Analysis of 2,570 responses to Dog Aging Project End of Life Survey demonstrates that euthanasia is associated with cause of death but not age.

OBJECTIVE: The Dog Aging Project End of Life Survey was used to evaluate factors associated with manner of death (euthanasia vs unassisted death), including cause of death (CoD), reason for euthanasia (RFE) if performed, medical symptoms, old age characteristics, and perimortem quality of life (QoL). SAMPLE: Responses collected between the End of Life Survey launch (January 20, 2021) through December 31, 2021, from 2,570 participants whose dogs died. METHODS: Response frequencies were described. Associations between manner of death and medical symptoms or old age characteristics were evaluated using logistic regression. Factors associated with RFE were evaluated using multinomial regression. The effects of CoD, age at death, and QoL on the frequency of euthanasia as the manner of death were evaluated using multivariate logistic regression. RESULTS: 2,195 (85.4%) dogs were euthanized, and 375 (14.6%) experienced unassisted death. The most frequent owner-reported CoD was illness/disease (n = 1,495 [58.1%]). The most frequently reported RFE was pain/suffering (n = 1,080 [49.2% of those euthanized]). As age increased, RFE was more likely to be "poor QoL" than any other response. In a multivariate regression including CoD, chronologic age, and QoL, euthanasia as the manner of death was not significantly associated with age. CLINICAL RELEVANCE: Euthanasia was a common manner of death for dogs in the US. Compared with unassisted death, euthanasia was associated with CoD illness/disease, lower QoL scores, and the presence and number of medical symptoms and old age characteristics. Understanding factors associated with manner of death is important to veterinarians who care for dogs at the end of life.

Virtual Delivery of Stepped-Care Cognitive Behaviour Therapy for Cancer Related Fatigue: A Feasibility Study.

PURPOSE: About 1 in 3 people experience persistent fatigue after cancer treatment. People with severe fatigue describe a disabling lack of stamina, anxiety, depression and distressing cognitive changes. Cognitive behavior therapy (CBT) is recommended for people with severe fatigue after cancer treatment, however due to limited resources and lack of available clinicians very few people with cancer have access. This study explored feasibility of a virtual stepped-care CBT program. METHODS: English speaking adults experiencing persistent fatigue who had either completed cancer treatment, or with stable disease on maintenance therapies were recruited. All participants engaged in a 6-week supported self-help program using a CBT workbook targeting fatigue (STEP 1). After the self-help program, participants with severe ongoing fatigue were stepped-up to a telehealth CBT group focused to fatigue led by a Clinical Psychologist (STEP 2). Feasibility and perceived changes were assessed at baseline, 6 and 12 weeks. RESULTS: Of 19 participants, 17 completed STEP 1 and 8 completed STEP 2. Remotely delivered CBT was feasible with high retention, adherence, participant feasibility and satisfaction scores. Cost to deliver STEP 1 was AUD $145 and STEP 2, AUD $280 per participant. Overall, fatigue and self-efficacy improved significantly following STEP 1. Participants with higher baseline fatigue achieved limited improvements with self-help alone, requiring guidance to set achievable goals and reframe cognitions. Fatigue, self-efficacy and mood improved with STEP 2. CONCLUSIONS: Remotely delivered CBT for cancer fatigue was feasible. The effectiveness of stratified rather than stepped CBT approach, based on fatigue severity should be trialed. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN # 11 12622000420741).

A review of frailty instruments in human medicine and proposal of a frailty instrument for dogs.

Over the last few decades, frailty has become a pillar of research and clinical assessment in human gerontology. This complex syndrome, characterized by loss of physiologic reserves leading to decreased resilience to stressors, is of critical importance because it predicts higher risks of poor health outcomes, including mortality. Thus, identifying frailty among the elderly human population has become a key focus of gerontology. This narrative review presents current scientific literature on frailty in both humans and animals. The authors discuss the need for an accessible frailty instrument for companion dogs suitable for general use in veterinary medicine and the advances that would be facilitated by this instrument. A phenotypic frailty instrument for companion dogs, utilizing components that are easily collected by owners, or in the general practice setting, is proposed. The authors elaborate on the domains (physical condition, physical activity, mobility, strength, cognitive task performance, and social behavior), factors that will be included, and the data from the Dog Aging Project that inform each domain.

Identifying strategies for implementing a clinical guideline for cancer-related fatigue: a qualitative study.

BACKGROUND: Clinical practice guidelines assist health professionals' (HPs) decisions. Costly to develop, many guidelines are not implemented in clinical settings. This paper describes an evaluation of contextual factors to inform clinical guideline implementation strategies for the common and distressing problem of cancer-related fatigue (CRF) at an Australian cancer hospital. METHODS: A qualitative inquiry involving interviews and focus groups with consumers and multidisciplinary HPs explored key Canadian CRF guideline recommendations. Four HP focus groups examined the feasibility of a specific recommendation, while a consumer focus group examined experiences and preferences for managing CRF. Audio recordings were analysed using a rapid method of content analysis designed to accelerate implementation research. Strategies for implementation were guided by the Consolidated Framework for Implementation Research. RESULTS: Five consumers and 31 multidisciplinary HPs participated in eight interviews and five focus groups. Key HP barriers to fatigue management were insufficient knowledge and time; and lack of accessible screening and management tools or referral pathways. Consumer barriers included priority for cancer control during short health consultations, limited stamina for extended or extra visits addressing fatigue, and HP attitudes towards fatigue. Enablers of optimal fatigue management were alignment with existing healthcare practices, increased HP knowledge of CRF guidelines and tools, and improved referral pathways. Consumers valued their HPs addressing fatigue as part of treatment, with a personal fatigue prevention or management plan including self-monitoring. Consumers preferred fatigue management outside clinic appointments and use of telehealth consultations. CONCLUSIONS: Strategies that reduce barriers and leverage enablers to guideline use should be trialled. Approaches should include (1) accessible knowledge and practice resources for busy HPs, (2) time efficient processes for patients and their HPs and (3) alignment of processes with existing practice. Funding for cancer care must enable best practice supportive care.

Disabled, invisible and dismissed-The lived experience of fatigue in people with myeloproliferative neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are rare haematological cancers. Several studies report the most common MPN symptom leading to reduced quality of life is fatigue. Yet, how fatigue affects the lives of people with MPN is not well described. AIMS: The purpose of this qualitative study is to better understand the lived experience of fatigue associated with MPN. METHODS AND RESULTS: People with MPN who had experienced fatigue were invited to complete an online survey and if eligible, then to participate in semi-structured interviews and focus groups, exploring their experiences of fatigue. Thematic analysis of interview transcripts by two researchers produced themes describing the lived experience of fatigue. Twenty-three people with MPN participated in seven interviews and four focus groups. Qualitative data revealed how fatigue significantly affected participants' experiences of functional, social, family and emotional wellbeing. Participants reported that fatigue was infrequently acknowledged or addressed by health professionals, and a lack of information or support to manage their fatigue. Four themes including 12 sub-themes describe the experience of fatigue in MPN: (1) the distress of the MPN diagnosis, (2) sensations of fatigue, (3) daily life and emotional burden with fatigue and (4) how people managed their fatigue with limited guidance. CONCLUSION: Fatigue in MPN is common, debilitating and distressing. It affects all aspects of health, wellbeing and life. Health professionals could affect patients' lives substantially by acknowledging and understanding fatigue in MPN, including contributing factors and potential opportunities for management. More systematic data describing the causes and management of MPN fatigue is needed.

Stepped-care cognitive behaviour therapy program for treating cancer-related fatigue: protocol for a feasibility study.

BACKGROUND: Cancer-related fatigue (CRF) is a commonly experienced and often debilitating side effect of cancer treatment that can persist for years after treatment completion. The benefits of cognitive behaviour therapy (CBT) for CRF are well established; however, these interventions are typically not included in standard clinical care. Traditional CBT is resource-intensive, limiting implementation in hospital settings. Stepped-care approaches can offer benefits to more people, using the same personnel as traditional models. METHOD/DESIGN: This is a single-arm feasibility study. Fifty people with a cancer diagnosis, at least 12 weeks post-treatment or on long-term maintenance treatment, with persistent CRF that is affecting daily activities, will enrol in a stepped-care CBT program. INTERVENTION: The stepped-care program involves two steps. Step 1: All participants begin with a 5-week supported self-management CBT progam targeting fatigue. Step 2: If fatigue remains severe or has changed less than the minimal clinically important difference on the fatigue measure after step 1, participants will be offered four sessions of therapist-directed group CBT. MEASURES: Participants will complete questionnaires at baseline and 6 and 10 weeks. The primary outcome is feasibility of the REFRESH program. The implementation evaluation comprises acceptability, satisfaction, appropriateness, and feasibility of the study intervention, along with administrative data including cost, processes, procedures and implementation. Secondary outcomes are changes in fatigue, quality of life and self-efficacy. CONCLUSION: The REFRESH program will be the first stepped-care CBT intervention for persistent CRF in Australia. Assessing feasibility of REFRESH is an important first step to establishing future implementation and efficacy.

Exploring the Use of Two Brief Fatigue Screening Tools in Cancer Outpatient Clinics.

PURPOSE: Cancer fatigue guidelines recommend routine fatigue screening, with further assessment for people reporting moderate to severe fatigue. There is neither a gold-standard, nor a broadly accepted screening method, and knowledge about the impact of screening on care processes is limited. This study aimed to explore the feasibility of 2 fatigue screening methods and current clinical practice in cancer outpatient clinics. METHODS: Hospital outpatients attending cancer clinics during 1 week completed a five-item survey: a numeric scale for current tiredness, 2 categorical pictorial scales rating tiredness last week and the impact of fatigue (Fatigue Pictogram), screening tool preference and help needed for survey completion. Participant demographics and fatigue documentation by clinical staff for that appointment were extracted from medical records. Analyses used descriptive statistics. Groups were compared using appropriate statistical tests. RESULTS: Over 75% of participants rated their fatigue consistently as mild or significant on both screening tools. Of 1709 eligible outpatients, 533 (31%) completed the survey. Records were audited for 430 (81%) identifiable participants. Over half of the participants reported moderate or severe tiredness either "now" (237, 57%) and/or "last week" (226, 53%). Clinician documentation of fatigue seldom matched self-reports. Fatigue was rated as severe by 103 participants (24%), yet was noted in only 21 (20%) of these individuals' clinical notes. Both screening tools were equally preferred. CONCLUSION: The numeric rating scale and Fatigue Pictogram are equally applicable for screening fatigue in cancer outpatient care. There is a high prevalence of clinically significant fatigue in a hospital outpatient setting that is not documented. Adequate care pathways for further management should be established alongside fatigue screening.

Design of a Drug-Eluting Subcutaneous Implant of the Antiretroviral Tenofovir Alafenamide Fumarate.

PURPOSE: Sexual transmission of HIV has been clinically proven to be preventable with a once-daily oral tablet; however, missed doses dramatically increase the risk of HIV infection. Long-acting subcutaneous implants do not allow the user to miss a dose. A desirable long-acting drug-eluting implant can deliver a constant amount of drug, adjust the delivered dose, and be readily manufactured. We present a long-acting, subcutaneous implant design composed of tenofovir alafenamide hemifumarate (TAF) pellets loaded in a sealed polyether urethane tube for the prevention of HIV transmission. METHODS: Implants were prepared with pressed drug pellets and extruded polyurethane tubing. In vitro release rate of implants using different pellet formulations, rate-controlling membranes, and geometries were measured. RESULTS: Tenofovir alafenamide release appeared to be governed by a pseudo-steady state and followed a mass transport model of release from a cylindrical drug reservoir. Implant seal integrity was tested and confirmed using mechanical testing. The inclusion of sodium chloride in the pellet increased the release rate and reduced initial lag. The release was sustained for 100 days. CONCLUSIONS: The release rate of tenofovir alafenamide mechanistically varied with geometry and rate controlling membrane composition. The polyether urethane implant presented herein is modular and tunable to adjust the release rate and duration of the TAF release.

i-Move, a personalised exercise intervention for patients with advanced melanoma receiving immunotherapy: a randomised feasibility trial protocol.

INTRODUCTION: There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue. METHODS AND ANALYSIS: Thirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC-2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients. TRIAL REGISTRATION NUMBER: ACTRN12619000952145; Pre-results.

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques.

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 µg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

Pseudomonas aeruginosa pyocyanin production reduced by quorum-sensing inhibiting nanocarriers.

Pseudomonas aeruginosa is an opportunistic gram-negative pathogen that causes a wide range of infections; it is becoming increasingly difficult to treat due to antibiotic resistance. Quorum-sensing (QS) based therapeutics, which function by disabling pathogen virulence without killing pathogens, are a promising class of drugs that may be used to treat bacterial infections without eliciting resistance development. The use of QS drugs to treat pulmonary P. aeruginosa infections, however, has been greatly limited due to the inability to deliver QS drugs at sufficiently high concentrations past physiological barriers such as pulmonary mucus. Here we apply a block copolymer-directed self-assembly process, Flash NanoPrecipitation, to develop a series of QS-active formulations that are fully water dispersible, stable, and mucus-penetrating. These formulations inhibit P. aeruginosa virulence without inhibiting cell growth. Particle size (70 nm-400 nm) and release rate (1 h-14 days) can be tuned by altering constructs' physical properties and formulation excipients. We also demonstrate, to the best of our knowledge, the first instance of a QS nanocarrier platform technology that can penetrate through human cystic fibrosis pulmonary mucus. This work highlights the need to incorporate nanoformulation strategies into the development of next-generation antimicrobial therapeutics.

Cancer related fatigue: implementing guidelines for optimal management.

BACKGROUND: Cancer-related fatigue (CRF) is a key concern for people living with cancer and can impair physical functioning and activities of daily living. Evidence-based guidelines for CRF are available, yet inconsistently implemented globally. This study aimed to identify barriers and enablers to applying a cancer fatigue guideline and to derive implementation strategies. METHODS: A mixed-method study explored the feasibility of implementing the CRF guideline developed by the Canadian Association for Psychosocial Oncology (CAPO). Health professionals, managers and consumers from different practice settings participated in a modified Delphi study with two survey rounds. A reference group informed the design of the study including the surveys. The first round focused on guideline characteristics, compatibility with current practice and experience, and behaviour change. The second survey built upon and triangulated the first round. RESULTS: Forty-five health practitioners and managers, and 68 cancer survivors completed the surveys. More than 75% of participants endorsed the CAPO cancer related fatigue guidelines. Some respondents perceived a lack of resources for accessible and expert fatigue management services. Further barriers to guideline implementation included complexity, limited practical details for some elements, and lack of clinical tools such as assessment tools or patient education materials. Recommendations to enhance guideline applicability centred around four main themes: (1) balancing the level of detail in the CAPO guideline with ease of use, (2) defining roles of different professional disciplines in CRF management, (3) how best to integrate CRF management into policy and practice, (4) how best to ensure a consumer-focused approach to CRF management. CONCLUSIONS: Translating current knowledge on optimal management of CRF into clinical practice can be enhanced by the adoption of valid guidelines. This study indicates that it is feasible to adopt the CAPO guidelines. Clinical application may be further enhanced with guideline adaptation, professional education and integration with existing practices.

Cancer-related fatigue: appraising evidence-based guidelines for screening, assessment and management.

PURPOSE: There is inconsistent management of cancer-related fatigue (CRF) by health professionals worldwide. This research aims to identify the most appropriate guidelines for the management of cancer-related fatigue. METHODS: A systematic search of international literature identified evidence-based clinical practice guidelines for CRF. Four reviewers independently appraised the highest quality guidelines using the AGREE-II instrument and National Heath and Medical Research Council (NHMRC) guideline standards. RESULTS: Five guidelines met the inclusion criteria. Of these, the 2015 Canadian Association of Psychosocial Oncology (CAPO) CRF guidelines and the 2014 American Society of Clinical Oncology (ASCO) fatigue guidelines for cancer survivors were selected for in-depth appraisal. The CAPO guideline scored higher than the ASCO for five domains of the AGREE-II. For one domain, the differences were statistically significant (p ≤ 0.05). The CAPO guideline met 37 of 47 NHMRC mandatory guideline standards and the ASCO guideline met 20. The difference in the proportion of standards met was statistically significant for one domain (p ≤ 0.05). Both guidelines had low scores for applicability and implementation. CONCLUSIONS: Currently, the CAPO guideline for cancer-related fatigue has the strongest evidence for use. To enhance implementation, further strategies for guideline dissemination and application are needed.

Cancer-related fatigue: a survey of health practitioner knowledge and practice.

PURPOSE: This study aims to identify the current practices of health professionals in the assessment and treatment of cancer-related fatigue (CRF). METHODS: Health professionals working with oncology clients participated in an electronic survey distributed via professional associations and oncology societies. RESULTS: One hundred twenty-nine professionals from nursing, medical, and allied health disciplines participated in an electronic survey. Overall, there was a perception that CRF was inadequately managed at some facilities. Routine fatigue screening processes in the workplace were reported by more than half of participants; however, less than one quarter used a clinical guideline or conducted in-depth CRF assessments. Awareness of interventions for CRF varied amongst participants with one quarter able to list five appropriate interventions for cancer-related fatigue. Access to services for managing fatigue was inconsistent across service types, with post-treatment triage a high priority for CRF in some organisations yet not others. Participants identified a need for improved guidelines, enhanced expertise and better access to services for people with CRF. CONCLUSIONS: There is a need for further education in CRF management for a range of health disciplines in oncology and additional resources to facilitate translation of CRF guidelines into clinical practice.

Saying yes to taxes: the politics of tax reform campaigns in three northwestern states, 1965-1973.

This article analyzes factors shaping popular support for new taxes by examining variation in the outcomes of votes in nine American states during the 1960s and early 1970s. New taxes were endorsed in five states but rejected in four. Using comparative and historical methods focused on the cases of Oregon, Washington, and Idaho, the author argues that the sequence of policy making shapes popular vetoes through three mechanisms: the mobilization of interest groups, the information available to voters about a policy, and how the costs and benefits of a policy appear to voters. The findings demonstrate that voter perceptions of the potential gains and losses of a new policy are sociologically mobilized through the policy process. Controlling when popular veto points appear in a policy process is an understudied strategy that is employed by American state builders to overcome ambivalence toward the fiscal imperatives of the activist state.

A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice.

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Arom(hum) mice were higher than in wild-type mice, whereas circulating levels were similar. Arom(hum) mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.

Weight gain increases human aromatase expression in mammary gland.

Adulthood weight gain predicts estrogen receptor-positive breast cancer. Because local estrogen excess in the breast likely contributes to cancer development, and aromatase is the key enzyme in estrogen biosynthesis, we investigated the role of local aromatase expression in weight gain-associated breast cancer risk in a humanized aromatase (Arom(hum)) mouse model containing the coding region and the 5'-regulatory region of the human aromatase gene. Compared with littermates on normal chow, female Arom(hum) mice on a high fat diet gained more weight, and had a larger mammary gland mass with elevated total human aromatase mRNA levels via promoters I.4 and II associated with increased levels of their regulators TNFα and C/EBPß. There was no difference in total human aromatase mRNA levels in gonadal white adipose tissue. Our data suggest that diet-induced weight gain preferentially stimulates local aromatase expression in the breast, which may lead to local estrogen excess and breast cancer risk.