Prostaglandin E2 Inhibits Histamine-Evoked Ca2+ Release in Human Aortic Smooth Muscle Cells through Hyperactive cAMP Signaling Junctions and Protein Kinase A

In human aortic smooth muscle cells (ASMC), prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca2+ concentration ([Ca2+]i) evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca2+ signals by PGE2. Exchange proteins activated by cAMP (EPACs) were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3. The rate of Ca2+ removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca2+ signals by PGE2 or butaprost (to selectively activate EP2 receptors), but it modestly attenuated responses to EP4 receptors, activation of which generated less cAMP than EP2 receptors. We conclude that inhibition of histamine-evoked Ca2+ signals by PGE2 occurs through ‘hyperactive signalling junctions’, wherein cAMP is locally delivered to PKA at super-saturating concentrations to cause uncoupling of H1 receptors from phospholipase C. This sequence allows digital signalling from PGE2 receptors, through cAMP and PKA, to histamine-evoked Ca2+ signals.This work was supported by the Medical Research Council [G0900049], Biotechnology and Biological Sciences Research Council [L000075] and the Wellcome Trust [101844]

National variation in pulmonary metastasectomy for colorectal cancer

AIM: Evidence on patterns of use of pulmonary metastasectomy in colorectal cancer patients is limited. This population‐based study aims to investigate the use of pulmonary metastasectomy in the colorectal cancer population across the English National Health Service (NHS) and quantify the extent of any variations in practice and outcome. METHODS: All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2013 were identified in the COloRECTal cancer data Repository (CORECT‐R). All inpatient episodes corresponding to pulmonary metastasectomy, occurring within 3 years of the initial colorectal resection, were identified. Multi‐level logistic regression was used to determine patient and organizational factors associated with the use of pulmonary metastasectomy for colorectal cancer, and Kaplan–Meier and Cox models were used to assess survival following pulmonary metastasectomy. RESULTS: In all, 173 354 individuals had a major colorectal resection over the study period, with 3434 (2.0%) undergoing pulmonary resection within 3 years. The frequency of pulmonary metastasectomy increased from 1.2% of patients undergoing major colorectal resection in 2005 to 2.3% in 2013. Significant variation was observed across hospital providers in the risk‐adjusted rates of pulmonary metastasectomy (0.0%–6.8% of patients). Overall 5‐year survival following pulmonary resection was 50.8%, with 30‐day and 90‐day mortality of 0.6% and 1.2% respectively. CONCLUSIONS: This study shows significant variation in the rates of pulmonary metastasectomy for colorectal cancer across the English NHS

Variation in post-colonoscopy colorectal cancer across colonoscopy providers in English National Health Service: population based cohort study

Objectives: To quantify post-colonoscopy colorectal cancer (PCCRC) rates in England by using recent World Endoscopy Organisation guidelines, compare incidence among colonoscopy providers, and explore associated factors that could benefit from quality improvement initiatives. Design: Population based cohort study. Setting: National Health Service in England between 2005 and 2013. Population: All people undergoing colonoscopy and subsequently diagnosed as having colorectal cancer up to three years after their investigation (PCCRC-3yr). Main outcome measures: National trends in incidence of PCCRC (within 6-36 months of colonoscopy), univariable and multivariable analyses to explore factors associated with occurrence, and funnel plots to measure variation among providers. Results: The overall unadjusted PCCRC-3yr rate was 7.4% (9317/126 152), which decreased from 9.0% in 2005 to 6.5% in 2013 (P<0.01). Rates were lower for colonoscopies performed under the NHS bowel cancer screening programme (593/16 640, 3.6%), while they were higher for those conducted by non-NHS providers (187/2009, 9.3%). Rates were higher in women, in older age groups, and in people with inflammatory bowel disease or diverticular disease, in those with higher comorbidity scores, and in people with previous cancers. Substantial variation in rates among colonoscopy providers remained after adjustment for case mix. Conclusions: Wide variation exists in PCCRC-3yr rates across NHS colonoscopy providers in England. The lowest incidence was seen in colonoscopies performed under the NHS bowel cancer screening programme. Quality improvement initiatives are needed to address this variation in rates and prevent colorectal cancer by enabling earlier diagnosis, removing premalignant polyps, and therefore improving outcomes

National variation in pulmonary metastasectomy for colorectal cancer

Aim Evidence on patterns of use of pulmonary metastasectomy in colorectal cancer patients is limited. This population‐based study aims to investigate the use of pulmonary metastasectomy in the colorectal cancer population across the English National Health Service (NHS) and quantify the extent of any variations in practice and outcome. Methods All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2013 were identified in the COloRECTal cancer data Repository (CORECT‐R). All inpatient episodes corresponding to pulmonary metastasectomy, occurring within 3 years of the initial colorectal resection, were identified. Multi‐level logistic regression was used to determine patient and organizational factors associated with the use of pulmonary metastasectomy for colorectal cancer, and Kaplan–Meier and Cox models were used to assess survival following pulmonary metastasectomy. Results In all, 173 354 individuals had a major colorectal resection over the study period, with 3434 (2.0%) undergoing pulmonary resection within 3 years. The frequency of pulmonary metastasectomy increased from 1.2% of patients undergoing major colorectal resection in 2005 to 2.3% in 2013. Significant variation was observed across hospital providers in the risk‐adjusted rates of pulmonary metastasectomy (0.0%–6.8% of patients). Overall 5‐year survival following pulmonary resection was 50.8%, with 30‐day and 90‐day mortality of 0.6% and 1.2% respectively. Conclusions This study shows significant variation in the rates of pulmonary metastasectomy for colorectal cancer across the English NHS

Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

BACKGROUND: Circulating levels of chemerin are significantly higher in hypertensive patients and positively correlate with blood pressure. Chemerin activates chemokine-like receptor 1 (CMKLR1 or ChemR23) and is proposed to activate the "orphan" G-protein-coupled receptor 1 (GPR1), which has been linked with hypertension. Our aim was to localize chemerin, CMKLR1, and GPR1 in the human vasculature and determine whether 1 or both of these receptors mediate vasoconstriction. METHODS AND RESULTS: Using immunohistochemistry and molecular biology in conduit arteries and veins and resistance vessels, we localized chemerin to endothelium, smooth muscle, and adventitia and found that CMKLR1 and GPR1 were widely expressed in smooth muscle. C9 (chemerin149-157) contracted human saphenous vein (pD2=7.30±0.31) and resistance arteries (pD2=7.05±0.54) and increased blood pressure in rats by 9.1±1.0 mm Hg at 200 nmol. Crucially, these in vitro and in vivo vascular actions were blocked by CCX832, which we confirmed to be highly selective for CMKLR1 over GPR1. C9 inhibited cAMP accumulation in human aortic smooth muscle cells and preconstricted rat aorta, consistent with the observed vasoconstrictor action. Downstream signaling was explored further and, compared to chemerin, C9 showed a bias factor=≈5000 for the Gi protein pathway, suggesting that CMKLR1 exhibits biased agonism. CONCLUSIONS: Our data suggest that chemerin acts at CMKLR1, but not GPR1, to increase blood pressure. Chemerin has an established detrimental role in metabolic syndrome, and these direct vascular actions may contribute to hypertension, an additional risk factor for cardiovascular disease. This study provides proof of principle for the therapeutic potential of selective CMKLR1 antagonists.This work was supported by the British Heart Foundation (FS/12/64/30001 [to AJK], FS/14/59/31282 [to CR], and PG/09/050/27734); Wellcome Trust (100780/Z/12/Z [to LY], 101844 [to CWT], 107715/Z/15/Z [to APD and JJM], and 096822/Z/11/Z [to APD and PY]); the Raymond and Beverley Sackler Fellowship (to LY), and the Medical Research Council (MRC MC_PC_14116; to APD) and by the Pulmonary Hypertension Association and the Cambridge Biomedical Research Centre. Biomedical Resources (grant 099156/Z/12/Z)

Rectal cancer in old age –is it appropriately managed? Evidence from population-based analysis of routine data across the English national health service

Background: There is significant debate as to where to draw the line between undertreating older rectal cancer patients and minimising treatment risks. This study sought to examine the use of radical rectal cancer treatments and associated outcomes in relation to age across the English NHS. Methods: Patient, tumour and treatment characteristics for all patients diagnosed with a first primary rectal cancer in England between 1st April 2009 and 31st December 2014 were obtained from the CORECT-R data repository. Descriptive analyses and adjusted logistic regression models were undertaken to examine any association between age and the use of major resection and post-surgical outcomes. Funnel plots were used to show variation in adjusted rates of major resection. Results: The proportion of patients who underwent a major surgical resection fell from 66.5% to 31.7%, amongst those aged <70 and aged ≥80 respectively. After adjustment, 30-day post-operative mortality, failure to rescue and prolonged length of stay were significantly higher among the oldest group when compared to the youngest. Patient reported outcomes were not significantly worse amongst older patients. Significant variation was observed in adjusted surgical resection rates in the oldest patients between NHS Trusts. The probability of death due to cancer was comparable across all age groups. Conclusions: Older patients who are selected for surgery have good outcomes, often comparable to their younger counterparts. Significant variation in the treatment of older patients could not be explained by differences in measured characteristics and required further investigation

Addressing the variation in adjuvant chemotherapy treatment for colorectal cancer: can a regional intervention promote national change?

Analysis of routine population‐based data has previously shown that patterns of surgical treatment for colorectal cancer can vary widely, but there is limited evidence available to determine if such variation is also seen in the use of chemotherapy. This study quantified variation in adjuvant chemotherapy across both England using cancer registry data and in more detail across the representative Yorkshire and Humber regions. Individuals with Stages II and III colorectal cancer who underwent major resection from 2014 to 2015 were identified. Rates of chemotherapy were calculated from the Systemic Anticancer Treatment database using multilevel logistic regression. Additionally, questionnaires addressing different clinical scenarios were sent to regional oncologists to investigate the treatment preferences of clinicians. The national adjusted chemotherapy treatment rate ranged from 2% to 46% (Stage II cancers), 19% to 81% (Stage III cancers), 24% to 75% (patients aged <70 years) and 5% to 46% (patients aged ≥70 years). Regionally, the rates of treatment and the proportions of treated patients receiving combination chemotherapy varied by stage (Stage II 4%‐26% and 0%‐55%, Stage III 48%‐71% and 40%‐84%) and by age (<70 years 35%‐68% and 49%‐91%; ≥70 years 15%‐39% and 6%‐75%). Questionnaire responses showed significant variations in opinions for high‐risk Stage II patients with both deficient and proficient mismatch repair tumours and Stage IIIB patients aged ≥70 years. Following a review of the evidence, open discussion in our region has enabled a consensus agreement on an algorithm for colorectal cancer that is intended to reduce variation in practice

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe