Systematic Review and Meta-analysis: Use of Statins Is Associated with a Reduced Incidence of Oesophageal Adenocarcinoma

Purpose: Laboratory studies have suggested that statins may have useful anti-cancer effects against Barrett’s epithelial cancer lines. A variety of effects have been reported in clinical studies. Methods: We performed a systematic review and meta-analysis of the association between statin use and the development of oesophageal cancer. Multiple databases were searched for studies reporting the association of statin use and oesophageal cancer. Meta-analysis on the relationship between statin use and cancer incidence was performed. Results: Twenty publications met eligibility criteria, yielding 22 datasets for meta-analysis. All were observational studies. Population-level studies included 372,206 cancer cases and 6,086,906 controls. Studies examining adenocarcinoma development in Barrett’s oesophagus included 1057 cancers and 17,741 controls. In patients with Barrett’s oesophagus, statin use was associated with a reduced incidence of adenocarcinoma (pooled adjusted odds ratio (OR) 0.59 (95% confidence intervals 0.50–0.68)), with no heterogeneity between 11 studies. Population-based studies demonstrated more heterogeneity but showed that statin use was associated with a lower incidence of both oesophageal adenocarcinoma (OR 0.57 (0.43–0.76)) and all oesophageal cancers (OR 0.82 (0.7–0.88)). Information on statin type, dose, and duration was reported too infrequently for statistical analysis but individual studies showed a tendency to a dose- and duration-dependant decrease in cancer incidence. Conclusions: Statin use is associated with a significantly lower incidence of oesophageal adenocarcinoma. This is seen in both Barrett’s cohorts and general populations. Further studies should focus on drug, dose, and duration and the interaction with other risk and preventative factors

Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials

PURPOSE: A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. METHODS: Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). RESULTS: Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. CONCLUSION: The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research

Left ventricular assist device implantation augments nitric oxide dependent control of mitochondrial respiration in failing human hearts

AbstractOBJECTIVESThe objective of the study was to evaluate nitric oxide (NO) mediated regulation of mitochondrial respiration after implantation of a mechanical assist device in end-stage heart failure.BACKGROUNDVentricular unloading using a left ventricular assist device (LVAD) can improve mitochondrial function in end-stage heart failure. Nitric oxide modulates the activity of the mitochondrial electron transport chain to regulate myocardial oxygen consumption (MVO2).METHODSMyocardial oxygen consumption was measured polarographically using a Clark-type oxygen electrode in isolated left ventricular myocardium from 26 explanted failing human hearts obtained at the time of heart transplantation.RESULTSThe rate of decrease in oxygen concentration was expressed as a percentage of baseline. Results of the highest dose of drug are shown. Decrease in MVO2 was greater in LVAD hearts (n = 8) compared with heart failure controls (n = 18) in response to the following drugs: bradykinin (−34 ± 3% vs. −24 ± 5%), enalaprilat (−37 ± 5% vs. −23 ± 5%) and amlodipine (−43 ± 13% vs. −16 ± 5%; p < 0.05 from controls). The decrease in MVO2 in LVAD hearts was not significantly different from controls in response to diltiazem (−22 ± 5% in both groups) and exogenous NO donor, nitroglycerin (−33 ± 7% vs. −30 ± 3%). Nw-nitro-L-arginine methyl ester, inhibitor of NO synthase, attenuated the response to bradykinin, enalaprilat and amlodipine. Reductions in MVO2 in response to diltiazem and nitroglycerin were not altered by inhibiting NO.CONCLUSIONSChronic LVAD support potentiates endogenous NO-mediated regulation of mitochondrial respiration. Use of medical or surgical interventions that augment NO bioavailability may promote myocardial recovery in end-stage heart failure

Efficient quantum walk on a quantum processor

The random walk formalism is used across a wide range of applications, from modelling share prices to predicting population genetics. Likewise, quantum walks have shown much potential as a framework for developing new quantum algorithms. Here we present explicit efficient quantum circuits for implementing continuous-time quantum walks on the circulant class of graphs. These circuits allow us to sample from the output probability distributions of quantum walks on circulant graphs efficiently. We also show that solving the same sampling problem for arbitrary circulant quantum circuits is intractable for a classical computer, assuming conjectures from computational complexity theory. This is a new link between continuous-time quantum walks and computational complexity theory and it indicates a family of tasks that could ultimately demonstrate quantum supremacy over classical computers. As a proof of principle, we experimentally implement the proposed quantum circuit on an example circulant graph using a two-qubit photonics quantum processor

Comprehensive ascertainment of bleeding in patients prescribed different combinations of dual antiplatelet therapy (DAPT) and triple therapy (TT) in the UK:Study protocol for three population-based cohort studies emulating a € target trials' (the ADAPTT Study)

