Vitamin E supplementation prevents obesogenic diet-induced developmental abnormalities in SR-B1 deficient embryos.

Introduction: Genetic and environmental factors influence the risk of neural tube defects (NTD), congenital malformations characterized by abnormal brain and spine formation. Mouse embryos deficient in Scavenger Receptor Class B Type 1 (SR-B1), which is involved in the bidirectional transfer of lipids between lipoproteins and cells, exhibit a high prevalence of exencephaly, preventable by maternal vitamin E supplementation. SR-B1 knock-out (KO) embryos are severely deficient in vitamin E and show elevated reactive oxygen species levels during neurulation. Methods: We fed SR-B1 heterozygous female mice a high-fat/high-sugar (HFHS) diet and evaluated the vitamin E and oxidative status in dams and embryos from heterozygous intercrosses. We also determined the incidence of NTD. Results and discussion: HFHS-fed SR-B1 HET females exhibited altered glucose metabolism and excess circulating lipids, along with a higher incidence of embryos with developmental delay and NTD. Vitamin E supplementation partially mitigated HFHS-induced maternal metabolic abnormalities and completely prevented embryonic malformations, likely through indirect mechanisms involving the reduction of oxidative stress and improved lipid handling by the parietal yolk sac.

Time in range and mean glucose cut-off points for reduction of fetal outcomes in pregnant women with type 1 diabetes using automated insulin delivery systems.

AIM: In pregnant women with Type 1 Diabetes (T1D), achieving a lower recommended time in range (TIRp,63-140 mg/dl) could have an impact on fetal outcomes. To determine the TIRp and mean glucose cut-off point associated with better fetal outcomes in pregnant women using automated insulin delivery (AID) systems. METHODS: A prospective cohort of pregnant women with T1D, using AID systems and followed-up in Latin America was analyzed. Optimal TIRp and mean glucose cut-off points for predicting large for gestational age (LGA) were determined using the Liu method. Fetal outcomes were evaluated for the identified cut-off point and the one recommended by guidelines (TIRp > 70 %). RESULTS: Sixty-two patients were included (mean age 31.9 ±â€¯5.9 years, HbA1c 7.57 %±1.29 %, TIRp 59.8 %±14.6 %). 27.5 % on advanced hybrid closed loop systems (AHCL). LGA (50 vs 17.9 %,p = 0.010) and hyperbilirubinemia (45 % vs 11.8 %,p = 0.016) were more common in patients with TIRp < 59.1 %. Optimal cut-off of TIRp in the second trimester for predicting LGA was < 59.1 % (sensitivity 75 %, specificity 61 %) with an AUC of 0.68(CI 0.48-0.88). Optimal cut-off for mean glucose was 133 mg/dL (sensitivity 69 %, specificity 70 %) with an AUC of 0.70(CI 0.51-0.88) in the same trimester. Better metabolic control during the third trimester was seen in the AHCL users compared to other devices. CONCLUSIONS: TIRp > 59.1 % and mean glucose < 133 mg/dl in the second trimester, is associated with lower fetal outcomes of large for gestational age. One of the strategies that would improve TIRp is the early use of AHCL systems. Further studies are needed before a strong recommendation can be made.

The Design of Novel 3D-Printed, Moulded, and Oral Viscous Budesonide Formulations for Paediatrics: A Comparative Evaluation of Their Mucoadhesive Properties.

BACKGROUND/OBJECTIVES: Paediatric eosinophilic oesophagitis (EoE) treatment is challenging due to the limited number of age-appropriate formulations. This study aims to develop and evaluate oral viscous suspensions and solid formulations of budesonide (BUD), focusing on their in vitro mucoadhesive properties, to enhance drug delivery and therapeutic outcomes in paediatric EoE. METHODS: This study encompasses the development of oral viscous suspensions and orodispersible solid formulations (moulded tablets and 3D-printed dosage forms) containing BUD. The formulations underwent quality control tests as per the European Pharmacopoeia, chemical stability assessments, and an in vitro evaluation of their mucoadhesiveness properties. RESULTS: A validated analytical method enabled accurate BUD quantification and efficient extraction, and all developed formulations demonstrated chemical stability for 30 days, meeting Ph. Eur. quality standards. Three-dimensional printing using SSE successfully produced 1 mg and 0.5 mg BUD printlets, complying with quality tests for conventional tablets. Formulations containing xanthan gum (L2-XG and P1-0.5-XG) exhibited superior mucoadhesive properties. L2-XG showed significantly higher mucoadhesion than L1-MC. Among the solid formulations, P1-0.5-XG demonstrated the highest mucoadhesive properties. CONCLUSIONS: This is the first study to develop solid oral dosage forms of BUD at a very low dose, specifically for paediatric use. The results highlight the potential of 3D printing for developing individualised orodispersible BUD formulations with improved bioadhesion for paediatric EoE treatment. The L2-XG formulation and the XG-containing printlets are the most promising formulations in terms of increasing contact time with the oesophageal mucosa, which could translate into improved therapeutic efficacy in this patient population.

Dibenzodioxin-Based Polymers of Intrinsic Microporosity with Enhanced Transport Properties for Lithium Ions in Aqueous Media.

Boosting the transport and selectivity properties of membranes based on polymers of intrinsic microporosity (PIMs) toward one specific working analyte of interest is challenging. In this work, a novel family of PIM membranes, prepared by casting and exhibiting optima mechanical properties and high thermal stability, was synthesized from 4,4'-(2,2,2-trifluoro-1-phenylethane-1,1-diyl) bis(benzene-1,2-diol) and two tetrafluoro-nitrile derivatives. Gas permeability measurements evidenced a CO2/CH4 selectivity up to 170% relative to the reference polymer, PIM-1, in agreement with their calculated fractional free volume and the analysis of the textural properties by N2 and CO2 gas adsorption. Besides, the chemical modification by acid hydrolysis of the PIM membranes favored the permeability for lithium ions (LiCl 2M, 6 × 10-9 cm2·s-1) compared to other alkali metal analogs such as sodium (NaCl 2M, 7.38 × 10-10 cm2·s-1) and potassium (KCl 2M, 1.05 × 10-9 cm2·s-1). Moreover, the complete mitigation of the crossover of redox species with higher molecular sizes than the ions from alkali metal salts was confirmed by using in-line benchtop NMR methods. Additionally, the modified PIM membranes were measured in a symmetric electrochemical flow cell using an aqueous electrolyte by combining lithium ferro/ferricyanide redox compounds and lithium chloride. The electrochemical tests showed low polarization, high-rate capability, and capacity retention values of 99% when cycled at 10 mA·cm-2 for over 50 cycles. Based on these results, these polymers could be used as highly selective and conducting membranes in electrodialysis for lithium separation and lithium-based redox flow batteries and as a protective layer in high-energy density lithium metal batteries.

Risperidone ISM®: review and update of its usefulness in all phases of schizophrenia.

One of the most important challenges in the management of patients with schizophrenia is to ensure adherence to antipsychotic treatment. The contribution of long-acting injectables (LAI) is undeniable in this matter, but there are still some unmet medical needs not covered by these drugs (e.g. quick onset of action for patients with acute exacerbation of schizophrenia). This article summarises the pharmacokinetics, efficacy and safety of Risperidone ISM (in situ microparticles). The aim of this review is to provide information about the potential uses of this new LAI formulation of risperidone for the treatment of schizophrenia, contextualising and diving into the published evidence. Risperidone ISM shows a rapid release which allows achieving within 12 h risperidone active moiety levels similar to those observed in the steady-state for oral risperidone treatment, achieving a mean average concentration of 38.63 ng/mL. The plasma concentration of active moiety achieved by Risperidone ISM comes with a predictable dopamine D2 receptor occupancy above 65% throughout the 28-day dosing period, which is accepted as a threshold for the efficacy of the antipsychotic treatment. This can be associated with the positive efficacy findings throughout its clinical development. In the short term, it provides an early and progressive reduction of symptoms in adult patients with acute exacerbation of schizophrenia without the need for loading doses or oral risperidone supplementation, which could contribute to reinforcing the therapeutic alliance between the patient and the psychiatrist. In addition, long-term treatment was effective, safe and well tolerated regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM during an acute exacerbation or switched from stable doses of oral risperidone. Improvement and maintenance of personal and social functioning and health-related quality of life were observed in each setting, respectively. All these findings endorse Risperidone ISM as a useful and valuable treatment for the acute and maintenance management of patients with schizophrenia.

