Semaglutide single-dose pen-injector: Post hoc analysis of summative usability testing for weight management.

Subcutaneous semaglutide, at a 2.4 mg once-weekly maintenance dose, is approved in the United States for weight management in individuals with a body mass index (BMI) of 30 kg/m2 or higher, or with a BMI of 27 kg/m2 or higher and at least one obesity-related co-morbidity. To investigate the usability of the semaglutide pen-injector in individuals who met these criteria, we report post hoc analysis of the summative (human factors validation) usability testing and safety analysis involving patients with type 2 diabetes (an obesity-related co-morbidity) with the same pen-injector, limited to the 26 out of 30 patients with a BMI of 27 kg/m2 or higher (11 pen-injector-naïve, 15 pen-injector-experienced) and 15 non-pharmacist healthcare professionals (HCPs). Participants performed two simulated injections into an injection pad. No potentially serious use errors occurred. Mean subjective ease-of-use rating on a seven-point scale, where 1 = difficult and 7 = easy, was 6.9 for the second injection in all three groups. These results suggest that the semaglutide pen-injector is easy to use and not associated with serious use errors when used by pen-injector-naïve or pen-injector-experienced patients meeting the requirement for weight management with semaglutide treatment, and by non-pharmacist HCPs.

Comparison of the injection-site experience of the starting doses with semaglutide and dulaglutide: A randomized, double-blind trial in healthy subjects.

This double-blind, randomized, single-site, crossover trial compared the injection-site experience with the starting doses of semaglutide and dulaglutide. Healthy subjects (aged 18-75 years; body mass index ≥ 25 kg/m2 ; n = 104) were randomized 1:1, using a pregenerated list, to semaglutide 0.25 mg as the first injection and dulaglutide 0.75 mg as the second injection or vice versa; each was administered using their proprietary pen-injectors, according to instructions for use. The primary endpoint was intensity of injection-site pain, measured using a visual analogue scale (VAS; 0 mm = no pain, 100 mm = unbearable pain). Exploratory endpoints included intensity category, duration and quality of injection-site pain, and comparative assessment of injection-site pain with the two injections. The point estimate of the VAS score for injection-site pain intensity was 11.5 mm with dulaglutide versus 5.6 mm with semaglutide; mean (95% confidence interval) estimated treatment difference 5.9 (3.6; 8.2) mm; p < .0001. Other endpoints corroborated a less painful injection experience with semaglutide versus dulaglutide. Safety was consistent with reported data for the drugs. In conclusion, the injection-site experience with semaglutide was rated as less painful than that with dulaglutide.

Evaluating the usability and safety of the semaglutide single-dose pen-injectors through summative (human factors) usability testing.

AIMS/INTRODUCTION: A single-dose, shield-activated pen-injector for each of the three approved dose variants (0.25, 0.5 and 1 mg) of once-weekly subcutaneous semaglutide has been developed to improve usability. This analysis presents findings from the summative usability testing process for the single-dose semaglutide pen-injectors, including the pen-injector four-pack cartons and instructions for use. MATERIALS AND METHODS: A total of 60 adults representing four user groups were included: patients with/without pen-injector experience, non-pharmacist healthcare professionals and pharmacists (each n = 15). Participants carried out four tasks: (i) pen-injector carton retrieval; (ii) first simulated injection; (iii) pen-injector retrieval; and (iv) second simulated injection. All participants carried out task 1, and patients and non-pharmacist healthcare professionals took part in tasks 2-4 (n = 45). The number and types of use errors, close calls and operational difficulties were evaluated, and participants subjectively rated the ease of each task on a scale of 1 (difficult) to 7 (easy). RESULTS: No potentially serious use errors and only one non-serious use error were reported. Eight participants committed use errors with no potential for harm, one participant committed an unclassified use error, one participant encountered a close call with no potential for harm and one participant experienced an operational difficulty. Mean ease-of-use ratings were 6.7 (task 1), 5.9 (task 2), 6.6 (task 3) and 6.9 (task 4). CONCLUSIONS: All three dose variants of the semaglutide single-dose pen-injector were considered easy to use (subjective feedback scores near 7) and not associated with any serious use errors, even when participants received no training before study participation.

Seasonal affective disorder and seasonal changes in weight and sleep duration are inversely associated with plasma adiponectin levels.

Overlapping pathways between mood and metabolic regulation have increasingly been reported. Although impaired regulation of adiponectin, a major metabolism-regulating hormone, has been implicated in major depressive disorder, its role in seasonal changes in mood and seasonal affective disorder-winter type (SAD), a disorder characterized by onset of mood impairment and metabolic dysregulation (e.g., carbohydrate craving and weight gain) in fall/winter and spontaneous alleviation in spring/summer, has not been previously studied. We studied a convenience sample of 636 Old Order Amish (mean (± SD), 53.6 (±14.8) years; 50.1% males), a population with self-imposed restriction on network electric light at home, and low prevalence of total SAD (t-SAD = syndromal + subsyndromal). We calculated the global seasonality score (GSS), estimated SAD and subsyndromal-SAD after obtaining Seasonal Pattern Assessment Questionnaires (SPAQs), and measured overnight fasting plasma adiponectin levels. We then tested associations between plasma adiponectin levels and GSS, t-SAD, winter-summer difference in self-reported sleep duration, and self-reported seasonal weight change, by using analysis of co-variance (ANCOVA) and linear regression analysis after adjusting for age, gender, and BMI. Participants with t-SAD (N = 14; 2.2%) had significantly lower plasma adiponectin levels (mean ± SEM, 8.76 ± 1.56 µg/mL) than those without t-SAD (mean ± SEM, 11.93 ± 0.22 µg/mL) (p = 0.035). In addition, there was significant negative association between adiponectin levels and winter-summer difference in self-reported sleep duration (p = 0.025) and between adiponectin levels and self-reported seasonal change in weight (p = 0.006). There was no significant association between GSS and adiponectin levels (p = 0.88). To our knowledge, this is the first study testing the association of SAD with adiponectin levels. Replication and extension of our findings longitudinally and, then, interventionally, may implicate low adiponectin as a novel target for therapeutic intervention in SAD.

Self-Reported Sleep Duration and Pattern in Old Order Amish and Non-Amish Adults.

STUDY OBJECTIVES: We hypothesized that sleep duration in the Amish would be longer than in non-Amish. METHODS: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015-2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. RESULTS: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18-29 years and ≥ 70 years, compared to those aged 30-69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h² approximately 0) after adjustment for household. CONCLUSIONS: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population. CITATION: Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321-1328.

Association of Glucose Concentrations at Hospital Discharge With Readmissions and Mortality: A Nationwide Cohort Study.

CONTEXT: Low blood glucose concentrations during the discharge day may affect 30-day readmission and posthospital discharge mortality rates. OBJECTIVE: To investigate whether patients with diabetes and low glucose values during the last day of hospitalization are at increased risk of readmission or mortality. DESIGN AND OUTCOMES: Minimum point of care glucose values were collected during the last 24 hours of hospitalization. We used adjusted rates of 30-day readmission rate, 30-, 90-, and 180-day mortality rates, and combined 30-day readmission/mortality rate to identify minimum glucose thresholds above which patients can be safely discharged. PATIENTS AND SETTING: Nationwide cohort study including 843,978 admissions of patients with diabetes at the Veteran Affairs hospitals 14 years. RESULTS: The rate ratios (RRs) increased progressively for all five outcomes as the minimum glucose concentrations progressively decreased below the 90 to 99 mg/dL category, compared with the 100 to 109 mg/dL category: 30-day readmission RR, 1.01 to 1.45; 30-day readmission/mortality RR, 1.01 to 1.71; 30-day mortality RR, 0.99 to 5.82; 90-day mortality RR, 1.01 to 2.40; 180-day mortality RR, 1.03 to 1.91. Patients with diabetes experienced greater 30-day readmission rates, 30-, 90- and 180-day postdischarge mortality rates, and higher combined 30-day readmission/mortality rates, with glucose levels <92.9 mg/dL, <45.2 mg/dL, 65.8 mg/dL, 67.3 mg/dL, and <87.2 mg/dL, respectively. CONCLUSION: Patients with diabetes who had hypoglycemia or near-normal glucose values during the last day of hospitalization had higher rates of 30-day readmission and postdischarge mortality.

Increased usual physical activity is associated with a blunting of the triglyceride response to a high-fat meal.

BACKGROUND: Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state. OBJECTIVE: In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal. METHODS: The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period. RESULTS: Physical activity levels decreased with increasing age and were higher in men than women (both P < .001). The triglyceride AUC increased with increasing age in both men and women (both P < .001) and was also higher in men than in women (age-adjusted P = 9.2 × 10-12). Higher physical activity levels were associated with a lower triglyceride AUC (P = .003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein. CONCLUSION: These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response.

Association of QT-Prolonging Medication Use in CKD with Electrocardiographic Manifestations.

BACKGROUND AND OBJECTIVES: Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their association with QT duration. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 3252 Chronic Renal Insufficiency Cohort participants with at least one study electrocardiogram between 2003 and 2011 were included. QT-prolonging medications used in 100 or more visits (n=16,451 visits) along with diuretics and proton pump inhibitors, given their potential for electrolyte disturbances, were examined for QT interval prolongation. RESULTS: Mean QT interval corrected for heart rate was at 414±21 (±SD) milliseconds and prolonged (≥450 milliseconds) in 4.6% of electrocardiograms. QT interval corrected for heart rate was inversely related to serum potassium and calcium. Medications classified as QT prolonging were taken at 76% of visits, with two or more of these taken at 33% of visits. Of 30 medications examined, eight were associated with statistically significant QT interval corrected for heart rate prolongation after adjustment for comorbidities, potassium, and calcium, including amiodarone (+10±2 milliseconds), metolazone (+7±2 milliseconds), fluoxetine (+4±1 milliseconds), citalopram (+4±1 milliseconds), hydroxyzine (+4±1 milliseconds), escitalopram (+3±2 milliseconds), venlafaxine (+3±1 milliseconds), and furosemide (+3±0 milliseconds). Potassium-depleting diuretics were associated with minimal decrements in potassium (between 0.1 and 0.3 mEq/L) and smaller changes in calcium. Diuretics associated with a change in QT interval corrected for heart rate before adjustment for potassium and calcium were metolazone (+8±3 milliseconds), furosemide (+4±1 milliseconds), and spironolactone (-3±3 milliseconds). Most of the QT prolongation associated with metolazone and furosemide, but not spironolactone, remained after adjustment for potassium and calcium. Proton pump inhibitors were not associated with QT prolongation. CONCLUSIONS: Use of medications associated with QT prolongation is common in CKD; the safety implications of these findings should be considered in these high-risk patients. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_09_CJASNPodcast_17_09_b.mp3.

Prediction of outcome of bright light treatment in patients with seasonal affective disorder: Discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome.

BACKGROUND: We tested the hypothesis that the early improvement in mood after the first hour of bright light treatment compared to control dim-red light would predict the outcome at six weeks of bright light treatment for depressed mood in patients with Seasonal Affective Disorder (SAD). We also analyzed the value of Body Mass Index (BMI) and atypical symptoms of depression at baseline in predicting treatment outcome. METHODS: Seventy-eight adult participants were enrolled. The first treatment was controlled crossover, with randomized order, and included one hour of active bright light treatment and one hour of control dim-red light, with one-hour washout. Depression was measured on the Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD version (SIGH-SAD). The predictive association of depression scores changes after the first session. BMI and atypical score balance with treatment outcomes at endpoint were assessed using multivariable linear and logistic regressions. RESULTS: No significant prediction by changes in depression scores after the first session was found. However, higher atypical balance scores and BMI positively predicted treatment outcome. LIMITATIONS: Absence of a control intervention for the six-weeks of treatment (only the first session in the laboratory was controlled). Exclusion of patients with comorbid substance abuse, suicidality and bipolar I disorder, and patients on antidepressant medications, reducing the generalizability of the study. CONCLUSION: Prediction of outcome by early response to light treatment was not replicated, and the previously reported prediction of baseline atypical balance was confirmed. BMI, a parameter routinely calculated in primary care, was identified as a novel predictor, and calls for replication and then exploration of possible mediating mechanisms.

Sleep onset insomnia, daytime sleepiness and sleep duration in relationship to Toxoplasma gondii IgG seropositivity and serointensity.

