Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab

Background: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab. Patients and methods: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF). Results: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD. Conclusions: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agent

AN INITIAL DESIGN FRAMEWORK FOR VIRTUAL HISTORIC DUBLIN

As a single coherent model, the proposed Virtual Historic Dublin City will improve the current approaches for planning, conserving, presenting and interpreting cultural heritage buildings and their environments. The combination of digital recording, modelling and data management systems enable the interaction with complex, interlinked three-dimensional structures containing rich and diverse underlying data. End users can encompass architectural and engineering conservation, education and research, in addition to public engagement and cultural tourism. In this paper a digital design framework is presented, based on state of the art current approaches for recording, modelling and presenting Virtual Historic Dublin. The modelling sites and structures is based on remotely sensed survey data which is processed and modelled in Historic BIM or GIS allowing the addition of semantic attributes. Archiving and storage of both models and knowledge and information attributes requires open systems and server data base capable of handling vector and point cloud information in addition to other digital data. The dissemination and interaction with the models and attached knowledge attributions is based on combining game engine platforms, Historic BIM, Historic GIS and access to compatible storage and data base

Culturable Root Endophyte Communities are Shaped by Both Warming and Plant Host Identity in the Rocky Mountains, USA

Understanding the biogeographic patterns of root-associated fungi and their sensitivity to temperature may improve predictions of future changes in terrestrial biodiversity and associated ecosystem processes, but data are currently limited. Anticipating change will require combining observational data, which predict how climatic factors limit current species distributions, with direct manipulations of climate, which can isolate responses to specific climate variables. Root endophytes are common symbionts of plants, particularly in arctic and alpine environments, yet their responses to climate warming are not resolved. Here, we directly cultured endophytic fungi from roots collected along altitudinal gradients in replicated mountain watersheds and from a 27 y field warming experiment in the Rocky Mountains, USA, to improve understanding of climate impacts on fungal root endophytes. Fungal taxa that were common at high elevations declined most under climate warming, whereas low elevation dominants responded neutrally or increased with experimental warming. Altitudinal gradients in fungal communities were strongly specific to the plant host species. Specifically, Poa species had 25–60% greater fungal isolate abundance and 25–38% greater fungal diversity at high elevations than at low elevation sites. In contrast, Festuca thurberi had 64% lower fungal diversity on roots at high elevation than at low elevation. Our results help to improve understanding of the potential for climate change to alter plant-fungal interactions in mountain ecosystems

Demonstration of Universal Parametric Entangling Gates on a Multi-Qubit Lattice

We show that parametric coupling techniques can be used to generate selective entangling interactions for multi-qubit processors. By inducing coherent population exchange between adjacent qubits under frequency modulation, we implement a universal gateset for a linear array of four superconducting qubits. An average process fidelity of $\mathcal{F}=93\%$ is estimated for three two-qubit gates via quantum process tomography. We establish the suitability of these techniques for computation by preparing a four-qubit maximally entangled state and comparing the estimated state fidelity against the expected performance of the individual entangling gates. In addition, we prepare an eight-qubit register in all possible bitstring permutations and monitor the fidelity of a two-qubit gate across one pair of these qubits. Across all such permutations, an average fidelity of $\mathcal{F}=91.6\pm2.6\%$ is observed. These results thus offer a path to a scalable architecture with high selectivity and low crosstalk

Current-Induced Entanglement of Nuclear Spins in Quantum Dots

We propose an entanglement mechanism of nuclear spins in quantum dots driven by the electric current accompanied by the spin flip. This situation is relevant to a leakage current in spin-blocked regions where electrons cannot be transported unless their spins are flipped. The current gradually increases the components of larger total spin of nuclei. This correlation among the nuclear spins markedly enhances the spin-flip rate of electrons and hence the leakage current. The enhancement of the current is observable when the residence time of electrons in the quantum dots is shorter than the dephasing time T*_2 of nuclear spins.Comment: 4 pages, 4 figure

Long-term survival in people with transthyretin amyloid cardiomyopathy who took tafamidis: A Plain Language Summary

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. WHAT DID RESEARCHERS FIND OUT?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. WHAT DO THE RESULTS MEAN?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration: NCT02791230 (ClinicalTrials.gov)

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

What’s Next for Acute Heart Failure Research?

Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either “inpatient” or “ED-based.” Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high-priority research areas

A REVIEW OF 3D GIS FOR USE IN CREATING VIRTUAL HISTORIC DUBLIN

This paper illustrates how BIM integration with GIS is approached as part of the workflow in creating Virtual Historic Dublin. A design for a WEB based interactive 3D model of historic buildings and centres in Dublin City (Virtual Historic Dublin City) paralleling smart city initiates is now under construction and led by the National Monuments at the Office of Public Works in Ireland. The aim is to facilitate the conservation and maintenance of historic infrastructure and fabric and the dissemination of knowledge for education and cultural tourism using an extensive Historic Building Information Model. Remote sensing data is now processed with greater ease to create 3D intelligent models in Historic BIM. While the use of remote sensing, HBIM and game engine platforms are the main applications used at present, 3D GIS has potential to form part of the workflow for developing the Virtual Historic City. 2D GIS is now being replaced by 3D spatial data allowing more complex analysis to be carried out, 3D GIS can define and depict buildings, urban rural centres in relation to their geometry topological, semantic and visualisation properties. The addition of semantic attributes allows complex analysis and 3D spatial queries for modelling city and urban elements. This analysis includes fabric and structural elements of buildings, relief, vegetation, transportation, water bodies, city furniture and land use