Examining the benefits and harms of Alzheimer's disease screening for family members of older adults: study protocol for a randomized controlled trial

BACKGROUND: Multiple national expert panels have identified early detection of Alzheimer's disease and related dementias (ADRD) as a national priority. However, the United States Preventive Services Task Force (USPSTF) does not currently support screening for ADRD in primary care given that the risks and benefits are unknown. The USPSTF stresses the need for research examining the impact of ADRD screening on family caregiver outcomes. METHODS: The Caregiver Outcomes of Alzheimer's Disease Screening (COADS) is a randomized controlled trial that will examine the potential benefits or harms of ADRD screening on family caregivers. It will also compare the effectiveness of two strategies for diagnostic evaluation and management after ADRD screening. COADS will enroll 1800 dyads who will be randomized into three groups (n = 600/group): the 'Screening Only' group will receive ADRD screening at baseline and disclosure of the screening results, with positive-screen participants receiving a list of local resources for diagnostic follow-up; the 'Screening Plus' group will receive ADRD screening at baseline coupled with disclosure of the screening results, with positive-screen participants referred to a dementia collaborative care program for diagnostic evaluation and potential care; and the control group will receive no screening. The COADS trial will measure the quality of life of the family member (the primary outcome) and family member mood, anxiety, preparedness and self-efficacy (the secondary outcomes) at baseline and at 6, 12, 18 and 24 months. Additionally, the trial will examine the congruence of depressive and anxiety symptoms between older adults and family members at 6, 12, 18 and 24 months and compare the effectiveness of two strategies for diagnostic evaluation and management after ADRD screening between the two groups randomized to screening (Screening Only versus Screening Plus). DISCUSSION: We hypothesize that caregivers in the screening arms will express higher levels of health-related quality of life, lower depressive and anxiety symptoms, and better preparation for caregiving with higher self-efficacy at 24 months. Results from this study will directly inform the National Plan to Address Alzheimer's Disease, the USPSTF and other organizations regarding ADRD screening and early detection policies

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)

Supporting breast cancer screening decisions for caregivers of older women with dementia: study protocol for a randomized controlled trial

BACKGROUND: Alzheimer's disease and related dementias (ADRD) impact a woman's life expectancy and her ability to participate in medical decision-making about breast cancer screening, necessitating the involvement of family caregivers. Making decisions about mammography screening for women with ADRD is stressful. There are no data that suggest that breast cancer screening helps women with ADRD live longer or better. Decision aids may improve the quality of decision-making about mammography for ADRD patients and may inform family caregivers about the risks, benefits, and need for decision-making around mammography screening. METHODS/DESIGN: The Decisions about Cancer Screening in Alzheimer's Disease (DECAD) trial, a randomized controlled clinical trial, will enroll 426 dyads of older women with ADRD (≥75 years) and a family caregiver from clinics and primary-care practices in Indiana to test a novel, evidence-based decision aid. This decision aid includes information about the impact of ADRD on life expectancy, the benefit of mammograms, and the impact on the quality of life for older women with ADRD. Dyads will be randomized to receive the decision aid or active control information about home safety. This trial will examine the effect on the caregiver's decisional conflict (primary outcome) and the caregiver's decision-making self-efficacy (secondary outcome). A second follow-up at 15 months will include a brief, semi-structured interview with the caregiver regarding the patient's experience with mammograms and decision-making about mammograms. At the same time, a review of the patient's electronic medical record (EMR) will look at discussions about mammography with their primary-care physician and mammogram orders, receipt, results, and burden (e.g., additional diagnostic procedures due to false-positive results, identification of an abnormality on the screening exam but further work-up declined, and identification of a clinically unimportant cancer). A third follow-up at 24 months will extract EMR data on mammogram orders, occurrences, results, and the burden of mammograms. DISCUSSION: We hypothesize that caregivers who receive the decision aid will have lower levels of decisional conflict and higher levels of decision-making self-efficacy compared to the control group. We also hypothesize that the DECAD decision aid will reduce mammography use among older women with ADRD