Standardization of gut microbiome analysis in sports.

The gut microbiome plays a significant role in physiological functions such as nutrient processing, vitamin production, inflammatory response, and immune modulation, which, in turn, are important contributors to athlete health and performance. To date, the interpretation, discussion, and visualization of microbiome results of athletes are challenging, due to a lack of standard parameters and reference data for collection and comparison. The purpose of this perspective piece is to provide researchers with an easy-to-understand framework for the collection, analysis, and data management related to the gut microbiome with a specific focus on athletic populations. In the absence of a consensus on microbiome research in the sports field, we hope that these considerations serve as foundational "best practice." Adherence to these standard operating procedures will accelerate the path toward improving the quality of data and ultimately our understanding of the influence of the gut microbiome in sport settings.

Influence of Subclinical Atherosclerosis Burden and Progression on Mortality.

BACKGROUND: Atherosclerosis is a dynamic process. There is little evidence regarding whether quantification of atherosclerosis extent and progression, particularly in the carotid artery, in asymptomatic individuals predicts all-cause mortality. OBJECTIVES: This study sought to evaluate the independent predictive value (beyond cardiovascular risk factors) of subclinical atherosclerosis burden and progression and all-cause mortality. METHODS: A population of 5,716 asymptomatic U.S. adults (mean age 68.9 years, 56.7% female) enrolled between 2008 and 2009 in the BioImage (A Clinical Study of Burden of Atherosclerotic Disease in an At Risk Population) study underwent examination by vascular ultrasound to quantify carotid plaque burden (cPB) (the sum of right and left carotid plaque areas) and by computed tomography for coronary artery calcium (CAC). Follow-up carotid vascular ultrasound was performed on 732 participants a median of 8.9 years after the baseline exam. All participants were followed up for all-cause mortality, the primary outcome. Trend HRs are the per-tertile increase in each variable. RESULTS: Over a median 12.4 years' follow-up, 901 (16%) participants died. After adjustment for cardiovascular risk factors and background medication, baseline cPB and CAC score were both significantly associated with all-cause mortality (fully adjusted trend HR: 1.23; 95% CI: 1.16-1.32; and HR: 1.15; 95% CI: 1.08-1.23), respectively (both P < 0.001), thus providing additional prognostic value. cPB performed better than CAC score. In participants with a second vascular ultrasound evaluation, median cPB progressed from 29.2 to 91.3 mm3. cPB progression was significantly associated with all-cause mortality after adjusting for cardiovascular risk factors and baseline cPB (HR: 1.03; 95% CI: 1.01-1.04 per absolute 10-mm3 change; P = 0.01). CONCLUSIONS: Subclinical atherosclerosis burden (cPB and CAC) in asymptomatic individuals was independently associated with all-cause mortality. Moreover, atherosclerosis progression was independently associated with all-cause mortality.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

Exogenous Glucose Oxidation During Exercise Is Positively Related to Body Size.

There is little evidence that body size alters exogenous glucose oxidation rates during exercise. This study assessed whether larger people oxidize more exogenous glucose during exercise than smaller people. Fifteen cyclists were allocated into two groups based on body mass (SMALL, <70 kg body mass, n = 9, two females) or (LARGE, >70 kg body mass, n = 6) matched for lactate threshold (SMALL: 2.3 ± 0.4 W/kg, LARGE: 2.3 ± 0.3 W/kg). SMALL completed 120 min of cycling at 95% of lactate threshold1. LARGE completed two trials in a random order, one at 95% of lactate threshold1 (thereby exercising at the same relative intensity [RELATIVE]) and one at an absolute intensity matched to SMALL (ABSOLUTE). In all trials, cyclists ingested 90 g/hr of 13C-enriched glucose. Total exogenous glucose oxidation was (mean ± SD) 33 ± 8 g/hr in SMALL versus 45 ± 13 g/hr in LARGE-RELATIVE (mean difference: 13 g/hr, 95% confidence interval [2, 24] g/hr, p = .03). Large positive correlations were observed for measures of exogenous carbohydrate oxidation versus body size (body mass, height, and body surface area; e.g., body surface area vs. peak exogenous glucose oxidation, r = .85, 95% confidence interval [.51, .95], p < .01). When larger athletes reduced the intensity from RELATIVE to ABSOLUTE, total exogenous glucose oxidation was 39 ± 7 g/hr (p = .43 vs. LARGE-RELATIVE). In conclusion, the capacity for exogenous glucose oxidation is, on average, higher in larger athletes than smaller athletes during exercise. The extent to which this is due to higher absolute exercise intensity requires further research, but body size may be a consideration in tailoring sports nutrition guidelines for carbohydrate intake during exercise.

Effect of Diflunisal in Patients with Transthyretin Cardiomyopathy: A Pilot Study.

Background: ATTR-CM is becoming more prevalent, and disease-modifying therapy has been investigated in recent years with promising results. Diflunisal has shown TTR-stabilizing properties assessed by biomarkers and echocardiography, but there are no trials addressing the evolution of morphological changes with CMR. Methods and Results: AMILCA-DIFLU is an exploratory pilot study prospective, single-center, non-randomized, open-label clinical trial. Patients diagnosed with ATTR-CM underwent clinical, functional, biochemical and imaging assessment before and one year after diflunisal therapy initiation. Of the twelve ATTR-CM patients included, only nine patients completed treatment and study protocol in 12 months. To increase the sample size, we included seven real-world patients with one year of diflunisal treatment. Among the group of patients who completed treatment, diflunisal therapy did not show improvement in cardiac disease status as assessed by many cardiac and inflammatory biomarkers, 6MWT and CMR parameters after one year of treatment. However, a non-significant trend towards stabilization of CMR parameters such as LVEF, ECV and T2 at one year was found. When comparing the group of patients who completed diflunisal therapy and those who did not, a significant decrease in the distance performed in the 6MWT was found in the group of patients who completed treatment at one year (-14 ± 81.8 vs. -173 ± 122.2; p = 0.032). Diflunisal was overall well tolerated, showing only a statistically significant worsening in renal function in the group of diflunisal-treatment patients with no clinical relevance or need for treatment discontinuation. Conclusions: In patients with ATTR-CM, treatment with diflunisal was overall well tolerated and tended to stabilize or slow down amyloid cardiac disease progression assessed by CMR parameters, cardiac and inflammatory biomarkers and functional capacity.

Initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia.

The extended period of coexistence between Neanderthals and Homo sapiens in Europe coincided with the emergence of regionally distinctive lithic industries, signalling the onset of the Upper Palaeolithic. The Iberian Peninsula was on the periphery of pioneering Upper Palaeolithic developments, with archaeological remains primarily found in northern territories. We report the discovery of an initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia. This industry, termed here Arlanzian, not only represents the earliest and southernmost evidence of such industries in Iberia but also lacks a direct counterpart. However, it exhibits chronological and technological parallels with the lithic industries associated with the earliest expansion of Homo sapiens throughout Eurasia. We interpret this as potential evidence of its intrusive nature, but not necessarily associated with a migration event, as more complex scenarios derived from inter-population connectivity must be also considered. The biological identity of the Arlanzian makers remains unknown, but they coexisted with declining Neanderthal groups from neighbouring territories.

