Depth profiling of the modification induced by high-flux deuterium plasma in tungsten and tungsten-tantalum alloys

The present work reports the results of an experimental study of the depth distribution and fluence dependence of deuterium plasma-induced material modification of tungsten and tungsten-tantalum alloys. Plasma-induced damage was created by exposure to high-flux deuterium plasma in the plasma generator Pilot-PSI, followed by the degassing and subsequent decoration of created defects with deuterium by another plasma exposure. The depth distribution of deuterium from the decorating exposure reflects the distribution of plasma-induced defects. Depth profiling of this decorating deuterium, was performed by nuclear reaction analysis. It was found that plasma-induced material modification, which manifested itself as an increase of the deuterium concentration in the samples pre-exposed with high-flux plasma in comparison to the samples without such pre-exposure extends down to more than 5 mu m from the surface. This increase features a tendency to saturation with increasing fluence of the damaging high-flux plasma. Over the entire probing range, with the exception of the narrow surface region and the deep region beyond 5 mu m, the deuterium content is lower in pre-exposed W-Ta than in similarly pre-exposed W. Sub-surface features formed as a result of high-flux plasma exposure were studied with the help of focused ion beam cross-sectioning. W was found to contain plasma-induced cavities down to much larger depth than W-Ta

The validation of the Dutch SF-Qualiveen, a questionnaire on urinary-specific quality of life, in spinal cord injury patients

Background: Optimizing the patients' quality of life is one of the main goals in the urological management of spinal cord injury (SCI) patients. In this study we validated the Dutch SF-Qualiveen, a short questionnaire that measures the urinary-specific quality of life, in SCI patients. No such measure is yet available for this patient group. Methods: In 2015-2016 SCI patients with urinary symptomatology who visited the outpatient clinics of Urology at the Erasmus Medical Centre and Rehabilitation at Rijndam Revalidation completed the SF-Qualiveen and UDI-6 during the visit and 1-2 weeks later. The UDI-6, a urinary tract symptom inventory, served as gold standard. Controls, recruited from the Otolaryngology outpatient clinic, completed the questionnaires once. Content-, construct-, and criterion validity and reliability (internal consistency and reproducibility) of the SF-Qualiveen were determined. Results: Fifty seven SCI patients and 50 controls were included. 12 SCI patients asserted that the SF-Qualiveen covered their bladder problems (good content validity). Patients' SF-Qualiveen scores being positively associated with severity of urinary symptoms and patients' scores being higher than those of controls indicated good construct validity. The positive association that was found between SF-Qualiveen and UDI-6 in patients (r = 0.66-0.67, P < 0.001) and controls (r = 0.63, P < 0.001) confirmed good criterion validity. Internal consistency (Cronbach's alpha 0.89-0.92) and reproducibility (intraclass correlation coefficient 0.94) of the SF-Qualiveen were good. Conclusions: The Dutch SF-Qualiveen is a valid and reliable tool to measure the urinary-specific quality of life in SCI patients

HIV/AIDS Drugs for Sub-Saharan Africa: How Do Brand and Generic Supply Compare?

BACKGROUND: Significant quantities of antiretroviral drugs (ARVs) to treat HIV/AIDS have been procured for Sub-Saharan Africa for the first time in their 20-year history. This presents a novel opportunity to empirically study the roles of brand and generic suppliers in providing access to ARVs. METHODOLOGY/PRINCIPAL FINDINGS: An observational study of brand and generic supply based on a dataset of 2,162 orders of AIDS drugs for Sub-Saharan Africa reported to the Global Price Reporting Mechanism at the World Health Organization from January 2004-March 2006 was performed. Generic companies supplied 63% of the drugs studied, at prices that were on average about a third of the prices charged by brand companies. 96% of the procurement was of first line drugs, which were provided mostly by generic firms, while the remaining 4%, of second line drugs, was sourced primarily from brand companies. 85% of the generic drugs in the sample were manufactured in India, where the majority of the drugs procured were ineligible for patent protection. The remaining 15% was manufactured in South Africa, mostly under voluntary licenses provided by brand companies to a single generic company. In Sub-Saharan African countries, four first line drugs in the dataset were widely patented, however no general deterrent to generic purchasing based on a patent was detected. CONCLUSIONS/SIGNIFICANCE: Generic and brand companies have played distinct roles in increasing the availability of ARVs in Sub-Saharan Africa. Generic companies provided most of the drugs studied, at prices below those charged by brand companies, and until now, almost exclusively supplied several fixed-dose combination drugs. Brand companies have supplied almost all second line drugs, signed voluntary licenses with generic companies, and are not strictly enforcing patents in certain countries. Further investigation into how price reductions in second line drugs can be achieved and the cheapest drugs can actually be procured is warranted

Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy

Background Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment. Methods and Findings We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in theTNFRSF10Agene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N= 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results. Conclusion We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker

Strap associates with Csde1 and affects expression of select Csde1-bound transcripts

Erythropoiesis is regulated at many levels, including control of mRNA translation. Changing environmental conditions, such as hypoxia or the availability of nutrients and growth factors, require a rapid response enacted by the enhanced or repressed translation of existing transcripts. Cold shock domain protein e1 (Csde1/Unr) is an RNA-binding protein required for erythropoiesis and strongly upregulated in erythroblasts relative to other hematopoietic progenitors. The aim of this study is to identify the Csde1-containing protein complexes and investigate their role in post-transcriptional expression control of Csde1-bound transcripts. We show that Serine/Threonine kinase receptor-associated protein (Strap/Unrip), was the protein most strongly associated with Csde1 in erythroblasts. Strap is a WD40 protein involved in signaling and RNA splicing, but its role when associated with Csde1 is unknown. Reduced expression of Strap did not alter the pool of transcripts bound by Csde1. Instead, it altered the mRNA and/or protein expression of several Csde1-bound transcripts that encode for proteins essential for translational regulation during hypoxia, such as Hmbs, eIF4g3 and Pabpc4. Also affected by Strap knockdown were Vim, a Gata-1 target crucial for erythrocyte enucleation, and Elavl1, which stabilizes Gata-1 mRNA. The major cellular processes affected by both Csde1 and Strap were ribosome function and cell cycle control

Transferable data exclusivity vouchers are not the solution to the antimicrobial drug development

Access to pharmaceutical products worsened during the COVID-19 pandemic when key developers of active pharmaceutical ingredients and medicinal products prioritised their national markets. These challenges led to a stronger commitment by the European Union (EU) to become more autonomous in developing and providing access to pharmaceutical products for its population.1 In April 2023, the European Commission (EC) proposed a reform of the EU pharma regulation to improve patient-centredness, strengthen the European pharmaceutical industry and incentivise pharmaceutical innovation.1 This reform needs to be approved by the European Parliament. In its present form, it includes the introduction of Transferable Data Exclusivity Vouchers (TDEVs) to address the crisis in antimicrobial innovation. In this commentary, we assess the use of TDEVs as an important element of the EC’s proposed pharma strategy on antimicrobial resistance (AMR)