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.

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.

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).

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.

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.

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.

Serum alanine aminotransferase is correlated with hematocrit in healthy human subjects.

BACKGROUND: Serum alanine aminotransferase (ALT) activity is a widely-used surrogate marker for liver injury. However, mild elevation of serum ALT is frequently observed in apparently healthy individuals, making it sometimes challenging to interpret whether this laboratory abnormality is medically benign or serious. To obtain a better understanding of the factors influencing ALT levels, we examined the relation between ALT and a number of anthropometric and biochemistry measurements in humans. METHODS: We assessed the associations of ALT with hematocrit (HCT) in 1,200 apparently healthy adults from an Amish population. Multivariate analyses were carried out to determine whether observed associations were independent of other factors known to modulate ALT and HCT, including body mass index (BMI) and sex. The correlation detected in the Amish was then replicated in an independent population sample (N = 9,842) from the National Health and Nutrition Examination Survey (NHANES) III. RESULTS: ALT levels were positively correlated with HCT (r = 0.33, p < 0.0001) in both Amish and NHANES III. The magnitude of association was unchanged after adjustment for BMI, but was reduced by age/sex adjustment to r = 0.18 (p < 0.0001) and r = 0.17 (p < 0.0001) in the Amish and NHANES populations, respectively. HCT accounts for about 3% of the population variation in ALT, which is smaller than the contributions of gender and BMI, but larger than individual blood pressure and cholesterol components. CONCLUSIONS: We observed a correlation between ALT and HCT, suggesting that HCT may be a newly identified modulator of ALT in humans.

Improvement in depression scores after 1 hour of light therapy treatment in patients with seasonal affective disorder.

The purpose of this study was to investigate possible rapid effects of light therapy on depressed mood in patients with seasonal affective disorder. Participants received 1 hour of bright light therapy and 1 hour of placebo dim red light in a randomized order crossover design. Depressed mood was measured at baseline and after each hour of light treatment using two self-report depression scales (Profile of Mood States-Depression-Dejection [POMS-D] subscale and the Beck Depression Inventory II [BDI-II]). When light effects were grouped for the two sessions, there was significantly greater reduction in self-report depression scores by -1.3 (p = 0.02) on the BDI-II and -1.2 (p = 0.02) on the POMS-D. A significant but modest improvement was detected after a single active light session. This is the first study, to our knowledge, to document an immediate improvement with light treatment using a placebo-controlled design with a clinical sample of depressed individuals.

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

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.

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.

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.

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 physical activity and body composition with insulin sensitivity in a community sample of adolescents.

OBJECTIVE: To examine how body composition and physical activity are related to insulin sensitivity and secretion in adolescents. DESIGN: Cross-sectional. SETTING: Baltimore, Maryland. PARTICIPANTS: Fifty-six healthy adolescents (34 boys and 22 girls; mean [SD] age, 13.3 [1.3] years; 95% were African American) who had been recruited at infancy from a health care clinic serving a low-income, urban community. Main Exposures Physical activity was measured for 5 to 7 days by a uniaxial accelerometer placed on the right ankle. Proportion of time spent in play-equivalent physical activity (PEPA) was defined as 1800 or more counts per minute. Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was converted to an age- and sex-specific z score. MAIN OUTCOME MEASURES: Insulin sensitivity, insulin secretion, and disposition index calculated from a fasting oral glucose tolerance test. RESULTS: Thirty-nine percent of the adolescents had a BMI in the 85th percentile or higher; half of those were overweight (BMI > or = 95th percentile). Play-equivalent physical activity and BMI z score were not correlated. In multivariate analyses, BMI z score and time spent in PEPA together explained 21% of the variance in insulin sensitivity and 18% in insulin secretion. Independent of each other, high BMI z score and low proportion of PEPA were significantly associated with low insulin sensitivity (partial r(2) = 0.14 and 0.10, respectively) and high insulin secretion (partial r(2) = 0.10 and 0.10, respectively), but not with disposition index. CONCLUSIONS: In a cohort of urban, predominantly African American adolescents, both body composition and physical activity were independently associated with insulin sensitivity. At this point, insulin secretion is appropriately regulated.

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.

Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.

BACKGROUND: Obesity is associated with low-grade chronic inflammation, and serum markers of inflammation are independent risk factors for cardiovascular disease (CVD). However, the molecular and cellular mechanisms that link obesity to chronic inflammation and CVD are poorly understood. METHODS AND FINDINGS: Acute-phase serum amyloid A (A-SAA) mRNA levels, and A-SAA adipose secretion and serum levels were measured in obese and nonobese individuals, obese participants who underwent weight-loss, and persons treated with the insulin sensitizer rosiglitazone. Inflammation-eliciting activity of A-SAA was investigated in human adipose stromal vascular cells, coronary vascular endothelial cells and a murine monocyte cell line. We demonstrate that A-SAA was highly and selectively expressed in human adipocytes. Moreover, A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively). Serum A-SAA levels decreased significantly after weight loss in obese participants (p = 0.006), as well as in those treated with rosiglitazone (p = 0.033). The magnitude of the improvement in insulin sensitivity after weight loss was significantly correlated with decreases in serum A-SAA (r = -0.74; p = 0.034). SAA treatment of vascular endothelial cells and monocytes markedly increased the production of inflammatory cytokines, e.g., interleukin (IL)-6, IL-8, tumor necrosis factor alpha, and monocyte chemoattractant protein-1. In addition, SAA increased basal lipolysis in adipose tissue culture by 47%. CONCLUSIONS: A-SAA is a proinflammatory and lipolytic adipokine in humans. The increased expression of A-SAA by adipocytes in obesity suggests that it may play a critical role in local and systemic inflammation and free fatty acid production and could be a direct link between obesity and its comorbidities, such as insulin resistance and atherosclerosis. Accordingly, improvements in systemic inflammation and insulin resistance with weight loss and rosiglitazone therapy may in part be mediated by decreases in adipocyte A-SAA production.