Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives.

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40-19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.

Oleic acid regulates the circadian rhythm of adipose tissue in obesity.

The effect of oleic acid (OA) on the regulation of the circadian rhythm present in human visceral (VAT) and subcutaneous (SAT) adipose tissue from patients with morbid obesity has not been analyzed yet. VAT and SAT explants from patients with morbid obesity were incubated with OA to analyze the circadian regulation of clock and other genes related to lipid metabolism (SREBP-1c, FAS, LPL and CPT1), and their association with baseline variables and the improvement of these patients after bariatric surgery. There were significant differences in amplitude and acrophase in VAT with respect to SAT. In VAT, body weight negatively correlated with BMAL1 and CRY1 amplitude, and REVERBα acrophase; body mass index (BMI) negatively correlated with REVERBα acrophase; and waist circumference negatively correlated with PER3 acrophase. In SAT, BMI negatively correlated with CLOCK amplitude, and CLOCK, REVERBα and CRY2 MESOR; and waist circumference negatively correlated with PER3 amplitude and acrophase. A greater short-term improvement of body weight, BMI and waist circumference in patients with morbid obesity after bariatric surgery was associated with a lower CRY1 and CRY2 amplitude and an earlier PER1 and PER3 acrophase in SAT. OA produced a more relevant circadian rhythm and increased the amplitude of most clock genes and lipid metabolism-related genes. OA regulated the acrophase of most clock genes in VAT and SAT, placing CLOCK/BMAL1 in antiphase with regard to the other genes. OA increased the circadian rhythmicity, although with slight differences between adipose tissues. These differences could determine its different behavior in obesity.

Practical and Ethical Considerations of Using Personal DNA Tests with Middle-School-Aged Learners.

Personalized genetic information is not widely utilized as a resource in learning environments, in part because of concerns about data privacy and the treatment of sensitive personal information. Here we describe the implementation of a curriculum centered on analyzing personalized genetic-ancestry test results during two-week science summer camps for middle-school-aged youth. Our research focused on how the examination of personalized DNA results affected learners' subsequent perceptions and performance, as measured by in-camp pre- and post-tests and surveys, analysis of voluntary student talk captured by audio and video recordings, and periodic one-on-one post-camp follow-ups. The curriculum was grounded in Next Generation Science Standards (NGSS) and focused around the central question of "Who am I?" Campers approached this question via guided lessons designed to shed light on their genetic uniqueness, the many attributes of their genotype and phenotype shared with others, their more distant genetic and evolutionary ancestries, and their roles as active agents in the healthy continuation of their lives. Data relevant to these questions came from edited subsets of ancestry-informative single-nucleotide polymorphisms (SNPs) and phenotype-related SNPs from the campers' genotype results, which their parents had received from a direct-to-consumer vendor. Our approaches to data privacy and the discovery, disclosure, and discussion of sensitive information on paternity, carrier status, and ancestry can be usefully applied and modified for many educational contexts. On the basis of our pilot implementations, we recommend additional and expanded research on how to incorporate personalized genetic ancestry information in a variety of learning contexts.

SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process.

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.

In Vitro and Clinical Evaluation of Cannabigerol (CBG) Produced via Yeast Biosynthesis: A Cannabinoid with a Broad Range of Anti-Inflammatory and Skin Health-Boosting Properties.

Cannabigerol (CBG) is a minor non-psychoactive cannabinoid present in Cannabis sativa L. (C. sativa) at low levels (<1% per dry weight) that serves as the direct precursor to both cannabidiol (CBD) and tetrahydrocannabinol (THC). Consequently, efforts to extract and purify CBG from C. sativa is both challenging and expensive. However, utilizing a novel yeast fermentation technology platform, minor cannabinoids such as CBG can be produced in a more sustainable, cost-effective, and timely process as compared to plant-based production. While CBD has been studied extensively, demonstrating several beneficial skin properties, there are a paucity of studies characterizing the activity of CBG in human skin. Therefore, our aim was to characterize and compare the in vitro activity profile of non-psychoactive CBG and CBD in skin and be the first group to test CBG clinically on human skin. Gene microarray analysis conducted using 3D human skin equivalents demonstrates that CBG regulates more genes than CBD, including several key skin targets. Human dermal fibroblasts (HDFs) and normal human epidermal keratinocytes (NHEKs) were exposed in culture to pro-inflammatory inducers to trigger cytokine production and oxidative stress. Results demonstrate that CBG and CBD reduce reactive oxygen species levels in HDFs better than vitamin C. Moreover, CBG inhibits pro-inflammatory cytokine (Interleukin-1ß, -6, -8, tumor necrosis factor α) release from several inflammatory inducers, such as ultraviolet A (UVA), ultraviolet B (UVB), chemical, C. acnes, and in several instances does so more potently than CBD. A 20-subject vehicle-controlled clinical study was performed with 0.1% CBG serum and placebo applied topically for 2 weeks after sodium lauryl sulfate (SLS)-induced irritation. CBG serum showed statistically significant improvement above placebo for transepidermal water loss (TEWL) and reduction in the appearance of redness. Altogether, CBG's broad range of in vitro and clinical skin health-promoting activities demonstrates its strong potential as a safe, effective ingredient for topical use and suggests there are areas where it may be more effective than CBD.

COVID-19 in transplant recipients: The Spanish experience.

We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID-19) in Spain until 13 July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range [IQR]: 52-70), and 66% were male. The incidence of COVID-19 in SOT recipients was two-fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18-131). Infection was hospital-acquired in 13% of cases. No donor-derived COVID-19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon-ß (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow-up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio [OR]: 2.5; 95% CI: 1.4-4.6), age >60 years (OR: 3.7; 95% CI: 2.5-5.5), and hospital-acquired COVID-19 (OR: 3.0; 95% CI: 1.9-4.9).

Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial.

AIMS: The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction. METHODS AND RESULTS: In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)]. CONCLUSION: Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00741585.

AGSE: A Novel Grape Seed Extract Enriched for PP2A Activating Flavonoids That Combats Oxidative Stress and Promotes Skin Health.

Environmental stimuli attack the skin daily resulting in the generation of reactive oxygen species (ROS) and inflammation. One pathway that regulates oxidative stress in skin involves Protein Phosphatase 2A (PP2A), a phosphatase which has been previously linked to Alzheimer's Disease and aging. Oxidative stress decreases PP2A methylation in normal human dermal fibroblasts (NHDFs). Thus, we hypothesize agents that increase PP2A methylation and activity will promote skin health and combat aging. To discover novel inhibitors of PP2A demethylation activity, we screened a library of 32 natural botanical extracts. We discovered Grape Seed Extract (GSE), which has previously been reported to have several benefits for skin, to be the most potent PP2A demethylating extract. Via several fractionation and extraction steps we developed a novel grape seed extract called Activated Grape Seed Extract (AGSE), which is enriched for PP2A activating flavonoids that increase potency in preventing PP2A demethylation when compared to commercial GSE. We then determined that 1% AGSE and 1% commercial GSE exhibit distinct gene expression profiles when topically applied to a 3D human skin model. To begin to characterize AGSE's activity, we investigated its antioxidant potential and demonstrate it reduces ROS levels in NHDFs and cell-free assays equal to or better than Vitamin C and E. Moreover, AGSE shows anti-inflammatory properties, dose-dependently inhibiting UVA, UVB and chemical-induced inflammation. These results demonstrate AGSE is a novel, multi-functional extract that modulates methylation levels of PP2A and supports the hypothesis of PP2A as a master regulator for oxidative stress signaling and aging in skin.

Physiological Significance of Discrimination on Stress Markers, Obesity, and LDL Oxidation among a European American and African American Cohort of Females.

BACKGROUND: Factors underlying physiological reactions from perceived discrimination and its relation to adverse health outcomes are not completely understood. The main purpose of this study was to test the hypothesis that experiences of discrimination (recent and lifetime) correlate with biomarkers of stress, oxidative stress, and obesity among adult females. METHOD: Data on 62 females who self-identify as African American (AA; n = 31) or European American (EA; n = 31) aged 21-45 years were included. Discrimination experiences (recent and lifetime) were evaluated based on a validated instrument. Stress was assessed based on hair cortisol (HC) and salivary cortisol (SC), hsC-reactive protein (hsCRP), cardiovascular markers, and LDL-cholesterol oxidation. Obesity was measured based on BMI, waist circumference, and body fat percent. Multiple linear regression analyses were performed to evaluate the influence of experiences of discrimination. RESULTS: Significant differences in experiences of discrimination were observed by race (p < 0.05) and were higher in AA females. Results for the multiple regression models assessing the contribution of discrimination indicate that hsCRP and pulse were significantly associated with recent experiences of discrimination, and SC, HC, hsCRP, diastolic blood pressure (DBP), and pulse were significantly associated with lifetime experiences of discrimination when adjusted for BMI and race (p < 0.05). Finally, oxidation of LDL-cholesterol was significantly associated with salivary cortisol (p = 0.0420) when adjusted by lifetime experiences of discrimination (p = 0.0366) but not for BMI (p = 0.6252). CONCLUSION: In this cross-sectional study, AA females experienced more discrimination compared to EA females. Levels of recent and lifetime experiences of discrimination were associated with some stress biomarkers. Salivary cortisol was associated with oxidation of LDL-cholesterol with shorter lag times and increased risk for cardiovascular disease.

Does Timing of Antihypertensive Medication Dosing Matter?

PURPOSE OF REVIEW: Current hypertension guidelines do not provide recommendation on when-to-treat. Herein, we review the current evidence on ingestion-time differences of hypertension medications in blood pressure (BP)-lowering effects and prevention of cardiovascular disease (CVD) events. RECENT FINDINGS: The vast (81.6%) majority of the 136 published short-term treatment-time trials document benefits, including enhanced reduction of asleep BP and increased sleep-time relative BP decline (dipping), when hypertension medications and their combinations are ingested before sleep rather than upon waking. Long-term outcome trials further document bedtime hypertension therapy markedly reduces risk of major CVD events. The inability of the very small 18.4% of the published trials to substantiate treatment-time difference in effects is mostly explained by deficiencies of study design and conduct. Our comprehensive review of the published literature reveals no single study has reported better benefits of the still conventional, yet scientifically unjustified, morning than bedtime hypertension treatment scheme.

Exercise plasma metabolomics and xenometabolomics in obese, sedentary, insulin-resistant women: impact of a fitness and weight loss intervention.

Insulin resistance has wide-ranging effects on metabolism, but there are knowledge gaps regarding the tissue origins of systemic metabolite patterns and how patterns are altered by fitness and metabolic health. To address these questions, plasma metabolite patterns were determined every 5 min during exercise (30 min, ∼45% of V̇o2peak, ∼63 W) and recovery in overnight-fasted sedentary, obese, insulin-resistant women under controlled conditions of diet and physical activity. We hypothesized that improved fitness and insulin sensitivity following a ∼14-wk training and weight loss intervention would lead to fixed workload plasma metabolomics signatures reflective of metabolic health and muscle metabolism. Pattern analysis over the first 15 min of exercise, regardless of pre- versus postintervention status, highlighted anticipated increases in fatty acid tissue uptake and oxidation (e.g., reduced long-chain fatty acids), diminution of nonoxidative fates of glucose [e.g., lowered sorbitol-pathway metabolites and glycerol-3-galactoside (possible glycerolipid synthesis metabolite)], and enhanced tissue amino acid use (e.g., drops in amino acids; modest increase in urea). A novel observation was that exercise significantly increased several xenometabolites ("non-self" molecules, from microbes or foods), including benzoic acid-salicylic acid-salicylaldehyde, hexadecanol-octadecanol-dodecanol, and chlorogenic acid. In addition, many nonannotated metabolites changed with exercise. Although exercise itself strongly impacted the global metabolome, there were surprisingly few intervention-associated differences despite marked improvements in insulin sensitivity, fitness, and adiposity. These results and previously reported plasma acylcarnitine profiles support the principle that most metabolic changes during submaximal aerobic exercise are closely tethered to absolute ATP turnover rate (workload), regardless of fitness or metabolic health status.

The influence of 15-week exercise training on dietary patterns among young adults.

BACKGROUND/OBJECTIVES: Little is currently known about how exercise may influence dietary patterns and/or food preferences. The present study aimed to examine the effect of a 15-week exercise training program on overall dietary patterns among young adults. SUBJECTS/METHODS: This study consisted of 2680 young adults drawn from the Training Intervention and Genetics of Exercise Response (TIGER) study. Subjects underwent 15 weeks of aerobic exercise training, and exercise duration, intensity, and dose were recorded for each session using computerized heart rate monitors. In total, 4355 dietary observations with 102 food items were collected using a self-administered food frequency questionnaire before and after exercise training (n = 2476 at baseline; n = 1859 at 15 weeks). Dietary patterns were identified using a Bayesian sparse latent factor model. Changes in dietary pattern preferences were evaluated based on the pre/post-training differences in dietary pattern scores, accounting for the effects of gender, race/ethnicity, and BMI. RESULTS: Within each of the seven dietary patterns identified, most dietary pattern scores were decreased following exercise training, consistent with increased voluntary regulation of food intake. A longer duration of exercise was associated with decreased preferences for the western (ß: -0.0793; 95% credible interval: -0.1568, -0.0017) and snacking (ß: -0.1280; 95% credible interval: -0.1877, -0.0637) patterns, while a higher intensity of exercise was linked to an increased preference for the prudent pattern (ß: 0.0623; 95% credible interval: 0.0159, 0.1111). Consequently, a higher dose of exercise was related to a decreased preference for the snacking pattern (ß: -0.0023; 95% credible interval: -0.0042, -0.0004) and an increased preference for the prudent pattern (ß: 0.0029; 95% credible interval: 0.0009, 0.0048). CONCLUSIONS: The 15-week exercise training appeared to motivate young adults to pursue healthier dietary preferences and to regulate their food intake.

Dietary Energy-Density and Adiposity Markers Among a Cohort of Multi-ethnic Children.

BACKGROUND: Evidence suggests that the association between dietary energy density (DED) and body composition in children is different than in adults. The purpose of this study was to measure if DED differed by race/ethnicity and if DED was associated with adiposity markers in children. METHODOLOGY: Dietary intake and body composition were measured in a multi-ethnic sample of 307 children aged seven to 12 (39% European American, EA; 35% African American, AA; and 26% Hispanic American, HA). Dietary intake was measured by two 24-h recalls, and DED was calculated including and excluding energy-from beverages. Body composition was measured by dual-energy X-ray absorptiometry, and other measurements included height, waist circumference, and body mass index (BMI). Participants were evaluated by total sample and plausibility of reported energy intake. Analysis of variance, independence tests, and multiple regression models were performed. RESULTS: A total of 33.5% of the children in the sample had a BMI ≥ 85 percentile. Among plausible reporters, the mean DEDSF+EB (solid food + energy-containing beverages) was ~ 128 kcal/100 g and mean DEDSF (solid food only) was 211 kcal/100 g. Pairwise comparisons among children showed that the mean of DED was higher in AA children compared to EA and HA children (p < 0.005). Regression models showed significant association (p < 0.05) between adiposity markers and DEDSF in both the total and plausible samples. CONCLUSION: This study provides evidence of a significant difference of DED by race/ethnicity. Increased DED showed being a significant risk factor for adiposity among children. The associations were stronger when only plausible reporters were considered.

Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention.

Aims: Sleep-time blood pressure (BP) is a stronger risk factor for cardiovascular disease (CVD) events than awake and 24 h BP means, but the potential role of asleep BP as therapeutic target for diminishing CVD risk is uncertain. We investigated whether CVD risk reduction is most associated with progressive decrease of either office or ambulatory awake or asleep BP mean. Methods and results: We prospectively evaluated 18 078 individuals with baseline ambulatory BP ranging from normotension to hypertension. At inclusion and at scheduled visits (mainly annually) during follow-up, ambulatory BP was measured for 48 consecutive hours. During the 5.1-year median follow-up, 2311 individuals had events, including 1209 experiencing the primary outcome (composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke). The asleep systolic blood pressure (SBP) mean was the most significant BP-derived risk factor for the primary outcome [hazard ratio 1.29 (95% CI) 1.22-1.35 per SD elevation, P < 0.001], regardless of office [1.03 (0.97-1.09), P = 0.32], and awake SBP [1.02 (0.94-1.10), P = 0.68]. Most important, the progressive attenuation of asleep SBP was the most significant marker of event-free survival [0.75 (95% CI 0.69-0.82) per SD decrease, P < 0.001], regardless of changes in office [1.07 (0.97-1.17), P = 0.18], or awake SBP mean [0.96 (0.85-1.08), P = 0.47] during follow-up. Conclusion: Asleep SBP is the most significant BP-derived risk factor for CVD events. Furthermore, treatment-induced decrease of asleep, but not awake SBP, a novel hypertension therapeutic target requiring periodic patient evaluation by ambulatory monitoring, is associated with significantly lower risk for CVD morbidity and mortality.

Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study.

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients.

Hypertension: New perspective on its definition and clinical management by bedtime therapy substantially reduces cardiovascular disease risk.

Diagnosis of hypertension-elevated blood pressure (BP) associated with increased cardiovascular disease (CVD) risk-and its management for decades have been based primarily on single time-of-day office BP measurements (OBPM) assumed representative of systolic (SBP) and diastolic BP (DBP) during the entire 24-hours span. Around-the-clock ambulatory blood pressure monitoring (ABPM), however, reveals BP undergoes 24-hours patterning characterized in normotensives and uncomplicated hypertensives by striking morning-time rise, 2 daytime peaks-one ~2-3 hours after awakening and the other early evening, small midafternoon nadir and 10-20% decline (BP dipping) in the asleep BP mean relative to the wake-time BP mean. A growing number of outcome trials substantiate correlation between BP and target organ damage, vascular and other risks is greater for the ABPM-derived asleep BP mean, independent and stronger predictor of CVD risk, than daytime OBPM or ABPM-derived awake BP. Additionally, bedtime hypertension chronotherapy, that is, ingestion of ≥1 conventional hypertension medications at bedtime to achieve efficient attenuation of asleep BP, better reduces total CVD events by 61% and major events (CVD death, myocardial infarction, ischaemic and haemorrhagic stroke) by 67%-even in more vulnerable chronic kidney disease, diabetes and resistant hypertension patients-than customary on-awaking therapy that targets wake-time BP. Such findings of around-the-clock ABPM and bedtime hypertension outcome trials, consistently indicating greater importance of asleep BP than daytime OBPM or ambulatory awake BP, call for a new definition of true arterial hypertension plus modern approaches for its diagnosis and management.

SIG1459: A novel phytyl-cysteine derived TLR2 modulator with in vitro and clinical anti-acne activity.

Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll-like receptor-2 (TLR2), a key step in comedogenesis. Tetramethyl-hexadecenyl-cysteine-formylprolinate (SIG1459), a novel anti-acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 µmol\L), minimal bactericidal concentration (MBC = 16.1 µmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 µmol\L). To assess SIG1459's anti-inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL-1, Pam3CSK4) that induce pro-inflammatory cytokine IL-8 and IL-1α production. Results demonstrate SIG1459 inhibits TLR2-induced IL-8 release from TLR2/TLR2 (IC50  = 0.086 µmol\L), TLR2/6 (IC50  = 0.209 µmol\L) and IL-1α from TLR2/TLR2 (IC50  = 0.050 µmol\L). To assess the safety and in vivo anti-acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head-to-head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti-acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.

Advanced Dietary Patterns Analysis Using Sparse Latent Factor Models in Young Adults.

Background: Principal components analysis (PCA) has been the most widely used method for deriving dietary patterns to date. However, PCA requires arbitrary ad hoc decisions for selecting food variables in interpreting dietary patterns and does not easily accommodate covariates. Sparse latent factor models can be utilized to address these issues. Objective: The objective of this study was to compare Bayesian sparse latent factor models with PCA for identifying dietary patterns among young adults. Methods: Habitual food intake was estimated in 2730 sedentary young adults from the Training Interventions and Genetics of Exercise Response (TIGER) Study [aged 18-35 y; body mass index (BMI; in kg/m2): 26.5 ± 6.1] who exercised <30 min/wk during the previous 30 d without restricting caloric intake before study enrollment. A food-frequency questionnaire was used to generate the frequency intakes of 102 food items. Sparse latent factor modeling was applied to the standardized food intakes to derive dietary patterns, incorporating additional covariates (sex, race/ethnicity, and BMI). The identified dietary patterns via sparse latent factor modeling were compared with the PCA derived dietary patterns. Results: Seven dietary patterns were identified in both PCA and sparse latent factor analysis. In contrast to PCA, the sparse latent factor analysis allowed the covariate information to be jointly accounted for in the estimation of dietary patterns in the model and offered probabilistic criteria to determine the foods relevant to each dietary pattern. The derived patterns from both methods generally described common dietary behaviors. Dietary patterns 1-4 had similar food subsets using both statistical approaches, but PCA had smaller sets of foods with more cross-loading elements between the 2 factors. Overall, the sparse latent factor analysis produced more interpretable dietary patterns, with fewer of the food items excluded from all patterns. Conclusion: Sparse latent factor models can be useful in future studies of dietary patterns by reducing the intrinsic arbitrariness involving the choice of food variables in interpreting dietary patterns and incorporating covariates in the assessment of dietary patterns.

Dissection of hepatic versus extra-hepatic insulin clearance: Ethnic differences in childhood.

AIMS: Adult African American (AA) women have one third of the hepatic insulin clearance of European American (EA) women. This lower hepatic (but not extra-hepatic) insulin clearance in AA individuals is associated with higher plasma insulin concentrations. This study aims to understand whether impairment of hepatic insulin clearance is seen in AA individuals since childhood, possibly suggesting that genetic/epigenetic factors, rather than lifestyle only, contribute to this. MATERIALS AND METHODS: A total of 203 children (105 male and 98 female (55 AA, 88 EA and 60 Hispanic American [HA]; ages, 7-13 years; mean BMI, 19 kg/m2 )) underwent the frequently applied intravenous glucose tolerance test (FSIGT) at the University of Alabama at Birmingham, General Clinical Research Center and Department of Nutrition Sciences. Glucose, insulin and C-peptide levels were measured and hepatic and extra-hepatic insulin clearances were calculated using mathematical modelling. RESULTS: Fractional hepatic insulin extraction (FEL ) was lower in AA than in EA children (mean (SD), 19% (20%) vs 33% (20%); P = 0.0007). Adjusting for age, Tanner stage and body fat, FEL was lower in AA than in EA children (P = 0.0012), and there was a slight sex-related difference (FEL, 24% (10%) vs 29% (10%) in boys vs girls; P = 0.04). Extra-hepatic insulin clearance did not differ with ethnicity (27 (12), 21 (12) and 24 (28) mL/kg/min for AA, HA and EA children, respectively; P > 0.05). CONCLUSIONS: At a young age, FEL is lower in AAs than in EAs, which does not rule out genetic/epigenetic factors. These differences are related to hyperinsulinaemia and, over time, could possibly contribute to metabolic disorders in AA individuals.

Sleep-Time Ambulatory BP Is an Independent Prognostic Marker of CKD.

The prognostic value of clinic and ambulatory BP in predicting incident CKD and whether CKD risk reduction associates with progressive treatment-induced decrease of clinic, awake, or asleep BP are unknown. We prospectively evaluated 2763 individuals without CKD, 1343 men and 1420 women (mean±SD age: 51.5±14.3 years old), with baseline ambulatory BP ranging from normotension to hypertension. On recruitment and annually thereafter (more frequently if hypertension treatment was adjusted on the basis of ambulatory BP), we simultaneously monitored BP and physical activity (wrist actigraphy) for 48 hours to accurately derive individualized mean awake and asleep BP. During a median 5.9-year follow-up, 404 participants developed CKD. Mean asleep systolic BP was the most significant predictor of CKD in a Cox proportional hazard model adjusted for age, diabetes, serum creatinine concentration, urinary albumin concentration, previous cardiovascular event, and hypertension treatment time (on awakening versus at bedtime; per 1-SD elevation: hazard ratio, 1.44; 95% confidence interval, 1.31 to 1.56; P<0.001). The predictive values of mean clinic BP and mean awake or 48-hour ambulatory BP was not significant when corrected by mean asleep BP. Analyses of BP changes during follow-up revealed 27% reduction in the risk of CKD per 1-SD decrease in mean asleep systolic BP, independent of changes in mean clinic BP or awake ambulatory BP. In conclusion, sleep-time BP is a highly significant independent prognostic marker for CKD. Furthermore, progressive treatment-induced decrease of asleep BP, a potential therapeutic target requiring ambulatory BP evaluation, might be a significant method for reducing CKD risk.