Aid conditionalities, international Good Manufacturing Practice standards and local production rights: a case study of local production in Nepal

© 2015 Brhlikova et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This work was supported by the Economic and Social Research Council and the Department for International Development [RES-167-25-0110] through the collaborative research project Tracing Pharmaceuticals in South Asia (2006 – 2009). In addition to the authors of this paper, the project team included: Soumita Basu, Gitanjali Priti Bhatia, Erin Court, Abhijit Das, Stefan Ecks, Patricia Jeffery, Roger Jeffery, Rachel Manners, and Liz Richardson. Martin Chautari (Kathmandu) and the Centre for Health and Social Justice (New Delhi) provided resources drawn upon in writing this paper but are not responsible for the views expressed, nor are ESRC or DFID. Ethical review was provided by the School of Social and Political Science at the University of Edinburgh, and ethical approval in Nepal for the study granted by the Nepal Health Research Council (NHRC)

Global Ethics and Nanotechnology: A Comparison of the Nanoethics Environments of the EU and China

The following article offers a brief overview of current nanotechnology policy, regulation and ethics in Europe and The People’s Republic of China with the intent of noting (dis)similarities in approach, before focusing on the involvement of the public in science and technology policy (i.e. participatory Technology Assessment). The conclusions of this article are, that (a) in terms of nanosafety as expressed through policy and regulation, China PR and the EU have similar approaches towards, and concerns about, nanotoxicity—the official debate on benefits and risks is not markedly different in the two regions; (b) that there is a similar economic drive behind both regions’ approach to nanodevelopment, the difference being the degree of public concern admitted; and (c) participation in decision-making is fundamentally different in the two regions. Thus in China PR, the focus is on the responsibility of the scientist; in the EU, it is about government accountability to the public. The formulation of a Code of Conduct for scientists in both regions (China PR’s predicted for 2012) reveals both similarity and difference in approach to nanotechnology development. This may change, since individual responsibility alone cannot guide S&T development, and as public participation is increasingly seen globally as integral to governmental decision-making

Study of a Nonlocal Density scheme for electronic--structure calculations

An exchange-correlation energy functional beyond the local density approximation, based on the exchange-correlation kernel of the homogeneous electron gas and originally introduced by Kohn and Sham, is considered for electronic structure calculations of semiconductors and atoms. Calculations are carried out for diamond, silicon, silicon carbide and gallium arsenide. The lattice constants and gaps show a small improvement with respect to the LDA results. However, the corresponding corrections to the total energy of the isolated atoms are not large enough to yield a substantial improvement for the cohesive energy of solids, which remains hence overestimated as in the LDA.Comment: 4 postscript figure

Genotoksičnost metalnih nanočestica: osvrt na podatke istraživanja In vivo

With increasing production and application of a variety of nanomaterials (NMs), research on their cytotoxic and genotoxic potential grows, as the exposure to these nano-sized materials may potentially result in adverse health effects. In large part, indications for potential DNA damaging effects of nanoparticles (NPs) originate from inconsistent in vitro studies. To clarify these effects, the implementation of in vivo studies has been emphasised. This paper summarises study results of genotoxic effects of NPs, which are available in the recent literature. They provide indications that some NP types cause both DNA strand breaks and chromosomal damages in experimental animals. Their genotoxic effects, however, do not depend only on particle size, surface modifi cation (particle coating), and exposure route, but also on exposure duration. Currently available animal studies may suggest differing mechanisms (depending on the duration of exposure) by which living organisms react to NP contact. Nevertheless, due to considerable inconsistencies in the recent literature and the lack of standardised test methods - a reliable hazard assessment of NMs is still limited. Therefore, international organisations (e.g. NIOSH) suggest utmost caution when potential exposure of humans to NMs occurs, as long as evidence of their toxicological and genotoxic effect(s) is limited.S povećanjem proizvodnje i primjene niza različitih nanomaterijala (NM) raste i potreba istraživanja njihovih mogućih citotoksičnih i genotoksičnih učinaka kao i drugih štetnih učinaka na zdravlje u uvjetima profesionalne ili opće izloženost ljudi. Indikacije potencijanog oštećenja DNA kojeg uzrokuju nanočestice u velikoj mjeri proizlaze iz nedosljednih in vitro ispitivanja. Kako bi se razjasnili ti učinci, naglašena je potreba provedbe in vivo ispitivanja. Ovaj pregledni rad sažima rezultate procjene genotoksičnih učinaka nanočestica koji su objavljeni u novijoj stručnoj i znanstvenoj literaturi. Navedeni rezultati pokazuju da određene nanočestice uzrokuju lomove u molekuli DNA i oštećuju kromosome u eksperimentalnim životinjama. Njihovi genotoksični učinci ne ovise samo o veličini čestice, modifi kaciji površine (oblaganje čestice) i načinu izlaganja, već i o trajanju izloženosti nanočesticama. Postojeća istraživanja provedena na životinjama upućuju na različite mehanizme koji ovise o trajanju izlaganja i pomoću kojih živi organizmi reagiraju na doticaj s nanočesticama. Međutim postoje brojne nedosljednosti u novijoj literaturi, a standardne testne metode nisu dostupne pa je stoga pouzdanija procjena opasnosti od izlaganja nanomaterijalima u ljudi još uvijek veoma ograničena. Stoga se u međunarodnim dokumentima savjetuje oprez prilikom svakog izlaganja ljudi nanomaterijalima kako bi se spriječili mogući opći toksični genotoksični učinci

Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis

Background: The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA). Methods: A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted. Results: A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints. Conclusions: This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies

The Transcriptional Response to DNA-Double-Strand Breaks in Physcomitrella patens

The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting. Transcripts encoding DNA repair proteins active in multiple repair pathways were significantly up-regulated. These included Rad51, CtIP, DNA ligase 1, Replication protein A and ATR in homology-dependent repair, Xrcc4, DNA ligase 4, Ku70 and Ku80 in non-homologous end-joining and Rad1, Tebichi/polymerase theta, PARP in microhomology-mediated end-joining. Differentially regulated cell-cycle components included up-regulated Rad9 and Hus1 DNA-damage-related checkpoint proteins and down-regulated D-type cyclins and B-type CDKs, commensurate with the imposition of a checkpoint at G2 of the cell cycle characteristic of homology-dependent DNA-DSB repair. Candidate genes, including ATP-dependent chromatin remodelling helicases associated with repair and recombination, were knocked out and analysed for growth defects, hypersensitivity to DNA damage and reduced GT efficiency. Targeted knockout of PpCtIP, a cell-cycle activated mediator of homology-dependent DSB resection, resulted in bleomycin-hypersensitivity and greatly reduced GT efficiency

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Review of nanomaterials in dentistry: interactions with the oral microenvironment, clinical applications, hazards, and benefits.

Interest in the use of engineered nanomaterials (ENMs) as either nanomedicines or dental materials/devices in clinical dentistry is growing. This review aims to detail the ultrafine structure, chemical composition, and reactivity of dental tissues in the context of interactions with ENMs, including the saliva, pellicle layer, and oral biofilm; then describes the applications of ENMs in dentistry in context with beneficial clinical outcomes versus potential risks. The flow rate and quality of saliva are likely to influence the behavior of ENMs in the oral cavity, but how the protein corona formed on the ENMs will alter bioavailability, or interact with the structure and proteins of the pellicle layer, as well as microbes in the biofilm, remains unclear. The tooth enamel is a dense crystalline structure that is likely to act as a barrier to ENM penetration, but underlying dentinal tubules are not. Consequently, ENMs may be used to strengthen dentine or regenerate pulp tissue. ENMs have dental applications as antibacterials for infection control, as nanofillers to improve the mechanical and bioactive properties of restoration materials, and as novel coatings on dental implants. Dentifrices and some related personal care products are already available for oral health applications. Overall, the clinical benefits generally outweigh the hazards of using ENMs in the oral cavity, and the latter should not prevent the responsible innovation of nanotechnology in dentistry. However, the clinical safety regulations for dental materials have not been specifically updated for ENMs, and some guidance on occupational health for practitioners is also needed. Knowledge gaps for future research include the formation of protein corona in the oral cavity, ENM diffusion through clinically relevant biofilms, and mechanistic investigations on how ENMs strengthen the tooth structure