2021 ISHNE/ HRS/ EHRA/ APHRS collaborative statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/ Heart Rhythm Society/ European Heart Rhythm Association/ Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored

New Zealand’s Cultures: Histories, Sources, Futures (special issue)

The essays in this issue are revised and extended versions of a selection of the papers delivered at the inaugural conference of the New Zealand Studies Network (UK and Ireland), titled ‘New Zealand’s Cultures: Histories, Sources, Futures’, held at Birkbeck, University of London in July 2012. With an emphasis on the ‘making of New Zealand’ in the past, present and future, the conference set out to explore some of the origins, historical sources, influences on, contemporary changes and future developments of the nation and its cultures. The questions asked by the conference were those of the title of Gauguin’s late canvas, D’où-venons nous? Que sommes-nous? Où allons-nous? (Where do we come from? What are we? Where are we going?

Book Reviews

Book Reviews: the Cambridge History of the Pacific Islanders by Donald Denoon and Others; Merchant Prince of the Sandalwood Mountains by Bob Dye; Representing the South Pacific: Colonial Discourse From Cook To Gauguin by Rod Edmond; War in the Pacific by Jerome T. Hagen; Ke Kumu Aupuni by S. M. Kamakau; Guardians of Empire: the U.S. Army and the Pacific, 1902 - 1940 by Brian M. Linn; Sites of Maui by Elspeth Sterlin

Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors

Background Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities.Methods PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing.Results GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1–high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400–1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines.Conclusions GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade.Trial registration number NCT04049617