The All Wales Medicines Strategy Group: 18 years' experience of a national medicines optimisation committee

Aims To review the medicines optimisation activities of the All Wales Medicines Strategy Group (AWMSG), a committee established in 2002 to advise the Welsh Government on “all matters related to prescribing”. Although AWMSG conducts other activities (e.g., health technology appraisal for medicines), we focus here on its role in advising on medicines optimisation. Methods Prescribing indicators have been used in Wales to measure change, together with data on volumes and costs of medicines dispensed. A range of improvement strategies have been categorised under the “four Es”, namely educational initiatives, economic incentives, “engineering” and “enforcement”. Results AWMSG has helped health professionals in NHS Wales to reduce harm and waste, and to reduce inappropriate local or regional duplication and variation. Specific initiatives include the achievement of major cost savings by supporting increased generic prescribing and an “invest to save” approach related to prescribing of hypnotics and tranquillisers, non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors. AWMSG also successfully commissioned the introduction of a single national in-patient medication chart for Wales in 2004. Ongoing priorities include a focus on reducing prescribing of certain medicines deemed “low value for prescribing” and on optimising the use of biosimilar medicines. Conclusions Since 2002, AWMSG has acted as a national medicines optimisation committee in Wales. From the outset, pharmacists and clinical pharmacologists have collaborated closely and shared their complementary expertise to make a much greater contribution to the safe, effective and cost-effective use of medicines than either group could have achieved by working separately

Recent advances in the structural and molecular biology of type IV secretion systems

Bacteria use type IV secretion (T4S) systems to deliver DNA and protein substrates to a diverse range of prokaryotic and eukaryotic target cells. T4S systems have great impact on human health, as they are a major source of antibiotic resistance spread among bacteria and are central to infection processes of many pathogens. Therefore, deciphering the structure and underlying translocation mechanism of T4S systems is crucial to facilitate development of new drugs. The last five years have witnessed considerable progress in unraveling the structure of T4S system subassemblies, notably that of the T4S system core complex, a large 1 MegaDalton (MDa) structure embedded in the double membrane of Gram-negative bacteria and made of 3 of the 12 T4S system components. However, the recent determination of the structure of ∼3 MDa assembly of 8 of these components has revolutionized our views of T4S system architecture and opened up new avenues of research, which are discussed in this review

The Effectiveness of Non-pyrethroid Insecticide-treated Durable Wall Lining to Control Malaria in Rural Tanzania: Study Protocol for a Two-armed Cluster Randomized Trial.

Despite considerable reductions in malaria achieved by scaling-up long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), maintaining sustained community protection remains operationally challenging. Increasing insecticide resistance also threatens to jeopardize the future of both strategies. Non-pyrethroid insecticide-treated wall lining (ITWL) may represent an alternate or complementary control method and a potential tool to manage insecticide resistance. To date no study has demonstrated whether ITWL can reduce malaria transmission nor provide additional protection beyond the current best practice of universal coverage (UC) of LLINs and prompt case management. A two-arm cluster randomized controlled trial will be conducted in rural Tanzania to assess whether non-pyrethroid ITWL and UC of LLINs provide added protection against malaria infection in children, compared to UC of LLINs alone. Stratified randomization based on malaria prevalence will be used to select 22 village clusters per arm. All 44 clusters will receive LLINs and half will also have ITWL installed on interior house walls. Study children, aged 6 months to 11 years old, will be enrolled from each cluster and followed monthly to estimate cumulative incidence of malaria parasitaemia (primary endpoint), time to first malaria episode and prevalence of anaemia before and after intervention. Entomological inoculation rate will be estimated using indoor CDC light traps and outdoor tent traps followed by detection of Anopheles gambiae species, sporozoite infection, insecticide resistance and blood meal source. ITWL bioefficacy and durability will be monitored using WHO cone bioassays and household surveys, respectively. Social and cultural factors influencing community and household ITWL acceptability will be explored through focus-group discussions and in-depth interviews. Cost-effectiveness, compared between study arms, will be estimated per malaria case averted. This protocol describes the large-scale evaluation of a novel vector control product, designed to overcome some of the known limitations of existing methods. If ITWL is proven to be effective and durable under field conditions, it may warrant consideration for programmatic implementation, particularly in areas with long transmission seasons and where pyrethroid-resistant vectors predominate. Trial findings will provide crucial information for policy makers in Tanzania and other malaria-endemic countries to guide resource allocations for future control efforts

Identification and prioritization of critical success factors in faith-based and non-faith-based organizations’ humanitarian supply chain

In the last few decades, an exponential increase in the number of disasters, and their complexity has been reported, which ultimately put much pressure on relief organizations. These organizations cannot usually respond to the disaster on their own, and therefore, all actors involved in relief efforts should have end-to-end synchronization in order to provide relief effectively and efficiently. Consequently, to smoothen the flow of relief operation, a shared understanding of critical success factors in humanitarian supply chain serves as a pre-requisite for successful relief operation. Therefore, any member of the humanitarian supply chain might disrupt this synchronization by neglecting one or several of these critical success factors. However, in this study, we try to investigate how faith-based and non-faith-based relief organizations treat these critical success factors. Moreover, we also try to identify any differences between Islamic and Christian relief organizations in identifying and prioritizing these factors. To achieve the objective of this study, we used a two-stage approach; in the first stage, we collected the critical success factors from existing humanitarian literature. Whereas, in the second stage, using an online questionnaire, we collected data on the importance of selected factors from humanitarian relief organizations from around the world in collaboration with World Association of Non-Governmental Organizations (WANGO). Later, responses were analyzed to answer the research questions using non-parametric Binomial and Wilcoxon Rank-Sum tests. Test results indicate that for RQ1, two but all factors are significant for successful relief operation. For RQ2, we found significant differences for some CSF among faith-based and non-faith-based relief organizations. Similarly for RQ3, we found significant differences for some CSF among Islamic and Christian relief organizations

States Of Discontent

Latin America’s recent inclusionary turn centers on changing relationships between the popular sectors and the state. Yet the new inclusion unfolds in a region in which most states are weak and prone to severe pathologies, such as corruption, inefficiency, and particularism. The first part of the chapter outlines an argument, developed at more length elsewhere, regarding how “state crises” helped drive the consolidation of three distinct party system trajectories among the eight South American countries where the Left would eventually win power. The second part of the chapter argues that these trajectories differed in three ways that likely conditioned how the concomitant inclusionary Left turn unfolded in each case: the institutionalization of left-wing parties, the occurrence of state transformation via constitutional reform, and the level of state capacity. The discussion helps highlight the central role of the state and its pathologies in both driving alternative paths of political development and in conditioning the politics of inclusion. By putting the emphasis on the state and its pathologies, we can better consider not just the sources of sociopolitical exclusion but also the limits of sociopolitical inclusion

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049