Toxoplasma gondii (T. gondii) infects central nervous tissue and is kept in relative dormancy by a healthy immune system. Sleep disturbances have been found to precipitate mental illness, suicidal behavior and car accidents, which have been previously linked to T. gondii as well. We speculated that if sleep disruption, particularly insomnia, would mediate, at least partly, the link between T. gondii infection and related behavioral dysregulation, then we would be able to identify significant associations between sleep disruption and T. gondii. The mechanisms for such an association may involve dopamine (DA) production by T. gondii, or collateral effects of immune activation necessary to keep T. gondii in check. Sleep questionnaires from 2031 Old Order Amish were analyzed in relationship to T. gondii-IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). Toxoplasma gondii seropositivity and serointensity were not associated with any of the sleep latency variables or Epworth Sleepiness Scale (ESS). A secondary analysis identified, after adjustment for age group, a statistical trend toward shorter sleep duration in seropositive men (p = 0.07). In conclusion, it is unlikely that sleep disruption mediates links between T. gondii and mental illness or behavioral dysregulation. Trending gender differences in associations between T. gondii and shorter sleep need further investigation.

Patient-Reported Safety Events in Chronic Kidney Disease Recorded With an Interactive Voice-Inquiry Dial-Response System: Monthly Report Analysis.

BACKGROUND: Monitoring patient-reported outcomes (PROs) may improve safety of chronic kidney disease (CKD) patients. OBJECTIVE: Evaluate the performance of an interactive voice-inquiry dial-response system (IVRDS) in detecting CKD-pertinent adverse safety events outside of the clinical environment and compare the incidence of events using the IVDRS to that detected by paper diary. METHODS: This was a 6-month study of Stage III-V CKD patients in the Safe Kidney Care (SKC) study. Participants crossed over from a paper diary to the IVDRS for recording patient-reported safety events defined as symptoms or events attributable to medications or care. The IVDRS was adapted from the SKC paper diary to record event frequency and remediation. Participants were auto-called weekly and permitted to self-initiate calls. Monthly reports were reviewed by two physician adjudicators for their clinical significance. RESULTS: 52 participants were followed over a total of 1384 weeks. 28 out of 52 participants (54%) reported events using the IVDRS versus 8 out of 52 (15%) with the paper diary; hypoglycemia was the most common event for both methods. All IVDRS menu options were selected at least once except for confusion and rash. Events were reported on 121 calls, with 8 calls reporting event remediation by ambulance or emergency room (ER) visit. The event rate with the IVDRS and paper diary, with and without hypoglycemia, was 26.7 versus 4.7 and 18.3 versus 0.8 per 100 person weeks, respectively (P=.002 and P<.001). The frequent users (ie, >10 events) largely differed by method, and event rates excluding the most frequent user of each were 16.9 versus 2.5 per 100 person weeks, respectively (P<.001). Adjudicators found approximately half the 80 reports clinically significant, with about a quarter judged as actionable. Hypoglycemia was often associated with additional reports of fatigue and falling. Participants expressed favorable satisfaction with the IVDRS. CONCLUSIONS: Use of the IVDRS among CKD patients reveals a high frequency of clinically significant safety events and has the potential to be used as an important supplement to clinical care for improving patient safety.

Elevated blood pressure in adolescent girls: correlation to body size and composition.

BACKGROUND: To improve understanding of the pathophysiology of hypertension in adolescents and pave the way for risk stratification, studies have sought to determine the correlates of blood pressure (BP). Inconsistencies in dependent and independent variables have resulted in an elusive consensus. The aim of this report is to examine an inclusive array of correlates of BP, as a continuous (systolic and diastolic BP) and a dichotomous variable. METHODS: Subjects were a school-based sample of 730 urban, mostly African American, non-referred 6th and 7th grade girls. To find independent correlates of SBP/DBP, we used a stepwise model selection method based on the Schwarz Bayesian Information Criterion, enabling selection of a parsimonious model among highly correlated covariates. Candidate variables were: age, stature, heart rate, pubertal development, BMI, BMI z-score, waist circumference, waist-to-height ratio (WHtR), body surface area, fat mass (by bioelectrical impedance analysis), fat-free mass (FFM), percentage of body fat, and presence of overweight/obesity. RESULTS: The best-fitting models for DBP and SBP (considered separately) included fat-free mass, heart rate and, in the case of SBP, stature. The best-fitting model for high-normal/elevated blood pressure (H-N/EBP) included WHtR with no independent relation of any other variable. The prevalence of H-N/EBP tripled between a WHtR of 0.5 and 0.7. CONCLUSIONS: The easily obtained and calculated WHtR is the strongest correlate of elevated blood pressure among available variables and is a prime candidate for longitudinal studies of predictors of the development of hypertension. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT00746083.

Ankle Accelerometry for Assessing Physical Activity Among Adolescent Girls: Threshold Determination, Validity, Reliability, and Feasibility.

PURPOSE: Ankle accelerometry allows for 24-hr data collection and improves data volume/integrity versus hip accelerometry. Using Actical ankle accelerometry, the purpose of this study was to (a) develop sensitive/specific thresholds, (b) examine validity/reliability, (c) compare new thresholds with those of the manufacturer, and (d) examine feasibility in a community sample (low-income, urban adolescent girls). METHOD: Two studies were conducted with 6th- through 7th-grade girls (aged 10-14 years old): First was a laboratory study (n = 24), in which 2 Actical accelerometers were placed on the ankle and worn while measuring energy expenditure (Cosmed K4b2, metabolic equivalents [METs]) during 10 prescribed activities. Analyses included device equivalence reliability (intraclass correlation coefficient [ICC], activity counts of 2 Acticals), criterion-related validity (correlation, activity counts and METs), and calculations of sensitivity, specificity, kappa, and receiver-operating characteristic curves for thresholds. The second was a free-living study (n = 459), in which an Actical was worn for more than 7 days on the ankle (full 24-hr days retained). Analyses included feasibility (frequencies, missing data) and paired t tests (new thresholds vs. those of the manufacturer). RESULTS: In the laboratory study, the Actical demonstrated reliability (ICC = .92) and validity (r = .81). Thresholds demonstrated sensitivity (91%), specificity (84%), kappa = .73 (p = .043), area under curve range = .81-.97. In the free-living study, 99.6% of participants wore the accelerometer; 84.1% had complete/valid data (mean = 5.7 days). Primary reasons for missing/invalid data included: improper programming/documentation (5.2%), failure to return device (5.0%), and wear-time ≤ 2 days (2.8%). The moderate-to-vigorous physical activity threshold (> 3,200 counts/minute) yielded 37.2 min/day, 2 to 4.5 times lower than that of the manufacturer's software (effect size = 0.74-4.05). CONCLUSIONS: Validity, reliability, and feasibility evidences support Actical ankle accelerometry to assess physical activity in community studies of adolescent girls. When comparing manufacturers' software versus new thresholds, a major difference was observed.

Chronotype and seasonality: morningness is associated with lower seasonal mood and behavior changes in the Old Order Amish.

BACKGROUND: Several studies documented that lower scores on the Morningness-Eveningness Questionnaire (MEQ) are associated with a higher global seasonality of mood (GSS). As for the Modern Man artificial lighting predominantly extends evening activity and exposure to light, and as evening bright light phase is known to delay circadian rhythms, this chronic exposure could potentially lead to both lower Morningness as well as higher GSS. The aim of the study was to investigate if the MEQ-GSS relationship holds in the Old Order Amish of Lancaster County, PA, a population that does not use network electrical light. METHODS: 489 Old Order Amish adults (47.6% women), with average (SD) age of 49.7 (14.2) years, completed both the Seasonal Pattern Assessment Questionnaire (SPAQ) for the assessment of GSS, and MEQ. Associations between GSS scores and MEQ scores were analyzed using linear models, accounting for age, gender and relatedness by including the relationship matrix in the model as a random effect. RESULTS: GSS was inversely associated with MEQ scores (p=0.006, adjusted). LIMITATIONS: include a potential recall bias associated with self-report questionnaires and no actual light exposure measurements. CONCLUSION: We confirmed the previously reported inverse association between MEQ scores and lower seasonality of mood, for the first time in a population that does not use home network electrical lighting. This result suggests that the association is not a byproduct of exposure to network electric light, and calls for additional research to investigate mechanisms by which Morningness is negatively associated with seasonality.

Development of heart failure in Medicaid patients with type 2 diabetes treated with pioglitazone, rosiglitazone, or metformin.

BACKGROUND: Medicaid covers a high-risk population typically underrepresented in clinical trial data and largely absent in observational studies of real-world cardiovascular risks associated with thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, which are used to manage type 2 diabetes. In November 2013, the FDA removed prescribing restrictions for rosiglitazone in light of new evidence that rosiglitazone did not increase the risk of heart attack compared with standard type 2 diabetes medications. Further investigation is needed to elucidate whether the risk of heart failure (HF) associated with TZDs may be exacerbated in the Medicaid population. OBJECTIVE: To determine the relative risk of incident HF in patients initiating rosiglitazone, pioglitazone, and metformin therapy in a Medicaid population. METHODS: We retrospectively examined claims data for patients with type 2 diabetes enrolled in Maryland State Medicaid and managed care or fee-for-service programs between July 2005 and June 2010. Patients initiated on metformin, pioglitazone, or rosiglitazone treatments were extracted for analysis. Relative risks of incident HF after initiating treatment were compared using survival analysis, adjusting for switching or adding antidiabetic therapies during follow-up and other baseline risk factors for HF. RESULTS: Of 6,271 patients meeting inclusion criteria, 88% were started on metformin; 7% were started on pioglitazone; and 5% were started on rosiglitazone. Patients who initiated rosiglitazone had higher risk of HF than patients who initiated metformin using either univariate (HR = 1.81, 95% CI = 1.37-2.39), multivariate (HR = 1.57, 95% CI = 1.15-2.15), or propensity score-matched (HR = 1.79, 95% CI = 1.16-2.76) analysis. There was no significant difference in risk between patients who initiated pioglitazone and metformin therapy. CONCLUSIONS: Compared with metformin, there may be higher risk of developing HF in Medicaid patients started on rosiglitazone but not pioglitazone. While pioglitazone was associated with a lower risk of developing HF compared with rosiglitazone, health care professionals should continue to work closely with their patients to determine the treatment options most appropriate.

Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes.

BACKGROUND: Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders. METHODS: We sequenced 12 lipolytic-pathway genes in Old Order Amish participants whose fasting serum triglyceride levels were at the extremes of the distribution and identified a novel 19-bp frameshift deletion in exon 9 of LIPE, encoding hormone-sensitive lipase (HSL), a key enzyme for lipolysis. We genotyped the deletion in DNA from 2738 Amish participants and performed association analyses to determine the effects of the deletion on metabolic traits. We also obtained biopsy specimens of abdominal subcutaneous adipose tissue from 2 study participants who were homozygous for the deletion (DD genotype), 10 who were heterozygous (ID genotype), and 7 who were noncarriers (II genotype) for assessment of adipose histologic characteristics, lipolysis, enzyme activity, cytokine release, and messenger RNA (mRNA) and protein levels. RESULTS: Carriers of the mutation had dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. In adipose tissue from study participants with the DD genotype, the mutation resulted in the absence of HSL protein, small adipocytes, impaired lipolysis, insulin resistance, and inflammation. Transcription factors responsive to peroxisome-proliferator-activated receptor γ (PPAR-γ) and downstream target genes were down-regulated in adipose tissue from participants with the DD genotype, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism. CONCLUSIONS: These findings indicate the physiological significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis and underscore the severe metabolic consequences of impaired lipolysis. (Funded by the National Institutes of Health and others).

Effect of social networks intervention in type 2 diabetes: a partial randomised study.

BACKGROUND: In this partially randomised intervention study, we assessed the effect of social networks on the improvement of type 2 diabetes management in a largely African-American population in Baltimore. METHODS: Patients in the intervention group (n=68) were asked to recruit peers, form small groups, and attend monthly diabetes education sessions, emphasising peer support. Patients in the control group (n=70) were recruited individually to attend standard diabetes education sessions. The primary outcomes were changes in haemoglobin A1C (HbA1c) and blood glucose. Secondary outcomes included blood pressure, weight, functional status, self-efficacy, perceived cohesion, social network connectedness and diabetes knowledge. General linear mixed models were built to assess mean absolute changes in primary and secondary outcomes at 3 and 6 months. RESULTS: At 6 months from baseline, the social network intervention group achieved a larger reduction in HbA1c of -0.32% (p<0.0001) and blood glucose of -10.6 mg/dL, (p<0.0001) compared to the control group. In analyses of secondary endpoints, the intervention group had more favourable outcomes over time for weight, quality of life, self-efficacy, social network scores and diabetes knowledge, compared to the control group. While blood pressure decreased, and perceived cohesion increased in both groups over the duration of the study, the difference between groups was not statistically significant. CONCLUSIONS: The social networks intervention showed improved integration of patients within their existing networks leading to a greater reduction in HbA1c and blood glucose, as well as improved behaviour mediating outcomes.

Correlation of circulating MMP-9 with white blood cell count in humans: effect of smoking.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects. METHODS: We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group. RESULTS: Circulating MMP-9 and WBC count are significantly correlated in men (R(2) = 0.13, p<0.001) and women (R(2) = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R(2) = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R(2) = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers. CONCLUSIONS: WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans.