A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the YPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P =.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in YPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi

The ethical issues regarding consent to clinical trials with pre-term or sick neonates: a systematic review (framework synthesis) of the empirical research

Background: Conducting clinical trials with pre-term or sick infants is important if care for this population is to be underpinned by sound evidence. Yet approaching parents at this difficult time raises challenges for the obtaining of valid informed consent to such research. This study asked: what light does the empirical literature cast on an ethically defensible approach to the obtaining of informed consent in perinatal clinical trials? Methods: A systematic search identified 49 studies. Analysis began by applying philosophical frameworks which were then refined in light of the concepts emerging from empirical studies to present a coherent picture of a broad literature. Results: Between them, studies addressed the attitudes of both parents and clinicians concerning consent in neonatal trials; the validity of the consent process in the neonatal research context; and different possible methods of obtaining consent. Conclusions: Despite a variety of opinions among parents and clinicians there is a strongly and widely held view that it is important that parents do give or decline consent for neonatal participation in trials. However, none of the range of existing consent processes reviewed by the research is satisfactory. A significant gap is evaluation of the widespread practice of emergency ‘assent’, in which parents assent or refuse their baby’s participation as best they can during the emergency and later give full consent to ongoing participation and follow-up. Emergency assent has not been evaluated for its acceptability, how such a process would deal with bad outcomes such as neonatal death between assent and consent, or the extent to which late parental refusal might bias results. This review of a large number of empirical papers, while not making fundamental changes, has refined and developed the conceptual framework from philosophy for examining informed consent in this context

Des-Arg9Bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: Role of serum ACE and aminopeptidase P

NRC publication: Ye

Gender and neglected tropical disease front-line workers: Data from 16 countries.

BackgroundDelivery of preventive chemotherapy (PC) through mass drug administration (MDA) is used to control or eliminate five of the most common neglected tropical diseases (NTDs). The success of an MDA campaign relies on the ability of drug distributors and their supervisors-the NTD front-line workers-to reach populations at risk of NTDs. In the past, our understanding of the demographics of these workers has been limited, but with increased access to sex-disaggregated data, we begin to explore the implications of gender and sex for the success of NTD front-line workers.Methodology/principal findingsWe reviewed data collected by USAID-supported NTD projects from national NTD programs from fiscal years (FY) 2012-2017 to assess availability of sex-disaggregated data on the workforce. What we found was sex-disaggregated data on 2,984,908 trainees trained with financial support from the project. We then analyzed the percentage of males and females trained by job category, country, and fiscal year. During FY12, 59% of these data were disaggregated by sex, which increased to nearly 100% by FY15 and was sustained through FY17. In FY17, 43% of trainees were female, with just four countries reporting more females than males trained as drug distributors and three countries reporting more females than males trained as trainers/supervisors. Except for two countries, there were no clear trends over time in changes to the percent of females trained.Conclusions/significanceThere has been a rapid increase in availability of sex-disaggregated data, but little increase in recruitment of female workers in countries included in this study. Women continue to be under-represented in the NTD workforce, and while there are often valid reasons for this distribution, we need to test this norm and better understand gender dynamics within NTD programs to increase equity