Evolution, Ecology and Management of Wild Boar and Deer.

Wild boar (Sus scrofa) is the most widespread member of the order Artiodactyla, a group of even-toed ungulates that are prone to overabundance, with adverse consequences for conservation, agriculture, transportation and public health [...].

Are there interindividual differences in the reactive hypoglycaemia response to breakfast? A replicate crossover trial.

BACKGROUND: Following consumption of a meal, circulating glucose concentrations can rise and then fall briefly below the basal/fasting concentrations. This phenomenon is known as reactive hypoglycaemia but to date no researcher has explored potential inter-individual differences in response to meal consumption. OBJECTIVE: We conducted a secondary analysis of existing data to examine inter-individual variability of reactive hypoglycaemia in response to breakfast consumption. METHODS: Using a replicate crossover design, 12 healthy, physically active men (age: 18-30 y, body mass index: 22.1 to 28.0 kg⋅m- 2) completed two identical control (continued overnight fasting) and two breakfast (444 kcal; 60% carbohydrate, 17% protein, 23% fat) conditions in randomised sequences. Blood glucose and lactate concentrations, serum insulin and non-esterified fatty acid concentrations, whole-body energy expenditure, carbohydrate and fat oxidation rates, and appetite ratings were determined before and 2 h after the interventions. Inter-individual differences were explored using Pearson's product-moment correlations between the first and second replicates of the fasting-adjusted breakfast response. Within-participant covariate-adjusted linear mixed models and a random-effects meta-analytical approach were used to quantify participant-by-condition interactions. RESULTS: Breakfast consumption lowered 2-h blood glucose by 0.44 mmol/L (95%CI: 0.76 to 0.12 mmol/L) and serum NEFA concentrations, whilst increasing blood lactate and serum insulin concentrations (all p < 0.01). Large, positive correlations were observed between the first and second replicates of the fasting-adjusted insulin, lactate, hunger, and satisfaction responses to breakfast consumption (all r > 0.5, 90%CI ranged from 0.03 to 0.91). The participant-by-condition interaction response variability (SD) for serum insulin concentration was 11 pmol/L (95%CI: 5 to 16 pmol/L), which was consistent with the τ-statistic from the random-effects meta-analysis (11.7 pmol/L, 95%CI 7.0 to 22.2 pmol/L) whereas effects were unclear for other outcome variables (e.g., τ-statistic value for glucose: 0 mmol/L, 95%CI 0.0 to 0.5 mmol/L). CONCLUSIONS: Despite observing reactive hypoglycaemia at the group level, we were unable to detect any meaningful inter-individual variability of the reactive hypoglycaemia response to breakfast. There was, however, evidence that 2-h insulin responses to breakfast display meaningful inter-individual variability, which may be explained by relative carbohydrate dose ingested and variation in insulin sensitivity of participants.

Novel systematic processing of cardiac magnetic resonance imaging identifies target regions associated with infarct-related ventricular tachycardia.

AIMS: There is lack of agreement on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging processing for guiding ventricular tachycardia (VT) ablation. We aim at developing and validating a systematic processing approach on LGE-CMR images to identify VT corridors that contain critical VT isthmus sites. METHODS AND RESULTS: This is a translational study including 18 pigs with established myocardial infarction and inducible VT undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with VT maintenance. Clinical validation was conducted in a multicentre series of 33 patients with ischaemic cardiomyopathy undergoing VT ablation. Three-dimensional LGE-CMR images were processed using systematic scanning of 15 signal intensity (SI) cut-off ranges to obtain surface visualization of all potential VT corridors. Analysis and comparisons of imaging and electrophysiological data were performed in individuals with full electrophysiological characterization of the isthmus sites of at least one VT morphology. In both the experimental pig model and patients undergoing VT ablation, all the electrophysiologically defined isthmus sites (n = 11 and n = 19, respectively) showed overlapping regions with CMR-based potential VT corridors. Such imaging-based VT corridors were less specific than electrophysiologically guided ablation lesions at critical isthmus sites. However, an optimized strategy using the 7 most relevant SI cut-off ranges among patients showed an increase in specificity compared to using 15 SI cut-off ranges (70 vs. 62%, respectively), without diminishing the capability to detect VT isthmus sites (sensitivity 100%). CONCLUSION: Systematic imaging processing of LGE-CMR sequences using several SI cut-off ranges may improve and standardize procedure planning to identify VT isthmus sites.

Subclinical atherosclerosis and brain health in midlife: Rationale and design of the PESA-Brain study.

RATIONALE: Cognitive decline and dementia have been reportedly linked to atherosclerosis, the main cause of cardiovascular disease. Cohort studies identifying early brain alterations associated with subclinical atherosclerosis are warranted to understand the potential of prevention strategies before cerebral damage becomes symptomatic and irreversible. METHODS & DESIGN: The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal observational cohort study that recruited 4,184 asymptomatic middle-aged individuals (40-54 years) in 2010 in Madrid (Spain) to thoroughly characterize subclinical atherosclerosis development over time. In this framework, the PESA-Brain study has been designed to identify early structural, functional and vascular brain changes associated with midlife atherosclerosis and cardiovascular risk factors. The PESA-Brain study targets 1,000 participants at the 10-year follow-up PESA visit and consists of thorough neuropsychological testing, advanced multimodal neuroimaging, and quantification of blood-based neuropathological biomarkers. PRIMARY HYPOTHESIS: We hypothesize that, in middle-age, the presence of cardiovascular risk factors and a high burden of subclinical atherosclerosis will be associated with structural, functional and vascular brain alterations, greater amyloid burden and subtle cognitive impairment. We further hypothesize that the link between subclinical atherosclerosis and poor brain health in midlife will be mediated by cerebrovascular pathology and intracranial atherosclerosis. ENROLLMENT DATES: The PESA-Brain study started in October 2020 and is estimated to be completed by December 2024. CONCLUSION: This study is in a unique position to unveil novel relationships between cardiovascular and brain alterations in the health-to-disease transition, which may have important implications for interventional and therapeutic approaches. CLINICALTRIALS: gov identifier: NCT01410318.

Coronary Microvascular Function in Asymptomatic Middle-Aged Individuals With Cardiometabolic Risk Factors.

BACKGROUND: In patients with ischemic heart disease, coronary microvascular dysfunction is associated with cardiovascular risk factors and poor prognosis; however, data from healthy individuals are scarce. OBJECTIVES: The purpose of this study was to assess the impact of cardiovascular risk factors and subclinical atherosclerosis on coronary microvascular function in middle-aged asymptomatic individuals. METHODS: Myocardial perfusion was measured at rest and under stress using cardiac magnetic resonance in 453 individuals and used to generate myocardial blood flow (MBF) maps and calculate myocardial perfusion reserve (MPR). Subclinical atherosclerosis was assessed using 3-dimensional vascular ultrasound of the carotid and femoral arteries and coronary artery calcium scoring at baseline and at 3-year follow-up. RESULTS: Median participant age was 52.6 years (range: 48.9-55.8 years), and 84.5% were male. After adjusting for age and sex, rest MBF was directly associated with the number of the metabolic syndrome components present (elevated waist circumference, systolic and diastolic blood pressure, fasting glucose, and triglycerides and low high-density lipoprotein cholesterol), insulin resistance (homeostatic model assessment for insulin resistance), and presence of diabetes. MPR was reduced in the presence of several metabolic syndrome components, elevated homeostatic model assessment for insulin resistance, and diabetes. Stress MBF was inversely associated with coronary artery calcium presence and with global plaque burden. Higher stress MBF and MPR were associated with less atherosclerosis progression (increase in plaque volume) at 3 years. CONCLUSIONS: In asymptomatic middle-aged individuals free of known cardiovascular disease, the presence of cardiometabolic risk factors and systemic (poly-vascular) subclinical atherosclerosis are associated with impaired coronary microvascular function. Better coronary microvascular function reduces atherosclerosis progression at follow-up. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Rationale and design of RESILIENCE: A prospective randomized clinical trial evaluating remote ischaemic conditioning for the prevention of anthracycline cardiotoxicity.

AIMS: There is a lack of therapies able to prevent anthracycline cardiotoxicity (AC). Remote ischaemic conditioning (RIC) has shown beneficial effects in preclinical models of AC. METHODS: REmote iSchemic condItioning in Lymphoma PatIents REceiving ANthraCyclinEs (RESILIENCE) is a multinational, prospective, phase II, double-blind, sham-controlled, randomized clinical trial that evaluates the efficacy and safety of RIC in lymphoma patients receiving anthracyclines. Patients scheduled to undergo ≥5 chemotherapy cycles including anthracyclines and with ≥1 AC-associated risk factors will be randomized to weekly RIC or sham throughout the chemotherapy period. Patients will undergo three multiparametric cardiac magnetic resonance (CMR) studies, at baseline, after the third cycle (intermediate CMR), and 2 months after the end of chemotherapy. Thereafter, patients will be followed up for clinical events over an anticipated median of ≥24 months. The primary endpoint is the absolute change from baseline in CMR-based left ventricular ejection fraction (LVEF). The main secondary outcome is the incidence of AC events, defined as (1) a drop in CMR-based LVEF of ≥10 absolute points, or (2) a drop in CMR-based LVEF of ≥5 and <10 absolute points to a value <50%. Intermediate CMR will test the ability of T2 mapping to predict AC versus classical markers (left ventricular strain and cardiac injury biomarkers). A novel CMR sequence allowing ultrafast cine acquisition will be validated in this vulnerable population. CONCLUSIONS: The RESILIENCE trial will test RIC (a novel non-invasive intervention to prevent AC) in a cohort of high-risk patients. The trial will also test candidate markers for their capacity to predict AC and will validate a novel CMR sequence reducing acquisition time in a vulnerable population.

Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.

Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome.

Evaluation of Ultrasound Changes With the Use of Microneedling Versus Fractional CO2 Laser in Atrophic Acne Scars.

INTRODUCTION: Atrophic acne scarring, a common sequela of acne, can be treated by different interventions, including microneedling and laser resurfacing. OBJECTIVES: We sought to evaluate the comparative efficacy of microneedling versus fractional CO2 laser in treating atrophic acne facial scars using imaging with high and ultra-high frequency ultrasound. METHODS: Participants received 2 sessions, separated by 1 month, of microneedling on the left side of the face and fractional CO2 laser on the right. Color Doppler ultrasound evaluations (24 and 70 MHz) were conducted at baseline and 3 months after treatment. Each patient completed questionnaires on satisfaction, pain, and adverse effects. RESULTS: Nine subjects were enrolled. The frequency order of scar types was boxcar, ice-pick, and rolling. At 3 months, using the acne scar clinical evaluation scale, a decrease in scar scores of both methods was observed for total scars (P = 0.0005), ice-pick scars (P = 0.0128), and rolling scars (P = 0.0007). Twenty-two scars analyzed by ultrasound demonstrated a trend to decrease in size; however, no significant changes were observed for either microneedling or CO2 laser treatments. Moreover, there were no significant differences between these methods. Both treatments were rated as good or very good by patient assessments. There was a low frequency of pain and hyperpigmentation reported with both modalities, albeit somewhat higher with microneedling. CONCLUSIONS: Both microneedling and CO2 laser improved atrophic acne scars. Ultrasound did not show significant differences between these modalities.

Digital endpoints in clinical trials: emerging themes from a multi-stakeholder Knowledge Exchange event.

BACKGROUND: Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people's chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person's health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem. METHODS: A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day's discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination. RESULTS: Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event. CONCLUSIONS: The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.