Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Best Practices for Biostatistical Consultation and Collaboration in Academic Health Centers

Given the increasing level and scope of biostatistics expertise needed at academic health centers today, we developed best practices guidelines for biostatistics units to be more effective in providing biostatistical support to their institutions, and in fostering an environment in which unit members can thrive professionally. Our recommendations focus on the key areas of: 1) funding sources and mechanisms; 2) providing and prioritizing access to biostatistical resources; and 3) interacting with investigators. We recommend that the leadership of biostatistics units negotiate for sufficient long-term infrastructure support to ensure stability and continuity of funding for personnel, align project budgets closely with actual level of biostatistical effort, devise and consistently apply strategies for prioritizing and tracking effort on studies, and clearly stipulate with investigators prior to project initiation policies regarding funding, lead time, and authorship

Changes in postgraduate medical education and training in clinical radiology

Postgraduate medical education and training in many specialties, including Clinical Radiology, is undergoing major changes. In part this is to ensure that shorter training periods maximise the learning opportunities but it is also to bring medical education in line with broader educational theory. Learning outcomes need to be defined so that there is no doubt what knowledge, skills, attitudes and behaviours are expected of those in training. Curricula should be developed into competency or outcome based models and should state the aims, objectives, content, outcomes and processes of a training programme. They should include a description of the methods of learning, teaching, feedback and supervision. Assessment systems must be matched to the curriculum and must be fair, reliable and valid. Workplace based assessments including the use of multisource feedback need to be developed and validated for use during radiology training. These should be used in a formative and developmental way, although the overall results from a series of such assessments can be used in a more summative way to determine progress to the next phase of training. Formal standard setting processes need to be established for ‘high stakes’ summative assessments such as examinations. In addition the unique skills required of a radiologist in terms of image interpretation, pattern recognition, deduction and diagnosis need to be evaluated in robust, reliable and valid ways. Through a combination of these methods we can be assured that decisions about trainees’ progression through training is fair and standardised and that we are protecting patients by establishing national standards for training, curricula and assessment methods

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Drivers of aboveground wood production in a lowland tropical forest of West Africa:teasing apart the roles of tree density, tree diversity, soil phosphorus, and historical logging

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Wiley.1. Tropical forests currently play a key role in regulating the terrestrial carbon cycle and abating climate change by storing carbon in wood. However, there remains considerable uncertainty as to whether tropical forests will continue to act as carbon sinks in the face of increased pressure from expanding human activities. Consequently, understanding what drives productivity in tropical forests is critical. 2. We used permanent forest plot data from the Gola Rainforest National Park (Sierra Leone) – one of the largest tracts of intact tropical moist forest in West Africa – to explore how (i) stand basal area and tree diversity, (ii) past disturbance associated with past logging and (iii) underlying soil nutrient gradients interact to determine rates of aboveground wood production (AWP). We started by statistically modelling the diameter growth of individual trees and used these models to estimate AWP for 142 permanent forest plots. We then used structural equation modelling to explore the direct and indirect pathways which shape rates of AWP. 3. Across the plot network, stand basal area emerged as the strongest determinant of AWP, with densely packed stands exhibiting the fastest rates of AWP. In addition to stand packing density, both tree diversity and soil phosphorus content were also positively related to productivity. By contrast, historical logging activities negatively impacted AWP through the removal of large trees, which contributed disproportionately to productivity. 4. Synthesis. Understanding what determines variation in wood production across tropical forest landscapes requires accounting for multiple interacting drivers – with stand structure, tree diversity and soil nutrients all playing a key role. Importantly, our results also indicate that logging activities can have a long-lasting impact on a forest’s ability to sequester and store carbon, emphasizing the importance of safeguarding old-growth tropical forests.This study was funded through a grant from the Cambridge Conservation Initiative Collaborative Fund entitled “Applications of airborne remote sensing to the conservation management of a West African National Park”. T.J. was funded in part through NERC grant NE/K016377/1. A.C.S. was funded in part through a grant from the Percy Sladen Memorial Fund

A phylogenetic classification of the world’s tropical forests

Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition and dynamics. Such understanding will enable anticipation of region specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present the first classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (1) Indo-Pacific, (2) Subtropical, (3) African, (4) American, and (5) Dry forests. Our results do not support the traditional Neo- versus Palaeo-tropical forest division, but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar and India. Additionally, a northern hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern hemisphere forests

