Is experimental data quality the limiting factor in predicting the aqueous solubility of druglike molecules?

D.S.P. is grateful for funding from the European Commission through a Marie Curie Intra-European Fellowship within the seventh European Community Framework Programme (FP7-PEOPLE-2010-IEF). D.S.P. thanks the University of Strathclyde for support through its Strategic Appointment and Investment Scheme. Computations were performed at the EPSRC funded ARCHIE-WeSt High Performance Computer (www.archie-west.ac.uk, EPSRC grant no. EP K0005861). J.B.O.M. thanks the Scottish Universities Life Sciences Alliance (SULSA) for financial support and EaStCHEM for access to the EaStCHEM Research Computing Facility.We report the results of testing quantitative structure-property relationships (QSPR) that were trained upon the same druglike molecules but two different sets of solubility data: (i) data extracted from several different sources from the published literature, for which the experimental uncertainty is estimated to be 0.6-0.7 log S units (referred to mol/L); (ii) data measured by a single accurate experimental method (CheqSol), for which experimental uncertainty is typically <0.05 log S units. Contrary to what might be expected, the models derived from the CheqSol experimental data are not more accurate than those derived from the "noisy" literature data. The results suggest that, at the present time, it is the deficiency of QSPR methods (algorithms and/or descriptor sets), and not, as is commonly quoted, the uncertainty in the experimental measurements, which is the limiting factor in accurately predicting aqueous solubility for pharmaceutical molecules.Publisher PDFPeer reviewe

Health-care workers’ occupational exposures to body fluids in 21 countries in Africa: systematic review and meta-analysis

Objective:To estimate the lifetime and 12-month prevalence of occupational exposure to body fluids among health-care workers in Africa. Methods: Embase®, PubMed® and CINAHL databases were systematically searched for studies published from January 2000 to August 2017 that reported the prevalence of occupational exposure to blood or other body fluids among health-care workers in Africa. The continent-wide prevalence of exposure was estimated using random-effects meta-analysis. Findings: Of the 904 articles identified, 65 studies from 21 African countries were included. The estimated pooled lifetime and 12-month prevalence of occupational exposure to body fluids were 65.7% (95% confidence interval, CI: 59.7–71.6) and 48.0% (95% CI: 40.7–55.3), respectively. Exposure was largely due to percutaneous injury, which had an estimated 12-month prevalence of 36.0% (95% CI: 31.2–40.8). The pooled 12-month prevalence of occupational exposure among medical doctors (excluding surgeons), nurses (including midwives and nursing assistants) and laboratory staff (including laboratory technicians) was 46.6% (95% CI: 33.5–9.7), 44.6% (95% CI: 34.1–55.0) and 34.3% (95% CI: 21.8–46.7), respectively. The risk of exposure was higher among health-care workers with no training on infection prevention and those who worked more than 40 hours per week. Conclusion: The evidence available suggests that almost one half of health-care workers in Africa were occupationally exposed to body fluids annually. However, a lack of data from some countries was a major limitation. National governments and health-care institutions across Africa should prioritize efforts to minimize occupational exposure among health-care workers

Gemini pyridinium amphiphiles for the synthesis and stabilization of gold nanoparticles for drug delivery

Hypothesis Gemini pyridinium-based amphiphiles can play a triple role as: gold nanoparticles (AuNPs) synthesis facilitator, particle stabilizer and anion recognition centre. The so formed nanoparticles should be able to bind and release anionic drugs. Experiments We describe (a) Synthesis, by a phase transfer method, of both new organic media and water soluble AuNPs using gemini-type surfactants based on bis-pyridinium salts as ligands, acting as transfer agents into organic media and also as nanoparticle stabilizers, (b) Examination of their stability in solution, (c) Chemical and physical characterization of the nanoparticles, (d) Toxicity data concerning both the bis-pyridinium ligands and the bis-pyridinium coated nanoparticles, and (e) Study of their ability for delivering anionic pharmaceuticals such as ibuprofen and piroxicam. Findings Pyridinium gemini-type surfactants show the ability to play multiple roles such as transfer agent and stabilizer, as well as ionophores: They are responsible for the preparation, stability, and delivery properties of these AuNPs, which gold core is stabilized by the anions present in the bis-pyridinium salts. The tetrahydropyridine resulting from the reduction of the bis-pyridinium salt is capable of reduce gold, due to its spontaneous oxidation to the corresponding pyridinium salt, leading to the formation of stable AuNPs

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Nigeria’s oil rent can still count: Lessons from Kuwait

Nigeria and Kuwait were former British colonies, both having oil-based economies with exports of over 2.4 million barrels of oil per day and oil exports accounting for a clear majority of their export earnings. But funnily enough, the standards of living of the citizens of these two are poles apart as Kuwait’s oil rent has been successfully used to benefit its citizens while Nigerians still grapple with low living standards in the midst of plenty. This study employs a comparative approach in assessing the nexus between oil rents and living standards for both countries and seeks to draw the attention of Nigeria to the oil rent distribution channels of Kuwait. The conclusion of the study is that Nigeria can still change the fortunes of her citizenry by tapping into the wealth of knowledge from Kuwait’s oil rent distribution channels

Financing agriculture in Nigeria through the agricultural extension services of agricultural development programmes

The ADPs were designed in response to a fall in agricultural productivity and hence a concern to sustain domestic food supplies. The study examined “Financing Agriculture in Nigeria through Agricultural Extension Services of Agricultural Development Programmes.” It sought to ascertain the extent to which agricultural extension services of the agricultural development programmes have impacted the financing of agriculture in six selected local government areas in Edo South senatorial district, Nigeria using a sample of 120 respondents. Stratified random sampling was used to select the respondents. Interview schedule served as the research instrument. The research data were analyzed using t-test and Pearson correlation, which served as the inferential statistics. The research findings showed that the extension services of ADP have impacted significantly on crop development in the selected communities but have not had significant impact on employment creation and the development of infrastructural facilities. The study also revealed that there was no significant difference between the implementation of the projects in the selected communities, as revealed by the correlation test. On the basis of the research findings, the need for a complete redesign of the project to ensure that it achieves its stated goals as well as ensure proper monitoring of its implementation were suggested, among other

Double effect of La as a promoter for Ni/Al2O3 cordierite monoliths in the oxydehydrogenation of ethane (ODE)

In the present work different amounts of lanthanum were added to Ni/Al 2 O 3 cordierite monoliths with the objective to enhance the catalytic performance of the un-promoted structured catalyst in the oxidative dehydrogenation of ethane (ODE). The impact of the amount of promoter on the catalytic performance of the structured catalysts is discussed through the use of different characterization techniques: LRS, FTIR, Py-TPD, TPR, XPS and SEM-EDX. The incorporation of La was found to increase ethane conversion by an increase in the reducibility of Ni species, with a drop in the ethylene selectivity. Despite this drop, at constant reaction temperature the olefin selectivity maintained a constant value with the increase of ethane conversion, generating a beneficial effect in these catalysts. The presence of La generated: i) a new type of Ni 2+ species due to Ni-La-O interactions and ii) La-Al-O species, which moderated the Ni-Al ones promoting the drop of the ethylene selectivity. Both species also modify the total acidity and reduce the strong acid sites, preventing ethylene oxidation. Thus, as the ethylene production increases, its selectivity remains invariant. An optimal La/Ni ratio was found around 0.08, which generated appropriate interactions among the active species, boosting the ethylene yield at 400 °C by 2.7 times from 4.9% (un-promoted structured catalyst, Ni-M) to 13.4% (NiLa-M, La/Ni: 0.08).Fil: Brussino, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; ArgentinaFil: Bortolozzi, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; ArgentinaFil: Dalla Costa, B.O.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; ArgentinaFil: Banus, Ezequiel David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; ArgentinaFil: Ulla, Maria Alicia del H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; Argentin