Some further classes of pseudo-differential operators in the p-adic context and their applications.

The purpose of this article is to study new non-Archimedean pseudo-differential operators whose symbols are determined from the behavior of two functions defined on the p-adic numbers. Thanks to the characteristics of our symbols, we can find connections between these operators and new types of non-homogeneous differential equations, Feller semigroups, contraction semigroups and strong Markov processes.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial.

BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).

Background and Objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study. Methods: In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio. Results: Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, -0.39 [0.55] mm2; placebo, 0.08 [0.72] mm2; p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%). Discussion: The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA. Trial Registration Information: ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1. Classification of Evidence: This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.

Correlación de la variabilidad de la frecuencia cardíaca y el nivel de actividad física en hombres jóvenes saludables / Correlation between heart rate variability and physical activity level in young healthy men

Este estudio describe el comportamiento de la Variabilidad de la Frecuencia Cardíaca (VFC) en los dominios de tiempo y frecuencia con relaciónal nivel de Actividad Física, medido mediante el Cuestionario Mundial para Actividad Física (GPAQ). Se estudiaron 20 aprendices de género masculino, con promedios de edad 21,47 +3,36 años y peso 61,09 +7,30 Kg, categorizados en nivel de actividad física alto y moderado, según criterios de la Organización Mundial de la Salud, en un rango de peso normal, Índice de Masa Corporal de 21,18 +1,99 Kg/m2, no fumadores, a quienes se les realizó una historia clínica que descartó enfermedad aparente al examen clínico y se les midió la VFC en reposo. Se utilizaron Cardiofrecuenciómetros marca POLAR®. A través de la t-student y pruebas de correlación se realizó el tratamiento estadístico de los datos. Los resultados evidencian una co- rrelación significativa entre la VFC y el grupo de Actividad Física ALTA. La correlación más alta se encontró en el dominio de frecuencia, entre el logaritmo de Baja Frecuencia y el grupo Actividad Física ALTA (r=0,747). Las variables en dominio tiempo mostraron correlaciones moderadas (R-Ri r= 0,57, rMSSD r= 0,665), así como en el análisis no-lineal, la SD1 en la gráfica de Poincaré (r=0,665). Se concluye que la VFC es un instrumento útil, de bajo costo, no invasivo, de fácil aplicación y que tiene una significativa correlación con el nivel de actividad física en adultos jóvenes sanos. Son necesarios otros estudios para dilucidar los multivariados factores que inciden en la VFC.

This assay describes the Heart Rate Variability (VFC) behavioral in time and frequency domains related with de Physical Activity level, measured by means of the Global Physical Activity Questioner (GPAQ). Twenty male non smokers students were studied, with an average age of 21,47 + 3,36, an average weight of 61,09 + 7,30 Kg, with a Body Mass Rate of 21,18+ 1,99 Kg/m2, categorized in high, medium or low Physical Activity Level according to the GPAQ questioner. Evident illnesses were dismissed by a clinical exam, and the HRV was measured on rest. The equipments used were hearth rate monitors scale trademark POLAR. Parametric criteria were used for the data analysis, the t-student and correlation tests were applied. The results show a significant correlation between the (VFC) and the High Physical Activity group. The highest correlation was found in the frequency domain, between the logarithm of the Low Frequency (LnBF by its initials in Spanish) and the group High Physical Activity group (A.F.ALTA, by its initials in Spanish, r= 0,747). The variables in the domain showed moderated correlations (R-Ri r= 0,57, rMSSD r= 0,665), the same as the non-linear analysis, the SD1 in the Poincar‚ plot (r=0,665). In conclusion, the Heart Rate Variability (VFC) is a low cost useful tool, non invasive and of easy application, which has a significant correlation with the level of physical activity in young healthy and non obese adults. More studies are necessary in order to elucidate the diverse factors that fall upon the Heart Rate Variability.