Fidelity in complex behaviour change interventions : a standardised approach to evaluate intervention integrity

Objectives: The aim of this study was to (1) demonstrate the development and testing of tools and procedures designed to monitor and assess the integrity of a complex intervention for chronic pain (COping with persistent Pain, Effectiveness Research into Self-management (COPERS) course); and (2) make recommendations based on our experiences. Design: Fidelity assessment of a two-arm randomised controlled trial intervention, assessing the adherence and competence of the facilitators delivering the intervention. Setting: The intervention was delivered in the community in two centres in the UK: one inner city and one a mix of rural and urban locations. Participants: 403 people with chronic musculoskeletal pain were enrolled in the intervention arm and 300 attended the self-management course. Thirty lay and healthcare professionals were trained and 24 delivered the courses (2 per course). We ran 31 courses for up to 16 people per course and all were audio recorded. Interventions: The course was run over three and a half days; facilitators delivered a semistructured manualised course. Outcomes: We designed three measures to evaluate fidelity assessing adherence to the manual, competence and overall impression. Results: We evaluated a random sample of four components from each course (n=122). The evaluation forms were reliable and had good face validity. There were high levels of adherence in the delivery: overall adherence was two (maximum 2, IQR 1.67–2.00), facilitator competence exhibited more variability, and overall competence was 1.5 (maximum 2, IQR 1.25–2.00). Overall impression was three (maximum 4, IQR 2.00–3.00). Conclusions: Monitoring and assessing adherence and competence at the point of intervention delivery can be realised most efficiently by embedding the principles of fidelity measurement within the design stage of complex interventions and the training and assessment of those delivering the intervention. More work is necessary to ensure that more robust systems of fidelity evaluation accompany the growth of complex interventions

Living with multimorbidity: medical and lay healthcare approaches

Multimorbidity is rapidly becoming the norm rather than the exception in healthcare. Research on this issue is increasing and this review discusses a selection of clinical and social science literature. The focus is on understanding the complexity of the lived experience of multimorbidity and how this is presented in clinical encounters, drawing on examples of arthritis within a multimorbidity context. Taking into account the biophysical, psychological, social and cultural factors that shape multimorbidity this paper calls for a re-conceptualization of the concept, allowing a more dynamic and holistic approach

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins. IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat

Assessing the impact of headaches and the outcomes of treatment : a systematic review of patient-reported outcome measures (PROMs)

Aims: To critically appraise, compare and synthesise the quality and acceptability of multi-item PROMs for adults with chronic or episodic headache. Methods: Systematic literature searches of major databases (1980-2016) to identify published evidence of PROM measurement and practical properties. Data on study quality (COSMIN), measurement and practical properties per measure was extracted and assessed against accepted standards to inform an evidence synthesis. Results: From 10,903 reviewed abstracts, 103 articles were assessed in full; 46 provided evidence for 23 PROMs: eleven specific to the health-related impact of migraine (n=5) or headache (n=6); six assessed migraine-specific treatment response/satisfaction; six were generic measures. Evidence for measurement validity and score interpretation was strongest for two measures of impact - Migraine-Specific Quality of Life Questionnaire (MSQ v2.1) and Headache Impact Test 6-item (HIT-6), and one of treatment response - the Patient Perception of Migraine Questionnaire (PPMQ-R). Evidence of reliability was limited, but acceptable for the HIT-6. Responsiveness was rarely evaluated. Evidence for the remaining measures was limited. Patient involvement was limited and poorly reported. Conclusion: Whilst evidence is limited, three measures have acceptable evidence of reliability and validity - HIT-6, MSQ v2.1 and PPMQ-R. Only the HIT-6 has acceptable evidence supporting its completion by all ‘headache’ populations

Adverse events and manual therapy : a systematic review

Objective: To explore the incidence and risk of adverse events with manual therapies. Method: The main health electronic databases, plus those specific to allied medicine and manual therapy, were searched. Our inclusion criteria were: manual therapies only; administered by regulated therapists; a clearly described intervention; adverse events reported. We performed a meta-analysis using incident estimates of proportions and random effects models. Results: Eight prospective cohort studies and 31 manual therapy RCTs were accepted. The incidence estimate of proportions for minor or moderate transient adverse events after manual therapy was ∼41% (CI 95% 17–68%) in the cohort studies and 22% (CI 95% 11.1–36.2%) in the RCTs; for major adverse events ∼0.13%. The pooled relative risk (RR) for experiencing adverse events with exercise, or with sham/passive/control interventions compared to manual therapy was similar, but for drug therapies greater (RR 0.05, CI 95% 0.01–0.20) and less with usual care (RR 1.91, CI 95% 1.39–2.64). Conclusions: The risk of major adverse events with manual therapy is low, but around half manual therapy patients may experience minor to moderate adverse events after treatment. The relative risk of adverse events appears greater with drug therapy but less with usual care

Intra-articular facet injections for low back pain : design considerations, consensus methodology to develop the protocol for a randomised controlled trial

BACKGROUND: Since the publication of guidelines by the UK National Institute for Health and Care Excellence (NICE) and the American Pain Society guidelines for low back pain in 2009 there have been deep divisions in the pain treatment community about the use of therapeutic intraarticular facet joint injections. While evidence for the effectiveness or not of intraarticular facet joint injections remains sparse, uncertainty will remain. The Warwick feasibility study, along with a concurrent study with a different design led by another group, aims to provide a stable platform from which the effectiveness and cost effectiveness of intraarticular facet joint injections added to normal care could be evaluated in randomized controlled trials (RCTs). OBJECTIVES: To reach consensus on key design considerations for the Warwick facet feasibility study from which the study protocol and working manuals will be developed. STUDY DESIGN: A consensus conference involving expert professionals and lay members. METHODS: Preliminary work identified 5 key design considerations for deliberation at our consensus conference. Three concerned patient assessment and treatment: diagnosis of possible facet joint pain, interaarticular facet joint injection technique, and best usual care. Two concerned trial analysis: a priori sub-groups and minimally important difference and are reported elsewhere. We did systematic evidence reviews of the design considerations and summarized the evidence. Our design questions and evidence summaries were distributed to all delegates. This formed the basis for discussions on the day. Clinical experts in all aspects of facet joint injection from across the UK along with lay people were invited via relevant organizations. Nominal group technique was used in 15 facilitated initial small group discussions. Further discussion and ranking was undertaken in plenary. All small group and plenary results were recorded and checked and verified post conference. Where necessary participants were contacted via email to resolve outstanding issues. RESULTS: Fifty-two delegates attended the conference with lay people and all relevant professions represented. Consensus was reached on the details of how to assess patients for facet joint pain, undertake the injections, and deliver usual care. Where post conference checking of results revealed errors in calculating ranking results on the day, consensus was reached by email consultation. All but 3 delegates agreed to be associated with the outcome. LIMITATIONS: Allocating one day for discussing a wide range of topics imposed time pressure on discussion and calculation of the numerous rankings. CONCLUSIONS: Through the use of an evidence-based, systematic, inclusive, and transparent process we have established consensus from expert health professionals in the UK, with lay input, on the clinical assessment of suspected facet joint pain, interaarticular injection for facet joint pain, and best usual care for use in a feasibility study for a proposed pragmatic clinical trial of interaarticular facet joint injections. This provides a strong basis for a clinical trial that will be acceptable to the pain treatment community

Short-course adjunctive gentamicin as empirical therapy in patients with severe sepsis and septic shock : a prospective observational cohort study

Background.: Meta-analyses failed to demonstrate clinical benefits of beta lactam plus aminoglycoside combination therapy, compared to beta lactam monotherapy, in patients with sepsis. However, few data exist on the effects of short-course adjunctive aminoglycoside therapy in sepsis patients with organ failure or shock. Methods.: We prospectively enrolled consecutive patients with severe sepsis or septic shock in two intensive care units in the Netherlands from 2011 to 2015. Local antibiotic protocols recommended empiric gentamicin add-on therapy in only one of the units. We used logistic regression analyses to determine the association between gentamicin use and the number of days alive and free of renal failure, shock, and death, all on day 14. Results.: Of 648 patients enrolled, 245 received gentamicin (222 of 309 (72%) in hospital A and 23 of 339 (7%) in hospital B) for a median duration of 2 (IQR 1-3) days. The adjusted odds ratios associated with gentamicin use were 1.39 (95%CI 1.00-1.94) for renal failure, 1.34 (95%CI 0.96-1.86) for shock duration and 1.41 (95%CI 0.94-2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) Gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (p=0.62). Conclusion.: Short-course empirical gentamicin use in patients with severe sepsis or septic shock was associated with an increased incidence of acute kidney injury, but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance

Ribosomal DNA promoter recognition is determined in vivo by cooperation between UBTF1 and SL1 and is compromised in the UBTF-E210K neuroregression syndrome

Transcription of the ∼200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15.7 kbp nucleosome free region (NFR). Formation of this NFR is also essential for recruitment of the TBP-TAFI factor SL1 and for preinitiation complex (PIC) formation at the gene and enhancer-associated promoters of the rDNA. However, these promoters show little sequence commonality and neither UBTF nor SL1 display significant DNA sequence binding specificity, making what drives PIC formation a mystery. Here we show that cooperation between SL1 and the longer UBTF1 splice variant generates the specificity required for rDNA promoter recognition in cell. We find that conditional deletion of the TAF1B subunit of SL1 causes a striking depletion of UBTF at both rDNA promoters but not elsewhere across the rDNA. We also find that while both UBTF1 and -2 variants bind throughout the rDNA NFR, only UBTF1 is present with SL1 at the promoters. The data strongly suggest an induced-fit model of RPI promoter recognition in which UBTF1 plays an architectural role. Interestingly, a recurrent UBTFE210K mutation and the cause of a pediatric neurodegeneration syndrome provides indirect support for this model. E210K knock-in cells show enhanced levels of the UBTF1 splice variant and a concomitant increase in active rDNA copies. In contrast, they also display reduced rDNA transcription and promoter recruitment of SL1. We suggest the underlying cause of the UBTF-E210K syndrome is therefore a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation