Optimizing the design of invasive placebo interventions in randomized controlled trials.

BACKGROUND: Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs. METHODS: A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics. RESULTS: The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel. CONCLUSION: DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.

ANTECEDENTES: Los ensayos controlados con placebo juegan un papel importante en la evaluación de las intervenciones sanitarias. Sin embargo, pueden ser difíciles de diseñar e implementar en el caso de intervenciones invasivas, incluida la cirugía. Se necesita un conocimiento profundo de los componentes de la intervención terapéutica (para determinar qué se debe y qué no se debe administrar como parte del placebo). También se precisa de una evaluación del riesgo para los pacientes y de las estrategias para garantizar que el placebo imite el tratamiento de forma efectiva. Hasta la fecha no existen guías para el diseño de intervenciones invasivas con placebo. Este estudio tuvo como objetivo desarrollar un marco para optimizar el diseño y la práctica de intervenciones invasivas con placebo dentro en los ensayos clínicos aleatorizados (ECA). MÉTODOS: Utilizando la literatura publicada, se desarrolló un marco preliminar para i) ampliar el alcance de los modelos existentes para facilitar la deconstrucción de las actuaciones invasivas, y ii) identificar estrategias para optimizar el placebo. El marco se perfeccionó tras consultar con partes interesadas ​​en ensayos quirúrgicos, metodología de consenso y ética médica. RESULTADOS: El marco DITTO resultantes consiste en cinco etapas: Etapa 1: deconstrucción de la intervención de tratamiento en sus componentes esenciales y co-intervenciones; Etapa 2: identificar el(los) elemento(s) quirúrgico(s) básico(s); Etapa 3: eliminar el(los) elemento(s) básico(s); Etapa 4: considerar el riesgo, la viabilidad y el papel del placebo en el ensayo al tener en cuenta los demás componentes; y Etapa 5: optimizar el placebo para garantizar el cegamiento efectivo de los pacientes y del personal del ensayo. CONCLUSIÓN: DITTO considera de forma sistemática la naturaleza invasiva del placebo, teniendo en cuenta el riesgo, la viabilidad y la optimización del placebo. El uso de este marco de referencia puede ayudar al diseño de ECAs de alta calidad, necesarios para afianzar la implementación de intervenciones sanitarias.

Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials.

PURPOSE: The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a commonly used outcome measure for osteoarthritis. There are different versions of the WOMAC (Likert, visual analogue or numeric scales). A previous review of trials published before 2010 found poor reporting and inconsistency in how the WOMAC was used. This review explores whether these problems persist. METHODS: This systematic review included randomised trials of hip and/or knee osteoarthritis published in 2016 that used the WOMAC. Data were extracted on the version used, score range, analysis and results of the WOMAC, and whether these details were clearly reported. RESULTS: This review included 62 trials and 41 reported the WOMAC total score. The version used and item range for the WOMAC total score were unclear in 44% (n = 18/41) and 24% (n = 10/41) of trials, respectively. The smallest total score range was 0-10 (calculated by averaging 24 items scored 0-10); the largest was 0-2400 (calculated by summing 24 items scored 0-100). All trials reported the statistical analysis methods but only 29% reported the between-group mean difference and 95% confidence interval. CONCLUSION: Details on the use and scoring of the WOMAC were often not reported. We recommend that trials report the version of the WOMAC and the score range used. The between-group treatment effect and corresponding confidence interval should be reported. If all the items of the WOMAC are collected, the total score and individual subscale scores should be presented. Better reporting would facilitate the interpretation, comparison and synthesis of the WOMAC score in trials.

Considerations for the design, analysis and presentation of in vivo studies.

OBJECTIVE: To describe, explain and give practical suggestions regarding important principles and key methodological challenges in the study design, statistical analysis, and reporting of results from in vivo studies. CONCLUSIONS: Pre-specifying endpoints and analysis, recognizing the common underlying assumption of statistically independent observations, performing sample size calculations, and addressing multiplicity issues are important parts of an in vivo study. A clear reporting of results and informative graphical presentations of data are other important parts.

Randomized feasibility trial of replacing or discarding the nail plate after nail-bed repair in children.

BACKGROUND: Nail-bed injuries are the most common hand injury in children. Surgical dogma is to replace the nail plate after repairing the nail bed. Recent evidence suggests this might increase infection rates and returns to clinic. The aim of this feasibility trial was to inform the design and conduct of a definitive trial comparing replacing or discarding the nail plate after nail-bed repair. METHODS: This study recruited participants from four hand units in the UK between April and July 2015. Participants were children under the age of 16 years with a nail-bed injury requiring surgery. They were randomized to either having the nail plate replaced or discarded after nail-bed repair. The follow-up method was also allocated randomly (postal versus clinic). Information was collected on complications at 2 weeks and 30 days, and on nail-plate appearance at 4 months using the Zook classification. Two possible approaches to follow-up were also piloted and compared. RESULTS: During the recruitment phase, there were 156 potentially eligible children. Sixty were randomized in just over 3 months using remote web-based allocation. By 2 weeks, there were two infections, both in children with replaced nail plates. The nail-replaced group also experienced more complications. There was no evidence of a difference in return rates between postal and clinic follow-up. CONCLUSION: Recruitment was rapid and nail-bed repair appeared to have low complication and infection rates in this pilot trial. The findings have led to revision of the definitive trial protocol, including the mode and timing of follow-up, and modification of the Zook classification.

Arctic systems in the Quaternary: ecological collision, faunal mosaics and the consequences of a wobbling climate.

Climate oscillations and episodic processes interact with evolution, ecology and biogeography to determine the structure and complex mosaic that is the biosphere. Parasites and parasite-host assemblages are key components in a general explanatory paradigm for global biodiversity. We explore faunal assembly in the context of Quaternary time frames of the past 2.6 million years, a period dominated by episodic shifts in climate. Climate drivers cross a continuum from geological to contemporary timescales and serve to determine the structure and distribution of complex biotas. Cycles within cycles are apparent, with drivers that are layered, multifactorial and complex. These cycles influence the dynamics and duration of shifts in environmental structure on varying temporal and spatial scales. An understanding of the dynamics of high-latitude systems, the history of the Beringian nexus (the intermittent land connection linking Eurasia and North America) and downstream patterns of diversity depend on teasing apart the complexity of biotic assembly and persistence. Although climate oscillations have dominated the Quaternary, contemporary dynamics are driven by tipping points and shifting balances emerging from anthropogenic forces that are disrupting ecological structure. Climate change driven by anthropogenic forcing has supplanted a history of episodic variation and is eliminating ecological barriers and constraints on development and distribution for pathogen transmission. A framework to explore interactions of episodic processes on faunal structure and assembly is the Stockholm Paradigm, which appropriately shifts the focus from cospeciation to complexity and contingency in explanations of diversity.

Standardizing and monitoring the delivery of surgical interventions in randomized clinical trials.

BACKGROUND: The complexity of surgical interventions has major implications for the design of RCTs. Trials need to consider how and whether to standardize interventions so that, if successful, they can be implemented in practice. Although guidance exists for standardizing non-pharmaceutical interventions in RCTs, their application to surgery is unclear. This study reports new methods for standardizing the delivery of surgical interventions in RCTs. METHODS: Descriptions of 160 surgical interventions in existing trial reports and protocols were identified. Initially, ten reports were scrutinized in detail using a modified framework approach for the analysis of qualitative data, which informed the development of a preliminary typology. The typology was amended with iterative sequential application to all interventions. Further testing was undertaken within ongoing multicentre RCTs. RESULTS: The typology has three parts. Initially, the overall technical purpose of the intervention is described (exploration, resection and/or reconstruction) in order to establish its constituent components and steps. This detailed description of the intervention is then used to establish whether and how each component and step should be standardized, and the standards documented within the trial protocol. Finally, the typology provides a framework for monitoring the agreed intervention standards during the RCT. Pilot testing within ongoing RCTs enabled standardization of the interventions to be agreed, and case report forms developed to capture deviations from these standards. CONCLUSION: The typology provides a framework for use during trial design to standardize the delivery of surgical interventions and document these details within protocols. Application of this typology to future RCTs may clarify details of the interventions under evaluation and help successful interventions to be implemented.

The rise of big clinical databases.

BACKGROUND: The routine collection of large amounts of clinical data, 'big data', is becoming more common, as are research studies that make use of these data source. The aim of this paper is to provide an overview of the uses of data from large multi-institution clinical databases for research. METHODS: This article considers the potential benefits, the types of data source, and the use to which the data is put. Additionally, the main challenges associated with using these data sources for research purposes are considered. RESULTS: Common uses of the data include: providing population characteristics; identifying risk factors and developing prediction (diagnostic or prognostic) models; observational studies comparing different interventions; exploring variation between healthcare providers; and as a supplementary source of data for another study. The main advantages of using such big data sources are their comprehensive nature, the relatively large number of patients they comprise, and the ability to compare healthcare providers. The main challenges are demonstrating data quality and confidently applying a causal interpretation to the study findings. CONCLUSION: Large clinical database research studies are becoming ubiquitous and offer a number of potential benefits. However, the limitations of such data sources must not be overlooked; each research study needs to be considered carefully in its own right, together with the justification for using the data for that specific purpose.

Systematic review of intervention design and delivery in pragmatic and explanatory surgical randomized clinical trials.

BACKGROUND: Surgical interventions are complex, with multiple components that require consideration in trial reporting. This review examines the reporting of details of surgical interventions in randomized clinical trials (RCTs) within the context of explanatory and pragmatic study designs. METHODS: Systematic searches identified RCTs of surgical interventions published in 2010 and 2011. Included studies were categorized as predominantly explanatory or pragmatic. The extent of intervention details in the reports were compared with the CONSORT statement for reporting trials of non-pharmacological treatments (CONSORT-NPT). CONSORT-NPT recommends reporting the descriptions of surgical interventions, whether they were standardized and adhered to (items 4a, 4b and 4c). Reporting of the context of intervention delivery (items 3 and 15) and operator expertise (item 15) were assessed. RESULTS: Of 4541 abstracts and 131 full-text articles, 80 were included (of which 39 were classified as predominantly pragmatic), reporting 160 interventions. Descriptions of 129 interventions (80.6 per cent) were provided. Standardization was mentioned for 47 (29.4 per cent) of the 160 interventions, and 22 articles (28 per cent) reported measurement of adherence to at least one aspect of the intervention. Seventy-one papers (89 per cent) provided some information about context. For one-third of interventions (55, 34.4 per cent), some data were provided regarding the expertise of personnel involved. Reporting standards were similar in trials classified as pragmatic or explanatory. CONCLUSION: The lack of detail in trial reports about surgical interventions creates difficulties in understanding which operations were actually evaluated. Methods for designing and reporting surgical interventions in RCTs, contributing to the quality of the overall study design, are required. This should allow better implementation of trial results into practice.

Spontaneous firing patterns in the medial geniculate nucleus in a guinea pig model of tinnitus.

The mechanism of tinnitus, the perception of sound in the absence of acoustic stimulation, remains as yet unknown. It has been proposed that tinnitus is caused by altered spontaneous activity in the auditory pathway following cochlear damage in combination with inadequate gating at the level of the auditory thalamus, the medial geniculate nucleus (MGN). To investigate this further we made electrophysiological recordings in MGN of guinea pigs (n = 9) with and without tinnitus after acoustic trauma (continuous loud tone at 10 kHz, 124 dB SPL for 2 h). Parameters of interest were spontaneous tonic and burst firing. After acoustic trauma, 5 out of 9 guinea pigs developed signs of tinnitus as determined by the gap prepulse inhibition of acoustic startle. Spontaneous firing rates were significantly increased in the tinnitus animals as compared to the non-tinnitus animals and this change was specific to pure-tone responsive MGN neurons. However, burst firing parameters, including number of bursts per minute, burst duration, number of spikes in each burst, and percentage of spikes occurring in a burst, were not different between tinnitus and non-tinnitus animals. In addition, our data showed a strong dependence of spontaneous firing rates with heart rate, which implies that monitoring physiological status in animals is pertinent to obtaining reliable data when recording at higher levels of the auditory pathway. Our results suggest that increases in the tonic spontaneous fining rate of pure-tone responsive MGN neurons but not changes in burst firing parameters, are a robust neural signature of tinnitus in anaesthetised animals.

Nitric oxide potentiates hydrogen peroxide-induced killing of Escherichia coli.

Previously, we reported that nitric oxide (NO) provides significant protection to mammalian cells from the cytotoxic effects of hydrogen peroxide (H2O2). Murine neutrophils and activated macrophages, however, produce NO, H2O2, and other reactive oxygen species to kill microorganisms, which suggests a paradox. In this study, we treated bacteria (Escherichia coli) with NO and H2O2 for 30 min and found that exposure to NO resulted in minimal toxicity, but greatly potentiated (up to 1,000-fold) H2O2-mediated killing, as evaluated by a clonogenic assay. The combination of NO/H2O2 induced DNA double strand breaks in the bacterial genome, as shown by field-inverted gel electrophoresis, and this increased DNA damage may correlate with cell killing. NO was also shown to alter cellular respiration and decrease the concentration of the antioxidant glutathione to a residual level of 15-20% in bacterial cells. The iron chelator desferrioxamine did not stop the action of NO on respiration and glutathione decrease, yet it prevented the NO/H2O2 synergistic cytotoxicity, implicating metal ions as critical participants in the NO/H2O2 cytocidal mechanism. Our results suggest a possible mechanism of modulation of H2O2-mediated toxicity, and we propose a new key role in the antimicrobial macrophagic response for NO.

Randomized controlled trial comparing rubber band ligation with stapled haemorrhoidopexy for Grade II circumferential haemorrhoids: long-term results.

