The unique status of first-in-human studies: strengthening the social value requirement

For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials. Here, we provide some of necessary steps needed to assess the anticipated social value of the intervention

Нарушение репродуктивной функции при простатите/синдроме хронической тазовой боли

Показано, что нелеченное хроническое воспаление предстательной железы приводит к нарушению показателей спермограммы и в ряде случаев к бесплодию при нормальном развитии половых желез и достаточном гормональном обеспечении организма. Бактерии, вирусы, лейкоциты, свободные радикалы, цитокины, иммунологические изменения и обструкция семявыводящих путей при простате являются кофакторами в развитии бесплодия.It is shown that untreated chronic inflammation of the prostate gland causes disturbances of spermogram count and strility in a number of cases at normal development of sex glands and sufficient hormone supply of the organism. Bacteria, viruses, leukocytes, free radicals, cytokines, immunological changes and obstruction of the deferent ducts in prostatitis are co−factors of sterility development

What do international ethics guidelines say in terms of the scope of medical research ethics?

BACKGROUND: In research ethics, the most basic question would always be, "which is an ethical issue, which is not?" Interestingly, depending on which ethics guideline we consult, we may have various answers to this question. Though we already have several international ethics guidelines for biomedical research involving human participants, ironically, we do not have a harmonized document which tells us what these various guidelines say and shows us the areas of consensus (or lack thereof). In this manuscript, we attempted to do just that. METHODS: We extracted the imperatives from five internationally-known ethics guidelines and took note where the imperatives came from. In doing so, we gathered data on how many guidelines support a specific imperative. RESULTS: We found that there is no consensus on the majority of the imperatives and that in only 8.2% of the imperatives were there at least moderate consensus (i.e., consensus of at least 3 of the 5 ethics guidelines). Of the 12 clusters (Basic Principles; Research Collaboration; Social Value; Scientific Validity; Participant Selection; Favorable Benefit/Risk Ratio; Independent Review; Informed Consent; Respect for Participants; Publication and Registration; Regulatory Sanctions; and Justified Research on the Vulnerable Population), Informed Consent has the highest level of consensus and Research Collaboration and Regulatory Sanctions have the least. CONCLUSION: There was a lack of consensus in the majority of imperatives from the five internationally-known ethics guidelines. This may be partly explained by the differences among the guidelines in terms of their levels of specification as well as conceptual/ideological differences

Визначення вальпроєвої кислоти у крові методом реакційної високоефективної рідинної хроматографії

Здійснена взаємодія вальпроєвої кислоти з 3-(2'-бромацетил)-7-метоксикумарином і розроблено її визначення у крові методом реакційної високоефективної рідинної хроматографії. Вивчений вплив різних методів депротоїнізації на вивільнення вальпроєвої кислоти та оптимізовані умови пробопідготовки.Осуществлено взаимодействие вальпроевой кислоты с 3-(2'-бромацетил)-7-метоксикумарином и разработано ее определение в крови методом реакционной высокоэффективной жидкостной хроматографии. Изучено влияние различных методов депротеинизации на выходы вальпроевой кислоты и оптимизированы условия пробоподготовки.The interaction of the valproic acid with 3-(2'-bromoacetyl)-7-methoxicoumarin has been carried out and its determination in blood by the reaction high performance liquid chromatography method has been developed. The influence of various methods of deproteinization on the yields of the valproic acid has been studied and the conditions of the sample preparing has been optimized

Комбинированные гестаген/эстрогенные препараты в лечении гиперандрогении

Рассмотрены биохимические механизмы действия гестаген/эстрогенных препаратов при лечении синдрома гиперандрогении. Описаны преимущества комбинации дроспиренона с этинидэстрадиолом для лечения акне, себореи и гирсутизма у женщин, одновременно нуждающихся в контрацепции.The biochemical mechanisms of action of gestagen/estrogen drugs in treatment for syndrome of hyperandrogeny are featured. The advantages of Drospirenon and Etinidestradiol combination in treatment of acne, seborrhea and hirsutism in women simultaneously requiring contraception are described

Ethical and research governance approval across Europe:Experiences from three European palliative care studies

Background: Research requires high-quality ethical and governance scrutiny and approval. However, when research is conducted across different countries, this can cause challenges due to the differing ethico-legal framework requirements of ethical boards. There is no specific guidance for research which does not involve non-medicinal products. Aim: To describe and address differences in ethical and research governance procedures applied by research ethics committees for non-pharmaceutical palliative care studies including adult participants in collaborative European studies. Design: An online survey analysed using descriptive statistics. Setting/participants: Eighteen principal investigators in 11 countries conducting one of three European-funded studies. Results: There was variation in practice including whether ethical approval was required. The time to gain full approvals differed with the United Kingdom having governance procedures that took the longest time. Written consent was not required in all countries nor were data safety monitoring committees for trials. There were additional differences in relation to other data management issues. Conclusion: Researchers need to take the differences in research approval procedures into account when planning studies. Future research is needed to establish European-wide recommendations for policy and practice that dovetail ethical procedures and enhance transnational research collaborations

Combined Bacteriophage and Antibiotic Treatment Prevents Pseudomonas aeruginosa Infection of Wild Type and cftr- Epithelial Cells.

With the increase of infections due to multidrug resistant bacterial pathogens and the shortage of antimicrobial molecules with novel targets, interest in bacteriophages as a therapeutic option has regained much attraction. Before the launch of future clinical trials, in vitro studies are required to better evaluate the efficacies and potential pitfalls of such therapies. Here we studied in an ex vivo human airway epithelial cell line model the efficacy of phage and ciprofloxacin alone and in combination to treat infection by Pseudomonas aeruginosa. The Calu-3 cell line and the isogenic CFTR knock down cell line (cftr-) infected apically with P. aeruginosa strain PAO1 showed a progressive reduction in transepithelial resistance during 24 h. Administration at 6 h p.i. of single phage, phage cocktails or ciprofloxacin alone prevented epithelial layer destruction at 24 h p.i. Bacterial regrowth, due to phage resistant mutants harboring mutations in LPS synthesis genes, occurred thereafter both in vitro and ex vivo. However, co-administration of two phages combined with ciprofloxacin efficiently prevented PAO1 regrowth and maintained epithelial cell integrity at 72 p.i. The phage/ciprofloxacin treatment did not induce an inflammatory response in the tested cell lines as determined by nanoString <sup>®</sup> gene expression analysis. We conclude that combination of phage and ciprofloxacin efficiently protects wild type and cftr- epithelial cells from infection by P. aeruginosa and emergence of phage resistant mutants without inducing an inflammatory response. Hence, phage-antibiotic combination should be a safe and promising anti-Pseudomonas therapy for future clinical trials potentially including cystic fibrosis patients

Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation.

In cystic fibrosis (CF) patients, chronic airway infection by Pseudomonas leads to progressive lung destruction ultimately requiring lung transplantation (LT). Following LT, CF-adapted Pseudomonas strains, potentially originating from the sinuses, may seed the allograft leading to infections and reduced allograft survival. We investigated whether CF-adapted Pseudomonas populations invade the donor microbiota and adapt to the non-CF allograft. We collected sequential Pseudomonas isolates and airway samples from a CF-lung transplant recipient during two years, and followed the dynamics of the microbiota and Pseudomonas populations. We show that Pseudomonas invaded the host microbiota within three days post-LT, in association with a reduction in richness and diversity. A dominant mucoid and hypermutator mutL lineage was replaced after 11 days by non-mucoid strains. Despite antibiotic therapy, Pseudomonas dominated the allograft microbiota until day 95. We observed positive selection of pre-LT variants and the appearance of novel mutations. Phenotypic adaptation resulted in increased biofilm formation and swimming motility capacities. Pseudomonas was replaced after 95 days by a microbiota dominated by Actinobacillus. In conclusion, mucoid Pseudomonas adapted to the CF-lung remained able to invade the allograft. Selection of both pre-existing non-mucoid subpopulations and of novel phenotypic traits suggests rapid adaptation of Pseudomonas to the non-CF allograft