Conceptual and statistical analysis of complex interventions in the presence of confounding variables: An example from public health

Background: Meta-analyses of complex interventions are challenging because causality operates through multiple paths and confounding variables can be difficult to distinguish. Objectives: To meta-analyse public health interventions that engage members of the community in their conception, design, or delivery. To disentangle intervention complexity by analysing according to their theories of change. Study selection criteria: Published after 1990; outcome or process evaluation; community engagement intervention; written in English; reported health or community outcomes; study populations or differential impacts reported according to social determinants of health. Analysis: Intervention complexity was examined by conceptualising, operationalising, and mapping their theories of change; and through random effects subgroup analyses. Main results: 131 studies were included in the synthesis. Three main theories of change were identified, which were useful in describing trends in intervention effectiveness. Statistically significant between-group differences were not detected, since there were likely to have been too many confounding variables. Conclusions: Intervention complexity in systematic reviews can be addressed through examining theories of change and trends in effect size estimates. Such complexity appears to defy current meta-analytical methods when confounding variables undermine analysis of variance

RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma.

Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti-tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term "immunogenic cell death" is not fully defined, activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre-clinical application of an in vivo treatment protocol for soft-tissue sarcoma that directly engages RIPK1-mediated immunogenic cell death. We find that RIPK1-mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1-induced cell death in patients with advanced disease at limb extremities

Changing Pattern of Esophageal Cancer Incidence in New Mexico: A 30-Year Evaluation

The incidence of esophageal adenocarcinoma has increased over the last 30 years, especially in non-Hispanic whites (nHw). Recent work indicates an increase in Hispanic Americans (HA). It is important to understand the effect of ethnicity on cancer occurrence over a prolonged interval. We searched the New Mexico Tumor Registry for all cases of esophageal cancer from 1 January 1973 to 31 December 2002. Inclusion criteria were histologic diagnosis of adenocarcinoma or squamous cell carcinoma, ethnicity and gender. Incidence rates for both were compared among ethnic groups in 5-year intervals. Nine hundred eighty-eight patients met the criteria. Esophageal adenocarcinoma incidence rates/100,000 population increased significantly over 30 years; 1973–1977, 0.4 cases; 1978–1982, 0.4 cases; 1983–1987, 0.6 cases; 1988–1992, 1.2 cases, 1993–1997, 1.6 cases and 1998–2002, 2.2 cases; P < 0.001. Squamous cell carcinoma incidence rates remained unchanged during the interval. In nHw and HA, adenocarcinoma incidence rates increased significantly during the study period. In all minority groups, squamous cell carcinoma remained the major type. Esophageal adenocarcinoma incidence among nHw and HA increased from 1973 to 2002 in New Mexico. Squamous cell carcinoma remains predominant in minorities. Ethnicity may influence the histology or indicate an increased risk for certain types of esophageal cancer

Chondroblastoma of the cuboid with an associated aneurysmal bone cyst: a case report

We report the case of a young adult who presented with a painful foot due to chondroblastoma associated with an aneurismal bone cyst

Reconstruction of the Transmission History of RNA Virus Outbreaks Using Full Genome Sequences: Foot-and-Mouth Disease Virus in Bulgaria in 2011

<div><p>Improvements to sequencing protocols and the development of computational phylogenetics have opened up opportunities to study the rapid evolution of RNA viruses in real time. In practical terms, these results can be combined with field data in order to reconstruct spatiotemporal scenarios that describe the origin and transmission pathways of viruses during an epidemic. In the case of notifiable diseases, such as foot-and-mouth disease (FMD), these analyses provide important insights into the epidemiology of field outbreaks that can support disease control programmes. This study reconstructs the origin and transmission history of the FMD outbreaks which occurred during 2011 in Burgas Province, Bulgaria, a country that had been previously FMD-free-without-vaccination since 1996. Nineteen full genome sequences (FGS) of FMD virus (FMDV) were generated and analysed, including eight representative viruses from all of the virus-positive outbreaks of the disease in the country and 11 closely-related contemporary viruses from countries in the region where FMD is endemic (Turkey and Israel). All Bulgarian sequences shared a single putative common ancestor which was closely related to the index case identified in wild boar. The closest relative from outside of Bulgaria was a FMDV collected during 2010 in Bursa (Anatolia, Turkey). Within Bulgaria, two discrete genetic clusters were detected that corresponded to two episodes of outbreaks that occurred during January and March-April 2011. The number of nucleotide substitutions that were present between, and within, these separate clusters provided evidence that undetected FMDV infection had occurred. These conclusions are supported by laboratory data that subsequently identified three additional FMDV-infected livestock premises by serosurveillance, as well as a number of antibody positive wild boar on both sides of the border with Turkish Thrace. This study highlights how FGS analysis can be used as an effective on-the-spot tool to support and help direct epidemiological investigations of field outbreaks.</p> </div

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

Esophageal cooling for protection during left atrial ablation: a systematic review and meta-analysis.

PURPOSE: Thermal damage to the esophagus is a risk from radiofrequency (RF) ablation of the left atrium for the treatment of atrial fibrillation (AF). The most extreme type of thermal injury results in atrio-esophageal fistula (AEF) and a correspondingly high mortality rate. Various strategies for reducing esophageal injury have been developed, including power reduction, esophageal deviation, and esophageal cooling. One method of esophageal cooling involves the direct instillation of cold water or saline into the esophagus during RF ablation. Although this method provides limited heat-extraction capacity, studies of it have suggested potential benefit. We sought to perform a meta-analysis of published studies evaluating the use of esophageal cooling via direct liquid instillation for the reduction of thermal injury during RF ablation. METHODS: We searched PubMed for studies that used esophageal cooling to protect the esophagus from thermal injury during RF ablation. We then performed a meta-analysis using a random effects model to calculate estimated effect size with 95% confidence intervals, with an outcome of esophageal lesions stratified by severity, as determined by post-procedure endoscopy. RESULTS: A total of 9 studies were identified and reviewed. After excluding preclinical and mathematical model studies, 3 were included in the meta-analysis, totaling 494 patients. Esophageal cooling showed a tendency to shift lesion severity downward, such that total lesions did not show a statistically significant change (OR 0.6, 95% CI 0.15 to 2.38). For high-grade lesions, a significant OR of 0.39 (95% CI 0.17 to 0.89) in favor of esophageal cooling was found, suggesting that esophageal cooling, even with a low-capacity thermal extraction technique, reduces the severity of lesions resulting from RF ablation. CONCLUSIONS: Esophageal cooling reduces the severity of the lesions that may result from RF ablation, even when relatively low heat extraction methods are used, such as the direct instillation of small volumes of cold liquid. Further investigation of this approach is warranted, particularly with higher heat extraction capacity techniques

The Transit Phase of Migration: Circulation of Malaria and Its Multidrug-Resistant Forms in Africa

In the third article in a six-part <I>PLoS Medicine</I> series on Migration & Health, Cally Roper and Caroline Lynch use a case study of migration and anti-malarial drug resistance in Uganda to discuss the specific health risks and policy needs associated with the transit phase of migration

The relationship between a trusted adult and adolescent outcomes:A protocol of a scoping review

Abstract Background Although documentation of harm towards children and young people has existed for centuries, it was not until the 1960s that it became a specific focus for health professionals. Since that time, the importance of protective social networks has become better understood. The concept of trusted adults has come into sharper focus, with children being encouraged to develop networks of dependable adults to turn to for support in times of need. While many child protection processes highlight risks to younger children, there has been less emphasis on older children. The role of trusted adults may be particularly important during adolescence, due to burgeoning independence, developing sexuality, relationship formation, and associated vulnerabilities. While important choices relating to health and education are made during this period, there is little formal evidence relating to the impact of trusted adults on such outcomes. This review therefore aims to focus on the role and influence of trusted adults for adolescents. Methods This study is a scoping review. A broad range of databases will be searched, including MEDLINE, ERIC, Education Abstracts, Web of Science, ASSIA, Sociological Abstracts, and PsycINFO. Predefined inclusion/exclusion criteria will be used, with a focus on outcomes relating to health and education. Two reviewers will blind screen papers independently at all screening stages, with conflicts being resolved by a third reviewer. Quantitative and qualitative studies, as well as unpublished (grey) literature/reports, will be included. We will use the World Health Organization’s ‘second decade’ definition of adolescence. We aim to collate and map evidence in a broad overview and produce meta-analyses of homogenous data. Where this is not possible, a narrative summary will be produced. Discussion There appears to be sparse knowledge regarding the role of trusted adults for adolescents. Potential benefits to health and wellbeing may impact on educational attainment, and vice versa. These areas are of particular relevance during the second decade, when decisions that affect future direction, achievement, and wellbeing are being made. The increased understanding of the role of trusted adults provided by this review may help to inform practice and policy and lead to potential benefits for the health and education of adolescents. Systematic review registration PROSPERO CRD 4201707673

Access to primary care for socio-economically disadvantaged older people in rural areas: exploring realist theory using structural equation modelling in a linked dataset

Background: Realist approaches seek to answer questions such as ‘how?’, ‘why?’, ‘for whom?’, ‘in what circumstances?’ and ‘to what extent?’ interventions ‘work’ using context-mechanism-outcome (CMO) configurations. Quantitative methods are not well-established in realist approaches, but structural equation modelling (SEM) may be useful to explore CMO configurations. Our aim was to assess the feasibility and appropriateness of SEM to explore CMO configurations and, if appropriate, make recommendations based on our access to primary care research. Our specific objectives were to map variables from two large population datasets to CMO configurations from our realist review looking at access to primary care, generate latent variables where needed, and use SEM to quantitatively test the CMO configurations. Methods: A linked dataset was created by merging individual patient data from the English Longitudinal Study of Ageing and practice data from the GP Patient Survey. Patients registered in rural practices and who were in the highest deprivation tertile were included. Three latent variables were defined using confirmatory factor analysis. SEM was used to explore the nine full CMOs. All models were estimated using robust maximum likelihoods and accounted for clustering at practice level. Ordinal variables were treated as continuous to ensure convergence. Results: We successfully explored our CMO configurations, but analysis was limited because of data availability. Two hundred seventy-six participants were included. We found a statistically significant direct (context to outcome) or indirect effect (context to outcome via mechanism) for two of nine CMOs. The strongest association was between ‘ease of getting through to the surgery’ and ‘being able to get an appointment’ with an indirect mediated effect through convenience (proportion of the indirect effect of the total was 21%). Healthcare experience was not directly associated with getting an appointment, but there was a statistically significant indirect effect through convenience (53% mediated effect). Model fit indices showed adequate fit. Conclusions: SEM allowed quantification of CMO configurations and could complement other qualitative and quantitative techniques in realist evaluations to support inferences about strengths of relationships. Future research exploring CMO configurations with SEM should aim to collect, preferably continuous, primary data