How to estimate the association between change in a risk factor and a health outcome?

Estimating the effect of a change in a particular risk factor and a chronic disease requires information on the risk factor from two time points; the enrolment and the first follow-up. When using observational data to study the effect of such an exposure (change in risk factor) extra complications arise, namely (i) when is time zero? and (ii) which information on confounders should we account for in this type of analysis? From enrolment or the 1st follow-up? Or from both?. The combination of these questions has proven to be very challenging. Researchers have applied different methodologies with mixed success, because the different choices made when answering these questions induce systematic bias. Here we review these methodologies and highlight the sources of bias in each type of analysis. We discuss the advantages and the limitations of each method ending by making our recommendations on the analysis plan

Decidual Cell Polyploidization Necessitates Mitochondrial Activity

Cellular polyploidy has been widely reported in nature, yet its developmental mechanism and function remain poorly understood. In the present study, to better define the aspects of decidual cell polyploidy, we isolated pure polyploid and non-polyploid decidual cell populations from the in vivo decidual bed. Three independent RNA pools prepared for each population were then subjected to the Affymetrix gene chip analysis for the whole mouse genome transcripts. Our data revealed up-regulation of 1015 genes and down-regulation of 1207 genes in the polyploid populations, as compared to the non-polyploid group. Comparative RT-PCR and in situ hybridization results indeed confirmed differential expressional regulation of several genes between the two populations. Based on functional enrichment analyses, up-regulated polyploidy genes appeared to implicate several functions, which primarily include cell/nuclear division, ATP binding, metabolic process, and mitochondrial activity, whereas that of down-regulated genes primarily included apoptosis and immune processes. Further analyses of genes that are related to mitochondria and bi-nucleation showed differential and regional expression within the decidual bed, consistent with the pattern of polyploidy. Consistently, studies revealed a marked induction of mitochondrial mass and ATP production in polyploid cells. The inhibition of mitochondrial activity by various pharmacological inhibitors, as well as by gene-specific targeting using siRNA-mediated technology showed a dramatic attenuation of polyploidy and bi-nucleation development during in vitro stromal cell decidualization, suggesting mitochondria play a major role in positive regulation of decidual cell polyploidization. Collectively, analyses of unique polyploidy markers and molecular signaling networks may be useful to further characterize functional aspects of decidual cell polyploidy at the site of implantation

On the estimation of the effect of weight change on a health outcome using observational data, by utlilising the target trial emulation framework

Background/Objectives: When studying the effect of weight change between two time points on a health outcome using observational data, two main problems arise initially (i) ‘when is time zero?’ and (ii) ‘which confounders should we account for?’ From the baseline date or the 1st follow-up (when the weight change can be measured)? Different methods have been previously used in the literature that carry different sources of bias and hence produce different results. Methods: We utilised the target trial emulation framework and considered weight change as a hypothetical intervention. First, we used a simplified example from a hypothetical randomised trial where no modelling is required. Then we simulated data from an observational study where modelling is needed. We demonstrate the problems of each of these methods and suggest a strategy. Interventions: weight loss/gain vs maintenance. Results: The recommended method defines time-zero at enrolment, but adjustment for confounders (or exclusion of individuals based on levels of confounders) should be performed both at enrolment and the 1st follow-up. Conclusions: The implementation of our suggested method [adjusting for (or excluding based on) confounders measured both at baseline and the 1st follow-up] can help researchers attenuate bias by avoiding some common pitfalls. Other methods that have been widely used in the past to estimate the effect of weight change on a health outcome are more biased. However, two issues remain (i) the exposure is not well-defined as there are different ways of changing weight (however we tried to reduce this problem by excluding individuals who develop a chronic disease); and (ii) immortal time bias, which may be small if the time to first follow up is short

Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease

Background Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. Methods and Findings We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66). Conclusion Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research

Repeat Ablation for Atrial Fibrillation Recurrence Post Cryoballoon or Radiofrequency Ablation in the FIRE and ICE Trial

Background: The FIRE AND ICE trial assessed efficacy and safety of pulmonary vein (PV) isolation using cryoballoon versus radiofrequency current (RFC) ablation in patients with drug refractory, symptomatic, paroxysmal atrial fibrillation (AF). The purpose of the current study was to assess index lesion durability as well as reablation strategy and outcomes in trial patients undergoing a reablation procedure. Methods: Patients with reablation procedures during FIRE AND ICE were retrospectively consented and enrolled at 13 trial centers. The first reablation for each patient was included in the analysis. Documented arrhythmias before reablation, number and location of reconnected PVs, lesions created during reablations, procedural characteristics, and acute as well as long-term outcomes were assessed. Results: Eighty-nine (36 cryoballoon and 53 RFC) patients were included in this study. Paroxysmal atrial fibrillation was the predominant recurrent arrhythmia (69%) before reablation. Reablations occurred at a median of 173 and 182 days (P=0.54) in the cryoballoon and RFC cohorts, respectively. The number of reconnected PVs was significantly higher in the RFC than the cryoballoon group (2.1\ub11.4 versus 1.4\ub11.1; P=0.010), which was driven by significantly more reconnected left superior PVs and markedly more reconnected right superior PVs. The number of (predominantly RFC) lesions applied during reablation was significantly greater in patients originally treated with RFC (3.3\ub11.3 versus 2.5\ub11.5; P=0.015) with no difference in overall acute success (P=0.70). After reablation, no differences in procedure-related rehospitalization or antiarrhythmic drug utilization were observed between cohorts. Conclusions: At reablation, patients originally treated with the cryoballoon had significantly fewer reconnected PVs, which may reflect RFC catheter instability in certain left atrial regions, and thus required fewer lesions for reablation success. Repeat ablations were predominantly performed with RFC and resulted in similar acute success, duration of hospitalization, and antiarrhythmic drug prescription between the study cohorts. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03314753

Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study

Objectives: To investigate geographic variation in guideline-indicated treatments for NSTEMI in the English National Health Service (NHS). Design: Cohort study using registry data from the Myocardial Ischaemia National Audit Project. Setting: All Clinical Commissioning Groups (CCGs) (n=211) in the English NHS. Participants: 357,228 patients with NSTEMI between 1st January, 2003 and 30th June, 2013. Main outcome measure: Proportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication. Results: The proportion of NSTEMI who received optimal care was low (48,257/357,228; 13.5%) and varied between CCGs (median 12.8%, interquartile range 0.7 to 18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0 to 40.0%) and least for use of an electrocardiogram (96.7%, 92.5 to 98.7%). The highest rates of care were for acute aspirin (median 92.8%, interquartile range 88.6 to 97.1%), and aspirin (90.1%, 85.1 to 93.3%) and statins (86.4%, 82.3 to 91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, interquartile range 8.7 to 16.6%), dietary advice (32.4%, 23.9 to 41.7%) and the prescription of P2Y12 inhibitors (39.7%, 32.4 to 46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between hospitals differences (median 64.7%, interquartile range 57.4% to 70.0%; between hospital variance: 1.92, 95% confidence interval 1.51 to 2.44; interclass correlation 0.996, 0.976 to 0.999). Conclusions: Across the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths

Real world challenges in delivering person centred care: A community based case study

Community nurses face many challenges when trying to practice evidence-based, person-centred care. Ongoing concerns regarding the impact of the 2013 Francis Report (Ford and Lintern, 2017) suggest that individualised and holistic care is an impossible dream, one made harder when the client appears uncooperative. This paper presents a case study that sets out how some of these challenges were met in a potentially difficult situation experienced by a student nurse and her mentor in practice, in which the student was supported to further examine and explore issues that may have influenced the situation. In this instance, the solution came with the recognition that the client had expertise and knowledge that needed to be taken into account, alongside that of the nurses looking after him. His care became a partnership, not an imposition of expertise; a principle which is transferable to many other situations. Underpinning it was the recognition of our shared humanity, wherein lies the essence of truly holistic care, and student nurses learning this, through the guidance and support of their mentor.

Planning and Leveraging Event Portfolios: Towards a Holistic Theory

This conceptual paper seeks to advance the discourse on the leveraging and legacies of events by examining the planning, management, and leveraging of event portfolios. This examination shifts the common focus from analyzing single events towards multiple events and purposes that can enable cross-leveraging among different events in pursuit of attainment and magnification of specific ends. The following frameworks are proposed: (1) event portfolio planning and leveraging, and (2) analyzing events networks and inter-organizational linkages. These frameworks are intended to provide, at this infancy stage of event portfolios research, a solid ground for building theory on the management of different types and scales of events within the context of a portfolio aimed to obtain, optimize and sustain tourism, as well as broader community benefits