Levonorgestrel-releasing intrauterine system vs. usual medical treatment for menorrhagia: An economic evaluation alongside a randomised controlled trial

Objective: To undertake an economic evaluation alongside the largest randomised controlled trial comparing Levonorgestrel-releasing intrauterine device ('LNG-IUS') and usual medical treatment for women with menorrhagia in primary care; and compare the cost-effectiveness findings using two alternative measures of quality of life. Methods: 571 women with menorrhagia from 63 UK centres were randomised between February 2005 and July 2009. Women were randomised to having a LNG-IUS fitted, or usual medical treatment, after discussing with their general practitioner their contraceptive needs or desire to avoid hormonal treatment. The treatment was specified prior to randomisation. For the economic evaluation we developed a state transition (Markov) model with a 24 month follow-up. The model structure was informed by the trial women's pathway and clinical experts. The economic evaluation adopted a UK National Health Service perspective and was based on an outcome of incremental cost per Quality Adjusted Life Year (QALY) estimated using both EQ-5D and SF-6D. Results: Using EQ-5D, LNG-IUS was the most cost-effective treatment for menorrhagia. LNG-IUS costs £100 more than usual medical treatment but generated 0.07 more QALYs. The incremental cost-effectiveness ratio for LNG-IUS compared to usual medical treatment was £1600 per additional QALY. Using SF-6D, usual medical treatment was the most cost-effective treatment. Usual medical treatment was both less costly (£100) and generated 0.002 more QALYs. Conclusion: Impact on quality of life is the primary indicator of treatment success in menorrhagia. However, the most costeffective treatment differs depending on the quality of life measure used to estimate the QALY. Under UK guidelines LNG-IUS would be the recommended treatment for menorrhagia. This study demonstrates that the appropriate valuation of outcomes in menorrhagia is crucial. Copyright: © 2014 Sanghera et al

Laser-heated capillary discharge plasma waveguides for electron acceleration to 8 GeV

A plasma channel created by the combination of a capillary discharge and inverse Bremsstrahlung laser heating enabled the generation of electron bunches with energy up to 7.8 GeV in a laser-driven plasma accelerator. The capillary discharge created an initial plasma channel and was used to tune the plasma temperature, which optimized laser heating. Although optimized colder initial plasma temperatures reduced the ionization degree, subsequent ionization from the heater pulse created a fully ionized plasma on-axis. The heater pulse duration was chosen to be longer than the hydrodynamic timescale of ≈ 1 ns, such that later temporal slices were more efficiently guided by the channel created by the front of the pulse. Simulations are presented which show that this thermal self-guiding of the heater pulse enabled channel formation over 20 cm. The post-heated channel had lower on-axis density and increased focusing strength compared to relying on the discharge alone, which allowed for guiding of relativistically intense laser pulses with a peak power of 0.85 PW and wakefield acceleration over 15 diffraction lengths. Electrons were injected into the wake in multiple buckets and times, leading to several electron bunches with different peak energies. To create single electron bunches with low energy spread, experiments using localized ionization injection inside a capillary discharge waveguide were performed. A single injected bunch with energy 1.6 GeV, charge 38 pC, divergence 1 mrad, and relative energy spread below 2% full-width half-maximum was produced in a 3.3 cm-long capillary discharge waveguide. This development shows promise for mitigation of energy spread and future high efficiency staged acceleration experiments

Strengthening fairness, transparency and accountability in health care priority setting at district level in Tanzania

Health care systems are faced with the challenge of resource scarcity and have insufficient resources to respond to all health problems and target groups simultaneously. Hence, priority setting is an inevitable aspect of every health system. However, priority setting is complex and difficult because the process is frequently influenced by political, institutional and managerial factors that are not considered by conventional priority-setting tools. In a five-year EU-supported project, which started in 2006, ways of strengthening fairness and accountability in priority setting in district health management were studied. This review is based on a PhD thesis that aimed to analyse health care organisation and management systems, and explore the potential and challenges of implementing Accountability for Reasonableness (A4R) approach to priority setting in Tanzania. A qualitative case study in Mbarali district formed the basis of exploring the sociopolitical and institutional contexts within which health care decision making takes place. The study also explores how the A4R intervention was shaped, enabled and constrained by the contexts. Key informant interviews were conducted. Relevant documents were also gathered and group priority-setting processes in the district were observed. The study revealed that, despite the obvious national rhetoric on decentralisation, actual practice in the district involved little community participation. The assumption that devolution to local government promotes transparency, accountability and community participation, is far from reality. The study also found that while the A4R approach was perceived to be helpful in strengthening transparency, accountability and stakeholder engagement, integrating the innovation into the district health system was challenging. This study underscores the idea that greater involvement and accountability among local actors may increase the legitimacy and fairness of priority-setting decisions. A broader and more detailed analysis of health system elements, and socio-cultural context is imperative in fostering sustainability. Additionally, the study stresses the need to deal with power asymmetries among various actors in priority-setting contexts

Priority setting in developing countries health care institutions: the case of a Ugandan hospital

BACKGROUND: Because the demand for health services outstrips the available resources, priority setting is one of the most difficult issues faced by health policy makers, particularly those in developing countries. However, there is lack of literature that describes and evaluates priority setting in these contexts. The objective of this paper is to describe priority setting in a teaching hospital in Uganda and evaluate the description against an ethical framework for fair priority setting processes – Accountability for Reasonableness. METHODS: A case study in a 1,500 bed national referral hospital receiving 1,320 out patients per day and an average budget of US$ 13.5 million per year. We reviewed documents and carried out 70 in-depth interviews (14 health planners, 40 doctors, and 16 nurses working at the hospital). Interviews were recorded and transcribed. Data analysis employed the modified thematic approach to describe priority setting, and the description was evaluated using the four conditions of Accountability for Reasonableness: relevance, publicity, revisions and enforcement. RESULTS: Senior managers, guided by the hospital strategic plan make the hospital budget allocation decisions. Frontline practitioners expressed lack of knowledge of the process. Relevance: Priority is given according to a cluster of factors including need, emergencies and patient volume. However, surgical departments and departments whose leaders "make a lot of noise" are also prioritized. Publicity: Decisions, but not reasons, are publicized through general meetings and circulars, but this information does not always reach the frontline practitioners. Publicity to the general public was through ad hoc radio programs and to patients who directly ask. Revisions: There were no formal mechanisms for challenging the reasoning. Enforcement: There were no mechanisms to ensure adherence to the four conditions of a fair process. CONCLUSION: Priority setting decisions at this hospital do not satisfy the conditions of fairness. To improve, the hospital should: (i) engage frontline practitioners, (ii) publicize the reasons for decisions both within the hospital and to the general public, and (iii) develop formal mechanisms for challenging the reasoning. In addition, capacity strengthening is required for senior managers who must accept responsibility for ensuring that the above three conditions are met

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

Natriuretic Peptides and Assessment of Cardiovascular Disease Risk in Asymptomatic Persons

Current tools for cardiovascular disease (CVD) risk assessment in asymptomatic individuals are imperfect. Preventive measures aimed only at individuals deemed high risk by current algorithms neglect large numbers of low-risk and intermediate-risk individuals who are destined to develop CVD and who would benefit from early and aggressive treatment. Natriuretic peptides have the potential both to identify individuals at risk for future cardiovascular events and to help detect subclinical CVD. Choosing the appropriate subpopulation to target for natriuretic peptide testing will help maximize the performance and the cost effectiveness. The combined use of multiple risk markers, including biomarkers, genetic testing, and imaging or other noninvasive measures of risk, offers promise for further refining risk assessment algorithms. Recent studies have highlighted the utility of natriuretic peptides for preoperative risk stratification; however, cost effectiveness and outcomes studies are needed to affirm this and other uses of natriuretic peptides for cardiovascular risk assessment in asymptomatic individuals

Future directions in managing aniridia-associated keratopathy

Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies

Physiological and Biomechanical Responses of Highly Trained Distance Runners to Lower-Body Positive Pressure Treadmill Running

Background: As a way to train at faster running speeds, add training volume, prevent injury, or rehabilitate after an injury, lower-body positive pressure treadmills (LBPPT) have become increasingly commonplace among athletes. However, there are conflicting evidence and a paucity of data describing the physiological and biomechanical responses to LBPPT running in highly trained or elite caliber runners at the running speeds they habitually train at, which are considerably faster than those of recreational runners. Furthermore, data is lacking regarding female runners’ responses to LBPPT running. Therefore, this study was designed to evaluate the physiological and biomechanical responses to LBPPT running in highly trained male and female distance runners. Methods: Fifteen highly trained distance runners (seven male; eight female) completed a single running test composed of 4 × 9-min interval series at fixed percentages of body weight ranging from 0 to 30% body weight support (BWS) in 10% increments on LBPPT. The first interval was always conducted at 0% BWS; thereafter, intervals at 10, 20, and 30% BWS were conducted in random order. Each interval consisted of three stages of 3 min each, at velocities of 14.5, 16.1, and 17.7 km·h−1 for men and 12.9, 14.5, and 16.1 km·h−1 for women. Expired gases, ventilation, breathing frequency, heart rate (HR), rating of perceived exertion (RPE), and stride characteristics were measured during each running speed and BWS. Results: Male and female runners had similar physiological and biomechanical responses to running on LBPPT. Increasing BWS increased stride length (p \u3c 0.02) and flight duration (p \u3c 0.01) and decreased stride rate (p \u3c 0.01) and contact time (p \u3c 0.01) in small-large magnitudes. There was a large attenuation of oxygen consumption (VO2) relative to BWS (p \u3c 0.001), while there were trivial-moderate reductions in respiratory exchange ratio, minute ventilation, and respiratory frequency (p \u3e 0.05), and small-large effects on HR and RPE (p \u3c 0.01). There were trivial-small differences in VE, respiratory frequency, HR, and RPE for a given VO2 across various BWS (p \u3e 0.05). Conclusions: The results indicate the male and female distance runners have similar physiological and biomechanical responses to LBPPT running. Overall, the biomechanical changes during LBPPT running all contributed to less metabolic cost and corresponding physiological changes. Keywords: AlterG, Lower-body positive pressure, Body weight support, Anti-gravity, Running, Stride characteristics, Physiological characteristics, Metabolic demand, Oxygen demand, Oxygen cos

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission