Increased demand for rapid access to UK magnetic observatory data : implications for quality control procedures

During the last decade the demand for magnetic observatory data has steadily increased both from the scientific community and in particular from commercial organisations. Not only are the quantity of data products greater now but the speed at which they are delivered is faster and the quality of the data provided better. The modern user requirements for timely data have prompted the need for improved automatic procedures utilising the new technologies available. This has to be balanced against the user requirements for accuracy, which necessitate rigorous quality control procedures. While some of these have been automated, as is shown in the flow diagram, there remains a requirement for human interpretation and action if and when the data contain errors. Software development to reduce this human intervention is on-going

Building a Culture of Learning: Teaching a Complex Organization How to Fish

Many social sector organizations are looking to balance their strategic plans with an ability to respond more quickly to change as it unfolds in their communities. For many years — but gaining particular urgency in 2015 — Kaiser Permanente Community Health saw a need to better understand the progress and impact of its portfolio and use its data to adapt strategy in response to its changing context. To increase its capacity for strategic learning, Community Health worked with FSG to develop and implement a system called Measurement and Evaluation for Learning and Outcomes. While this process was tailored to Community Health, its underlying thinking, approach, and lessons learned can be informative to many others who are thinking about how to position their organizations and communities to thrive in times of change. This article shares the key approaches used to equip Community Health to operationalize learning and reflect on the results so far, as well as some of the ingredients for success that allowed it to make tremendous progress in a relatively short period of time

Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy

BACKGROUND: Autophagy (macroautophagy), a cellular process of “self-eating”, segregates damaged/aged organelles into vesicles, fuses with lysosomes, and enables recycling of the digested materials. The precise origin(s) of the autophagosome membrane is unclear and remains a critical but unanswered question. Endoplasmic reticulum, mitochondria, Golgi complex, and the plasma membrane have been proposed as the source of autophagosomal membranes. FINDINGS: Using electron microscopy, immunogold labeling techniques, confocal microscopy, and flow cytometry we show that mitochondria can directly donate their membrane material to form autophagosomes. We expand upon earlier studies to show that mitochondria donate their membranes to form autophagosomes during basal and drug-induced autophagy. Moreover, electron microscopy and immunogold labeling studies show the first physical evidence of mitochondria forming continuous structures with LC3-labeled autophagosomes. The mitochondria forming these structures also stain positive for parkin, indicating that these mitochondrial-formed autophagosomes represent a novel mechanism of parkin-associated mitophagy. CONCLUSIONS: With the on-going debate regarding autophagosomal membrane origin, this report demonstrates that mitochondria can donate membrane materials to form autophagosomes. These structures may also represent a novel form of mitophagy where the mitochondria contribute to the formation of autophagosomes. This novel form of parkin-associated mitophagy may be a more efficient bio-energetic process compared with de novo biosynthesis of a new membrane, particularly if the membrane is obtained, at least partly, from the organelle being targeted for later degradation in the mature autolysosome

Board Games for Health: A Systematic Literature Review and Meta-Analysis

Nondigital board games are being used to engage players and impact outcomes in health and medicine across diverse populations and contexts. This systematic review and meta-analysis describes and summarizes their impact based on randomized and nonrandomized controlled trials. An electronic search resulted in a review of n = 21 eligible studies. Sample sizes ranged from n = 17 to n = 3110 (n = 6554 total participants). A majority of the board game interventions focused on education to increase health-related knowledge and behaviors (76%, n = 16). Outcomes evaluated included self-efficacy, attitudes/beliefs, biological health indicators, social functioning, anxiety, and executive functioning, in addition to knowledge and behaviors. Using the Cochrane Collaboration tool for assessing bias, most studies (52%, n = 11) had an unclear risk of bias (33% [n = 7] had a high risk and 14% [n = 3] had a low risk). Statistical tests of publication bias were not significant. A random-effects meta-analysis showed a large average effect of board games on health-related knowledge (d* = 0.82, 95% confidence interval; CI [0.15–1.48]), a small-to-moderate effect on behaviors (d* = 0.33, 95% CI [0.16–0.51]), and a small-to-moderate effect on biological health indicators (d* = 0.37, 95% CI [0.21–0.52]). The findings contribute to the literature on games and gamified approaches in healthcare. Future research efforts should aim for more consistent high scientific standards in their evaluation protocols and reporting methodologies to provide a stronger evidence base

Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial.

ObjectivesThe objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.DesignThis was a phase 2, randomized, double-blind, placebo-controlled trial.SettingThe study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.ParticipantsWe enrolled 936 HIV-negative women at high risk of HIV infection into this study.InterventionParticipants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.Outcome measuresThe primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.ResultsStudy participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03-1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.ConclusionDaily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study

Ixazomib for relapsed or refractory multiple myeloma : review from an evidence review group on a NICE single technology appraisal

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer’s first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer’s use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group’s main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda’s third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties

Head-Up : co-designing novel neck orthosis for neck weakness in MND

Introduction : People with Motor Neurone Disease (MND) often develop weak neck muscles, leading to pain, restricted movement and problems with swallowing, breathing and communication. Ideally, a neck collar would help alleviate these. However, neck collars currently available are of limited use for people with MND and often rejected by patients. The same is true for patients with neck weakness due to other conditions. The Head-Up project is a 2 year study funded by the National Institute for Health Research's Invention for Innovation, or i4i, programme with a budget of £400k. Its principal aim is to develop a novel neck orthosis for neck weakness that supports whilst allowing freedom to move without negatively impacting quality of life. The research is a collaboration between clinicians, engineers, creative designers, patients and carer who will be working closely together is a co-design process. Manufacturers will be brought into this process at a later date. Ethical approval has been granted where necessary for all participatory elements. Methods The co-design process will inherently elicit subjective views. As such, prior to starting this workpackage, it was considered necessary to create a measure for this subjectivity and to give the design team a greater empathetic understanding of the inadequacies of current provision for this user group. This has been achieved by a combined clinical comfort assessment and engineering simulation. An engineering simulation of the head, neck and upper torso has been developed using Finite Element Analysis. This has been called the Neck Assessment Tool (NAT). Real body geometry was obtained via a 3D laser scan. The neck has been modelled without any structural integrity such that the head will drop without support. The body model has been meshed and constrained to represent this scenario. The geometry of different neck collar models were created in separate files and meshed. Individually they are imported into the body model, appropriate contact conditions applied and the model is processed. Each model tells the researchers where there is contact between body and collar and, relatively, the pressure of that contact. A clinical comfort assessment pilot study has been conducted using the design team members. This is based on location mapping from the McGill pain questionnaire and a Visual Analogue Scale. 5 different neck collars were identified based on common usage and distinct design differences. The members of the research team wore each collar for a day with recovery periods between. During each test period the participants recorded locations of pain/discomfort and perceptions of relative associated scales. They recorded other data relating to emotional reactions caused by the collars, impact on specific Activities of Daily Living (ADL's) and aesthetic considerations. Results The NAT has been conducted on 2 collars and the comfort assessment on 5, 2 of which are those tested in NAT. Comparisons between the comfort assessment and NAT demonstrate acceptable correlation, validating the simulation. The comfort assessment participant reporting forms have been refined and recruitment is under way to roll out to a wider population of health volunteers and use with MND volunteers to report about experiences of their specific collars as and when used. The design team reported significant differences in their perceptions of neck collars before and after the comfort assessment that will positively impact the co-design process. References 1. Ambrogio N et al, 'A Comparison of Three Types of Neck Support in Fibromyalgia Patients', Arthritis Care and Research (1998), v11, n5, pp 405-410 2. Bowen SJ, Chamberlain PM, 'Engaging the Ageing: Designing Artefacts to Provoke Dialogue', Designing Inclusive Futures (2008) Part I, 35-44, DOI: 10.1007/978-1-84800-211-1_4 3. 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Miller RG et al, ' Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management and cognitive/behavioural impairment(an evidence based review)', Neurology (2009), v73, pp 1218-1225 8. Motor Neurone Disease Association, 'Head Supports', www.mndassociation.org/documents.rm?id=28 9. Thumbikat P, Bailey C and Datta D, 'Orthoses for neck control', ACNR (2006) v6, pp 18-19 10. Qing Hang Zhanga, Ee Chon Teoa, Hong Wan Nga, Vee Sin Lee, 'Finite element analysis of moment-rotation relationships for human cervical spine', Journal of Biomechanics (2006), v39, n1, pp1 89–19