Endocrine treatment near the end of life among older women with metastatic breast cancer: a nationwide cohort study.

Background: The appropriate time to discontinue chemotherapy at the end of life has been widely discussed. In contrast, few studies have investigated the patterns of endocrine treatment near death. In this study, we aimed to investigate the end-of-life endocrine treatment patterns of older women with metastatic breast cancer and explore characteristics associated with treatment. Methods: A retrospective cohort study of all older women (age ≥65 years) with hormone receptor-positive breast cancer who died in Sweden, 2016 - 2020. We used routinely collected administrative and health data with national coverage. Treatment initiation was defined as dispensing during the last three months of life with a nine-month washout period, while continuation and discontinuation were assessed by previous use during the same period. We used log-binomial models to explore factors associated with the continuation and initiation of endocrine treatments. Results: We included 3098 deceased older women with hormone receptor-positive breast cancer (median age 78). Overall, endocrine treatment was continued by 39% and initiated by 5% and of women during their last three months of life, while 31% discontinued and 24% did not use endocrine treatment during their last year of life. Endocrine treatment continuation was more likely among older and less educated women, and among women who had multi-dose drug dispensing, chemotherapy, and CDK4/6 use. Only treatment-related factors were associated with treatment initiation. Conclusion: More than a third of women with metastatic breast cancer continue endocrine treatments potentially past the point of benefit, whereas late initiation is less frequent. Further research is warranted to determine whether our results reflect overtreatment at the end of life once patients' preferences and survival prognosis are considered.

Impact of early postoperative blood glucose variability on serum endocan level in cardiac surgery patients: a sub study of the ENDOLUNG observational study.

BACKGROUND: Early postoperative glycemic variability is associated with worse outcome after cardiac surgery, but the underlying mechanisms remain unknown. This study aimed to describe the relationship between postoperative glycemic variability and endothelial function, as assessed by serum endocan level in cardiac surgery patients. METHODS: We performed a post hoc analysis of patients included in the single-center observational ENDOLUNG study. Adult patients who underwent planned isolated coronary artery bypass graft surgery were eligible. Postoperative glycemic variability was assessed by calculating the coefficient of variability (CV) of blood glucose measured within 24 (CV24) and 48 (CV48) hours after surgery. Serum endocan level was measured at 24 (Endocan24) and 48 (Endocan48) hours after surgery. Pearson's correlation coefficient with 95% confidence interval (95% CI) was calculated between CV24 and Endocan24, and between CV48 and Endocan48. RESULTS: Data from 177 patients were analyzed. Median CV24 and CV48 were 18% (range 7 to 39%) and 20% (range 7 to 35%) respectively. Neither CV48 nor CV24 were significantly correlated to Endocan48 and Endocan24 respectively (r (95% CI) = 0.150 (0.001 to 0.290; and r (95% CI) = 0.080 (-0.070 to 0.220), respectively). CONCLUSIONS: Early postoperative glycemic variability within 48 h after planned cardiac surgery does not appear to be correlated with postoperative serum endocan level. CLINICAL TRIAL REGISTRATION NUMBER: NCT02542423.

Estimating pairwise overlap in umbrella reviews: Considerations for using the corrected covered area (CCA) index methodology.

Umbrella reviews (reviews of systematic reviews) are increasingly used to synthesize findings from systematic reviews. One important challenge when pooling data from several systematic reviews is publication overlap, that is, the same primary publications being included in multiple reviews. Pieper et al. have proposed using the corrected covered area (CCA) index to quantify the degree of overlap between systematic reviews to be pooled in an umbrella review. Recently, this methodology has been integrated in Excel- or R-based tools for easier use. In this short letter, we highlight an important consideration for using the CCA methodology for pairwise overlap assessment, especially when reviews include varying numbers of primary publications, and we urge researchers to fine-tune this method and exercise caution when review exclusion decisions are based on its output.

Effectiveness of interventions designed to mitigate the negative health outcomes of informal caregiving to older adults: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVES: This umbrella review aimed to evaluate whether certain interventions can mitigate the negative health consequences of caregiving, which interventions are more effective than others depending on the circumstances, and how these interventions are experienced by caregivers themselves. DESIGN: An umbrella review of systematic reviews was conducted. DATA SOURCES: Quantitative (with or without meta-analyses), qualitative and mixed-methods systematic reviews were included. ELIGIBILITY CRITERIA: Reviews were considered eligible if they met the following criteria: included primary studies targeting informal (ie, unpaid) caregivers of older people or persons presenting with ageing-related diseases; focused on support interventions and assessed their effectiveness (quantitative reviews) or their implementation and/or lived experience of the target population (qualitative reviews); included physical or mental health-related outcomes of informal caregivers. DATA EXTRACTION AND SYNTHESIS: A total of 47 reviews were included, covering 619 distinct primary studies. Each potentially eligible review underwent critical appraisal and citation overlap assessment. Data were extracted independently by two reviewers and cross-checked. Quantitative review results were synthesised narratively and presented in tabular format, while qualitative findings were compiled using the mega-aggregation framework synthesis method. RESULTS: The evidence regarding the effectiveness of interventions on physical and mental health outcomes was inconclusive. Quantitative reviews were highly discordant, whereas qualitative reviews only reported practical, emotional and relational benefits. Multicomponent and person-centred interventions seemed to yield highest effectiveness and acceptability. Heterogeneity among caregivers, care receivers and care contexts was often overlooked. Important issues related to the low quality of evidence and futile overproduction of similar reviews were identified. CONCLUSIONS: Lack of robust evidence calls for better intervention research and evaluation practices. It may be warranted to avoid one-size-fits-all approaches to intervention design. Primary care and other existing resources should be leveraged to support interventions, possibly with increasing contributions from the non-profit sector. PROSPERO REGISTRATION NUMBER: CRD42021252841; BMJ Open: doi:10.1136/bmjopen-2021-053117.

Variability in perceived burden and health trajectories among older caregivers: a population-based study in Sweden.

BACKGROUND: The negative effects of informal caregiving are determined by the characteristics of the caregiver-care receiver dyad and the context of care. In this study, we aimed to identify which subgroups of older informal caregivers (1) experience the greatest subjective burden and (2) incur a faster decline in objective health status. METHODS: From a total of 3363 older participants in the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), we identified 629 informal caregivers (19.2%, mean age 69.9 years). Limitations to life and perceived burden were self-reported, and objective health status was quantified using the comprehensive clinical and functional Health Assessment Tool (HAT) score (range: 0-10). Ordered logistic regressions and linear mixed models were used to estimate the associations between caregiving-related exposures and subjective outcomes (cross-sectionally) and objective health trajectories (over 12 years), respectively. RESULTS: Having a dual role (providing and receiving care simultaneously), caring for a spouse, living in the same household as the care receiver and spending more hours on caregiving were associated with more limitations and burden. In addition, having a dual role (ß=-0.12, 95% CI -0.23 to -0.02) and caring for a spouse (ß=-0.08, 95% CI -0.14 to -0.02) were associated with a faster HAT score decline. Being female and having a poor social network were associated with an exacerbation of the health decline. CONCLUSIONS: Both the heterogeneity among caregivers and the related contextual factors should be accounted for by policymakers as well as in future research investigating the health impact of informal caregiving.

Is research on 'smart living environments' based on unobtrusive technologies for older adults going in circles? Evidence from an umbrella review.

CONTEXT AND AIMS: To enable ageing in place, innovative and integrative technologies such as smart living environments may be part of the solution. Despite extensive published literature reviews on this topic, the effectiveness of smart living environments in supporting ageing in place, and in particular involving unobtrusive technologies, remains unclear. The main objective of our umbrella review was to synthesize evidence on this topic. METHODS: According to the PRIOR process, we included reviews from multiple databases that focused on unobtrusive technologies used to analyze and share information about older adults' behaviors and assessed the effectiveness of unobtrusive technologies to support ageing in place. Selection, extraction and quality appraisal were done independently by two reviewers. RESULTS: By synthesizing 17 published reviews that covered 191 distinct primary studies, we found that smart living environments based on unobtrusive technologies had low to moderate effectiveness to support older adults to age in place. Effectiveness appears to be strongest in the recognition of activities of daily living. The results must, however, be interpreted in light of the low overall level of evidence, i.e., low methodological value of the primary studies and poor methodological quality of the literature reviews. Most reviews concluded that unobtrusive technologies are not mature enough for widespread adoption. CONCLUSION: There is a necessity to support primary studies that can move beyond the proof-of-concept or pilot stages and expand scientific knowledge significantly on the topic. There is also an urgent need to publish high quality literature reviews to better support policy makers and funding agencies in the field of smart living environments.

Potential overtreatment in end-of-life care in adults 65 years or older dying from cancer: applying quality indicators on nationwide registries.

BACKGROUND: Quality indicators are frequently used to measure the quality of care at the end of life. Whether quality indicators of potential overtreatment (i.e., when the risks outweigh the benefits) at the end of life can be reliably applied to routinely collected data remains uncertain. This study aimed to identify quality indicators of overtreatment at the end of life in the published literature and to investigate their tentative prevalence among older adults dying with solid cancer. MATERIALS AND METHODS: Retrospective cohort study of decedents including all older adults (≥65 years) who died with solid cancer between 1 January 2013 and 31 December 2015 (n = 54,177) in Sweden. Individual data from the National Cause of Death Register were linked with data from the Total Population Register, the National Patient Register, and the Swedish Prescribed Drug Register. Quality indicators were applied for the last one and three months of life. RESULTS: From a total of 145 quality indicators of overtreatment identified in the literature, 82 (57%) were potentially operationalisable with routine administrative and healthcare data in Sweden. Unidentifiable procedures and hospital drug treatments were the reason for non-operationalisability in 52% of the excluded indicators. Among the 82 operationalisable indicators, 67 measured overlapping concepts. Based on the remaining 15 unique indicators, we tentatively estimated that overall, about one-third of decedents received at least one treatment or procedure indicative of 'potential overtreatment' during their last month of life. CONCLUSION: Almost half of the published overtreatment indicators could not be measured in routine administrative and healthcare data in Sweden due to a lack of means to capture the care procedure. Our tentative estimates suggest that potential overtreatment might affect one-third of cancer decedents near death. However, quality indicators of potential overtreatment for specific use in routinely collected data should be developed and validated.

Trends in management and outcomes of pulmonary embolism with a multidisciplinary response team.

Multidisciplinary pulmonary embolism (PE) response teams have garnered widespread adoption given the complexities of managing acute PE and provide a platform for assessment of trends in therapy and outcomes. We describe temporal trends in PE management and outcomes following the deployment of such a team. All consecutive patients managed by our multidisciplinary PE response team activated by the Emergency Department were included over a 5-year calendar period. We examined temporal trends in management and rates of a composite primary endpoint (all-cause-death, major bleeding, recurrent venous thromboembolism, and readmission) at 30 days and 6 months. We assessed 425 patients between 2015 and 2019. We observed an increase in PE acuity and use of systemic thrombolysis. The primary endpoint at 30 days decreased from 16.3% in 2015 to 7.1% in 2019 (adjusted rate ratio per period, 0.63; 95%CI, 0.47-0.84), driven by a decrease in the adjusted rate of major bleeding. Among 406 patients with complete follow-up, the adjusted rate ratio per year for the primary outcome at 6 months was 0.37 (95%CI, 0.19-0.71), driven by a decrease in all-cause mortality. We observed evidence of temporal changes in clinical presentation, therapeutic strategies, and outcomes for acute PE, in parallel to, but not necessarily because of, the implementation of a multidisciplinary response team. Over time, major bleeding, mortality and readmission rates decreased, despite an increase in PE risk category.

"A Delicate balance"-Perceptions and Experiences of ICU Physicians and Nurses Regarding Controlled Donation After Circulatory Death. A Qualitative Study.

Controlled donation after circulatory death (cDCD) is considered by many as a potential response to the scarcity of donor organs. However, healthcare professionals may feel uncomfortable as end-of-life care and organ donation overlap in cDCD, creating a potential barrier to its development. The aim of this qualitative study was to gain insight on the perceptions and experiences of intensive care units (ICU) physicians and nurses regarding cDCD. We used thematic analysis of in-depth semi-structured interviews and 6-month field observation in a large teaching hospital. 17 staff members (8 physicians and 9 nurses) participated in the study. Analysis showed a gap between ethical principles and routine clinical practice, with a delicate balance between end-of-life care and organ donation. This tension arises at three critical moments: during the decision-making process leading to the withdrawal of life-sustaining treatments (LST), during the period between the decision to withdraw LST and its actual implementation, and during the dying and death process. Our findings shed light on the strategies developed by healthcare professionals to solve these ethical tensions and to cope with the emotional ambiguities. cDCD implementation in routine practice requires a shared understanding of the tradeoff between end-of-life care and organ donation within ICU.

Last year of life of adults with congenital heart diseases: causes of death and patterns of care.

AIMS: Although life expectancy in adults with congenital heart diseases (CHD) has increased dramatically over the past five decades, still a substantial number of patients dies prematurely. To gain understanding in the trajectories of dying in adults with CHD, the last year of life warrants further investigation. Therefore, our study aimed to (i) define the causes of death and (ii) describe the patterns of healthcare utilization in the last year of life of adults with CHD. METHODS AND RESULTS: This retrospective mortality follow-back study used healthcare claims and clinical data from BELCODAC, which includes patients with CHD from Belgium. Healthcare utilization comprises cardiovascular procedures, CHD physician contacts, general practitioner visits, hospitalizations, emergency department (ED) visits, intensive care unit (ICU) admissions, and specialist palliative care, and was identified using nomenclature codes. Of the 390 included patients, almost half of the study population (45%) died from a cardiovascular cause. In the last year of life, 87% of patients were hospitalized, 78% of patients had an ED visit, and 19% of patients had an ICU admission. Specialist palliative care was provided to 17% of patients, and to only 4% when looking at the patients with cardiovascular causes of death. CONCLUSIONS: There is a high use of intensive and potentially avoidable care at the end of life. This may imply that end-of-life care provision can be improved. Future studies should further examine end-of-life care provision in the light of patient's needs and preferences, and how the healthcare system can adequately respond.

Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

Heavy alcohol consumption before and after negative life events in late mid-life: longitudinal latent trajectory analyses.

BACKGROUND: People who experience negative life events report more heavy alcohol consumption compared with people without these experiences, but little is known about patterns of change within this group. This study aims to identify trajectories of heavy alcohol consumption before and after experiencing either divorce, or severe illness or death in the family. Furthermore, the aim is to examine characteristics of individuals belonging to each trajectory. METHODS: Longitudinal study of public sector employees from the Finnish Retirement and Aging Study with up to 5 years of annual follow-ups (n=6783; eligible sample n=1393). Divorce and severe illness or death in the family represented negative life events. Heavy alcohol consumption was categorised as >14 units/week. RESULTS: Based on latent trajectory analysis, three trajectories of heavy drinking were identified both for divorce and for severe illness or death in the family: 'No heavy drinking' (82% illness/death, 75% divorce), 'Constant heavy drinking' (10% illness/death, 13% divorce) and 'Decreasing heavy drinking' (7% illness/death, 12% divorce). Constant heavy drinkers surrounding illness or death in the family were more likely to be men, report depression and anxiety and to smoke than those with no heavy drinking. Constant heavy drinkers surrounding divorce were also more likely to be men and to report depression compared with those with no heavy drinking. CONCLUSIONS: Most older workers who experience divorce or severe illness or death in the family have stable drinking patterns regarding heavy alcohol consumption, that is, most do not initiate or stop heavy drinking.

Statin Discontinuation and Cardiovascular Events Among Older People in Denmark.

Importance: Statin use is common in older persons. Given uncertainties in ongoing benefit, changes in health status, and shifting goals of care and preferences, statin discontinuation may be considered in some older persons, although there is currently little evidence to guide this decision. Objective: To evaluate the association between statin discontinuation and the rate of major adverse cardiovascular events (MACE) among people aged 75 years or older who receive long-term statin treatment. Design, Setting, and Participants: This cohort study included all persons in Denmark aged 75 years or older who were treated with statins for at least 5 consecutive years as of January 1, 2011. Participants were followed up until December 31, 2016. Data were analyzed from July to November, 2020. Exposure: Statin discontinuation. Main Outcomes and Measures: Rate of occurrence of MACE and its components (myocardial infarction, ischemic stroke or transient ischemic attack, coronary revascularization, and death due to myocardial infarction or ischemic stroke) in persons continuing statins compared with those discontinuing statins. Confounding adjustment was done using inverse probability of treatment weighting. Analyses were conducted separately for primary prevention (no history of cardiovascular disease) and secondary prevention (history of cardiovascular disease). Results: The study included 67 418 long-term statin users, including 27 463 in the primary prevention analysis (median age, 79 years [IQR, 77-83 years]; 18 134 [66%] female) and 39 955 in the secondary prevention analysis (median age, 80 years [IQR, 77-84 years]; 18 717 [47%] female). In both primary and secondary prevention analyses, the rate of MACE was higher among persons who discontinued statins compared with those who continued statins. In the primary prevention cohort, the weighted rate difference was 9 per 1000 person-years (95% CI, 5-12 per 1000 person-years) and the adjusted sub-hazard ratio was 1.32 (95% CI, 1.18-1.48), corresponding to 1 excess MACE per 112 persons who discontinued statins per year. In the secondary prevention cohort, the weighted rate difference was 13 per 1000 person-years (95% CI, 8-17 per 1000 person-years) and the adjusted sub-hazard ratio was 1.28 (95% CI, 1.18-1.39), corresponding to 1 excess MACE per 77 persons who discontinued statins per year. Conclusions and Relevance: In this cohort study, among older adults receiving long-term statin treatment, discontinuation of statins was associated with a higher rate of MACE compared with statin continuation in both the primary and the secondary prevention cohorts. These findings suggest a need for robust evidence from randomized clinical trials.

Effectiveness of interventions to address the negative health outcomes of informal caregiving to older adults: protocol for an umbrella review.

INTRODUCTION: Informal (unpaid) caregivers play an essential role in caring for older people, whose care needs are often not fully met by formal services. While providing informal care may be a positive experience, it can also exert a considerable strain on caregivers' physical and mental health. How to best support the needs of informal caregivers remains largely debated. This umbrella review (review of systematic reviews) aims to evaluate (1) whether effective interventions can mitigate the negative health outcomes of informal caregiving, (2) whether certain types of interventions are more effective than others, (3) whether effectiveness of interventions depends on caregiver/receiver, context or implementation characteristics and (4) how these interventions are perceived in terms of acceptability, feasibility and added value. METHODS AND ANALYSIS: We will include systematic reviews of primary studies focusing on the effectiveness of interventions (public or private, unifaceted or multifaceted, delivered by health or social care professionals or volunteers) aimed at reducing the impact of caregiving on caregivers' physical or mental health. This will also include quantitative and qualitative syntheses of implementation studies. The literature search will include the following databases: Medline, CINAHL, PsycINFO and Web of Science. A key informant-guided search of grey literature will be performed. Quality appraisal will be conducted with the AMSTAR-2 checklist for quantitative reviews and with an ad hoc checklist for qualitative syntheses. Narrative and tabular summaries of extracted data will be produced, and framework synthesis will be employed for weaving together evidence from quantitative studies in effectiveness reviews with findings on implementation from qualitative studies. ETHICS AND DISSEMINATION: This umbrella review will use data from secondary sources and will not involve interactions with study participants; it is thus exempt from ethical approval. Results will be presented at international conferences and will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021252841.

Growing Income-Based Inequalities in Old-Age Life Expectancy in Sweden, 2006-2015.

Sweden is known for high life expectancy and economic egalitarianism, yet in recent decades it has lost ground in both respects. This study tracked income inequality in old-age life expectancy and life span variation in Sweden between 2006 and 2015, and examined whether patterns varied across levels of neighborhood deprivation. Income inequality in remaining life expectancy at ages 65, 75, and 85 increased. The gap in life expectancy at age 65 grew by more than a year between the lowest and the highest income quartiles, for both men (from 3.4 years in 2006 to 4.5 years in 2015) and women (from 2.3 to 3.4 years). This widening income gap in old-age life expectancy was driven by different rates of mortality improvement: individuals with higher incomes increased their life expectancy at a faster rate than did those with lower incomes. Women with the lowest incomes experienced no improvement in old-age life expectancy. Furthermore, life span variation increased in the lowest income quartile, while it decreased slightly among those in the highest quartile. Income was found to be a stronger determinant of old-age life expectancy than neighborhood deprivation.

Lived Experiences of Family Members of Patients With Severe COVID-19 Who Died in Intensive Care Units in France.

Importance: During the initial surge of the COVID-19 pandemic, family members were often separated from their loved ones admitted to intensive care units (ICUs), with a potential for negative experiences and psychological burden. Objective: To better understand the experiences of bereaved family members of patients who died in an ICU during the COVID-19 pandemic, from the time of hospital admission until after the patient's death. Design, Setting, and Participants: This qualitative study used semistructured, in-depth interviews to collect experiences from bereaved family members of patients who died from severe COVID-19 in 12 ICUs during the first wave of the pandemic in France. Purposeful sampling was used to ensure the diversity of study participants with respect to sex, age, relationship with the patient, and geographic location. All data were collected between June and September 2020, and data analysis was performed from August to November 2020. Main Outcomes and Measures: Interviews were conducted 3 to 4 months after the patient's death and were audio-recorded and analyzed using thematic analysis. Results: Among 19 family members interviewed (median [range] age, 46 [23-75] years; 14 [74%] women), 3 major themes emerged from qualitative analysis. The first was the difficulty in building a relationship with the ICU clinicians and dealing with the experience of solitude: family members experienced difficulties in establishing rapport and bonding with the ICU team as well as understanding the medical information. Distance communication was not sufficient, and participants felt it increased the feeling of solitude. The second involved the patient in the ICU and the risks of separation: because of restricted access to the ICU, family members experienced discontinuity and interruptions in the relationship with their loved one, which were associated with feelings of powerlessness, abandonment, and unreality. The third was regarding disruptions in end-of-life rituals: family members described "stolen moments" after the patient's death, generating strong feelings of disbelief that may lead to complicated grief. Conclusions and Relevance: This qualitative study found that during the initial wave of the COVID-19 pandemic in France, bereaved family members described a disturbed experience, both during the ICU stay and after the patient's death. Specific family-centered crisis guidelines are needed to improve experiences for patients, families, and clinicians experiences.