OBJECTIVE: An improved understanding of the pathophysiology of haemorrhoids has resulted in the introduction of new surgical techniques including stapled haemorrhoidopexy (SH). This randomized controlled trial compared the long-term effectiveness of SH with rubber band ligation (RBL) in the treatment of grade II circumferential symptomatic haemorrhoids. METHOD: A consecutive cohort of patients was randomly allocated to either SH or RBL. Data on haemorrhoidal symptoms, Cleveland continence scores, sphincter assessment, SF-36, EQ-5D, HAD score and prior treatment history were assessed at enrollment and reassessed by long-term postal questionnaire. The details were analysed using spss 12.0 from Microsoft Access. RESULTS: Sixty patients were allocated by computer block randomization. Both groups were balanced for age, sex and symptoms. Recurrence favoured SH [3 vs 11; OR 0.18, 95% CI (0.03 to 0.86), P = 0.028] at 1 year and, at a mean of 40.67 (31-47) months [4 vs 12; OR 0.23, 95% CI (0.05, 0.95); P = 0.039]. SH patients experienced prolonged pain [Median (IQR) = 7 (5,7) vs 3 (1,7), P = 0.008] and took a longer time to return to work [6 (3,7) vs 3 (1,6) days, P = 0.018]. This was no significant difference in quality of life. CONCLUSION: Stapled haemorrhoidopexy achieved better disease control at 1 year without any major complication. This was sustained in the long-term. Further studies with greater patient numbers are needed to confirm this study.

Recruitment and retention of participants in UK surgical trials: survey of key issues reported by trial staff.

BACKGROUND: Recruitment and retention of participants in surgical trials is challenging. Knowledge of the most common and problematic issues will aid future trial design. This study aimed to identify trial staff perspectives on the main issues affecting participant recruitment and retention in UK surgical trials. METHODS: An online survey of UK surgical trial staff was performed. Respondents were asked whether or not they had experienced a range of recruitment and retention issues, and, if yes, how relatively problematic these were (no, mild, moderate or serious problem). RESULTS: The survey was completed by 155 respondents including 60 trial managers, 53 research nurses, 20 trial methodologists and 19 chief investigators. The three most common recruitment issues were: patients preferring one treatment over another (81·5 per cent of respondents); clinicians' time constraints (78·1 per cent); and clinicians preferring one treatment over another (76·8 per cent). Seven recruitment issues were rated moderate or serious problems by a majority of respondents, the most problematic being a lack of eligible patients (60·3 per cent). The three most common retention issues were: participants forgetting to return questionnaires (81·4 per cent); participants found to be ineligible for the trial (74·3 per cent); and long follow-up period (70·7 per cent). The most problematic retention issues, rated moderate or serious by the majority of respondents, were participants forgetting to return questionnaires (56·4 per cent) and insufficient research nurse time/funding (53·6 per cent). CONCLUSION: The survey identified a variety of common recruitment and retention issues, several of which were rated moderate or serious problems by the majority of participating UK surgical trial staff. Mitigation of these problems may help boost recruitment and retention in surgical trials.

ANTECEDENTES: El reclutamiento y la retención de participantes en los ensayos quirúrgicos es un desafío. Conocer los problemas más habituales y conflictivos ayudará al diseño de futuros ensayos. Este estudio tuvo como objetivo identificar la percepción de los participantes sobre cuáles son los principales problemas que afectan el reclutamiento y la retención de participantes en los ensayos quirúrgicos del Reino Unido. MÉTODOS: Encuesta electrónica a profesionales de la salud que habían participado en ensayos quirúrgicos del Reino Unido. Se preguntó a los encuestados si habían experimentado o no algún problema en temas de reclutamiento o retención y, en caso afirmativo, qué tan conflictivos fueron (ningún problema/problema leve/moderado/grave). RESULTADOS: Completaron la encuesta 155 participantes, de los que 60 eran directores del ensayo, 53 enfermeras de investigación, 20 metodólogos de ensayos y 19 investigadores principales. Los tres problemas más comunes en el reclutamiento fueron: pacientes que prefieren un tratamiento sobre otro (81,5% de los encuestados), escaso tiempo de dedicación de los médicos (78,1%) y médicos que prefieren un tratamiento sobre otro (76,8%). La mayoría de los encuestados calificaron siete problemas de reclutamiento como "moderados" o "graves", siendo el más conflictivo la falta de pacientes elegibles (60,3%). Los tres problemas de retención más habituales fueron: participantes que olvidaron devolver los cuestionarios (81,4%), participantes que no fueron elegibles para el ensayo (74,3%) y el largo período de seguimiento (70,7%). Los problemas de retención más conflictivos, calificados como "moderados" o "graves" por la mayoría de los encuestados, fueron el olvido de los participantes para devolver los cuestionarios (56,4%) y el escaso tiempo/financiación para la enfermera investigadora (53,6%). CONCLUSIÓN: La encuesta identificó una serie de problemas habituales en el reclutamiento y la retención de los pacientes, muchos ellos calificados como "moderados" o "graves" por la mayoría del personal involucrado en los ensayos quirúrgicos del Reino Unido. Mitigar estos problemas puede ayudar a impulsar el reclutamiento y la retención en los ensayos quirúrgicos.