Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

PURPOSE: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer. MATERIALS AND METHODS: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes. RESULTS: All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%. CONCLUSION: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.

Climate change, land cover change, and overharvesting threaten a widely used medicinal plant in South Africa.

Medicinal plants contribute substantially to the well-being of people in large parts of the world, providing traditional medicine and supporting livelihoods from trading plant parts, which is especially significant for women in low-income communities. However, the availability of wild medicinal plants is increasingly threatened; for example, the Natal Lily (Clivia miniata), which is one of the most widely traded plants in informal medicine markets in South Africa, lost over 40% of individuals over the last 90 years. Understanding the species' response to individual and multiple pressures is essential for prioritizing and planning conservation actions. To gain this understanding, we simulated the future range and abundance of C. miniata by coupling Species Distribution Models with a metapopulation model (RAMAS-GIS). We contrasted scenarios of climate change (RCP2.6 vs. RCP8.5), land cover change (intensification vs. expansion), and harvesting (only juveniles vs. all life-stages). All our scenarios pointed to continuing declines in suitable habitat and abundance by the 2050s. When acting independently, climate change, land cover change, and harvesting each reduced the projected abundance substantially, with land cover change causing the most pronounced declines. Harvesting individuals from all life stages affected the projected metapopulation size more negatively than extracting only juveniles. When the three pressures acted together, declines of suitable habitat and abundance accelerated but uncertainties were too large to identify whether pressures acted synergistically, additively, or antagonistically. Our results suggest that conservation should prioritize the protection of suitable habitat and ensure sustainable harvesting to support a viable metapopulation under realistic levels of climate change. Inadequate management of C. miniata populations in the wild will likely have negative consequences for the well-being of people relying on this ecosystem service, and we expect there may be comparable consequences relating to other medicinal plants in different parts of the world.

Prevalence, patterns, functional disability of Bertolotti syndrome among patients with low back pain at Mulago National Referral Hospital.

Background: Bertolotti syndrome is a differential diagnosis in back pain. We know little about it in Uganda. This study aimed to describe the prevalence, clinical and radiological patterns of Bertolotti syndrome and functional disability associated with it. Methods: We did a descriptive cross-sectional study at the spine outpatients' clinic of Mulago National Referral Hospital. We screened patients with chronic low back pain for lumbosacral transitional vertebrae over four months and classified them according to Castellvi. We collected demographics, clinical symptoms, and functional disability data and summarized it descriptively. Results: Out of 385 patients, we identified 39 with Bertolotti syndrome. The prevalence and the median age were at 10.1% and 49 years respectively, with most patients being females (66.7%) in the age range of (36 to 50) years, the pain started during the age range of 31-40. The commonest and least were type IIA (20.5%) and type IV (10.3%), respectively. Most patients (66.3%) had radicular symptoms, mainly the toe extension nerve root. The average visual analog scale was 6.3. However, most patients suffered from mild- to moderate disability (66.7%). Conclusion: Bertolotti syndrome is common and functionally debilitating. We should consider it in the differential diagnosis of chronic low back pain.

Potential for positive biodiversity outcomes under diet-driven land use change in Great Britain.

Background: A shift toward human diets that include more fruit and vegetables, and less meat is a potential pathway to improve public health and reduce food system-related greenhouse gas emissions. Associated changes in land use could include conversion of grazing land into horticulture, which makes more efficient use of land per unit of dietary energy and frees-up land for other uses. Methods: Here we use Great Britain as a case study to estimate potential impacts on biodiversity from converting grazing land to a mixture of horticulture and natural land covers by fitting species distribution models for over 800 species, including pollinating insects and species of conservation priority. Results: Across several land use scenarios that consider the current ratio of domestic fruit and vegetable production to imports, our statistical models suggest a potential for gains to biodiversity, including a tendency for more species to gain habitable area than to lose habitable area. Moreover, the models suggest that climate change impacts on biodiversity could be mitigated to a degree by land use changes associated with dietary shifts. Conclusions: Our analysis demonstrates that options exist for changing agricultural land uses in a way that can generate win-win-win outcomes for biodiversity, adaptation to climate change and public health.

Life Course Neighbourhood Deprivation and Self-Rated Health: Does It Matter Where You Lived in Adolescence and Do Neighbourhood Effects Build Up over Life?

There is an overreliance on concurrent neighbourhood deprivation as a determinant of health. Only a small section of the literature focuses on the cumulative exposure of neighbourhood deprivation over the life course. This paper uses data from the 1958 National Child Development Study, a British birth cohort study, linked to 1971-2011 Census data at the neighbourhood level to longitudinally model self-rated health between ages 23 and 55 by Townsend deprivation score between ages 16 and 55. Change in self-rated health is analysed using ordinal multilevel models to test the strength of association with neighbourhood deprivation at age 16, concurrently and cumulatively. The results show that greater neighbourhood deprivation at age 16 predicts worsening self-rated health between ages 33 and 50. The association with concurrent neighbourhood deprivation is shown to be stronger compared with the measurement at age 16 when both are adjusted in the model. The concurrent association with change in self-rated health is explained by cumulative neighbourhood deprivation. These findings suggest that neglecting exposure to neighbourhood deprivation over the life course will underestimate the neighbourhood effect. They also have potential implications for public policy suggesting that neighbourhood socioeconomic equality may bring about better population health.

Adverse childhood experiences and incident coronary heart disease: a counterfactual analysis in the Whitehall II prospective cohort study.

OBJECTIVES: Adverse childhood experience is thought to be associated with risk of coronary heart disease, but it is not clear which experiences are cardiotoxic, and whether risk increases with the accumulation of adverse childhood experiences. METHODS: Participants were 5149 adults (72.6% men) in the Whitehall II cohort study. Parental death was recorded at phase 1 (median age in years 44.3), and 13 other adverse childhood experiences at phase 5 (55.3). We applied Cox proportional hazards regression with person-time from phase 5 to examine associations of adverse childhood experiences with incident coronary heart disease. We predicted hazard ratios according to count of the experiences, and examined dose-response effect. We finally estimated reduction of coronary heart disease in a hypothetical scenario, the absence of adverse childhood experiences. RESULTS: Among study participants, 62.9% had at least one adversity, with "financial problems" having the highest prevalence (26.1%). There were 509 first episodes of coronary heart disease during an average 12.9 years follow-up. Among 14 adverse childhood experiences in a multiply adjusted model, "parental unemployment" showed the highest hazard of coronary heart disease incidence (hazard ratio; 95% confidence interval: 1.53; 1.16 to 2.02). No dose-response effect was observed (constant for proportionality in hazard ratio: 1.05, 0.99 to 1.11). Based on the estimates of final model, in the absence of childhood adversities, we estimated a 6.0% reduction in coronary heart disease (0.94; 0.87 to 1.01), but the confidence interval includes one. CONCLUSION: Although individual adverse childhood experiences show some association with coronary heart disease, there is no clear relationship with the number of adverse experiences. Further research is required to quantify effects of multiple and combinations of adverse childhood experiences considering timing, duration, and severity.

Life Course Neighborhood Deprivation Effects on Body Mass Index: Quantifying the Importance of Selective Migration.

Neighborhood effects research is plagued by the inability to circumvent selection effects -the process of people sorting into neighborhoods. Data from two British Birth Cohorts, 1958 (ages 16, 23, 33, 42, 55) and 1970 (ages 16, 24, 34, 42), and structural equation modelling, were used to investigate life course relationships between body mass index (BMI) and area deprivation (addresses at each age linked to the closest census 1971-2011 Townsend score [TOWN], re-calculated to reflect consistent 2011 lower super output area boundaries). Initially, models were examined for: (1) area deprivation only, (2) health selection only and (3) both. In the best-fitting model, all relationships were then tested for effect modification by residential mobility by inclusion of interaction terms. For both cohorts, both BMI and area deprivation strongly tracked across the life course. Health selection, or higher BMI associated with higher area deprivation at the next study wave, was apparent at three intervals: 1958 cohort, BMI at age 23 y and TOWN at age 33 y and BMI at age 33 y and TOWN at age 42 y; 1970 cohort, BMI at age 34 y and TOWN at age 42 y, while paths between area deprivation and BMI at the next interval were seen in both cohorts, over all intervals, except for the association between TOWN at age 23 y and BMI at age 33 y in the 1958 cohort. None of the associations varied by moving status. In conclusion, for BMI, selective migration does not appear to account for associations between area deprivation and BMI across the life course.

Pathways to "5-a-day": modeling the health impacts and environmental footprints of meeting the target for fruit and vegetable intake in the United Kingdom.

BACKGROUND: Fruit and vegetable consumption in the United Kingdom is currently well below recommended levels, with a significant associated public health burden. The United Kingdom has committed to reducing its carbon emissions to net zero by 2050, and this transition will require shifts towards plant-based diets. OBJECTIVE: The aim was to quantify the health effects, environmental footprints, and cost associated with 4 different pathways to meeting the United Kingdom's "5-a-day" recommendation for fruit and vegetable consumption. METHODS: Dietary data based on 18,006 food diaries from 4528 individuals participating in the UK National Diet and Nutrition Survey (2012/13-2016/17) constituted the baseline diet. Linear programming was used to model the hypothetical adoption of the 5-a-day (400 g) recommendation, which was assessed according to 4 pathways differing in their prioritization of fruits versus vegetables and UK-produced versus imported varieties. Increases in fruit and vegetable consumption were substituted for consumption of sweet snacks and meat, respectively. Changes in life expectancy were assessed using the IOMLIFET life table model. Greenhouse gas emissions (GHGEs), blue water footprint (WF), and total diet cost were quantified for each 5-a-day diet. RESULTS: Achieving the 5-a-day target in the United Kingdom could increase average life expectancy at birth by 7-8 mo and reduce diet-related GHGEs by 6.1 to 12.2 Mt carbon dioxide equivalents/y; blue WFs would change by -0.14 to +0.07 km3/y. Greater reductions in GHGEs were achieved by prioritizing increased vegetable consumption over fruit, whereas the greatest reduction in WF was obtained by prioritizing vegetable varieties produced in the United Kingdom. All consumption pathways increased diet cost (£0.34-£0.46/d). CONCLUSIONS: Benefits to both population and environmental health could be expected from consumption pathways that meet the United Kingdom's 5-a-day target for fruit and vegetables. Our analysis identifies cross-sectoral trade-offs and opportunities for national policy to promote fruit and vegetable consumption in the United Kingdom.

Patient and Public Involvement Refines the Design of ProtOeus: A Proposed Phase II Trial of Proton Beam Therapy in Oesophageal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy for oesophageal cancer significantly improves overall survival but is associated with severe post-operative complications. Proton beam therapy may reduce these toxicities by sparing normal tissues compared with standard radiotherapy. ProtOeus is a proposed randomised phase II study of neoadjuvant chemoradiotherapy in oesophageal cancer that compares proton beam therapy to standard radiotherapy techniques. As proton beam therapy services are often centralised in academic centres in major cities, proton beam therapy trials raise distinct challenges including patient acceptance of travelling for proton beam therapy, coordination of treatments with local centres and ensuring equity of access for patients. METHODS: Focus groups were held early in the trial development process to establish patients' views on the trial proposal. Topics discussed include perception of proton beam therapy, patient acceptability of the trial pathway and design, patient-facing materials, and common clinical scenarios. Focus groups were led by the investigators and facilitated by patient involvement teams from the institutions who are involved in this research. Responses for each topic were analysed, and fed back to the trial's development group. RESULTS: Three focus groups were held in separate locations in the UK (Manchester, Cardiff, Wigan). Proton beam therapy was perceived as superior to standard radiotherapy making the trial attractive. Patients felt strongly that travel costs should be reimbursed to ensure equity of access to proton beam therapy. They were very supportive of a shorter treatment schedule and felt that toxicity reduction was the most important endpoint. DISCUSSION AND CONCLUSIONS: Incorporating patient views early in the trial development process resulted in significant trial design refinements including travel/accommodation provisions, choice of primary endpoint, randomisation ratio and fractionation schedule. Focus groups are a reproducible and efficient method of incorporating the patient and public voice into research.

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; Hmean: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; Hmean: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated. CONCLUSION: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.

Association of attrition with mortality: findings from 11 waves over three decades of the Whitehall II study.

BACKGROUND: Attrition, the loss of participants as a study progresses, is a considerable challenge in longitudinal studies. This study examined whether two forms of attrition, 'withdrawal' (formal discontinued participation) and 'non-response' (non-response among participants continuing in the study), have different associations with mortality and whether these associations differed across time in a multi-wave longitudinal study. METHODS: Participants were 10 012 civil servants who participated at the baseline of the Whitehall II cohort study with 11 data waves over an average follow-up of 28 years. We performed competing-risks analyses to estimate sub-distribution HRs and 95% CIs, and likelihood ratio tests to examine whether hazards differed between the two forms of attrition. We then applied linear regression to examine any trend of hazards against time. RESULTS: Attrition rate at data collections ranged between 13% and 34%. There were 495 deaths recorded from cardiovascular disease and 1367 deaths from other causes. Study participants lost due to attrition had 1.55 (95% CI 1.26 to 1.89) and 1.56 (1.39 to 1.76) times higher hazard of cardiovascular and non-cardiovascular mortality than responders, respectively. Hazards for withdrawal and non-response did not differ for either cardiovascular (p value =0.28) or non-cardiovascular mortality (p value =0.38). There was no linear trend in hazards over the 11 waves (cardiovascular mortality p value =0.11, non-cardiovascular mortality p value =0.61). CONCLUSION: Attrition can be a problem in longitudinal studies resulting in selection bias. Researchers should examine the possibility of selection bias and consider applying statistical approaches that minimise this bias.

Trading water: virtual water flows through interstate cereal trade in India.

Cereals are an important component of the Indian diet, providing 47% of the daily dietary energy intake. Dwindling groundwater reserves in India especially in major cereal-growing regions are an increasing challenge to national food supply. An improved understanding of interstate cereal trade can help to identify potential risks to national food security. Here, we quantify the trade between Indian states of five major cereals and the associated trade in virtual (or embedded) water. To do this, we modelled interstate trade of cereals using Indian government data on supply and demand; calculated virtual water use of domestic cereal production using state- and product-specific water footprints and state-level data on irrigation source; and incorporated virtual water used in the production of internationally-imported cereals using country-specific water footprints. We estimate that 40% (94 million tonnes) of total cereal food supply was traded between Indian states in 2011-12, corresponding to a trade of 54.0 km3 of embedded blue water, and 99.4 km3 of embedded green water. Of the cereals traded within India, 41% were produced in states with over-exploited groundwater reserves (defined according to the Central Ground Water Board) and a further 21% in states with critically depleting groundwater reserves. Our analysis indicates a high dependency of Indian cereal consumption on production in states with stressed groundwater reserves. Substantial changes in agricultural practices and land use may be required to secure future production, trade and availability of cereals in India. Diversifying production systems could increase the resilience of India's food system.

The impact of life course exposures to neighbourhood deprivation on health and well-being: a review of the long-term neighbourhood effects literature.

BACKGROUND: In this review article, we detail a small but growing literature in the field of health geography that uses longitudinal data to determine a life course component to the neighbourhood effects thesis. For too long, there has been reliance on cross-sectional data to test the hypothesis that where you live has an effect on your health and well-being over and above your individual circumstances. METHODS: We identified 53 articles that demonstrate how neighbourhood deprivation measured at least 15 years prior affects health and well-being later in life using the databases Scopus and Web of Science. RESULTS: We find a bias towards US studies, the most common being the Panel Study of Income Dynamics. Definition of neighbourhood and operationalization of neighbourhood deprivation across most of the included articles relied on data availability rather than a priori hypothesis. CONCLUSIONS: To further progress neighbourhood effects research, we suggest that more data linkage to longitudinal datasets is required beyond the narrow list identified in this review. The limited literature published to date suggests an accumulation of exposure to neighbourhood deprivation over the life course is damaging to later life health, which indicates improving neighbourhoods as early in life as possible would have the greatest public health improvement.

Are there sensitive neighbourhood effect periods during the life course on midlife health and wellbeing?

Since the turn of the century there has been an explosion in the number of epidemiological studies that have analysed neighbourhood effects on health and wellbeing. The vast majority of these studies are cross-sectional in nature and assume that a contemporaneous place of residence captures a meaningful neighbourhood effect. Over the same time frame, social epidemiology has focussed increasingly on life course effects. This paper aims to bring these two areas of study together and tests whether there a certain ages during the life course when neighbourhoods are more important for our health and wellbeing than others. We use two British birth cohort studies (1958 National Child Development Study and British Cohort Study 1970) each comprising approximately 6,000 sample members at midlife linked to historic census measures used to derived Townsend neighbourhood deprivation scores over the life course. We find little evidence to support our hypothesis that adolescence is a key period of neighbourhood effect, rather we find late-early-adulthood neighbourhood deprivation and midlife neighbourhood deprivation are more strongly related to mid-life health and wellbeing. We are not able to conclude whether these effects are causal and encourage further investigation of selection mechanisms into neighbourhoods and mediation throughout the life course using our newly created dataset.

Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases: A CALIBER Cohort Study.

BACKGROUND: Neutrophil counts are a ubiquitous measure of inflammation, but previous studies on their association with cardiovascular disease (CVD) were limited by small numbers of patients or a narrow range of endpoints. OBJECTIVES: This study investigated associations of clinically recorded neutrophil counts with initial presentation for a range of CVDs. METHODS: We used linked primary care, hospitalization, disease registry, and mortality data in England. We included people 30 years or older with complete blood counts performed in usual clinical care and no history of CVD. We used Cox models to estimate cause-specific hazard ratios (HRs) for 12 CVDs, adjusted for cardiovascular risk factors and acute conditions affecting neutrophil counts (such as infections and cancer). RESULTS: Among 775,231 individuals in the cohort, 154,179 had complete blood counts performed under acute conditions and 621,052 when they were stable. Over a median 3.8 years of follow-up, 55,004 individuals developed CVD. Adjusted HRs comparing neutrophil counts 6 to 7 versus 2 to 3 × 109/l (both within the 'normal' range) showed strong associations with heart failure (HR: 2.04; 95% confidence interval [CI]: 1.82 to 2.29), peripheral arterial disease (HR: 1.95; 95% CI: 1.72 to 2.21), unheralded coronary death (HR: 1.78; 95% CI: 1.51 to 2.10), abdominal aortic aneurysm (HR: 1.72; 95% CI: 1.34 to 2.21), and nonfatal myocardial infarction (HR: 1.58; 95% CI: 1.42 to 1.76). These associations were linear, with greater risk even among individuals with neutrophil counts of 3 to 4 versus 2 to 3 × 109/l. There was a weak association with ischemic stroke (HR: 1.36; 95% CI: 1.17 to 1.57), but no association with stable angina or intracerebral hemorrhage. CONCLUSIONS: Neutrophil counts were strongly associated with the incidence of some CVDs, but not others, even within the normal range, consistent with underlying disease mechanisms differing across CVDs. (White Blood Cell Counts and Onset of Cardiovascular Diseases: a CALIBER Study [CALIBER]; NCT02014610).

Total Center Percutaneous Coronary Intervention Volume and 30-Day Mortality: A Contemporary National Cohort Study of 427 467 Elective, Urgent, and Emergency Cases.

BACKGROUND: The relationship between procedural volume and prognosis after percutaneous coronary intervention (PCI) remains uncertain, with some studies finding in favor of an inverse association and some against. This UK study provides a contemporary reassessment in one of the few countries in the world with a nationally representative PCI registry. METHODS AND RESULTS: A nationwide cohort study was performed using the national British Cardiovascular Intervention Society registry. All adult patients undergoing PCI in 93 English and Welsh NHS hospitals between 2007 and 2013 were analyzed using hierarchical modeling with adjustment for patient risk. Of 427 467 procedures (22.0% primary PCI) in 93 hospitals, 30-day mortality was 1.9% (4.8% primary PCI). 87.1% of centers undertook between 200 and 2000 procedures annually. Case mix varied with center volume. In centers with 200 to 399 PCI cases per year, a smaller proportion were PCI for ST-segment-elevation myocardial infarction (8.4%) than in centers with 1500 to 1999 PCI cases per year (24.2%), but proportionally more were for ST-segment-elevation myocardial infarction with cardiogenic shock (8.4% versus 4.3%). For the overall PCI cohort, after risk adjustment, there was no significant evidence of worse, or better, outcomes in lower volume centers from our own study, or in combination with results from other studies. For primary PCI, there was also no evidence for increased or decreased mortality in lower volume centers. CONCLUSIONS: After adjustment for differences in case mix and clinical presentation, this study supports the conclusion of no trend for increased mortality in lower volume centers for PCI in the UK healthcare system. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02184949.

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study.

BACKGROUND: Eosinophil and lymphocyte counts are commonly performed in clinical practice. Previous studies provide conflicting evidence of association with cardiovascular diseases. METHODS: We used linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records) programme). We included people aged 30 or older without cardiovascular disease at baseline, and used Cox models to estimate cause-specific HRs for the association of eosinophil or lymphocyte counts with the first occurrence of cardiovascular disease. RESULTS: The cohort comprised 775 231 individuals, of whom 55 004 presented with cardiovascular disease over median follow-up 3.8 years. Over the first 6 months, there was a strong association of low eosinophil counts (<0.05 compared with 0.15-0.25×10(9)/L) with heart failure (adjusted HR 2.05; 95% CI 1.72 to 2.43), unheralded coronary death (HR 1.94, 95% CI 1.40 to 2.69), ventricular arrhythmia/sudden cardiac death and subarachnoid haemorrhage, but not angina, non-fatal myocardial infarction, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, subarachnoid haemorrhage or abdominal aortic aneurysm. Low eosinophil count was inversely associated with peripheral arterial disease (HR 0.63, 95% CI 0.44 to 0.89). There were similar associations with low lymphocyte counts (<1.45 vs 1.85-2.15×10(9)/L); adjusted HR over the first 6 months for heart failure was 2.25 (95% CI 1.90 to 2.67). Associations beyond the first 6 months were weaker. CONCLUSIONS: Low eosinophil counts and low lymphocyte counts in the general population are associated with increased short-term incidence of heart failure and coronary death. TRIAL REGISTRATION NUMBER: NCT02014610; results.

Impact of operator volume for percutaneous coronary intervention on clinical outcomes: what do the numbers say?

The impact of operator and centre volume on clinical outcomes and quality of care has been of considerable debate in recent years in a number of surgical- and procedural-based specialities. A relationship between higher volumes at both the institutional and operator levels and better clinical outcomes would at first appear intuitive, based on the premise that performing a procedure very infrequently would be likely to lead to unfamiliarity, complications, and poorer outcomes. In the current review, we study the relationship between operator volume and outcomes in the setting of percutaneous coronary intervention (PCI), and examine the evidence for current clinical competency guidelines that advocate that a minimum number of PCI procedures be undertaken annually. Whilst both high institutional and operator volumes have been shown to be associated with better outcomes by reducing death and in-hospital mortality, these data are often derived from the pre-stent era, or when high-volume operators undertook far smaller numbers of procedures than is currently recommended to maintain clinical competency. The emphasis of specific volume requirements for optimal outcomes needs to be interpreted with caution, as volume is not a surrogate for quality and merely one of the variables associated with outcome. Healthcare providers should focus on other measures of quality such as robust clinical care pathways, evidence-based treatments, periodic case review, using validated risk assessment scores, and ascertainment of outcome to improve care and reduce adverse events.

Comparison of random forest and parametric imputation models for imputing missing data using MICE: a CALIBER study.

Multivariate imputation by chained equations (MICE) is commonly used for imputing missing data in epidemiologic research. The "true" imputation model may contain nonlinearities which are not included in default imputation models. Random forest imputation is a machine learning technique which can accommodate nonlinearities and interactions and does not require a particular regression model to be specified. We compared parametric MICE with a random forest-based MICE algorithm in 2 simulation studies. The first study used 1,000 random samples of 2,000 persons drawn from the 10,128 stable angina patients in the CALIBER database (Cardiovascular Disease Research using Linked Bespoke Studies and Electronic Records; 2001-2010) with complete data on all covariates. Variables were artificially made "missing at random," and the bias and efficiency of parameter estimates obtained using different imputation methods were compared. Both MICE methods produced unbiased estimates of (log) hazard ratios, but random forest was more efficient and produced narrower confidence intervals. The second study used simulated data in which the partially observed variable depended on the fully observed variables in a nonlinear way. Parameter estimates were less biased using random forest MICE, and confidence interval coverage was better. This suggests that random forest imputation may be useful for imputing complex epidemiologic data sets in which some patients have missing data.