Introduction a € Real world' bleeding in patients exposed to different regimens of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) have a clinical and economic impact but have not been previously quantified. Methods and analysis We will use linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations eligible for three a € target trials' in patient groups: percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); conservatively managed (medication only) acute coronary syndrome (ACS). Patients ≥18 years old will be eligible if, in CPRD records, they have: ≥1 year of data before the index event; no prescription for DAPT or anticoagulants in the preceding 3 months; a prescription for aspirin or DAPT within 2 months after discharge from the index event. The primary outcome will be any bleeding event (CPRD or HES) up to 12 months after the index event. We will estimate adjusted HR for time to first bleeding event comparing: aspirin and clopidogrel (reference) versus aspirin and prasugrel or aspirin and ticagrelor after PCI; and aspirin (reference) versus aspirin and clopidogrel after CABG and ACS. We will describe rates of bleeding in patients prescribed TT (DAPT plus an anticoagulant). Potential confounders will be identified systematically using literature review, semistructured interviews with clinicians and a short survey of clinicians. We will conduct sensitivity analyses addressing the robustness of results to the study's main limitation - that we will not be able to identify the intervention group for patients whose bleeding event occurs before a DAPT prescription in CPRD. Ethics and dissemination This protocol was approved by the Independent Scientific Advisory Committee for the UK Medicines and Healthcare Products Regulatory Agency Database Research (protocol 16-126R) and the South West Cornwall and Plymouth Research Ethics Committee (17/SW/0092). The findings will be presented in peer-reviewed journals, lay summaries and briefing papers to commissioners/other stakeholders. Trial registration number 76607611; Pre-results

IL-33 delivery induces serous cavity macrophage proliferation independent of interleukin-4 receptor alpha

IL-33 plays an important role in the initiation of type-2 immune responses, as well as the enhancement of type 2 effector functions. Engagement of the IL-33 receptor on macrophages facilitates polarization to an alternative activation state by amplifying IL-4 and IL-13 signaling to IL-4Rα. IL-4 and IL-13 also induce macrophage proliferation but IL-33 involvement in this process has not been rigorously evaluated. As expected, in vivo delivery of IL-33 induced IL-4Rα-dependent alternative macrophage activation in the serous cavities. IL-33 delivery also induced macrophages to proliferate but, unexpectedly, this was independent of IL-4Rα signaling. In a filarial nematode infection model in which IL-4Rα-dependent alternative activation and proliferation in the pleural cavity is well described, IL-33R was essential for alternative activation but not macrophage proliferation. Similarly, during Alternaria alternata induced airway inflammation, which provokes strong IL-33 responses, we observed that both IL-4Rα and IL-33R were required for alternative activation, while macrophage proliferation in the pleural cavity was still evident in the absence of either receptor alone. Our data show that IL-33R and IL-4Rα promote macrophage proliferation independently of each other, but both are essential for induction of alternative activation

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Combined three-dimensional electric and seismic tomography study on the Aknes rockslide in western Norway

We present a combined 3-D geoelectric and seismic tomography study conducted on the large Aknes rockslide in western Norway. Movements on the slope are strongly influenced by water infiltration, such that the hydrogeological regime is considered as a critical factor affecting the slope stability. The aim of our combined geophysical study was to identify and visualize the main shallow tension fractures and to determine their effect on hydraulic processes by comparing the geophysical results with information from borehole logging and tracer tests. To resolve the complex subsurface conditions of the highly fractured rock mass, a three-dimensional set-up was chosen for our seismic survey. To map the water distribution within the rock mass, a pattern of nine intersecting 2-D geoelectric profiles covered the complete unstable slope. Six of them that crossed the seismic survey area were considered as a single data set in a 3-D inversion. For both methods, smoothing-constraint inversion algorithms were used, and the forward calculations and parameterizations were based on unstructured triangular meshes. A pair of parallel shallow low-velocity anomalies (<1400 m/s) observed in the final seismic tomogram was immediately underlain by two anomalies with resistivities <13 k Omega m in the resistivity tomogram. In combination with borehole logging results, the low-velocity and resistivity anomalies could be associated with the drained and water-filled part of the tension fractures, respectively. There were indications from impeller flowmeter measurements and tracer tests that such tension fractures intersected several other water-filled fractures and were responsible for distinct changes of the main groundwater flow paths. (C) 2009 Elsevier B.V. All rights reserved

Real-world bleeding in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and prescribed different combinations of dual antiplatelet therapy (DAPT) in England : a population-based cohort study emulating a ‘target trial’

Objective: To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England. Design: A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT). Data sources: Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). Setting: Primary and secondary care. Participants: Patients ≥18 years old with ACS undergoing emergency PCI. Interventions: Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI). Main outcome measures: Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE). Results: In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only). Conclusions: In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel. Trial registration number: ISRCTN76607611