Initial Implementation of the My Heart, My Life Program by the National Heart Foundation of Australia: Pilot Mixed Methods Evaluation Study.

BACKGROUND: Coronary heart disease (CHD) remains the leading cause of death in Australia, with a high residual risk of repeat events in survivors. Secondary prevention therapy is crucial for reducing the risk of both death and other major adverse cardiac events. The National Heart Foundation of Australia has developed a consumer-facing support program called My Heart, My Life (MHML) to address the gap in the secondary prevention of CHD in Australia. The MHML pilot program supplies advice and support for both patients and their caregivers, and it was conducted over 8 months from November 2019 to June 2020. OBJECTIVE: This study aims to describe and examine the implementation of a novel multimodality secondary CHD prevention pilot program called MHML, which was delivered through booklets, text messages, emails, and telephone calls. METHODS: This pilot study consists of a mixed methods evaluation involving surveys of participants (patients and caregivers) and health professionals, in-depth interviews, and digital communication (SMS text message, electronic direct mail, and call record analytics). This study was performed in people older than 18 years with acute coronary syndrome or angina and their caregivers in 38 Australian hospitals from November 2019 to June 2020 through the National Heart Foundation of Australia web page. The main outcome measures were reach, accessibility, feasibility, barriers, and enablers to implementation of this program. RESULTS: Of the 1004 participants (838 patients and 164 caregivers; 2 missing), 60.9% (608/1001) were males, 50.7% (491/967) were aged between 45 and 64 years, 27.4% (276/1004) were from disadvantaged areas, 2.5% (24/946) were from Aboriginal or Torres Strait Islander background, and 16.9% (170/1004) reported English as their second language. The participants (patients and their caregivers) and health professionals reported high satisfaction with the MHML program (55/62, 88.7% and 33/38, 87%, respectively). Of the 62 participants who took the survey, 88% (55/62) used the text messaging service and reported a very high level of satisfaction. Approximately 94% (58/62) and 89% (55/62) of the participants were satisfied with the quick guide booklets 1 and 2, respectively; 79% (49/62) were satisfied with the monthly email journey and 71% (44/62) were satisfied with the helpline calls. Most participants reported that the MHML program improved preventive behaviors, that is, 73% (45/62) of them reported that they maintained increased physical activity and 84% (52/62) reported that they maintained a healthy diet even after the MHML program. CONCLUSIONS: The findings of our pilot study suggest that a multimodal support program, including digital, print, phone, and web-based media, for the secondary prevention of CHD is useful and could be a potential means of providing customized at-scale secondary prevention support for survivors of acute coronary syndrome.

Telehealth is here to stay but not without challenges: a consultation of cardiac rehabilitation clinicians during COVID-19 in Victoria, Australia.

AIMS: Delivery of cardiac rehabilitation (CR) was challenged during the pandemic caused by the Coronavirus disease (COVID-19), due to government stay-at-home directives which restricted in-person programmes. The Australian state of Victoria experienced the longest and most severe COVID-19 restrictions and was in lockdown for ∼6 months of 2020. We aimed to explore (i) clinicians' experiences and perceptions and (ii) identify barriers and enablers, for delivering CR during the COVID-19 pandemic. METHODS AND RESULTS: Victorian members of the Australian Cardiovascular Health and Rehabilitation Association (ACRA) were invited to attend an exploratory qualitative online consultation in November 2020. An inductive thematic analysis was undertaken, before deductively applying the Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework to identify barriers and enablers for technology adoption in CR. Thirty members participated in a 106-min consultation. Seventeen members who provided demographics represented multiple disciplines (nursing n = 13, exercise physiology n = 3, and physiotherapy n = 1) and geographical settings (metropolitan n = 10, regional n = 4, and rural n = 3). Four main themes were inductively identified: consequences of change; use of technology; capacity; and the way forward. The deductive NASSS analysis demonstrated the main challenges of continuing remotely delivered CR lie with adopters (staff, patients, and carers) and with organizations. CONCLUSION: The COVID-19 pandemic expedited significant changes to CR delivery models. While clinicians are eager to retain technology-enabled delivery in addition to resuming in-person CR, it is now timely to review remote models of care, tools used and plan how they will be integrated with traditional in-person programmes.

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates.

Purpose: To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity.Experimental Design: A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).Results: Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (Cmax). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with Cmax than AUC.Conclusions: We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. Clin Cancer Res; 23(19); 5858-68. ©2017 AACR.

Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment.

UNLABELLED: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+) Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells within the CD11b(+) Gr-1(high) cell fraction that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+) Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced. CONCLUSION: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease.

Thymic stromal lymphopoietin and interleukin-4 mediate the pathogenesis of halothane-induced liver injury in mice.

UNLABELLED: Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease has remained largely unknown. In this regard, it was recently shown that eosinophils played a pathogenic role in a mouse model of halothane-induced liver injury (HILI). However, the signaling events that drove hepatic expression of eosinophil-associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating hepatic epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) and type 2 immunity, in particular, interleukin-4 (IL-4) production, in mediating hepatic eosinophilia and injury during HILI. TSLP was constitutively expressed by mouse hepatocytes and increased during HILI. Moreover, the severity of HILI was reduced in mice deficient in either the TSLP receptor (TSLPR) or IL-4 and was accompanied by decreases in serum levels of eotaxins and hepatic eosinophilia. Similarly, concanavalin A-induced liver injury, where type 2 cytokines and eosinophils play a significant role in its pathogenesis, was also reduced in TSLPR-deficient mice. Studies in vitro revealed that mouse and human hepatocytes produce TSLP and eotaxins in response to treatment with combinations of IL-4 and proinflammatory cytokines IL-1ß and tumor necrosis factor alpha. CONCLUSION: This report provides the first evidence implicating roles for hepatic TSLP signaling, type 2 immunity, and eosinophilia in mediating liver injury caused by a drug.

Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.

In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4(-/-)) or by depletion with an antibody, were more susceptible to AILI than mice not depleted of IL-4. The increased susceptibility of IL-4(-/-) mice was not due to elevated levels of hepatic APAP-protein adducts but was associated with a prolonged reduction in hepatic GSH that was attributed to decreased gene expression of γ-glutamylcysteine ligase (γ-GCL). Moreover, administration of recombinant IL-4 to IL-4(-/-) mice postacetaminophen treatment diminished the severity of liver injury and increased γ-GCL and GSH levels. We also report that the prolonged reduction of GSH in APAP-treated IL-4(-/-) mice appeared to contribute toward increased liver injury by causing a sustained activation of c-Jun-N-terminal kinase (JNK) since levels of phosphorylated JNK remained significantly higher in the IL-4(-/-) mice up to 24 h after APAP treatment. Overall, these results show for the first time that IL-4 has a role in regulating the synthesis of GSH in the liver under conditions of cellular stress. This mechanism appears to be responsible at least in part for the protective role of IL-4 against AILI in mice and may have a similar role not only in AILI in humans but also in pathologies of the liver caused by other drugs and etiologies.

Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice.

UNLABELLED: We previously reported that acetaminophen (APAP)-induced liver injury (AILI) in mice is associated with a rise in serum levels of the glucocorticoid (GC), corticosterone. In the current study, we provide evidence that endogenous GC play a pathologic role in AILI. Specifically, pretreatment of mice with the GC receptor (GCR) inhibitor, RU486 (mifepristrone), protected normal but not adrenalectomized mice from AILI, while pretreatment with dexamethasone, a synthetic GC, exacerbated AILI. RU486 did not affect the depletion of whole liver reduced GSH or the formation of APAP-protein adducts. It also had no effects on the formation of reactive oxygen species or the depletion of mitochondrial GSH or ATP. While RU486 pretreatment also protected against halothane-induced liver injury, it exacerbated concanavalin A (ConA)- and carbon tetrachloride (CCl(4))-induced liver injury, demonstrating the complexity of GC effects in different types of liver injury. CONCLUSION: These results suggest that under certain conditions, elevated levels of GC might represent a previously unappreciated risk factor for liver injury caused by APAP and other drugs through the diverse biological processes regulated by GCR.

Disruption of the endoplasmic reticulum by cytotoxins in LLC-PK1 cells.

Prior induction of an endoplasmic reticulum stress response results in protection against reactive cytotoxins in the LLC-PK1 cell line. The purpose of this investigation was to determine therefore if the endoplasmic reticulum was disrupted by iodoacetamide, tert-butylhydroperoxide or sulfamethoxazole hydroxylamine. Toxic concentrations of the three toxins caused a dramatic loss of GRP94 protein within 3-8h of exposure, while induction of GRP78 and calreticulin occurred at 8 and 24h following exposure. There was no evidence of cytosolic elevation of calcium and neither dantrolene nor xestospongin were able to block the cytotoxicity of IDAM and TBHP. Exposure to the toxins led to DNA degradation and cleavage of procaspase-12. There was only evidence of procaspase-3 cleavage after TBHP exposure. These results demonstrate that the ER is disrupted by the reactive cytotoxins examined in LLC-PK1cells and suggest that the cytoprotection against low to moderate concentrations of cytotoxins observed following endoplasmic reticulum stress protein induction is likely due to a mechanism other than maintenance of calcium homeostasis.