Physicochemical equivalence of generic antihypertensive medicines (EQUIMEDS): protocol for a quality of medicines assessment.

BACKGROUND: Prevention and optimal management of hypertension in the general population is paramount to the achievement of the World Heart Federation (WHF) goal of reducing premature cardiovascular disease (CVD) mortality by 25% by the year 2025 and widespread access to good quality antihypertensive medicines is a critical component for achieving the goal. Despite research and evidence relating to other medicines such as antimalarials and antibiotics, there is very little known about the quality of generic antihypertensive medicines in low-income and middle-income countries. The aim of this study was to determine the physicochemical equivalence (percentage of active pharmaceutical ingredient, API) of generic antihypertensive medicines available in the retail market of a developing country. METHODS: An observational design will be adopted, which includes literature search, landscape assessment, collection and analysis of medicine samples. To determine physicochemical equivalence, a multistage sampling process will be used, including (1) identification of the 2 most commonly prescribed classes of antihypertensive medicines prescribed in Nigeria; (2) identification of a random sample of 10 generics from within each of the 2 most commonly prescribed classes; (3) a geographical representative sampling process to identify a random sample of 24 retail outlets in Nigeria; (4) representative sample purchasing, processing to assess the quality of medicines, storage and transport; and (5) assessment of the physical and chemical equivalence of the collected samples compared to the API in the relevant class. In total, 20 samples from each of 24 pharmacies will be tested (total of 480 samples). DISCUSSION: Availability of and access to quality antihypertensive medicines globally is therefore a vital strategy needed to achieve the WHF 25×25 targets. However, there is currently a scarcity of knowledge about the quality of antihypertensive medicines available in developing countries. Such information is important for enforcing and for ensuring the quality of antihypertensive medicines

Equivalence in Active Pharmaceutical Ingredient of Generic Antihypertensive Medicines Available in Nigeria (EQUIMEDS): A Case for Further Surveillance.

BACKGROUND: Widespread access to good quality antihypertensive medicines is a critical component for reducing premature cardiovascular disease (CVD) mortality. Poor-quality medicines pose serious health concerns; however, there remains a knowledge gap about the quality of cardiovascular medicines available in low- and middle-income countries. OBJECTIVES: The aim of this study was to determine the quality of generic antihypertensive medicines available in the retail market of a developing country. METHODS: Samples of the 2 most commonly prescribed classes of antihypertensive medicines were collected from 3 states in 3 different geopolitical zones in Nigeria following a semirandom sampling framework. Medicine samples were purchased by mystery shoppers from 22 pharmacy outlets from 6 local government areas across the 3 states. Medicine quality was determined by measuring the amount of stated active pharmaceutical ingredient using high-performance liquid chromatography with photodiode array detection and classified according to their compliance to the specified pharmacopeia tolerance limits for each antihypertensive drug. RESULTS: Amlodipine and lisinopril were identified as the most commonly prescribed antihypertensive drugs in Nigeria. In total, 361 samples from 22 pharmacies were collected and tested. In total, 24.6% of amlodipine and 31.9% of lisinopril samples were of substandard quality and significantly more samples purchased in rural (59 of 161, 36.7%) compared with urban (32 of 200, 16%) outlets were found to be of substandard quality (p < 0.001). No falsified samples of either amlodipine or lisinopril were detected. There was large variation in price paid for the antihypertensive medicines (range ₦150 to ₦9,750). Of the 24 pharmacy outlets surveyed, 46% stated that patients did not always require a prescription and 21% had previously reported a medicine as falsified or substandard. CONCLUSIONS: More than one-quarter of some commonly prescribed antihypertensive medicines available in Nigeria may be of substandard quality. Enhanced quality assurance processes in low- and middle-income countries, such as Nigeria, are needed to support optimum management

Transdisciplinary diagnostic framework for biodiversity decision-making assessment. D1.7

This deliverable describes the process of developing a transdisciplinary diagnostic framework for biodiversity decision-making carried out in Work Package 1 (WP1) of the EU funded research project PLANET4B. The aim of the process was to help researchers and practitioners in our project become more conscious of the theoretical approaches and languages that may condition the interventions we study and the policy and additional recommendations that we make to societal actors. The starting proposition for this work was that we as PLANET4B partners come from a wide range of different disciplines and practices. Therefore, we needed a shared learning process of our different theoretical and practical lenses and languages. This is necessary to increase our potential as a project to design for transformational change in Work Packages to follow. We report on our testing of Meadows’ (1999) leverage points framework (LPF) as a potential shared conceptual language for transformational change across the places, actors and theories that situate both placebased and sectoral case studies in the project. We report on the opportunities and limitations of the LPF in connecting to (i) theories of change used by research partners in their cases, as well as (ii) bridging conceptually to other “integrating analytical approaches” where PLANET4B has partner expertise; namely “intersectionality analysis”, “discourse analysis” and “reflexivity-contextualisation of interventions”. The report recognises that these integrating approaches are but a subset of possible systems analysis tools in transformative change research. The process of understanding and applying Meadows’ (1999) leverage points framework achieved some shared language and understanding across research disciplines. It helped us to compare assumptions about transformative change across our different case studies. As such, we think we achieved the “process objective” of this initial stage of PLANET4B of using a common framework to diagnose our case studies. However, case studies and experts on other integrating analytical approaches identified several limitations of the LPF. Limitations include the LPF itself being a particular theoretical systems analysis lens which in some cases could exclude practitioners through its unfamiliar concepts. Furthermore, the LPF was identified as being ‘structuralist’ or ‘mechanistic’ in the particular way we tested it in our case studies, not addressing concepts such as agency, power and decision-making. It was critiqued for not being specific to decisions about biodiversity and the related nature values.publishedVersio

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P=0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.

Improved Heterosis Prediction by Combining Information on DNA- and Metabolic Markers

Background: Hybrids represent a cornerstone in the success story of breeding programs. The fundamental principle underlying this success is the phenomenon of hybrid vigour, or heterosis. It describes an advantage of the offspring as compared to the two parental lines with respect to parameters such as growth and resistance against abiotic or biotic stress. Dominance, overdominance or epistasis based models are commonly used explanations. Conclusion/Significance: The heterosis level is clearly a function of the combination of the parents used for offspring production. This results in a major challenge for plant breeders, as usually several thousand combinations of parents have to be tested for identifying the best combinations. Thus, any approach to reliably predict heterosis levels based on properties of the parental lines would be highly beneficial for plant breeding. Methodology/Principal Findings: Recently, genetic data have been used to predict heterosis. Here we show that a combination of parental genetic and metabolic markers, identified via feature selection and minimum-description-length based regression methods, significantly improves the prediction of biomass heterosis in resulting offspring. These findings will help furthering our understanding of the molecular basis of heterosis, revealing, for instance, the presence of nonlinear genotype-phenotype relationships. In addition, we describe a possible approach for accelerated selection in plant breeding

Correction to: The relationship between endogenous thymidine concentrations and [18F]FLT uptake in a range of preclinical tumour models.

Unfortunately, the original version of Figs. 4, 5 and 6b in the article [1] contained errors in the n numbers as indicated on the columns. Please note that column heights and error bars in the original figures and data in the ESM tables are correct and statistical tests are valid. These corrections do not affect any results or conclusions in this article

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P=0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.

Randomized Controlled Trial of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

Background:The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01E and RTS,S/AS02D in infants and young children 5&ndash;17 months of age in Ghana.Methodology:A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule), of 19 months duration was conducted in two (2) centres in Ghana between August 2006 and May 2008. Subjects were allocated randomly (1:1:1:1:1:1) to one of six study groups at each study site, each defining which vaccine should be given and by which schedule (0,1-, 0,1,2- or 0,1,7-months). For the 0,1,2-month schedule participants received RTS,S/AS01E or rabies vaccine at one center and RTS,S/AS01E or RTS,S/AS02D at the other. For the other schedules at both study sites, they received RTS,S/AS01E or RTS,S/AS02D. The primary outcome measure was the occurrence of serious adverse events until 10 months post dose 1.Results:The number of serious adverse events reported across groups was balanced. One child had a simple febrile convulsion, which evolved favourably without sequelae, considered to be related to RTS,S/AS01E vaccination. Low grade reactions occurred slightly more frequently in recipients of RTS,S/AS than rabies vaccines; grade 3 reactions were infrequent. Less local reactogenicity occurred with RTS,S/AS01E than RTS,S/AS02D. Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies. Recipients of RTS,S/AS01E compared to RTS,S/AS02D had higher peak anti-circumsporozoite antibody responses for all 3 schedules. Three dose schedules were more immunogenic than 2 dose schedules. Area under the curve analyses for anti-circumsporozoite antibodies were comparable between the 0,1,2- and 0,1,7-month RTS,S/AS01E schedules.Conclusions:Both candidate malaria vaccines were well tolerated. Anti-circumsporozoite responses were greater with RTS,S/AS01E than RTS,S/AS02D and when 3 rather than 2 doses were given. This study supports the selection of RTS,S/AS01E and a 3 dose schedule for further development in children and infants