Phenotyping and genotyping of CYP2C19 using comparative metabolism of proguanil in sickle‐cell disease patients and healthy controls in Nigeria

Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle‐cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported. One hundred seventy‐seven unrelated subjects comprising 131 SCD patients and 46 non‐SCD volunteers were phenotyped. This was carried out by collecting pooled urine samples over 8 h following PG administration. Proguanil and its major CYP2C19‐dependent metabolites were measured by high‐performance liquid chromatography. Metabolic ratios (MRs) were computed and employed in classifying subjects into poor or extensive metabolizers. Among SCD group, 130 (99.2%) were extensive metabolizers (EMs) and 1 (0.8%) was poor metabolizer (PM) of PG, while 95.7 and 4.3% non‐SCDs were EMs and PMs, respectively. MRs ranged from 0.02 to 8.70 for SCD EMs and from 0.22 to 8.33 for non‐SCD EMs. Two non‐SCDs with MRs of 18.18 and 25.76 and the SCD with MR of 16.77 regarded as PMs had earlier been genotyped as CYP2C19*2/*2. Poor metabolizers of proguanil in SCD patients are reported for the first time. Regardless of clinical significance, a difference in metabolic disposition of proguanil and CYP2C19 by SCDs and non‐SCDs was established

A focus on selected perspectives of the NUMEN project

The use of double charge exchange reactions is discussed in view of their application to extract information that may be helpful to determinate the nuclear matrix elements entering in the expression of neutrinoless double beta decay half-life. The strategy adopted in the experimental campaigns performed at INFN - Laboratori Nazionali del Sud and in the analysis methods within the NUMEN project is briefly described, emphasizing the advantages of the multi-channel approach to nuclear reaction data analysis. An overview on the research and development activities on the MAGNEX magnetic spectrometer is also given, with a focus on the chosen technological solutions for the focal plane detector which will guarantee the performances at high-rate conditions

NUMEN project @ LNS: Status and perspectives

The aim of the NUMEN project is to access the Nuclear Matrix Elements (NME), involved in the half life of the neutrinoless double beta decay (0?ββ), by measuring the cross sections of Heavy Ions (HI) induced Double Charge Exchange (DCE) reactions with high accuracy. First evidence of the possibility to get quantitative information about NME from experiments is shown in the reaction 40Ca(18O,18Ne)40Ar at 270 MeV, performed with MAGNEX spectrometer using Superconducting Cyclotron (CS) beams at INFN - Laboratory Nazionali del Sud (LNS) in Catania. Preliminary tests on 116Sn and 116Cd target are already performed. High beam intensity is the new frontiers for these studies

Recent results on Heavy-Ion induced reactions of interest for 0νββ decay

An updated overview of recent results on Heavy-Ion induced reactions of interest for neutrinoless double beta decay is reported in the framework of the NUMEN project. The NUMEN idea is to study heavy-ion induced Double Charge Exchange (DCE) reactions with the aim to get information on the nuclear matrix elements for neutrinoless double beta (0νββ) decay. Moreover, to infer the neutrino average masses from the possible measurement of the half- life of 0νββ decay, the knowledge of the nuclear matrix elements is a crucial aspec

Recent results on heavy-ion direct reactions of interest for 0νββ decay at INFN LNS

Neutrinoless double beta decay of nuclei, if observed, would have important implications on fundamental physics. In particular it would give access to the effective neutrino mass. In order to extract such information from 0νββ decay half-life measurements, the knowledge of the Nuclear Matrix Elements (NME) is of utmost importance. In this context the NUMEN and the NURE projects aim to extract information on the NME by measuring cross sections of Double Charge Exchange reactions in selected systems which are expected to spontaneously decay via 0νββ. In this work an overview of the experimental challenges that NUMEN is facing in order to perform the experiments with accelerated beams and the research and development activity for the planned upgrade of the INFN-LNS facilities is reported

Baseline characteristics of patients in the reduction of events with darbepoetin alfa in heart failure trial (RED-HF)

<p>Aims: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.</p> <p>Methods and results: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.</p> <p>Conclusion: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.</p&gt

Broad and narrow personality traits as markers of one-time and repeated suicide attempts: A population-based study

<p>Abstract</p> <p>Background</p> <p>Studying personality traits with the potential to differentiate between individuals engaging in suicide attempts of different degrees of severity could help us to understand the processes underlying the link of personality and nonfatal suicidal behaviours and to identify at-risk groups. One approach may be to examine whether narrow, i.e., lower-order personality traits may be more useful than their underlying, broad personality trait dimensions.</p> <p>Methods</p> <p>We investigated qualitative and quantitative differences in broad and narrow personality traits between one-time and repeated suicide attempters in a longitudinal, population-based sample of young French Canadian adults using two multivariate regression models.</p> <p>Results</p> <p>One broad (Compulsivity: OR = 2.0; 95% CI 1.2–3.5) and one narrow personality trait (anxiousness: OR = 1.1; 95% CI 1.01–1.1) differentiated between individuals with histories of repeated and one-time suicide attempts. Affective instability [(OR = 1.1; 95% CI 1.04–1.1)] and anxiousness [(OR = .92; 95% CI .88–.95)], on the other hand, differentiated between nonattempters and one-time suicide attempters.</p> <p>Conclusion</p> <p>Emotional and cognitive dysregulation and associated behavioural manifestations may be associated with suicide attempts of different severity. While findings associated with narrow traits may be easier to interpret and link to existing sociobiological theories, larger effect sizes associated with broad traits such as Compulsivity may be better suited to objectives with a more clinical focus.</p

The background model of the CUPID-Mo 0νββ0\nu\beta\beta experiment

CUPID-Mo, located in the Laboratoire Souterrain de Modane (France), was a demonstrator for the next generation $0\nu\beta\beta$ decay experiment, CUPID. It consisted of an array of 20 enriched Li$_{2}$$^{100}$MoO$_4$ bolometers and 20 Ge light detectors and has demonstrated that the technology of scintillating bolometers with particle identification capabilities is mature. Furthermore, CUPID-Mo can inform and validate the background prediction for CUPID. In this paper, we present a detailed model of the CUPID-Mo backgrounds. This model is able to describe well the features of the experimental data and enables studies of the $2\nu\beta\beta$ decay and other processes with high precision. We also measure the radio-purity of the Li$_{2}$$^{100}$MoO$_4$ crystals which are found to be sufficient for the CUPID goals. Finally, we also obtain a background index in the region of interest of 3.7$^{+0.9}_{-0.8}$(stat)$^{+1.5}_{-0.7}$(syst)$\times10^{-3}$counts/$\Delta$E$_{FWHM}$/mol$_{iso}$/yr, the lowest in a bolometric $0\nu\beta\beta$ decay experiment