Lessons from the evaluation of the UK's NHS R&D Implementation Methods Programme

Background: Concern about the effective use of research was a major factor behind the creation of the NHS R&D Programme in 1991. In 1994, an advisory group was established to identify research priorities in research implementation. The Implementation Methods Programme (IMP) flowed from this, and its commissioning group funded 36 projects. In 2000 responsibility for the programme passed to the National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, which asked the Health Economics Research Group (HERG), Brunel University, to conduct an evaluation in 2002. By then most projects had been completed. This evaluation was intended to cover: the quality of outputs, lessons to be learnt about the communication strategy and the commissioning process, and the benefits from the projects. Methods: We adopted a wide range of quantitative and qualitative methods. They included: documentary analysis, interviews with key actors, questionnaires to the funded lead researchers, questionnaires to potential users, and desk analysis. Results: Quantitative assessment of outputs and dissemination revealed that the IMP funded useful research projects, some of which had considerable impact against the various categories in the HERG payback model, such as publications, further research, research training, impact on health policy, and clinical practice. Qualitative findings from interviews with advisory and commissioning group members indicated that when the IMP was established, implementation research was a relatively unexplored field. This was reflected in the understanding brought to their roles by members of the advisory and commissioning groups, in the way priorities for research were chosen and developed, and in how the research projects were commissioned. The ideological and methodological debates associated with these decisions have continued among those working in this field. The need for an effective communication strategy for the programme as a whole was particularly important. However, such a strategy was never developed, making it difficult to establish the general influence of the IMP as a programme. Conclusion: Our findings about the impact of the work funded, and the difficulties faced by those developing the IMP, have implications for the development of strategic programmes of research in general, as well as for the development of more effective research in this field

Improved Treatment Effect of Triamcinolone Acetonide Extended-Release in Patients with Concordant Baseline Pain Scores on the Average Daily Pain and Western Ontario and McMaster Universities Osteoarthritis Index Pain Scales

Introduction A phase 3 randomized controlled study comparing triamcinolone acetonide extended-release (TA-ER) to conventional TA crystalline suspension (TAcs) reported variable efficacy results. Enrollment criteria may have contributed to this discrepancy, as moderate-to-severe average daily pain (ADP) was required at baseline, whereas no limitations were placed on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A) pain severity. We conducted a post hoc sensitivity analysis to compare treatment effects in patients reporting moderate-to-severe osteoarthritis (OA) pain on both scales. Methods Participants > 40 years old with symptomatic knee OA were randomly assigned to a single intra-articular injection of TA-ER 32 mg, TAcs 40 mg, or saline-placebo and followed for 24 weeks. Patient-reported ADP, WOMAC-A, rescue medication usage, and adverse events (AEs) were assessed. Participants who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥ 5 to ≤ 9, maximum 10 and WOMAC-A ≥ 2, maximum 4) were categorized as “concordant” pain reporters; patients with baseline moderate-to-severe OA on ADP only were termed “discordant” pain reporters. Results Two-hundred-ninety-two concordant pain reporters of 484 total subjects received TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or saline-placebo (n = 97). Baseline characteristics and AE profiles of the concordant and discordant pain responders were consistent with the full analysis population. Among concordant pain reporters, TA-ER significantly (p < 0.05) improved ADP scores vs. TAcs (weeks 5–19; area-under-the-effect [AUE]weeks1–12; AUEweeks1–24) and saline-placebo (weeks 1–20; AUEweeks1–12; AUEweeks1–24). At week 12, a higher proportion reported no knee pain (ADP = 0) with TA-ER (~ 28%) vs. TAcs (~ 8%). TA-ER significantly improved WOMAC-A vs. TAcs at weeks 4, 8, and 12, with significant reduction in rescue medication usage observed with TA-ER from weeks 2 to 20 vs. TAcs. Conclusions In patients reporting moderate-to-severe knee OA pain at baseline based on concordant ADP and WOMAC-A scores, TA-ER provided statistically significant pain relief for ≥ 12 weeks compared with conventional TAcs. Trial Registration ClinicalTrials.gov Identifier: NCT02357459

Discovering unique tobacco use patterns among Alaska Native people

Background . Alaska Native people are disproportionately impacted by tobacco-related diseases in comparison to non-Native Alaskans. Design. We used Alaska&#x0027;s Behavioral Risk Factor Surveillance System (BRFSS) to describe tobacco use among more than 4,100 Alaska Native adults, stratified by geographic region and demographic groups. Results . Overall tobacco use was high: approximately 2 out of every 5 Alaska Native adults reported smoking cigarettes (41.2%) and 1 in 10 reported using smokeless tobacco (SLT, 12.3%). A small percentage overall (4.8%) reported using iq&#x0027;mik, an SLT variant unique to Alaska Native people. When examined by geographic region, cigarette smoking was highest in remote geographic regions; SLT use was highest in the southwest region of the state. Use of iq&#x0027;mik was primarily confined to a specific area of the state; further analysis showed that 1 in 3 women currently used iq&#x0027;mik in this region. Conclusion . Our results suggest that different types of tobacco use are epidemic among diverse Alaska Native communities. Our results also illustrate that detailed analysis within racial/ethnic groups can be useful for public health programme planning to reduce health disparities

The breadth of primary care: a systematic literature review of its core dimensions

Background: Even though there is general agreement that primary care is the linchpin of effective health care delivery, to date no efforts have been made to systematically review the scientific evidence supporting this supposition. The aim of this study was to examine the breadth of primary care by identifying its core dimensions and to assess the evidence for their interrelations and their relevance to outcomes at (primary) health system level. Methods: A systematic review of the primary care literature was carried out, restricted to English language journals reporting original research or systematic reviews. Studies published between 2003 and July 2008 were searched in MEDLINE, Embase, Cochrane Library, CINAHL, King's Fund Database, IDEAS Database, and EconLit. Results: Eighty-five studies were identified. This review was able to provide insight in the complexity of primary care as a multidimensional system, by identifying ten core dimensions that constitute a primary care system. The structure of a primary care system consists of three dimensions: 1. governance; 2. economic conditions; and 3. workforce development. The primary care process is determined by four dimensions: 4. access; 5. continuity of care; 6. coordination of care; and 7. comprehensiveness of care. The outcome of a primary care system includes three dimensions: 8. quality of care; 9. efficiency care; and 10. equity in health. There is a considerable evidence base showing that primary care contributes through its dimensions to overall health system performance and health. Conclusions: A primary care system can be defined and approached as a multidimensional system contributing to overall health system performance and health

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the secretory pathway of perforin/granzymes to kill their target cells. In contrast to NK cells, CTL responses are MHC class I restricted. In this study we analysed the relative activation of CTL and NK cells in relation with MHC class I expression on oral squamous cell carcinomas (OSCCs). MHC class I expression was investigated in 47 OSCCs by immunohistochemistry using HCA2, HC10 and β2-m antibodies. The presence of CTLs, NK cells, and its activation, was investigated in 21 of these OSCCs using respectively, CD8, CD57 and GrB7 antibodies. The Q-Prodit measuring system was used for quantification of cytotoxic cells. All OSCCs showed weak or absent staining of β2-m on the cell surface. The absence of β2-m was significantly associated with absent expression of MHC class I heavy chain as detected by HC10 antibody (P = 0.004). In tumour infiltrates CTLs always outnumbered NK cells, as reflected by the ratio CD57/CD8 being always inferior to one (mean: 0.19; SD: 0.15). The proportion of activated cytotoxic cells as detected by granzyme B expression was generally low (mean: 8.6%; SD 8.9). A clear correlation between MHC class I expression and the relative proportion of NK cells/CTLs was not found. This study shows that the majority of OSCCs show weak or absent expression of MHC class I molecules on the cell surface, possibly due to alterations in the normal β2-m pathway. The low proportion of granzyme B-positive CTLs/NK cells indicates that the secretory pathway of cytotoxicity is poor in these patients. The lack of correlation between MHC class I expression and CTL/NK cell activation as detected by granzyme B expression suggests that, next to poor antigen presentation, also local factors seem to determine the final outcome of the cytotoxic immune response. © 1999 Cancer Research Campaig

EST Analysis of Ostreococcus lucimarinus, the Most Compact Eukaryotic Genome, Shows an Excess of Introns in Highly Expressed Genes

Background: The genome of the pico-eukaryotic (bacterial-sized) prasinophyte green alga Ostreococcus lucimarinus has one of the highest gene densities known in eukaryotes, yet it contains many introns. Phylogenetic studies suggest this unusually compact genome (13.2 Mb) is an evolutionarily derived state among prasinophytes. The presence of introns in the highly reduced O. lucimarinus genome appears to be in opposition to simple explanations of genome evolution based on unidirectional tendencies, either neutral or selective. Therefore, patterns of intron retention in this species can potentially provide insights into the forces governing intron evolution. Methodology/Principal Findings: Here we studied intron features and levels of expression in O. lucimarinus using expressed sequence tags (ESTs) to annotate the current genome assembly. ESTs were assembled into unigene clusters that were mapped back to the O. lucimarinus Build 2.0 assembly using BLAST and the level of gene expression was inferred from the number of ESTs in each cluster. We find a positive correlation between expression levels and both intron number (R = +0.0893, p =,0.0005) and intron density (number of introns/kb of CDS; R = +0.0753, p =,0.005). Conclusions/Significance: In a species with a genome that has been recently subjected to a great reduction of non-coding DNA, these results imply the existence of selective/functional roles for introns that are principally detectable in highly expressed genes. In these cases, introns are likely maintained by balancing the selective forces favoring their maintenanc

Exercise therapy for chronic low back pain:protocol for an individual participant data meta-analysis

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is one of the leading causes of disability and has a major socioeconomic impact. Despite a large amount of research in the field, there remains uncertainty about the best treatment approach for chronic LBP, and identification of relevant patient subgroups is an important goal. Exercise therapy is a commonly used strategy to treat chronic low back pain and is one of several interventions that evidence suggests is moderately effective.</p> <p>In parallel with an update of the 2005 Cochrane review, we will undertake an individual participant data (IPD) meta-analysis, which will allow us to standardize analyses across studies and directly derive results, and to examine differential treatment effects across individuals to estimate how patients’ characteristics modify treatment benefit.</p> <p>Methods/design</p> <p>We will use standard systematic review methods advocated by the Cochrane Collaboration to identify relevant trials. We will include trials evaluating exercise therapy compared to any or no other interventions in adult non-specific chronic LBP. Our primary outcomes of interest include pain, functional status, and return-to-work/absenteeism. We will assess potential risk of bias for each study meeting selection criteria, using criteria and methods recommended by the Cochrane BRG.</p> <p>The original individual participant data will be requested from the authors of selected trials having moderate to low risk of bias. We will test original data and compile a master dataset with information about each trial mapped on a pre-specified framework, including reported characteristics of the study sample, exercise therapy characteristics, individual patient characteristics at baseline and all follow-up periods, subgroup and treatment effect modifiers investigated. Our analyses will include descriptive, study-level meta-analysis and meta-regression analyses of the overall treatment effect, and individual-level IPD meta-analyses of treatment effect modification. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies.</p> <p>Discussion</p> <p>We will analyze IPD across a large number of LBP trials. The resulting larger sample size and consistent presentation of data will allow additional analyses to explore patient-level heterogeneity in treatment outcomes and prognosis of chronic LBP.</p

Human Mena Associates with Rac1 Small GTPase in Glioblastoma Cell Lines

Mammarian enabled (Mena), a member of the Enabled (Ena)/Vasodilator-stimulated phosphoprotein (VASP) family of proteins, has been implicated in cell motility through regulation of the actin cytoskeleton assembly, including lamellipodial protrusion. Rac1, a member of the Rho family GTPases, also plays a pivotal role in the formation of lamellipodia. Here we report that human Mena (hMena) colocalizes with Rac1 in lamellipodia, and using an unmixing assisted acceptor depletion fluorescence resonance energy transfer (u-adFRET) analysis that hMena associates with Rac1 in vivo in the glioblastoma cell line U251MG. Depletion of hMena by siRNA causes cells to be highly spread with the formation of lamellipodia. This cellular phenotype is canceled by introduction of a dominant negative form of Rac1. A Rac activity assay and FRET analysis showed that hMena knock-down cells increased the activation of Rac1 at the lamellipodia. These results suggest that hMena possesses properties which help to regulate the formation of lamellipodia through the modulation of the activity of Rac1

Deconvoluting Post-Transplant Immunity: Cell Subset-Specific Mapping Reveals Pathways for Activation and Expansion of Memory T, Monocytes and B Cells

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L− effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant