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Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual‐level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse‐variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1‐SD increase: 0.88, 95% CI: 0.78‐0.99, P =.04; OR: 0.93, 95% CI: 0.88‐0.98, P =.01]. The protective effect of eosinophils remained [OR per 1‐SD increase: 0.88, 95% CI: 0.80‐0.97, P =.01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76‐0.93, P = 6.70e‐4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1‐SD increase: 0.96, 95% CI: 0.93‐0.99, P =.02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93‐0.99, P =.001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships. [ABSTRACT FROM AUTHOR]

Over 20 years ago a series of papers identified a strikingly dominant economic cluster – the UK's Motorsport Valley (MSV) – which led to MSV becoming an international exemplar of concepts such as agglomeration, clusters and knowledge-driven systems of regional development. Utilising an evolutionary perspective on cluster development, this paper asks 'whatever happened to MSV?'. Drawing on the framework of strategic cluster coupling, four cluster development episodes are conceptualised that each depict the dynamic evolution of the cluster's multi-scalar institutional environment, strategic coupling trajectories and economic development outcomes. Reflecting the emerging synthesis between evolutionary economic geography and geographical political economy, the paper describes an extended case study of cluster development, an evolutionary process of strategic cluster coupling and, ultimately, an example of cluster resilience. Through a focus on strategic cluster coupling, the paper provides further understanding of cluster evolution and path development mechanisms at key moments of cluster reconfiguration – and an empirical update and continuation of the economic story and cluster lifecycle of MSV. [ABSTRACT FROM AUTHOR]

Lockdowns during the COVID-19 pandemic had a disruptive effect on medical education when they prevented medical students accessing real patients. To address this, we piloted 35 medical students at home consulting remotely with patients. We evaluated the intervention using qualitative analysis of post-experience interviews with a sample of 13 students and 10 clinical supervisors. The experience was perceived by all those interviewed to be both acceptable and educationally valuable. Data analysis revealed different models of implementation according to type of patients involved (acute, recently treated or expert patients) and type of communication platform used (AccuRx, Microsoft Teams or telephone). Practical and educational challenges were identified in relation to the following elements of the experience: patients consulting with students remotely, students being remotely supervised and students undertaking patient contact from home. Strategies for addressing these challenges were directly suggested by interviewees and also inferred from our analysis of the data. Remotely supervised medical students at home undertaking remote consultations with patients can be acceptable and educationally valuable. The intervention was piloted in a UK graduate entry medical course and so it would be useful to replicate this study in other medical student populations. [ABSTRACT FROM AUTHOR]

Background Mutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence. Methods Population-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4. Results The prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations. Conclusions There is a low probability (<2%) of detecting a germline CDKN2A mutation in people with melanoma except for those with a strong family history of melanoma (≥2 affected relatives, 25%), three or more primary melanomas (29%), or more than one primary melanoma who also have other affected relatives (27%). [ABSTRACT FROM AUTHOR]

• Paper illustrates the effects that P2P trading can have on the network operation. • Presents OPF based tool to integrate P2P into distribution network operation. • Investigates influences of P2P on DGs under Last-In-First-Out principle of access. • Understanding unintended consequences of P2P trading on network and DGs is key. The increasing uptake of Distributed Energy Resources and advancement in blockchain technology has led to the growth in interest in the peer-to-peer (P2P) based energy trading. However, there has been a lack of consideration how these trades may affect the network operation, in particular in networks that apply Active Network Management using Last-in-First-out (LIFO) access rules, such as in the UK. This paper presents a novel application of Optimal Power Flow that manages the P2P trading whilst optimising legacy DGs under a LIFO access agreement. Analysis show that under such arrangements, and in combination with autonomous P2P trading, lower priority DGs are vulnerable to excessive curtailment levels. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR)., Methods: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (OR SD ) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions., Results: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (OR SD  = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown., Conclusions: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development., Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10 -4 ). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10 -5 ). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2., Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)