Could the therapeutic effect of physical activity on irritable bowel syndrome be mediated through changes to the gut microbiome? A narrative and hypothesis generating review

Background: Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal (GI) disorders worldwide. Defined as a disorder of gut-brain interaction, its pathophysiology is still not completely clear. Consequently, current treatments primarily target symptoms rather than addressing the cause of the condition. The gut microbiome is increasingly acknowledged as central to IBS pathophysiology and, thus, may have therapeutic potential. Several national treatment guidelines recommend increasing physical activity for IBS management. Aims: This review summarises the evidence about the relationship between physical activity, IBS symptoms, and the gut microbiome, investigating the hypothesis that physical activity's therapeutic effects on IBS may be explained via modulation of the gut microbiome. Results: This review revealed that routine exercise was associated with a 15%-66% reduction in symptom severity and up to 41% enhanced QoL in IBS participants, and modulates the gut microbiome in healthy controls. Discussion: This review generates the hypothesis that routine physical activity may favorably alter gut microbiome composition in IBS to improve IBS symptomology. While a plausible hypothesis, research needs to confirm whether gut microbiome modulation is involved in physical activity associated IBS symptom relief. Conclusion: Furthermore, the establishment of the most effective mode, duration, and intensity of physical activity for each sex and IBS-subtype is needed, with patient input during this process crucial to successfully translate science into practice

Contributions to early HIV diagnosis among patients linked to care vary by testing venue

<p>Abstract</p> <p>Objective</p> <p>Early HIV diagnosis reduces transmission and improves health outcomes; screening in non-traditional settings is increasingly advocated. We compared test venues by the number of new diagnoses successfully linked to the regional HIV treatment center and disease stage at diagnosis.</p> <p>Methods</p> <p>We conducted a retrospective cohort study using structured chart review of newly diagnosed HIV patients successfully referred to the region's only HIV treatment center from 1998 to 2003. Demographics, testing indication, risk profile, and initial CD4 count were recorded.</p> <p>Results</p> <p>There were 277 newly diagnosed patients meeting study criteria. Mean age was 33 years, 77% were male, and 46% were African-American. Median CD4 at diagnosis was 324. Diagnoses were earlier via partner testing at the HIV treatment center (N = 8, median CD4 648, p = 0.008) and with universal screening by the blood bank, military, and insurance companies (N = 13, median CD4 483, p = 0.05) than at other venues. Targeted testing by health care and public health entities based on patient request, risk profile, or patient condition lead to later diagnosis.</p> <p>Conclusion</p> <p>Test venues varied by the number of new diagnoses made and the stage of illness at diagnosis. To improve the rate of early diagnosis, scarce resources should be allocated to maximize the number of new diagnoses at screening venues where diagnoses are more likely to be early or alter testing strategies at test venues where diagnoses are traditionally made late. Efforts to improve early diagnosis should be coordinated longitudinally on a regional basis according to this conceptual paradigm.</p

Prevalence and demographics of methicillin resistant Staphylococcus aureus in culturable skin and soft tissue infections in an urban emergency department

<p>Abstract</p> <p>Background</p> <p>The rising incidence of methicillin resistant <it>Staph. aureus </it>(MRSA) infections is a concern for emergency practitioners. While studies have examined MRSA in inpatients, few have focused on emergency department populations. We sought to describe predictors of MRSA skin infections in an emergency department population.</p> <p>Methods</p> <p>This was a prospective observational cohort study conducted over three months in 2005. A convenience sample of patients with culturable skin infections presenting to a busy, urban emergency department was enrolled. Demographic and risk factor information was collected by structured interview. The predictive value of each risk factor for MRSA, as identified by culture, was tested using univariable logistic regression, and a multivariable predictive model was developed.</p> <p>Results</p> <p>Patients were 43% black, 40% female and mean age was 39 years (SD 14 years). Of the 182 patients with cultures, prevalence of MRSA was 58% (95%CI 50% to 65%). Significant predictors of MRSA were youth, lower body mass index, sexual contact in the past month, presence of an abscess cavity, spontaneous infection, and incarceration. The multivariable model had a C-statistic of 0.73 (95%CI 0.67 to 0.79) with four significant variables: age, group living, abscess cavity, and sexual contact within one month.</p> <p>Conclusion</p> <p>In this population of emergency department patients, MRSA skin infection was related to youth, recent sexual contact, presence of abscess, low body mass index, spontaneity of infection, incarceration or contact with an inmate, and group home living.</p