCLUSIONS: Infrequent exacerbators have an increased risk for future exacerbations compared with nonexacerbators and, on a total sample-level, incur greater costs compared with frequent exacerbators, demonstrating a significant economic burden.

Treatment patterns of chronic obstructive pulmonary disease in employed adults in the United States.

BACKGROUND: This study evaluated patterns of pharmacotherapy in chronic obstructive pulmonary disease (COPD) as they relate to recommended guidelines in a prevalent COPD patient population with employer-sponsored health insurance in the US. METHODS: Health care claims data from 2007 and 2008 were retrospectively analyzed for the study population defined as patients aged 40 years and older, continuously enrolled during the study period, and having at least one inpatient or one emergency department (ED) visit, or at least two outpatient claims coded with COPD (International Classification of Diseases, 9th Revision, Clinical Modification code 491.xx, 492.xx, 496.xx). Rates of any pharmacotherapy (both maintenance and reliever), long-acting maintenance pharmacotherapy in patients with an exacerbation history, and short-term treatment of acute exacerbations of COPD were evaluated in the overall population, newly diagnosed, and previously diagnosed patients (including maintenance-naïve and maintenance-experienced). Stratified analyses were also conducted by age group (40-64 years, ≥65 years) and physician specialty. RESULTS: A total of 55,361 patients met study criteria of whom 39% were newly diagnosed. The mean age was 66 years, and 46% were male. Three-fourths (74%) of all COPD patients had some pharmacotherapy (maintenance or reliever) with less than half (45%) being treated with maintenance medications. The combination of an inhaled corticosteroid and a long-acting beta-agonist was the most prevalent drug class for maintenance treatment followed by tiotropium. Only 64% of patients with an exacerbation history had a prescription for a long-acting maintenance medication, and short-term treatment with oral corticosteroids or antibiotics was higher for hospitalization exacerbations compared to ED visit exacerbations (68% vs 44%). In general, the rates of pharmacotherapy were highest in patients who were maintenance-experienced followed by newly diagnosed and maintenance-naïve. CONCLUSION: The majority of COPD patients received maintenance or reliever COPD medications, but less than half received guideline-recommended care, especially those with an exacerbation history or receiving short-term treatment for acute exacerbations.

Migraine-related healthcare resource use and costs for subjects prescribed fixed-dose combination sumatriptan/naproxen sodium vs. single-entity oral triptans in a managed care population in the USA.

BACKGROUND: Randomized clinical trials have demonstrated that the efficacy of a fixed-dose single-tablet combination containing sumatriptan and naproxen sodium (S/NS) was greater than either of its individual components. Simplifying drug regimens (e.g., via a fixed-dose combination) has been shown to improve "real-world" outcomes by reducing pill burden and treatment regimen complexity, improving adherence, and reducing healthcare resource use and associated costs; however, no studies assessing such outcomes have been conducted to date for the acute treatment of migraine. OBJECTIVE: To assess migraine-related healthcare resource use and associated costs for subjects prescribed S/NS vs. subjects prescribed single-entity oral triptans (SOTs) within a managed care population in the USA. METHODS: In this retrospective analysis of administrative claims data from July 1, 2008 to December 31, 2009 (IMS LifeLink), subjects meeting the following criteria were selected: one or more pharmacy claim(s) for either S/NS or SOT (index date), aged 18-64 years; at least one migraine diagnosis, and continuous enrollment in the 6 months prior to and post the index date. The study population was subsequently stratified for two analyses: triptan-naïve (triptan naïve in the 6-month period prior to the index date) and triptan-switch (triptan user in the 6-month period prior to the index date and switching to another triptan). Subjects prescribed S/NS were propensity-score matched with subjects prescribed SOT (triptan-naïve analysis: 1:3; triptan-switch analysis: 1:1) to assess differences in healthcare resource use and associated costs (2009 US$) between the S/NS and SOT groups. RESULTS: Results from the triptan-naïve and triptan-switch analyses suggest that subjects prescribed S/NS are likely to have similar healthcare resource use patterns as those either newly initiated on an SOT or switching SOTs, as measured by migraine medication use, migraine-related healthcare resource use, and all-cause healthcare resource use. One exception was the observed increased use of opioids in the SOT group compared with the S/NS group (change in mean number of tablets pre-index vs. post-index, S/NS vs. SOT; triptan-naïve analysis: 8.6 vs.18.3, p = 0.045; triptan-switch analysis: -8.2 vs. 17.7; p = 0.120). Total costs from the triptan-naïve analysis indicated that the S/NS group had lower migraine-related (US$744 vs. US$820; p = 0.067) and all-cause healthcare costs (US$4,391 vs. US$4,870; p = 0.040) when compared with the SOT group, driven by savings in medical costs (migraine-related: US$252 vs. US$380; p = 0.001; all-cause: US$3,023 vs. US$3,599; p = 0.014). However, no significant differences were observed for total costs from the triptan-switch analysis (migraine-related healthcare costs, S/NS vs. SOT: US$1,159 vs. US$1,117; p = 0.929; all-cause healthcare costs: US$5,128 vs. US$4,788; p = 0.381). CONCLUSION: Study results suggest similar healthcare resource use patterns and associated costs when comparing S/NS and SOT across a triptan-naïve and triptan-experienced population. While the current study focuses on direct medical costs, future studies should extend beyond such a perspective to explore functional status, productivity, and health-related quality of life and satisfaction, attributes not captured in administrative claims data, but nonetheless important treatment goals.

Economic implications of weight change in patients with type 2 diabetes mellitus.

OBJECTIVE: Assess the impact of weight change on costs, resource use, and treatment discontinuation among metformin-treated patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Observational, retrospective cohort. METHODS: Adults with T2DM who were pre existing metformin-treated patients were included. Insulin users were excluded. Administrative data from January 1, 2000, to December 31, 2010, were linked to clinical data, and patients were placed into cohorts based on relative change in body weight. Three cohorts were created: weight loss (decrease >3%), and weight neutral (change ≤3%), weight gain (increase > 3%). Inter-cohort differences in resource utilization, costs (2010 US$), and treatment discontinuation were evaluated using statistical models that adjusted for baseline characteristics. RESULTS: A total of 2110 patients (weight loss = 967; weight neutral = 970; weight gain = 173) were included; mean age was 59.6 years, 52.2% were women, 64.1% were Caucasian, and average baseline weight was 98.7 kg. The weight-loss cohort incurred significantly lower costs per year compared with the weight-neutral cohort, driven mainly by lower medical costs from reduced utilization. Weight reduction was associated with approximately $2200 and approximately $440 lower annual all-cause and T2DM-specific costs (P < .05), respectively. Patients who lost weight were 21% less likely to discontinue therapy. Weight gain was associated with a significant increase in all-cause costs of $3400 per year compared with the weight-neutral cohort; however, differences in T2DM-specific costs and discontinuation rates did not reach significance levels. CONCLUSIONS: Weight loss (> 3%) among patients with T2DM was associated with decreased costs and lower rates of treatment discontinuation. Hence weight-focused treatment approaches can help reduce the economic burden for patients with T2DM.

Leptin deficiency in rats results in hyperinsulinemia and impaired glucose homeostasis.

Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of ß-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 µg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance.