The effectiveness of using patient-reported outcome measures as quality improvement tools

Aim: To investigate the value of using PROMs as quality improvement tools. Methods: Two systematic reviews were undertaken. The first reviewed the quantitative literature on the impact of PROMs feedback and the second reviewed the qualitative literature on the use of PROMs in practice. These reviews informed the focus of the primary research. A cluster randomised controlled trial (PROFILE) examined the impact of providing peer benchmarked PROMs feedback to consultant orthopaedic surgeons on improving outcomes for hip replacement surgery. Qualitative interviews with surgeons in the intervention arm of the trial examined the view of and reactions to the feedback. Results: The quantitative review of 17 studies found weak evidence to suggest that providing PROMs feedback to professionals improves patient outcomes. The qualitative review of 16 studies identified the barriers and facilitators to the use of PROMs based on four themes: practical considerations, attitudes towards the data, methodological concerns and the impact of feedback on care. The PROFILE trial included 11 surgeons and 215 patients in the intervention arm, and 10 surgeons and 217 patients in the control arm. The trial found no significant difference in the Oxford Hip Score between the arms (-0.7, 95% CI -1.9-0.5, p=0.2). Interviews with surgeons revealed mixed opinions about the value of the PROMs feedback and the information did not promote explicit changes to their practice. Conclusion: It is important to use PROMs which have been validated for the specific purpose of performance measurement, consult with professionals when developing a PROMs feedback intervention, communicate with professionals about the objectives of the data collection, educate professionals on the properties and interpretation of the data, and support professionals in using the information to improve care. It is also imperative that the burden of data collection and dissemination of the information is minimised.

Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

BACKGROUND: The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS: The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS: We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS: In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses.

Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long-run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology.

Phylotastic! Making tree-of-life knowledge accessible, reusable and convenient.

BACKGROUND: Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces. RESULTS: With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (http://www.phylotastic.org), and a server image. CONCLUSIONS: Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.

Oceans and Human Health (OHH): a European Perspective from the Marine Board of the European Science Foundation (Marine Board-ESF)

The oceans and coastal seas provide mankind with many benefits including food for around a third of the global population, the air that we breathe and our climate system which enables habitation of much of the planet. However, the converse is that generation of natural events (such as hurricanes, severe storms and tsunamis) can have devastating impacts on coastal populations, while pollution of the seas by pathogens and toxic waste can cause illness and death in humans and animals. Harmful effects from biogenic toxins produced by algal blooms (HABs) and from the pathogens associated with microbial pollution are also a health hazard in seafood and from direct contact with water. The overall global burden of human disease caused by sewage pollution of coastal waters has been estimated at 4 million lost person-years annually. Finally, the impacts of all of these issues will be exacerbated by climate change. A holistic systems approach is needed. It must consider whole ecosystems, and their sustainability, such as integrated coastal zone management, is necessary to address the highly interconnected scientific challenges of increased human population pressure, pollution and over-exploitation of food (and other) resources as drivers of adverse ecological, social and economic impacts. There is also an urgent and critical requirement for effective and integrated public health solutions to be developed through the formulation of politically and environmentally meaningful policies. The research community required to address "Oceans & Human Health" in Europe is currently very fragmented, and recognition by policy makers of some of the problems, outlined in the list of challenges above, is limited. Nevertheless, relevant key policy issues for governments worldwide include the reduction of the burden of disease (including the early detection of emerging pathogens and other threats) and improving the quality of the global environment. Failure to effectively address these issues will impact adversely on efforts to alleviate poverty, sustain the availability of environmental goods and services and improve health and social and economic stability; and thus, will impinge on many policy decisions, both nationally and internationally. Knowledge exchange (KE) will be a key element of any ensuing research. KE will facilitate the integration of biological, medical, epidemiological, social and economic disciplines, as well as the emergence of synergies between seemingly unconnected areas of science and socio-economic issues, and will help to leverage knowledge transfer across the European Union (EU) and beyond. An integrated interdisciplinary systems approach is an effective way to bring together the appropriate groups of scientists, social scientists, economists, industry and other stakeholders with the policy formulators in order to address the complexities of interfacial problems in the area of environment and human health. The Marine Board of the European Science Foundation Working Group on "Oceans and Human Health" has been charged with developing a position paper on this topic with a view to identifying the scientific, social and economic challenges and making recommendations to the EU on policy-relevant research and development activities in this arena. This paper includes the background to health-related issues linked to the coastal environment and highlights the main arguments for an ecosystem-based whole systems approach.

Influences of the Oceans on Human Health and Well-Being

Human health and well-being are tied to the vitality of the global ocean and coastal systems on which so many live and rely. We engage with these extraordinary environments to enhance both our health and our well-being. But, we need to recognize that introducing contaminants and otherwise altering these ocean systems can harm human health and well-being in significant and substantial ways. These are complex, challenging, and critically important themes. How the human relationship to the oceans evolves in coming decades may be one of the most important connections in understanding our personal and social well-being. Yet, our understanding of this relationship is far too limited. This remarkable volume brings experts from diverse disciplines and builds a workable understanding of breadth and depth of the processes – both social and environmental – that will help us to limit future costs and enhance the benefits of sustainable marine systems. In particular, the authors have developed a shared view that the global coastal environment is under threat through intensified natural resource utilization, as well as changes to global climate and other environmental systems. All these changes contribute individually, but more importantly cumulatively, to higher risks for public health and to the global burden of disease. This pioneering book will be of value to advanced undergraduate and postgraduate students taking courses in public health, environmental, economic, and policy fields. Additionally, the treatment of these complex systems is of essential value to the policy community responsible for these questions and to the broader audience for whom these issues are more directly connected to their own health and well-being.

The Effect of Human RIghts on Criminal Evidentiary Processes: Convergence, Divergence or Realignment?

This article examines the contribution which the European Court of Human Rights has made to the development of common evidentiary processes across the common law and civil law systems of criminal procedure in Europe. It is argued that the continuing use of terms such as 'adversarial' and 'inquisitorial' to describe models of criminal proof and procedure has obscured the genuinely transformative nature of the Court's jurisprudence. It is shown that over a number of years the Court has been steadily developing a new model of proof that is better characterised as 'participatory' than as 'adversarial' or 'inquisitorial'. Instead of leading towards a convergence of existing 'adversarial' and 'inquisitorial' models of proof, this is more likely to lead towards a realignment of existing processes of proof which nonetheless allows plenty of scope for diverse application in different institutional and cultural settings.

Prevalence of early and late age-related macular degeneration in a rural population in Northern India: The INDEYE Feasibility Study

PURPOSE. To assess the prevalence of age-related macular degeneration (AMD) in a rural population in Northern India. METHODS. In a pilot feasibility study, 1443 people (median age, 60 years; 52% women), were identified from enumeration of the 50+ age group in 11 randomly sampled villages from a rural, periurban district of Haryana, Northern India. Of those identified, 87% attended an eye examination that included digital fundus photography. Fundus images were graded at a single reading center using definitions from the Wisconsin Age-Related Maculopathy Grading System. RESULTS. Fundus photographs were available for 1101 participants. Overall, 28.8% of participants had ungradable fundus images due to cataract. Including all with ungradable images in the denominator, the prevalence of soft drusen was 34.0% (95% confidence interval [CI] 26.1–42.9); of soft indistinct drusen, 2.2% (95% CI, 1.1–4.4); and of pigmentary irregularities, 10.8% (95% CI, 7.1–16.1). There were 15 (1.4%) cases of late-stage AMD (95% CI, 0.8–2.3) with the prevalence rising from 0.4% in the 50- to 59-year age range to 4.6% in those aged 70 years or older. CONCLUSIONS. Drusen and pigmentary irregularities are common among the rural northern Indian population. The prevalence of late AMD is similar to that encountered in Western settings and is likely to contribute significantly to the burden of vision loss in older people in the developing world.

Evaluation of N (epsilon)-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy.

AIMS/HYPOTHESIS: Recent studies suggest that oxidative stress should be monitored alongside HbA(1c) to identify subgroups of diabetic patients at high risk of initiation or progression of retinopathy. The acrolein-derived advanced lipoxidation end-product (ALE), [Formula: see text]-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine), is a useful biomarker that reflects the cumulative burden of oxidative stress over long periods of time. The purpose of the present study was to investigate whether serum and haemoglobin levels of FDP-lysine are associated with the severity of diabetic retinopathy in type 1 and type 2 diabetic patients.

METHODS: Serum and haemoglobin levels of FDP-lysine were measured by competitive ELISA in 59 type 1 and 76 type 2 diabetic patients with no retinopathy, non-proliferative retinopathy or proliferative retinopathy (mean age [+/-SEM] 54.3 +/- 1.3 years), and in 47 non-diabetic control individuals (mean age 51.9 +/- 2.1 years).

RESULTS: Serum and haemoglobin levels of FDP-lysine were significantly increased in diabetic patients compared with control individuals (p = 0.04 and p = 0.002, respectively). However, no significant association was found between levels of serum FDP-lysine and the severity of diabetic retinopathy (p = 0.97). In contrast, increased haemoglobin FDP-lysine levels were observed in patients with proliferative retinopathy compared with patients without retinopathy and with non-proliferative retinopathy (p = 0.04). The relationship of FDP-lysine with proliferative retinopathy was unaltered after adjustment for HbA(1c), or other clinical parameters.

CONCLUSIONS/INTERPRETATION: Our data suggest that haemoglobin FDP-lysine may provide a useful risk marker for the development of proliferative diabetic retinopathy independently of HbA(1c), and that elevated intracellular ALE formation may be involved in the pathogenesis of this sight-threatening complication of diabetes.

Quantifying Alcohol-Related Mortality: Should Alcohol-Related Contributory Causes of Death be Included?

Aims: The aim of the study was to assess whether alcohol-related mortality data in the UK should be extended to include contributory as well as underlying cause of death. Methods: A total of 101,320 deaths registered in Northern Ireland between 2001 and 2007 were analysed to determine the quantity and characteristics of those with an underlying or contributory alcohol-related cause of death. Results: Alcohol was found to be an underlying cause of death in 1690 cases (1.7% of deaths) and a contributory cause in a further 1105 cases. Analyses show that the addition of alcohol-related contributory causes of deaths would increase the male-female ratio, result in steeper socio-economic gradients and amplify the apparent rate of increase of alcohol-related deaths. The significant contribution of alcohol to external causes of death, such as accidents and suicide, is also more evident. Conclusions: Using only underlying cause of death undoubtedly underestimates the burden of alcohol-related harm and may provide an inaccurate picture of those most likely to suffer from an alcohol-related death, especially among younger men.

The Social Politics of Breastfeeding: Norms, Situations and Policy Implications

This paper aims to explore the assumptions concerning the dynamics of human action underpinning breastfeeding promotion campaigns in the UK. Drawing on qualitative interviews with mothers, the ways in which three problematic assumptions shape both the promotion and experience of contemporary breastfeeding promotion campaigns are explored, in the light of Joas’s theorisation of action’s creativity and pragmatism. Public health efforts to establish breastfeeding as a rational standard against which good mothering can be judged, in ways which rely on a de-contextualised understanding of human action as instrumentally rational, where bodies are imagined as pliable instruments of human intentions, are explored as they play out in the experiences of women embarking on motherhood. The paper concludes that a target-driven health-promotion policy, relying on a mechanistic account of social and emotional life, is contributing to the burden of early motherhood in ways that are not conducive to infant and maternal health and attachment.

Protection of cattle against a natural infection of Fasciola hepatica by vaccination with recombinant cathepsin L1 (rFhCL1)

The liver fluke, Fasciola hepatica causes liver fluke disease, or fasciolosis, in ruminants such as cattle and sheep. An effective vaccine against the helminth parasite is essential to reduce our reliance on anthelmintics, particularly in light of frequent reports of resistance to some frontline drugs. In our study, Friesian cattle (13 per group) were vaccinated with recombinant F. hepatica cathepsin L1 protease (rFhCL1) formulated in mineral-oil based adjuvants, Montanide (TM) ISA 70VG and ISA 206VG. Following vaccination the animals were exposed to fluke-contaminated pastures for 13 weeks. At slaughter, there was a significant reduction in fluke burden of 48.2% in the cattle in both vaccinated groups, relative to the control non-vaccinated group, at p

Evaluation of hepatic changes and local and systemic immune responses in goats immunized with recombinant Peroxiredoxin (Prx) and challenged with Fasciola hepatica

Protection against Fasciola hepatica in goats immunized with Peroxiredoxin (Prx) was assessed. The experimental trial consisted of three groups of seven animals: group 1 were unimmunized and uninfected, group 2 were immunized with adjuvant only and group 3 were immunized with recombinant Prx in adjuvant (immunized and infected). Immunization with Prx in Quil A adjuvant, group 3, induced a reduction in fluke burden of 33.04% when compared to adjuvant control, group 2, although this difference was not significant. The hepatic gross and microscopical morphometric study revealed lower damage in the Prx-immunized compared to group 2 (p

Living and coping with Parkinson's disease: Perceptions of informal carers

A review of the literature highlights the important role informal carers play in the provision of palliative care in the community. In order to explore the caring experience of relatives with Parkinson's Disease (PD), interviews were conducted with 26 informal family caregivers. Interviews were taped, transcribed and subjected to content analysis. All caregivers were spouses, the majority female (n=17) and all were responsible for providing physical, social and emotional care in the home. Although they viewed care giving as their role and duty, the results highlight the widespread burden of providing care on the emotional and physical health of the caregivers. The financial implications for providing care were outlined, with many reporting difficulty in accessing benefits. From the point of diagnosis, which had a huge emotional impact on relatives and carers, carers did not feel health professionals integrated them within the caring journey. Since diagnosis, carers commented on the lack of continued and coordinated care plans for relatives, resulting in symptoms being mismanaged and care opportunities for relatives and carers missed. Stereotypes of the meaning and timing of palliative care were common with many viewing it as being synonymous with cancer and not applicable to a person with PD. As the well-being of the informal carer directly influences the care of the person with PD, support interventions are required to relieve their burden, maximize outcomes and ensure targeting of services. © The Author(s) 2010.

The Interlaboratory Robustness Of Next-Generation Sequencing (IRON) Study Phase II: Deep-Sequencing Analyses Of Hematological Malignancies Performed In 8,867 Cases By An International Network Involving 27 Laboratories

Introduction: Amplicon deep-sequencing using second-generation sequencing technology is an innovative molecular diagnostic technique and enables a highly-sensitive detection of mutations. As an international consortium we had investigated previously the robustness, precision, and reproducibility of 454 amplicon next-generation sequencing (NGS) across 10 laboratories from 8 countries (Leukemia, 2011;25:1840-8).

Aims: In Phase II of the study, we established distinct working groups for various hematological malignancies, i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and multiple myeloma. Currently, 27 laboratories from 13 countries are part of this research consortium. In total, 74 gene targets were selected by the working groups and amplicons were developed for a NGS deep-sequencing assay (454 Life Sciences, Branford, CT). A data analysis pipeline was developed to standardize mutation interpretation both for accessing raw data (Roche Amplicon Variant Analyzer, 454 Life Sciences) and variant interpretation (Sequence Pilot, JSI Medical Systems, Kippenheim, Germany).

Results: We will report on the design, standardization, quality control aspects, landscape of mutations, as well as the prognostic and predictive utility of this assay in a cohort of 8,867 cases. Overall, 1,146 primer sequences were designed and tested. In detail, for example in AML, 924 cases had been screened for CEBPA mutations. RUNX1 mutations were analyzed in 1,888 cases applying the deep-sequencing read counts to study the stability of such mutations at relapse and their utility as a biomarker to detect residual disease. Analyses of DNMT3A (n=1,041) were focused to perform landscape investigations and to address the prognostic relevance. Additionally, this working group is focusing on TET2, ASXL1, and TP53 analyses. A novel prognostic model is being developed allowing stratification of AML into prognostic subgroups based on molecular markers only. In ALL, 1,124 pediatric and adult cases have been screened, including 763 assays for TP53 mutations both at diagnosis and relapse of ALL. Pediatric and adult leukemia expert labs developed additional content to study the mutation incidence of other B and T lineage markers such as IKZF1, JAK2, IL7R, PAX5, EP300, LEF1, CRLF2, PHF6, WT1, JAK1, PTEN, AKT1, IL7R, NOTCH1, CREBBP, or FBXW7. Further, the molecular landscape of CLL is changing rapidly. As such, a separate working group focused on analyses including NOTCH1, SF3B1, MYD88, XPO1, FBXW7 and BIRC3. Currently, 922 cases were screened to investigate the range of mutational burden of NOTCH1 mutations for their prognostic relevance. In MDS, RUNX1 mutation analyses were performed in 977 cases. The prognostic relevance of TP53 mutations in MDS was assessed in additional 327 cases, including isolated deletions of chromosome 5q. Next, content was developed targeting genes of the cellular splicing component, e.g. SF3B1, SRSF2, U2AF1, and ZRSR2. In BCR-ABL1-negative MPN, nine genes of interest (JAK2, MPL, TET2, CBL, KRAS, EZH2, IDH1, IDH2, ASXL1) have been analyzed in a cohort of 155 primary myelofibrosis cases searching for novel somatic mutations and addressing their relevance for disease progression and leukemia transformation. Moreover, an assay was developed and applied to CMML cases allowing the simultaneous analysis of 25 leukemia-associated target genes in a single sequencing run using just 20 ng of starting DNA. Finally, nine laboratories are studying CML, applying ultra-deep sequencing of the BCR-ABL1 tyrosine kinase domain. Analyses were performed on 615 cases investigating the dynamics of expansion of mutated clones under various tyrosine kinase inhibitor therapies.

Conclusion: Molecular characterization of hematological malignancies today requires high diagnostic sensitivity and specificity. As part of the IRON-II study, a network of laboratories analyzed a variety of disease entities applying amplicon-based NGS assays. Importantly, the consortium not only standardized assay design for disease-specific panels, but also achieved consensus on a common data analysis pipeline for mutation interpretation. Distinct working groups have been forged to address scientific tasks and in total 8,867 cases had been analyzed thus far.