Leveraging WHO's Global Benchmarking Tool to strengthen capacity in clinical trials oversight for public health emergencies: the GHPP VaccTrain model.

BACKGROUND: A stable, well-functioning and integrated national medicines regulatory system is a core component of health systems resilient against infectious disease outbreaks. In many low- and middle-income countries, however, sizable gaps exist in the emergency preparedness framework of national regulatory authorities (NRAs). RegTrain-VaccTrain is a project of Germany Ministry of Health's Global Health Protection Programme that contributes to global efforts aimed at strengthening such regulatory systems by providing technical support and advice to partner NRAs. In this study, we probed the outputs of our capacity-strengthening activities for clinical trials oversight (CTO) to take stock of progress made and examine remaining priorities in order to provide specialized technical assistance in addressing them to improve operational readiness for emergencies. METHOD: Data validated from NRA self-benchmarking results in 2017 and worksheet records of November 2021 were utilized to assess the emergency preparedness capacity for CTO in three VaccTrain partner NRAs (Liberia, Sierra Leone, The Gambia) before and after interventional capacity-strengthening partnership, using specific public health emergency-related (sub-)indicators of the WHO Global Benchmarking Tool. RESULTS: A generally weak and vulnerable structural framework for CTO characterized the emergency preparedness capacity in all three partner NRAs at baseline, thus putting their operational readiness for public health emergencies at risk. VaccTrain's collaborative work was successful at supporting individual NRAs to develop the full spectrum of operational structures (including (draft) regulations, guidelines, and standard operating procedures) required to improve regulatory preparedness. A gap in the formal approval and implementation of developed legal documents in two of three NRAs still remains. Notwithstanding, a robust emergency framework now exists and the NRAs stand better prepared to respond to (future) locally-concerning health emergencies, during which time clinical trials activity was observed to heighten. CONCLUSIONS: These results exemplify a north-south capacity-strengthening partnership model that effectively contributes in developing structures to enhance regulatory oversight and support expeditious product development in response to crises. They further underscore the equally critical role local/national processes play in facilitating the full implementation of developed structures.

Genetic polymorphism in patients with early and late onset of ulcerative colitis.

OBJECTIVE: The aim was to investigate SNPs of TLR-2,3,4, NOD2/CARD15, JAK-2, and IL-10 in patients with the early and late UC onset. PATIENTS AND METHODS: Matherials and methods: 126 patients with UC were investigated. To assess the predisposition of the early and late UC onset the incidence of the following SNPs: Arg753Gln TLR2 gene, Phe412Leu TLR3 gene, Asp299Gly and Thr399Ile TLR4 gene, C-819T, G-1082A and C-592A gene IL-10, Val617Phe gene JAK2, Gly908Arg gene NOD2/CARD15 were analyzed. RESULTS: Results: 76 patients had early disease onset and 50 had a late one. SNPs of TLR3 were observed in 50.8% cases. TLR4 polymorphism was more common than TLR3, and was observed in 81 (64.3%) UC patients. Polymorphism of NOD2/CARD15 and IL-10 genes were revealed with almost the same frequency 49 (38.9%) and 50 (39.9%) patients, respectively. CONCLUSION: Conclusions: Polymorphisms of TLR-2,3 genes and TLR4 Asp299Gly, NOD2/CARD15 prevailed in patients with the late UC onset that allows to suppose that bacterial flora plays one of the key roles in modification of immune response and UC development. In patients with early UC onset polymorphisms of the JAK2 and IL-10 genes prevailed responsible for the cytokine cascade activation and cause the immune mechanism that might lead to a more aggressive course of the disease.

Cation binding to 15-TBA quadruplex DNA is a multiple-pathway cation-dependent process.

A combination of explicit solvent molecular dynamics simulation (30 simulations reaching 4 µs in total), hybrid quantum mechanics/molecular mechanics approach and isothermal titration calorimetry was used to investigate the atomistic picture of ion binding to 15-mer thrombin-binding quadruplex DNA (G-DNA) aptamer. Binding of ions to G-DNA is complex multiple pathway process, which is strongly affected by the type of the cation. The individual ion-binding events are substantially modulated by the connecting loops of the aptamer, which play several roles. They stabilize the molecule during time periods when the bound ions are not present, they modulate the route of the ion into the stem and they also stabilize the internal ions by closing the gates through which the ions enter the quadruplex. Using our extensive simulations, we for the first time observed full spontaneous exchange of internal cation between quadruplex molecule and bulk solvent at atomistic resolution. The simulation suggests that expulsion of the internally bound ion is correlated with initial binding of the incoming ion. The incoming ion then readily replaces the bound ion while minimizing any destabilization of the solute molecule during the exchange.

Clinical, endoscopical and morphological efficacy of mesalazine in patients with irritable bowel syndrome.

OBJECTIVES: The aim of this study was to analyze the clinical efficacy and cytomorphologic changes of colon mucosa following the treatment of patients suffering from irritable bowel syndrome (IBS) with mesalazine (5-aminosalicylic acid [5-ASA]). METHODS: In this controlled, randomized, blind clinical trial, a total of 360 patients with varying subtypes of IBS were randomly treated with 500 mg of mesalazine qid or by standard therapy without mesalazine for a period of 28 days. Pre- and post-treatment pain intensity, pain duration, meteorism, stool abnormalities and endoscopic parameters were monitored, and biopsies or brush biopsies were examined histologically. RESULTS: Treatment of IBS patients with mesalazine significantly reduced intensity and duration of pain in all subtypes of IBS, except for duration of pain in the subtype "undifferentiated", where the difference was not significant. In addition, in patients with diarrhea type and undifferentiated type of IBS, mesalazine also significantly reduced the abnormal stool pattern. In comparison to the control group, administration of mesalazine reduced the incidence of endoscopic and cytomorphologic changes of the bowel mucosa, including changes in colon mucus, mucus production, cytologic or histologic parameters, epithelial cell degeneration, appearance of leukocytes and macrophages and cell infiltrations. CONCLUSION: Mesalazine was effective in reducing several symptoms characteristic of IBS. It significantly reduced pain intensity and duration and improved cytohistologic parameters of the bowel mucosa.