Fasted Sprint Interval Training Results in Some Beneficial Skeletal Muscle Metabolic, but Similar Metabolomic and Performance Adaptations Compared With Carbohydrate-Fed Training in Recreationally Active Male.

Endurance training in fasted conditions (FAST) induces favorable skeletal muscle metabolic adaptations compared with carbohydrate feeding (CHO), manifesting in improved exercise performance over time. Sprint interval training (SIT) is a potent metabolic stimulus, however nutritional strategies to optimize adaptations to SIT are poorly characterized. Here we investigated the efficacy of FAST versus CHO SIT (4-6 × 30-s Wingate sprints interspersed with 4-min rest) on muscle metabolic, serum metabolome and exercise performance adaptations in a double-blind parallel group design in recreationally active males. Following acute SIT, we observed exercise-induced increases in pan-acetylation and several genes associated with mitochondrial biogenesis, fatty acid oxidation, and NAD+-biosynthesis, along with favorable regulation of PDK4 (p = .004), NAMPT (p = .0013), and NNMT (p = .001) in FAST. Following 3 weeks of SIT, NRF2 (p = .029) was favorably regulated in FAST, with augmented pan-acetylation in CHO but not FAST (p = .033). SIT induced increases in maximal citrate synthase activity were evident with no effect of nutrition, while 3-hydroxyacyl-CoA dehydrogenase activity did not change. Despite no difference in the overall serum metabolome, training-induced changes in C3:1 (p = .013) and C4:1 (p = .010) which increased in FAST, and C16:1 (p = .046) and glutamine (p = .021) which increased in CHO, were different between groups. Training-induced increases in anaerobic (p = .898) and aerobic power (p = .249) were not influenced by nutrition. These findings suggest some beneficial muscle metabolic adaptations are evident in FAST versus CHO SIT following acute exercise and 3 weeks of SIT. However, this stimulus did not manifest in differential exercise performance adaptations.

Divergent serum metabolomic, skeletal muscle signaling, transcriptomic, and performance adaptations to fasted versus whey protein-fed sprint interval training.

Sprint interval training (SIT) is a time-efficient alternative to endurance exercise, conferring beneficial skeletal muscle metabolic adaptations. Current literature has investigated the nutritional regulation of acute and chronic exercise-induced metabolic adaptations in muscle following endurance exercise, principally comparing the impact of training in fasted and carbohydrate-fed (CHO) conditions. Alternative strategies such as exercising in low CHO, protein-fed conditions remain poorly characterized, specifically pertaining to adaptations associated with SIT. Thus, this study aimed to compare the metabolic and performance adaptations to acute and short-term SIT in the fasted state with preexercise hydrolyzed (WPH) or concentrated (WPC) whey protein supplementation. In healthy males, preexercise protein ingestion did not alter exercise-induced increases in PGC-1α, PDK4, SIRT1, and PPAR-δ mRNA expression following acute SIT. However, supplementation of WPH beneficially altered acute exercise-induced CD36 mRNA expression. Preexercise protein ingestion attenuated acute exercise-induced increases in muscle pan-acetylation and PARP1 protein content compared with fasted SIT. Acute serum metabolomic differences confirmed greater preexercise amino acid delivery in protein-fed compared with fasted conditions. Following 3 wk of SIT, training-induced increases in mitochondrial enzymatic activity and exercise performance were similar across nutritional groups. Interestingly, resting muscle acetylation status was downregulated in WPH conditions following training. Such findings suggest preexercise WPC and WPH ingestion positively influences metabolic adaptations to SIT compared with fasted training, resulting in either similar or enhanced performance adaptations. Future studies investigating nutritional modulation of metabolic adaptations to exercise are warranted to build upon these novel findings.NEW & NOTEWORTHY These are the first data to show the influence of preexercise protein on serum and skeletal muscle metabolic adaptations to acute and short-term sprint interval training (SIT). Preexercise whey protein concentrate (WPC) or hydrolysate (WPH) feeding acutely affected the serum metabolome, which differentially influenced acute and chronic changes in mitochondrial gene expression, intracellular signaling (acetylation and PARylation) resulting in either similar or enhanced performance outcomes when compared with fasted training.

Development of a multiplex assay to determine the expression of mitochondrial genes in human skeletal muscle.

NEW FINDINGS: What is the central question of this study? Can a custom-designed multiplex gene expression assay be used to quantify expression levels of a targeted group of mitochondrial genes in human skeletal muscle? What is the main finding and its importance? A custom-designed GeXP multiplex assay was developed, and the ability to accurately quantify expression of a targeted set of mitochondrial genes in human skeletal muscle was demonstrated. It holds distinct methodological and practical advantages over other commonly used quantification methods. ABSTRACT: Skeletal muscle is an important endocrine tissue demonstrating plasticity in response to external stimuli, including exercise and nutrition. Mitochondrial biogenesis is a common hallmark of adaptations to aerobic exercise training. Furthermore, altered expression of several genes implicated in the regulation of mitochondrial biogenesis, substrate oxidation and nicotinamide adenine dinucleotide (NAD+ ) biosynthesis following acute exercise underpins longer-term muscle metabolic adaptations. Gene expression is typically measured using real-time quantitative PCR platforms. However, interest has developed in the design of multiplex gene expression assays (GeXP) using the GenomeLab GeXP™ genetic analysis system, which can simultaneously quantify gene expression of multiple targets, holding distinct advantages in terms of throughput, limiting technical error, cost effectiveness, and quantifying gene co-expression. This study describes the development of a custom-designed GeXP assay incorporating the measurement of proposed regulators of mitochondrial biogenesis, substrate oxidation, and NAD+ biosynthetic capacity in human skeletal muscle and characterises the resting gene expression (overnight fasted and non-exercised) signature within a group of young, healthy, recreationally active males. The design of GeXP-based assays provides the capacity to more accurately characterise the regulation of a targeted group of genes with specific regulatory functions, a potentially advantageous development for future investigations of the regulation of muscle metabolism by exercise and/or nutrition.

Inter-Individual Variation in Postprandial Glycemic Responses in Women Co-Ingesting Green Leafy Vegetables with a Carbohydrate Meal: Interactions with the Sirtuin System.

SCOPE: Green leafy vegetables (GLV) may improve postprandial glycemic responses (PGR) and metabolic health. However, inter-individual variations (IIV) preclude conclusive evidence. Sirtuin system is emerging as a key player in blood glucose control. This study investigates IIV in PGR in women co-ingesting GLV with a carbohydrate meal and interactions with the sirtuin system. METHODS AND RESULTS: Volunteers (n = 31 women) consume rice, rice with bok choy, or spinach (75g available carbohydrate) on separate occasions. Postprandial glucose, insulin, adropin, and lipid levels are measured. Anthropometric measurements and sex hormones are measured. GeXP assay measures whole blood postprandial gene expression profiles of 25 markers involved in sirtuin signaling. GLV consumption has no significant effect on PGR, which shows high variation. PGR correlated with age, but no other consistent associations are observed. Sirtuin gene expression profiles reveal distinct stratified subgroups associated with PGR, lipid, insulin, fat mass, waist/hip circumferences, and adropin levels. CONCLUSION: PGR to co-ingesting GLV with a carbohydrate meal are highly variable in this cohort and fail to reveal a significant reduction in PGR. Variable responses are largely independent of menopausal status and meal consumed. However, lower expression of sirtuin gene targets is associated with higher PGR and with markers linked to health status.

Limited Systemic Exposure with Topical Glycopyrronium Tosylate in Primary Axillary Hyperhidrosis.

BACKGROUND: Glycopyrronium tosylate (GT; Qbrexza® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years. OBJECTIVE: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies. METHODS: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies. RESULTS: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures. CONCLUSIONS: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).

Long-term efficacy and safety of topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Post hoc pediatric subgroup analysis from a 44-week open-label extension study.

BACKGROUND/OBJECTIVES: Glycopyrronium tosylate (GT) cloth, 2.4% is a topical anticholinergic approved in the United States for primary axillary hyperhidrosis in patients ≥9 years. This post hoc analysis evaluated long-term response (efficacy and safety) in pediatric patients (≥9 to ≤16 years) to GT in the 44-week, open-label extension (NCT02553798) of two, phase 3, double-blind, vehicle-controlled, 4-week trials (NCT02530281, NCT02530294). METHODS: In the double-blind trials, patients ≥9 years with primary axillary hyperhidrosis were randomized 2:1 to once-daily GT:vehicle. Those who completed the study could receive open-label GT for up to an additional 44 weeks. Safety assessments included treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs). Descriptive efficacy assessments included gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale response (≥2-grade improvement), and Children's Dermatology Life Quality Index. RESULTS: Of 43 pediatric patients completing either double-blind trial, 38 (88.4%) entered the open-label extension (age, years: 9 [n = 1], 12 [n = 2], 13 [n = 7], 14 and 15 [n = 9 each], 16 [n = 10]). The safety profile observed was similar to the double-blind trials. Most TEAEs (>95%) were mild/moderate, related to anticholinergic activity, and infrequently led to discontinuation (n = 1/38 [2.6%]). No pediatric patients experienced a serious TEAE. Most anticholinergic TEAEs did not require a dose modification and resolved within 7 days. Approximately, one-third of patients (n = 13/38 [34.2%]) had LSRs; most were mild/moderate in severity. Improvements in efficacy measures were maintained from the double-blind trials. CONCLUSIONS: Long-term, once-daily GT for up to 48 weeks (4-week double-blind plus 44 week open label) provides a noninvasive, well-tolerated treatment option for pediatric patients with primary axillary hyperhidrosis.

Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis: A Phase 2b Randomized Clinical Trial.

Importance: Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology. Objective: To evaluate the efficacy and safety of lebrikizumab, a novel, high-affinity, monoclonal antibody targeting IL-13 that selectively prevents formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling complex, in adults with moderate to severe AD. Design, Setting, and Participants: A phase 2b, double-blind, placebo-controlled, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks was conducted from January 23, 2018, to May 23, 2019, at 57 US centers. Participants were adults 18 years or older with moderate to severe AD. Interventions: Patients were randomized 2:3:3:3 to placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: 125 mg every 4 weeks (250-mg loading dose [LD]), 250 mg every 4 weeks (500-mg LD), or 250 mg every 2 weeks (500-mg LD at baseline and week 2). Main Outcomes and Measures: The primary end point was percentage change in the Eczema Area and Severity Index (EASI) (baseline to week 16). Secondary end points for week 16 included proportion of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA 0/1); EASI improvement of at least 50%, 75%, or 90% from baseline; percentage change in the pruritus numeric rating scale (NRS) score; and pruritus NRS score improvement of at least 4 points. Safety assessments included treatment-emergent adverse events. Results: A total of 280 patients (mean [SD] age, 39.3 [17.5] years; 166 [59.3%] female) were randomized to placebo (n = 52) or to lebrikizumab at doses of 125 mg every 4 weeks (n = 73), 250 mg every 4 weeks (n = 80), or 250 mg every 2 weeks (n = 75). Compared with placebo (EASI least squares mean [SD] percentage change, -41.1% [56.5%]), lebrikizumab groups showed dose-dependent, statistically significant improvement in the primary end point vs placebo at week 16: 125 mg every 4 weeks (-62.3% [37.3%], P = .02), 250 mg every 4 weeks (-69.2% [38.3%], P = .002), and 250 mg every 2 weeks (-72.1% [37.2%], P < .001). Differences vs placebo-treated patients (2 of 44 [4.5%]) in pruritus NRS improvement of at least 4 points were seen as early as day 2 in the high-dose lebrikizumab group (9 of 59 [15.3%]). Treatment-emergent adverse events were reported in 24 of 52 placebo patients (46.2%) and in lebrikizumab patients as follows: 42 of 73 (57.5%) for 125 mg every 4 weeks, 39 of 80 (48.8%) for 250 mg every 4 weeks, and 46 of 75 (61.3%) for 250 mg every 2 weeks; most were mild to moderate and did not lead to discontinuation. Low rates of injection-site reactions (1 of 52 [1.9%] in the placebo group vs 13 of 228 [5.7%] in all lebrikizumab groups), herpesvirus infections (2 [3.8%] vs 8 [3.5%]), and conjunctivitis (0% vs 6 [2.6%]) were reported. Conclusions and Relevance: During 16 weeks of treatment, lebrikizumab provided rapid, dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AD and demonstrated a favorable safety profile. These data support the central role of IL-13 in AD pathophysiology. If these findings replicate in phase 3 studies, lebrikizumab may meaningfully advance the standard of care for moderate to severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03443024.

Challenges of the heterogeneous nutrition response: interpreting the group mean.

Extensive research demonstrates unequivocally that nutrition plays a fundamental role in maintaining health and preventing disease. In parallel nutrition research provides evidence that the risks and benefits of diet and lifestyle choices do not affect people equally, as people are inherently variable in their responses to nutrition and associated interventions to maintain health and prevent disease. To simplify the inherent complexity of human subjects and their nutrition, with the aim of managing expectations for dietary guidance required to ensure healthy populations and individuals, nutrition researchers often seek to group individuals based on commonly used criteria. This strategy relies on demonstrating meaningful conclusions based on comparison of group mean responses of assigned groups. Such studies are often confounded by the heterogeneous nutrition response. Commonly used criteria applied in grouping study populations and individuals to identify mechanisms and determinants of responses to nutrition often contribute to the problem of interpreting the results of group comparisons. Challenges of interpreting the group mean using diverse populations will be discussed with respect to studies in human subjects, in vivo and in vitro model systems. Future advances in nutrition research to tackle inter-individual variation require a coordinated approach from funders, learned societies, nutrition scientists, publishers and reviewers of the scientific literature. This will be essential to develop and implement improved study design, data recording, analysis and reporting to facilitate more insightful interpretation of the group mean with respect to population diversity and the heterogeneous nutrition response.

Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4.

A high-fat diet induces hypothalamic inflammation in rodents which, in turn, contributes to the development of obesity by eliciting both insulin and leptin resistance. However, the mechanism by which long-chain saturated fatty acids trigger inflammation is still contentious. To elucidate this mechanism, the effect of fatty acids on the expression of the pro-inflammatory cytokines IL-6 and TNFα was investigated in the mHypoE-N42 hypothalamic cell line (N42). N42 cells were treated with lauric acid (LA) and palmitic acid (PA). PA challenge was carried out in the presence of either a TLR4 inhibitor, a ceramide synthesis inhibitor (L-cycloserine), oleic acid (OA) or eicosapentaenoic acid (EPA). Intracellular ceramide accumulation was quantified using LC-ESI-MS/MS. PA but not LA upregulated IL-6 and TNFα. L-cycloserine, OA and EPA all counteracted PA-induced intracellular ceramide accumulation leading to a downregulation of IL-6 and TNFα. However, a TLR4 inhibitor failed to inhibit PA-induced upregulation of pro-inflammatory cytokines.In conclusion, PA induced the expression of IL-6 and TNFα in N42 neuronal cells independently of TLR4 but, partially, via ceramide synthesis with OA and EPA being anti-inflammatory by decreasing PA-induced intracellular ceramide build-up. Thus, ceramide accumulation represents one on the mechanisms by which PA induces inflammation in neurons.

A 44-Week Open-Label Study Evaluating Safety and Efficacy of Topical Glycopyrronium Tosylate in Patients with Primary Axillary Hyperhidrosis.

BACKGROUND: Glycopyrronium tosylate is a topical anticholinergic approved in the USA for primary axillary hyperhidrosis in patients aged ≥ 9 years (Qbrexza™ [glycopyrronium] cloth, 2.4%). OBJECTIVE: This 44-week open-label extension study assessed glycopyrronium tosylate safety and descriptive efficacy in patients completing one of two, phase III, double-blind, vehicle-controlled, 4-week trials (NCT02530281; NCT02530294). METHODS: Patients aged ≥ 9 years with primary axillary hyperhidrosis were randomized 2:1 (glycopyrronium tosylate: vehicle, once daily) in the double-blind trials. Completers could receive open-label glycopyrronium tosylate for up to an additional 44 weeks. Treatment-emergent adverse events and local skin reactions were assessed. Descriptive efficacy assessments were gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale responder rate (≥ 2 grade improvement), and Dermatology Life Quality Index/children's Dermatology Life Quality Index. RESULTS: Of 651 patients completing the double-blind trials, 564 (86.6%) entered the open-label extension; 550 were analyzed. Most patients experiencing treatment-emergent adverse events had mild or moderate events (> 90%). Discontinuation because of treatment-emergent adverse events remained low and relatively stable, with a cumulative rate of 8.0% (44/550) over 44 weeks. Common treatment-emergent adverse events (> 5%) were dry mouth (16.9%), vision blurred (6.7%), application-site pain (6.4%), nasopharyngitis (5.8%), and mydriasis (5.3%). Most patients (67.5%) had no local skin reactions; those occurring were predominantly mild/moderate. Glycopyrronium tosylate efficacy was maintained throughout the trial; at week 44, the Hyperhidrosis Disease Severity Scale responder rate was 63.2%, and improvements from baseline (double blind) in sweat production were - 71.3% and 8.7 ± 6.2/6.2 ± 4.9 for Dermatology Life Quality Index/children's Dermatology Life Quality Index. CONCLUSIONS: Daily long-term application of glycopyrronium tosylate for up to 48 weeks (double blind plus open label) was generally well tolerated and efficacy was maintained. No new safety signals emerged. TRIAL REGISTRY: Clinicaltrials.gov NCT02553798.

Topical Glycopyrronium Tosylate for the Treatment of Primary Axillary Hyperhidrosis: Patient-Reported Outcomes from the ATMOS-1 and ATMOS-2 Phase III Randomized Controlled Trials.

BACKGROUND: Glycopyrronium tosylate (GT) is a topical anticholinergic approved in the USA for primary axillary hyperhidrosis in patients aged ≥ 9 years. GT was evaluated for primary axillary hyperhidrosis in replicate, randomized, double-blind, vehicle-controlled, phase III trials. GT reduced sweating severity and production versus vehicle and was generally well tolerated. OBJECTIVE: Our objective was to evaluate patient-reported outcomes (PROs) from these trials. METHODS: Patients aged ≥ 9 years with primary axillary hyperhidrosis ≥ 6 months, gravimetrically measured sweat production ≥ 50 mg/5 min in each axilla, Axillary Sweating Daily Diary (ASDD) Item 2 severity score ≥ 4, and Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 3 were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. The 4-item ASDD, 6 Weekly Impact (WI) items, Patient Global Impression of Change (PGIC), HDSS, and Dermatology Life Quality Index (DLQI) were utilized. RESULTS: In the pooled population, 463 patients were randomized to GT and 234 to vehicle; 426 (92.0%) and 225 (96.2%) completed the trials. At baseline, most patients considered their axillary sweating to be at least moderate in severity, impact, and bothersomeness (ASDD items 2, 3, and 4, respectively). Improvement was substantially greater for GT than for vehicle at every study week, and, at week 4, ASDD scores improved from baseline by 62.6 versus 34.0% (severity), 65.5 versus 40.3% (impact), and 65.4 versus 39.0% (bothersomeness). Improvements favoring GT versus vehicle also occurred for WI items, PGIC, HDSS, and DLQI. CONCLUSIONS: PRO results demonstrated that GT reduced the disease burden of primary axillary hyperhidrosis. TRIAL REGISTRATION: Clinicaltrials.gov; ATMOS-1 (NCT02530281), ATMOS-2 (NCT02530294).

Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials.

BACKGROUND: Glycopyrronium tosylate (GT) is a topical anticholinergic developed for once-daily treatment of primary axillary hyperhidrosis. OBJECTIVE: Assess the efficacy and safety of GT for primary axillary hyperhidrosis. METHODS: ATMOS-1 and ATMOS-2 were replicate randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Patients were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. Coprimary endpoints were responder rate (≥4-point improvement from baseline) on item 2 (severity of sweating) of the Axillary Sweating Daily Diary (ASDD), which is a newly developed patient-reported outcome measure, and absolute change from baseline in axillary gravimetric sweat production at week 4. Safety evaluation included treatment-emergent adverse events. RESULTS: Pooled data, which are consistent with the individual trial results, show that significantly more GT-treated patients achieved an ASDD-Item 2 response than did those treated with vehicle (59.5% vs 27.6%), and they had reduced sweat production from baseline (-107.6 mg/5 min vs -92.1 mg/5 min) at week 4 (P < .001 for both coprimary end points). Most treatment-emergent adverse events were mild or moderate and infrequently led to discontinuation. LIMITATIONS: Short trial duration and inherent challenges in gravimetrically assessing sweat production. CONCLUSIONS: GT applied topically on a daily basis over 4 weeks reduced the severity of sweating as measured by ASDD-Item 2, reduced sweat production as measured gravimetrically, and was generally well tolerated in patients with primary axillary hyperhidrosis.

Glycopyrronium tosylate in pediatric primary axillary hyperhidrosis: Post hoc analysis of efficacy and safety findings by age from two phase three randomized controlled trials.

OBJECTIVES: Hyperhidrosis in pediatric patients has been understudied. Post hoc analyses of two phase 3 randomized, vehicle-controlled, 4-week trials (ATMOS-1 [NCT02530281] and ATMOS-2 [NCT02530294]) were performed to assess efficacy and safety of topical anticholinergic glycopyrronium tosylate (GT) in pediatric patients. METHODS: Patients had primary axillary hyperhidrosis ≥ 6 months, average Axillary Sweating Daily Diary (ASDD/ASDD-Children [ASDD-C]) Item 2 (sweating severity) score ≥ 4, sweat production ≥ 50 mg/5 min (each axilla), and Hyperhidrosis Disease Severity Scale (HDSS) ≥ 3. Coprimary end points were ≥ 4-point improvement on ASDD/ASDD-C Item 2 (a validated patient-reported outcome) and change in gravimetrically measured sweat production at Week 4. Efficacy and safety data are shown through Week 4 for the pediatric (≥ 9 to ≤ 16 years) vs older (> 16 years) subgroups. RESULTS: Six hundred and ninety-seven patients were randomized in ATMOS-1/ATMOS-2 (GT, N = 463; vehicle, N = 234); 44 were ≥ 9 to ≤ 16 years (GT, n = 25; vehicle, n = 19). Baseline disease characteristics were generally similar across subgroups. GT-treated pediatric vs older patients had comparable improvements in ASDD/ASDD-C Item 2 (sweating severity) responder rate, HDSS responder rate (≥ 2-grade improvement]), sweat production, and quality of life (mean change from Baseline in Dermatology Life Quality Index [DLQI]/children's DLQI), with greater improvement vs vehicle. Treatment-emergent adverse events were similar between subgroups, and most were mild, transient, and infrequently led to discontinuation. CONCLUSIONS: Topical, once-daily GT improved disease severity (ASDD/ASDD-C, HDSS), sweat production, and quality of life (DLQI), with similar findings in children, adults, and the pooled population. GT was well tolerated, and treatment-emergent adverse events were qualitatively similar between subgroups and consistent with other anticholinergics.

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice.

BACKGROUND: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. RESULTS: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1 -/- ) mice. CONCLUSIONS: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.

Dietary fibers inhibit obesity in mice, but host responses in the cecum and liver appear unrelated to fiber-specific changes in cecal bacterial taxonomic composition.

Dietary fibers (DF) can prevent obesity in rodents fed a high-fat diet (HFD). Their mode of action is not fully elucidated, but the gut microbiota have been implicated. This study aimed to identify the effects of seven dietary fibers (barley beta-glucan, apple pectin, inulin, inulin acetate ester, inulin propionate ester, inulin butyrate ester or a combination of inulin propionate ester and inulin butyrate ester) effective in preventing diet-induced obesity and links to differences in cecal bacteria and host gene expression. Mice (n = 12) were fed either a low-fat diet (LFD), HFD or a HFD supplemented with the DFs, barley beta-glucan, apple pectin, inulin, inulin acetate ester, inulin propionate ester, inulin butyrate ester or a combination of inulin propionate ester and inulin butyrate ester for 8 weeks. Cecal bacteria were determined by Illumina MiSeq sequencing of 16S rRNA gene amplicons. Host responses, body composition, metabolic markers and gene transcription (cecum and liver) were assessed post intervention. HFD mice showed increased adiposity, while all of the DFs prevented weight gain. DF specific differences in cecal bacteria were observed. Results indicate that diverse DFs prevent weight gain on a HFD, despite giving rise to different cecal bacteria profiles. Conversely, common host responses to dietary fiber observed are predicted to be important in improving barrier function and genome stability in the gut, maintaining energy homeostasis and reducing HFD induced inflammatory responses in the liver.

Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2).

BACKGROUND: Certolizumab pegol, the only Fc-free, PEGylated anti-tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk-benefit balance in phase 2 studies in adults with moderate-to-severe chronic plaque psoriasis. OBJECTIVE: Assess certolizumab efficacy and safety versus placebo in phase 3 studies. METHODS: Patients with moderate-to-severe chronic plaque psoriasis were randomized 2:2:1 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks. At week 16, certolizumab-treated patients achieving a 50% reduction in Psoriasis Area and Severity Index continued treatment through week 48. Coprimary endpoints were week 16 responder rates, defined as a 75% reduction in Psoriasis Area and Severity Index and Physician's Global Assessment 0/1 (clear/almost clear) and ≥2-point improvement. Safety was assessed by treatment-emergent adverse events. RESULTS: Week-16 endpoints were significantly greater for both doses of certolizumab versus placebo, and the responses were maintained through week 48. For most measures, improvement was numerically greater for certolizumab 400 mg. No unexpected safety signals were identified. LIMITATION: There was no active comparator. CONCLUSION: Treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate-to-severe psoriasis. The 400-mg dose could provide additional clinical benefit. The safety profile was consistent with the therapeutic class.

Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT).

BACKGROUND: Phase 2 psoriasis studies with the Fc-free, PEGylated, anti-tumor necrosis factor biologic certolizumab pegol demonstrated meaningful clinical activity. OBJECTIVE: Assess safety and efficacy of certolizumab in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Patients were randomized 3:3:1:3 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks for 16 weeks or etanercept 50 mg twice weekly for 12 weeks. Certolizumab-treated patients achieving a ≥75% reduction in Psoriasis Area and Severity Index (PASI) at week 16 from baseline PASI were rerandomized to certolizumab or placebo for 32 weeks. The primary endpoint was responder rate (≥75% reduction in PASI from baseline PASI) versus placebo (primary analysis) and etanercept (secondary analysis) at week 12; secondary endpoints included responder rates on various measures versus placebo at weeks 12, 16, and 48. Safety was assessed by treatment-emergent adverse events. RESULTS: All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. Certolizumab 400 mg was superior to and 200 mg was noninferior to etanercept. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. LIMITATIONS: Etanercept was administered by unblinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor. CONCLUSION: Both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. No new safety signals were observed.

Specific substrate-driven changes in human faecal microbiota composition contrast with functional redundancy in short-chain fatty acid production.

The diet provides carbohydrates that are non-digestible in the upper gut and are major carbon and energy sources for the microbial community in the lower intestine, supporting a complex metabolic network. Fermentation produces the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, which have health-promoting effects for the human host. Here we investigated microbial community changes and SCFA production during in vitro batch incubations of 15 different non-digestible carbohydrates, at two initial pH values with faecal microbiota from three different human donors. To investigate temporal stability and reproducibility, a further experiment was performed 1 year later with four of the carbohydrates. The lower pH (5.5) led to higher butyrate and the higher pH (6.5) to more propionate production. The strongest propionigenic effect was found with rhamnose, followed by galactomannans, whereas fructans and several α- and ß-glucans led to higher butyrate production. 16S ribosomal RNA gene-based quantitative PCR analysis of 22 different microbial groups together with 454 sequencing revealed significant stimulation of specific bacteria in response to particular carbohydrates. Some changes were ascribed to metabolite cross-feeding, for example, utilisation by Eubacterium hallii of 1,2-propanediol produced from fermentation of rhamnose by Blautia spp. Despite marked inter-individual differences in microbiota composition, SCFA production was surprisingly reproducible for different carbohydrates, indicating a level of functional redundancy. Interestingly, butyrate formation was influenced not only by the overall % butyrate-producing bacteria in the community but also by the initial pH, consistent with a pH-dependent shift in the stoichiometry of butyrate production.

Inter-individual responses to sprint interval training, a pilot study investigating interactions with the sirtuin system.

Sprint interval training (SIT) is reported to improve blood glucose control and may be a useful public health tool. The sirtuins and associated genes are emerging as key players in blood glucose control. This study investigated the interplay between the sirtuin/NAD system and individual variation in insulin sensitivity responses after SIT in young healthy individuals. Before and after 4 weeks of SIT, body mass and fat percentage were measured and oral glucose tolerance tests performed in 20 young healthy participants (7 females). Blood gene expression profiles (all 7 mammalian sirtuin genes and 15 enzymes involved in conversion of tryptophan, bioavailable vitamin B3, and metabolic precursors to NAD). NAD/NADP was measured in whole blood. Significant reductions in body weight and body fat post-SIT were associated with altered lipid profiles, NAD/NADP, and regulation of components of the sirtuin/NAD system (NAMPT, NMNAT1, CD38, and ABCA1). Variable improvements in measured metabolic health parameters were evident and attributed to different responses in males and females, together with marked inter-individual variation in responses of the sirtuin/NAD system to SIT.

Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study.

BACKGROUND: Olumacostat glasaretil (OG) inhibits acetyl-coenzyme A carboxylase, the enzyme responsible for the first, rate-limiting step in de novo fatty acid synthesis. OG inhibited in vitro human sebocyte lipid production and reduced in vivo sebaceous gland size in hamster ears. OBJECTIVES: Safety and efficacy of OG 7.5% gel were evaluated in patients with moderate to severe facial acne vulgaris. METHODS: Patients were randomized (1:1) to twice-daily application of OG or vehicle for 12 weeks. Efficacy was measured through changes in lesion counts and improvement in acne severity scores. RESULTS: A total of 108 patients received OG (n = 53) or vehicle (n = 55); these groups had mean baseline counts of 29.7 and 28.6 inflammatory and 40.9 and 38.8 noninflammatory lesions, respectively. At week 12, OG treatment showed greater reductions from baseline in inflammatory lesions (-63.9% vs -45.9%; P = .0006) and noninflammatory lesions (-48.1% vs -28.8%; P = .0025), and more patients with greater than or equal to 2-grade improvement in investigator global assessment score (24.5% vs 7.3%; P = .0070) than vehicle. Application-site adverse events (typically mild or moderate intensity) were more common with OG. LIMITATIONS: Larger trials are needed to optimize OG dosing and confirm the current results. CONCLUSION: OG was well tolerated and showed evidence of efficacy, suggesting further development is warranted.