Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

Proceedings of the Canadian Frailty Network Workshop: Identifying Biomarkers of Frailty to Support Frailty Risk Assessment, Diagnosis and Prognosis. Toronto, January 15, 2018.

The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.

Implementing Frailty Measures in the Canadian Healthcare System.

Canadian healthcare is changing to include individuals living with frailty, but frailty must be better operationalized and better framed by sound data standards and policy. Frailty results from deficit accumulation in multiple body systems, with exaggerated vulnerability to external stressors. A growing consensus on defining frailty sets the stage for consensus on operationalization and widespread implementation in care settings. Frailty measurement is not yet integrated into daily clinical practice in Canada. Here, we will present how this integration might occur. We hope to demonstrate that implementation must appeal to inter-professional practice needs in different settings or circumstances. In some settings, methods for frailty case finding are expected to evolve as deemed to be most appropriate to the front-line users. In this "hands-off" approach, care providers, supported by emerging knowledge translation on frailty operationalization, would be informed by their setting and local practices to establish patterns of ad hoc case finding and component definition of frailty. This more nimble case finding strategy would be opportunistic, and would appeal to expert clinicians and self-directed teams who emphasize an individualized health care experience for their patients. In other settings, we can shape frailty case finding by building care algorithms around existing standardized practices and data repositories, leading to a systematic application of frailty measures and a more coordinated process of component definition and care protocols. Here, recommended instruments and data standards must be endorsed by health networks locally, provincially and nationally. The interRAI suite of assessment instruments has pan-Canadian standards in place and its pervasiveness makes it the most obvious starting point, especially in home care and long-term care. We anticipate the evolution of an integrated model informed by stakeholders and settings, where policy makers focus on system supports for frailty case finding, while front-line clinicians use case finding strategies to pinpoint and act on key frailty components.

A comprehensive profile of the sociodemographic, psychosocial and health characteristics of Ontario home care clients with dementia.

INTRODUCTION: This study provides a comprehensive summary of the sociodemographic, psychosocial and health characteristics of a large population-based cohort of Ontario home care clients (aged 50 years and over) with dementia and examines the variation in these characteristics in those with co-existing neurological conditions. METHODS: Clients were assessed with the Resident Assessment Instrument-Home Care (RAI-HC) between January 2003 and December 2010. Descriptive analyses examined the distribution of these characteristics among clients with dementia relative to several comparison groups, as well as clients with other recorded neurological conditions. RESULTS: Approximately 22% of clients (n=104 802) had a diagnosis of dementia (average age 83 years, 64% female) and about one in four within this group had a co-existing neurological condition (most commonly stroke or Parkinson disease). About 43% of those with dementia did not live with their primary caregiver. Relative to several comparison groups, clients with dementia showed considerably higher levels of cognitive and functional impairment, aggression, anxiety, wandering, hallucinations/delusions, caregiver distress and a greater risk for institutionalization. Conversely, they showed a lower prevalence of several chronic conditions and lower levels of recent health service use. Depressive symptoms were relatively common in the dementia and other neurological groups. CONCLUSION: Clients with co-existing neurological conditions exhibited unique clinical profiles illustrating the need for tailored and flexible home care services and enhanced caregiver assistance programs.

TITRE: Profil complet des caractéristiques sociodémographiques, psychosociales et sanitaires des clients des soins à domicile atteints de démence en Ontario. INTRODUCTION: Cette étude fournit une synthèse des caractéristiques sociodémographiques, psychosociales et sanitaires d'une vaste cohorte représentative des clients des soins à domicile en Ontario (âgés de 50 ans ou plus) atteints de démence et elle examine les variations de ces caractéristiques chez les clients atteints de maladies neurologiques concomitantes. MÉTHODOLOGIE: Les clients ont été évalués à l'aide de l'Instrument d'évaluation des résidents ­ Soins à domicile (RAI-HC) entre janvier 2003 et décembre 2010. Les analyses descriptives fournissent la répartition de ces caractéristiques en comparant les clients atteints de démence et ceux de plusieurs autres groupes ainsi que ceux atteints d'autres maladies neurologiques documentées. RÉSULTATS: Environ 22 % des clients (n = 104 802) avaient reçu un diagnostic de démence (âge moyen de 83 ans, 64 % de femmes) et un sur quatre parmi eux était atteint d'une maladie neurologique concomitante (AVC ou maladie de Parkinson la plupart du temps). Environ 43 % des clients atteints de démence n'habitaient pas avec leur principal aidant. Par rapport aux clients des groupes de comparaison, les clients atteints de démence présentaient des taux considérablement plus élevés de déficit cognitif et fonctionnel, d'agressivité, d'anxiété, d'errance et d'hallucinations ou de délire, avaient plus souvent un aidant en détresse et couraient un plus grand risque de placement en établissement. Par contre, ils étaient moins souvent atteints de diverses maladies chroniques et étaient moins nombreux à avoir eu recours à des services de santé récemment. Les symptômes de dépression étaient relativement fréquents chez les clients atteints de démence et chez ceux atteints d'une autre maladie neurologique. CONCLUSION: Les clients atteints de maladies neurologiques concomitantes présentaient des profils cliniques bien particuliers illustrant la nécessité de personnaliser et d'assouplir les services de soins à domicile et d'améliorer les programmes de soutien pour les aidants.

A profile of older community-dwelling home care clients with heart failure in Ontario.

INTRODUCTION: The aging of the Canadian population is associated with a rising burden of heart failure (HF), a condition associated with significant morbidity, mortality and health service use. METHODS: We used data from the Ontario Resident Assessment Instrument-Home Care database for all long-stay home care clients aged 65 years or older to (1) describe the demographic and clinical characteristics of home care clients with HF and (2) examine service use among home care clients with HF to promote management at home with appropriate services. RESULTS: Compared with other home care clients, HF clients exhibit more health instability, take more medications, experience more comorbid conditions and receive significantly more nursing, homemaking and meal services. They are hospitalized more frequently, have significantly more emergency department visits and use more emergent care. DISCUSSION: HF clients are a more complex group than home care clients in general. Patient self-care must be tailored to the clinical characteristics, patterns of service use and barriers to self-care of the client. This is particularly true for older, frail and medically complex HF patients, many of whom require home care services. This work provides a background upon which to base initiatives to help these higher-needs clients manage their HF at home with appropriate support and services.

The Canadian Heart Health Strategy and Action Plan: Cardiac rehabilitation as an exemplar of chronic disease management.

BACKGROUND: In October 2006, federal funding was announced for the development of a national strategy to fight cardiovascular disease (CVD) in Canada. The comprehensive, independent, stakeholder-driven Canadian Heart Health Strategy and Action Plan (CHHS-AP) was delivered to the Minister of Health on February 24, 2009. OBJECTIVES: The mandate of CHHS-AP Theme Working Group (TWG) 6 was to identify the optimal chronic disease management model that incorporated timely access to rehabilitation services and end-of-life planning and care. The purpose of the present paper was to provide an overview of worldwide approaches to CVD and cardiac rehabilitation (CR) strategies and recommendations for CR care in Canada, within the context of the well-known Chronic Care Model (CCM). A separate paper will address end-of-life issues in CVD. METHODS: TWG 6 was composed of content representatives, primary care representatives and patients. Input in the area of Aboriginal and indigenous cardiovascular health was obtained through individual expert consultation. Information germane to the present paper was gathered from international literature and best practice guidelines. The CCM principles were discussed and agreed on by all. Prioritization of recommendations and overall messaging was discussed and decided on within the entire TWG. The full TWG report was presented to the CHHS-AP Steering Committee and was used to inform the recommendations of the CHHS-AP. RESULTS: Specific actionable recommendations for CR are made in accordance with the key principles of the CCM. CONCLUSIONS: The present CR blueprint, as part of the CHHS-AP, will be a first step toward reducing the health care burden of CVD in Canada.

Systemic lupus erythematosus presenting as subacute delirium in an 82-year-old woman.

OBJECTIVES: To describe an older patient with delirium attributed to systemic lupus erythematosus (SLE) and to review the literature on neuropsychiatric manifestations of SLE in older people. DESIGN: Case report and literature review. MEDLINE search using terms systemic lupus erythematosus, neurologic, psychiatric, neuropsychiatric, autoantibodies (anti-nuclear antibody (ANA), antiphospholipid, anticardiolipin, anti-double stranded deoxyribonucleic acid (anti-dsDNA), anti-Smith), and elderly. Additional articles obtained from hand-searched references and through experts. SETTING: Hospital (case report). PARTICIPANTS: Case report and literature cases. MEASUREMENTS: None. RESULTS: SLE is increasingly diagnosed in older adults. Onset is insidious and diagnosis is delayed because of a different clinical spectrum and immunological profile than in younger adults. Autoantibodies have an important role in the pathogenesis of neuropsychiatric manifestations, while vasculitis is less common. Aggressive immunosuppressive therapy is typically indicated, although recent case reports suggest that lower doses may suffice. The American College of Rheumatology 1982 revised criteria may be inadequate to diagnose neuropsychiatric lupus in older persons. CONCLUSION: Neuropsychiatric symptoms can be prominent in older people, presenting features of SLE. This case illustrates the lowest dose of corticosteroids shown to be effective in an older patient with delirium due to SLE.

Timing of artificial insemination of dairy cows: fixed time once daily versus morning and afternoon.

Nonreturn rates to professional technician service of 7240 first AI Holstein cows were calculated to evaluate differences between once daily and a.m.-p.m. AI. To determine whether management practices affected nonreturn rates, participating herd owners were surveyed for methods used for detection of estrus. Nonreturn rates for once daily and a.m.-p.m. AI were 64.6 and 65.6% for 60-d, 60.1 and 60.6% for 75-d, and 58.4 and 57.8% for 90-d nonreturn periods. Signs of estrus for AI and interval from detection of estrus to AI were related to nonreturn rates. Nonreturn rate was highest, 63.4%, when cows were in standing estrus. Nonreturn rates were lowest, 36%, when cows were bred after treatment with PGF2 alpha without being detected in estrus or bred strictly on veterinary advice based on palpation. Nonreturn rates were similar for different times of the day when once daily AI was practiced. However, AI in the midmorning may have some advantages. The highest nonreturn rate for a 3-h period was 68.2% for 0800 and 1100 h; the lowest was 54.7% for 1300 to 1600 h. Movement before observation for estrus and an observation period > 15 min improved nonreturn rates for once daily AI. Once daily AI can be used effectively with no difference from the traditional a.m.-p.m. system; results are best when AI is based on standing estrus and performed between 0800 and 1100 h.

Prediction and evaluation of solar particle events based on precursor information.

Protection from the radiation effects of solar particle events for deep space mission crews requires a warning system to observe solar flares and predict subsequent charged particle fluxes. Such a system relates precursor information observed in each flare to the intensity, delay, and duration of the subsequent Solar Particle Event (SPE) at other locations in the solar system. A warning system of this type is now in operation at the NOAA Space Environment Services Center in Boulder, Colorado for support of space missions. It has been used to predict flare particle fluxes at the earth for flares of Solar Cycle 22. The flare parameters used and the effectiveness of the current warning system, based on Solar Cycle 22 experience, are presented, with an examination of the shortcomings. Needed improvements to the system include more complete observations of solar activity, especially information on the occurrences of solar mass ejections; and consideration of the effects of propagation conditions in the solar corona and interplanetary medium. Requirements for solar observations and forecasting systems on board the spacecraft are discussed.

Structure-activity relationships of novel vasopressin antagonists containing C-terminal diaminoalkanes and (aminoalkyl)guanidines.

We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)nNH2] or (aminoalkyl)guanidine [NH(CH2)nNHC(= NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an "optimal" distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.

Strategies for dealing with solar particle events in missions beyond the magnetosphere.

For long duration missions beyond the magnetosphere, the hazards posed by solar particle events (SPE) require the development of new strategies to minimize both the radiation dose and the effects. Potential strategies include the development of improved short-term forecasting of SPE through better observations and research, consideration of HZE particles in real-time forecasting and monitoring, improved knowledge of the biological effects of the particles involved in SPE, and the development of methods for combining SPE forecasts with temporary shielding and chemical countermeasures. Evaluation of present capabilities and the identification of areas of further research to achieve the necessary capabilities are discussed.

Oxytocin induces a transient increase in cytosolic free [Ca2+] in renal tubular epithelial cells: evidence for oxytocin receptors on LLC-PK1 cells.

We examined the effects of oxytocin on renal tubular epithelial LLC-PK1 cells. In cells loaded with Fura 2, we found that 1 microM oxytocin induced a rapid increase in cytosolic free [Ca2+]i from 120 nM to 250 nM within 12 sec. [Ca2+]i then decreased and leveled at 148 nM. Calcium was mobilized from intra- and extra-cellular sources. Oxytocin-induced calcium mobilization was dose dependent (EC50 between 5 and 30 nM). Oxytocin also stimulated calcium efflux which was blocked by the selective oxytocin antagonist KB-5-21. Calcium mobilization was a likely consequence of enhanced phosphatidylinositol turnover, because oxytocin rapidly increased the formation of inositol phosphates including Ins1,4,5P3. Calcium transients were induced by oxytocin and the oxytocin selective analog AM-2-40 and blocked by the oxytocin-selective antagonist KB-5-21. Lysine vasopressin, the selective V2 agonist dDAVP, and the V1-selective agonist SK&F 105349 were at least 10- to 100-fold less potent than oxytocin and exhibited only partial agonist activity. Using peptide analogs, a poor correlation was found between antagonism of oxytocin-induced calcium transients of LLC-PK1 cells and pig kidney V2 and rat liver V1 receptor affinity. These data indicate that oxytocin-induced calcium transients in LLC-PK1 cells were not mediated by V1 or V2 vasopressin receptors, but by oxytocin receptors. However, the poor correlation between antagonism at the LLC-PK1 receptors and the rat uterus oxytocin receptors suggests marked differences in antagonist recognition. We have also identified specific, saturable, high affinity oxytocin-binding sites of low density on intact LLC-PK1 cells (KD = 1.9 nM; Bmax = 3.2 fmol/10(6) cells). The relative analog affinities for these binding sites correlated well with their effects on oxytocin-induced calcium transients. We conclude that in LLC-PK1 cells, oxytocin stimulates a transient rise in cytosolic free [Ca2+]i and the formation of inositol phosphates, including Ins1,4,5P3. The effects on [Ca2+]i probably are not mediated by V1 and V2 vasopressin receptors, but by putative oxytocin receptors.

Potent vasopressin antagonists modified at the carboxy-terminal tripeptide tail.

In a continuing effort to design more potent renal vasopressin (V2 receptor) antagonists, we have focused our attention on the carboxy-terminal tripeptide tail (Pro-Arg-Gly-NH2), a fragment common to both agonists and antagonists. Vasopressin antagonist analogues having a dibasic dipeptide tail, e.g., Arg-Arg-NH2 or Arg-Lys-NH2, attached directly to the cyclic hexapeptide ring are potent V2-receptor antagonists. Similar modification of a representative agonist drastically reduces its potency. We report the synthesis and pharmacological properties of a series of potent V2-receptor antagonists 3-9 where a combination of D or L dibasic dipeptide has been utilized to replace the common tripeptide fragment. Our results suggest a difference in the way agonists and antagonists bind to vasopressin receptor and further support the difference in the structure-activity relationships of agonists and antagonists. These results provide potentially useful insights for the design of novel V2-receptor antagonists.

Identification and characterization of vascular (V1) vasopressin receptors of an established smooth muscle cell line.

We report the identification and characterization of specific vasopressin-binding sites on intact cells and membranes of the established vascular smooth muscle cell line A-10, the fate of vasopressin associated with the cells, the role of guanine nucleotides in the regulation of the affinity of the vasopressin-binding sites, and the determination of the vasopressin receptor subtype. We have found specific vasopressin-binding sites on intact cells in monolayer (110,000 sites per cell during log growth and 60,000 sites per cell in stationary culture) with a KD of 6 nM at 37 degrees. After incubation of [3H]-8-arginine vasopressin ([3H]AVP) and cells for less than 20 min, cell-associated AVP was intact; with longer incubation times, AVP was progressively degraded. The major metabolites included phenylalanine and a fraction that eluted from a C18 reverse phase high performance liquid chromatography column between AVP and 8-arginine, 9-desglycinamide vasopressin. Extensive degradation also occurred when AVP was allowed to dissociate from the cells. With increased time of incubation, the amount of specifically bound AVP that could dissociate decreased, suggesting receptor-mediated endocytosis. In saturation equilibrium binding experiments with plasma membranes, two affinity states with KD of 0.7 nM and 379 nM were observed. The number of high affinity binding sites was similar to the number of receptors found on intact cells. Guanosine 5'-(beta,gamma-imido)triphosphate decreased vasopressin binding to the high affinity sites and did not significantly affect the low affinity sites. Competition binding experiments indicated that the vasopressin-binding sites of A-10 cells belong to the vascular V1 receptor subtype. We conclude that the established vascular smooth muscle cell line A-10 expressed vasopressin receptors of the vascular V1 subtype. Vasopressin bound to the receptors reversibly, but could also be degraded by the cells presumably after receptor-mediated endocytosis. The receptors might exist in different affinity states; guanosine 5'-(beta,gamma-imido)triphosphate decreased the affinity of the high affinity binding state.

A novel radiolabeled vasopressin antagonist: [3H-Phe]-desGlyd(CH2)5D-Tyr(Et)VAVP, [3H]-SK&F 101926.

We report the vasopressin receptor-binding properties of [3H-Phe]-desGlyd(CH2)5D-Tyr(Et)VAVP, [3H]-SK&F 101926, the first radiolabeled vasopressin receptor antagonist. We chose to radiolabel SK&F 101926 because this vasopressin analog is a potent antagonist of vascular V1 and renal V2 vasopressin receptors in all species studied. [3H]-SK&F 101926 bound with a single high affinity to intact vascular smooth muscle cells (A-10; KD = 0.5 nM), and plasma membranes A-10 cells (KD = 0.4 nM) and rat liver (KD = 0.2 nM). In competition experiments with [3H]-SK&F 101926 and [3H]arginine vasopressin ([3H]AVP) using cell and liver membranes, the affinity rank orders of vasopressin analogs were the same and were typical for the V1 receptor subtype. In competition binding experiments with [3H]-SK&F 101926 using cell and liver membranes, guanosine 5'-(beta,gamma-imido)triphosphate did not significantly alter the affinity of the V1 antagonist d(CH2)5Tyr(Me)AVP, but the affinity of AVP was decreased. These data indicate that the V1 receptor can exist in at least two affinity states that are modulated by guanine nucleotides. [3H]-SK&F 101926 also bound specifically and with high affinity to V2 receptors of MDCK cells. We conclude that [3H]-SK&F 101926 binds with high affinity to V1 and V2 vasopressin receptors and is a powerful new tool for the identification of vasopressin receptors and the study of molecular mechanisms involved in the interaction of vasopressin with its receptors.

Induction of functional beta-adrenergic receptors in rat aortic smooth muscle cells by sodium butyrate.

Rat aortic smooth muscle cells in culture (A-10; ATCC CRL 1476) exhibited low levels of beta-adrenergic receptors as determined by specific binding of [125I]cyanopindolol ([125I]CYP) and marginal stimulation of adenylate cyclase in plasma membranes by (-)isoproterenol. When these cells were exposed to 5 mM sodium butyrate, the number of beta-adrenergic receptors and the beta-agonist-stimulated adenylate cyclase activity increased markedly. However, basal, GTP, Gpp(NH)p, and fluoride-stimulated activities did not change. The induction of beta-adrenergic receptors and beta-agonist stimulated adenylate cyclase activity was time- and dose-dependent, and was relatively specific for sodium butyrate. Propionate and valerate were less effective than butyrate, while isobutyrate, succinate, and malonate were ineffective. The induction involved RNA and protein synthesis because induction was prevented by treatment with cycloheximide, puromycin, and actinomycin D. Butyrate did not cause a general increase in cell surface receptors, because the number of vasopressin receptors did not change. The sustained presence of butyrate appeared to be necessary for the maintenance of the induced beta-receptors. When butyrate was removed, receptor number and beta-agonist-stimulated adenylate cyclase activity were decreased by 90% over 24 hr. We conclude that the poor response of rat aortic smooth muscle cell plasma membranes to beta-adrenergic agonists is due to the presence of a low number of beta-adrenergic receptors. Butyrate markedly increased the number of beta-receptors which resulted in a proportional increase in beta-agonist-stimulated adenylate cyclase activity. The increase in receptor number was dependent on RNA and protein synthesis. Butyrate treatment did not affect the activity of the cyclase unit and the efficiency of coupling between the receptors and the guanine nucleotide regulatory protein, Ns.

Vasopressin antagonist analogs modified at position 7.

Vasopressin antagonist analogs having alanine or glycine at position 7 were essentially equipotent with analogs with proline, N-methylalanine or sarcosine at position 7. This demonstrates that the conformational constraint imposed by an N-alkyl residue at position 7 is not necessary for binding of antagonist to the receptor, the exact opposite of what is seen in agonists. This suggests that antagonists bind to the receptor in a manner which is very different from that of agonists.