Genetic Risk Score Predicts Late-Life Cognitive Impairment

Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms

Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract

A healthy, balanced diet is essential for both physical and mental well-being. Such a diet must include an adequate intake of micronutrients, essential fatty acids, amino acids and antioxidants. The monoamine neurotransmitters, serotonin, dopamine and noradrenaline, are derived from dietary amino acids and are involved in the modulation of mood, anxiety, cognition, sleep regulation and appetite. The capacity of nutritional interventions to elevate brain monoamine concentrations and, as a consequence, with the potential for mood enhancement, has not been extensively evaluated. The present study investigated an extract from oregano leaves, with a specified range of active constituents, identified via an unbiased, high-throughput screening programme. The oregano extract was demonstrated to inhibit the reuptake and degradation of the monoamine neurotransmitters in a dose-dependent manner, and microdialysis experiments in rats revealed an elevation of extracellular serotonin levels in the brain. Furthermore, following administration of oregano extract, behavioural responses were observed in mice that parallel the beneficial effects exhibited by monoamine-enhancing compounds when used in human subjects. In conclusion, these data show that an extract prepared from leaves of oregano, a major constituent of the Mediterranean diet, is brain-active, with moderate triple reuptake inhibitory activity, and exhibits positive behavioural effects in animal models. We postulate that such an extract may be effective in enhancing mental well-being in human

Concepts émergents dans le référentiel de compétences CanMEDS pour les médecins

Background: The CanMEDS physician competency framework will be updated in 2025. The revision occurs during a time of disruption and transformation to society, healthcare, and medical education caused by the COVID-19 pandemic and growing acknowledgement of the impacts of colonialism, systemic discrimination, climate change, and emerging technologies on healthcare and training. To inform this revision, we sought to identify emerging concepts in the literature related to physician competencies. Methods: Emerging concepts were defined as ideas discussed in the literature related to the roles and competencies of physicians that are absent or underrepresented in the 2015 CanMEDS framework. We conducted a literature scan, title and abstract review, and thematic analysis to identify emerging concepts. Metadata for all articles published in five medical education journals between October 1, 2018 and October 1, 2021 were extracted. Fifteen authors performed a title and abstract review to identify and label underrepresented concepts. Two authors thematically analyzed the results to identify emerging concepts. A member check was conducted. Results: 1017 of 4973 (20.5%) of the included articles discussed an emerging concept. The thematic analysis identified ten themes: Equity, Diversity, Inclusion, and Social Justice; Anti-racism; Physician Humanism; Data-Informed Medicine; Complex Adaptive Systems; Clinical Learning Environment; Virtual Care; Clinical Reasoning; Adaptive Expertise; and Planetary Health. All themes were endorsed by the authorship team as emerging concepts. Conclusion: This literature scan identified ten emerging concepts to inform the 2025 revision of the CanMEDS physician competency framework. Open publication of this work will promote greater transparency in the revision process and support an ongoing dialogue on physician competence. Writing groups have been recruited to elaborate on each of the emerging concepts and how they could be further incorporated into CanMEDS 2025.Contexte : Le référentiel de compétences CanMEDS pour les médecins sera mis à jour en 2025. Cette révision intervient à un moment où la société, les soins de santé et l’enseignement médical sont bouleversés et en pleine mutation à cause de la pandémie de la COVID-19; on est aussi à l’heure où l’on reconnaît de plus en plus les effets du colonialisme, de la discrimination systémique, des changements climatiques et des nouvelles technologies sur les soins de santé et la formation des médecins. Pour éclairer cette révision, nous avons tenté d’extraire de la littérature scientifique les concepts émergents se rapportant aux compétences des médecins. Méthodes : Les concepts émergents ont été définis comme des idées ayant trait aux rôles et aux compétences des médecins qui sont débattues dans la littérature, mais qui sont absentes ou sous-représentées dans le cadre CanMEDS 2015. Nous avons réalisé une recherche documentaire, un examen des titres et des résumés, et une analyse thématique pour repérer les concepts émergents. Les métadonnées de tous les articles publiés dans cinq revues d’éducation médicale entre le 1er octobre 2018 et le 1er octobre 2021 ont été extraites. Quinze auteurs ont effectué un examen des titres et des résumés pour relever et étiqueter les concepts sous-représentés. Deux auteurs ont procédé à une analyse thématique des résultats pour dégager les concepts émergents. Une vérification a été faite par les membres de l’équipe. Résultats : Parmi les 4973 articles dépouillés, 1017 (20,5 %) abordaient un concept émergent. Les dix thèmes suivants sont ressortis de l’analyse thématique : l’équité, la diversité, l’inclusion et la justice sociale; l’antiracisme; humanisme des médecin; la médecine fondée sur les données; les systèmes adaptatifs complexes; l’environnement de l’apprentissage clinique; les soins virtuels; le raisonnement clinique; l’expertise adaptative; et la santé planétaire. L’ensemble de ces thèmes ont été approuvés comme concepts émergents par l’équipe de rédaction. Conclusion : Cet examen de la littérature a permis de relever dix concepts émergents qui peuvent servir à éclairer la révision du référentiel de compétences CanMEDS pour les médecins qui aura lieu en 2025. La publication en libre accès de ce travail favorisera la transparence du processus de révision et le dialogue continu sur les compétences des médecins. Des groupes de rédaction ont été recrutés pour développer chacun des concepts émergents et pour examiner la façon dont ils pourraient être intégrés dans la version du référentiel CanMEDS de 2025

Developing the Agile Implementation Playbook for Integrating Evidence-Based Health Care Services into Clinical Practice

Problem: Despite the more than $32 billion the National Institutes of Health has invested annually, evidence-based health care services are not reliably implemented, sustained, or distributed in health care delivery organizations, resulting in suboptimal care and patient harm. New organizational approaches and frameworks that reflect the complex nature of health care systems are needed to achieve this goal. Approach: To guide the implementation of evidence-based health care services at their institution, the authors used a number of behavioral theories and frameworks to develop the Agile Implementation (AI) Playbook, which was finalized in 2015. The AI Playbook leverages these theories in an integrated approach to selecting an evidence-based health care service to meet a specific opportunity, rapidly implementing the service, evaluating its fidelity and impact, and sustaining and scaling up the service across health care delivery organizations. The AI Playbook includes an interconnected eight-step cycle: (1) identify opportunities; (2) identify evidence-based health care services; (3) develop evaluation and termination plans; (4) assemble a team to develop a minimally viable service; (5) perform implementation sprints; (6) monitor implementation performance; (7) monitor whole system performance; and (8) develop a minimally standardized operating procedure. Outcomes: The AI Playbook has helped to improve care and clinical outcomes for intensive care unit survivors and is being used to train clinicians and scientists in AI to be quality improvement advisors. Next Steps: The authors plan to continue disseminating the details of the AI Playbook and illustrating how health care delivery organizations can successfully leverage it

Foraging Behavior and Success of a Mesopelagic Predator in the Northeast Pacific Ocean: Insights from a Data-Rich Species, the Northern Elephant Seal

The mesopelagic zone of the northeast Pacific Ocean is an important foraging habitat for many predators, yet few studies have addressed the factors driving basin-scale predator distributions or inter-annual variability in foraging and breeding success. Understanding these processes is critical to reveal how conditions at sea cascade to population-level effects. To begin addressing these challenging questions, we collected diving, tracking, foraging success, and natality data for 297 adult female northern elephant seal migrations from 2004 to 2010. During the longer post-molting migration, individual energy gain rates were significant predictors of pregnancy. At sea, seals focused their foraging effort along a narrow band corresponding to the boundary between the sub-arctic and sub-tropical gyres. In contrast to shallow-diving predators, elephant seals target the gyre-gyre boundary throughout the year rather than follow the southward winter migration of surface features, such as the Transition Zone Chlorophyll Front. We also assessed the impact of added transit costs by studying seals at a colony near the southern extent of the species’ range, 1,150 km to the south. A much larger proportion of seals foraged locally, implying plasticity in foraging strategies and possibly prey type. While these findings are derived from a single species, the results may provide insight to the foraging patterns of many other meso-pelagic predators in the northeast Pacific Ocean

Genome Sequence of the Model Mushroom Schizophyllum Commune

Much remains to be learned about the biology of mushroom-forming fungi, which are an important source of food, secondary metabolites and industrial enzymes. The wood-degrading fungus Schizophyllum commune is both a genetically tractable model for studying mushroom development and a likely source of enzymes capable of efficient degradation of lignocellulosic biomass. Comparative analyses of its 38.5-megabase genome, which encodes 13,210 predicted genes, reveal the species\u27s unique wood-degrading machinery. One-third of the 471 genes predicted to encode transcription factors are differentially expressed during sexual development of S. commune. Whereas inactivation of one of these, fst4, prevented mushroom formation, inactivation of another, fst3, resulted in more, albeit smaller, mushrooms than in the wild-type fungus. Antisense transcripts may also have a role in the formation of fruiting bodies. Better insight into the mechanisms underlying mushroom formation should affect commercial production of mushrooms and their industrial use for producing enzymes and pharmaceuticals

Lentivirus-mediated gene therapy for Fabry disease

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy