Endogenous driving and synchronization in cardiac and uterine virtual tissues: bifurcations and local coupling

Cardiac and uterine muscle cells and tissue can be either autorhythmic or excitable. These behaviours exchange stability at bifurcations produced by changes in parameters, which if spatially localized can produce an ectopic pacemaking focus. The effects of these parameters on cell dynamics have been identified and quantified using continuation algorithms and by numerical solutions of virtual cells. The ability of a compact pacemaker to drive the surrounding excitable tissues depends on both the size of the pacemaker and the strength of electrotonic coupling between cells within, between, and outside the pacemaking region. We investigate an ectopic pacemaker surrounded by normal excitable tissue. Cell–cell coupling is simulated by the diffusion coefficient for voltage. For uniformly coupled tissues, the behaviour of the hybrid tissue can take one of the three forms: (i) the surrounding tissue electrotonically suppresses the pacemaker; (ii) depressed rate oscillatory activity in the pacemaker but no propagation; and (iii) pacemaker driving propagations into the excitable region. However, real tissues are heterogeneous with spatial changes in cell–cell coupling. In the gravid uterus during early pregnancy, cells are weakly coupled, with the cell–cell coupling increasing during late pregnancy, allowing synchronous contractions during labour. These effects are investigated for a caricature uterine tissue by allowing both excitability and diffusion coefficient to vary stochastically with space, and for cardiac tissues by spatial gradients in the diffusion coefficient

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies:a case series

Advanced Access publication on May 7, 2014Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m² on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.A.W. Horne, M.M. Skubisz, S. Tong, W.C. Duncan, P. Neil, E.M.Wallace, and T.G. John

Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts

Background To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over-expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg). Methodology Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well. Conclusion and significance SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting Cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart

Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied \u201ccountry-specific\u201d factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a \u201cone-size-fits-all\u201d approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Search for dark matter produced in association with a hadronically decaying vector boson in pp collisions at sqrt (s) = 13 TeV with the ATLAS detector

A search is presented for dark matter produced in association with a hadronically decaying W or Z boson using 3.2 fb−1 of pp collisions at View the MathML sources=13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Events with a hadronic jet compatible with a W or Z boson and with large missing transverse momentum are analysed. The data are consistent with the Standard Model predictions and are interpreted in terms of both an effective field theory and a simplified model containing dark matter

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe