Pragmatic Trials in Long-Term Care: Implementation and Dissemination Challenges and Opportunities

Randomized controlled trials are considered the most rigorous research design in efficacy and effectiveness research; however, such trials present numerous challenges that limit their applicability in real-world settings. As a consequence, pragmatic trials are increasingly viewed as a research design that overcomes some of these barriers with the potential to produce findings that are more reproducible. Although pragmatic methodology in long-term care is receiving increasing attention as an approach to improve successful dissemination and implementation, pragmatic trials present complexities of their own. To address these complexities and related issues, experts with experience conducting pragmatic trials, developing nursing home policy, participating in advocacy efforts, and providing clinical care in long-term care settings participated in a virtual consensus conference funded by the National Institute on Aging in Spring 2021. Participants identified 4 cross-cutting principles key to dissemination and implementation of pragmatic trial interventions: (1) stakeholder engagement, (2) diversity and inclusion, (3) organizational strain and readiness, and (4) learn from adaptations. Participants emphasized that implementation processes must be grounded in the perspectives of the people who will ultimately be responsible for implementing the intervention once it is proven to be effective. In addition, messaging must speak to long-term care staff and all others who have a stake in its outcomes. Although our understanding of dissemination and implementation strategies remains underdeveloped, this article is designed to guide long-term care researchers and community providers who are increasingly aware of the need for pragmatism in disseminating and implementing evidence-based care interventions.     

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults

BackgroundAnticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.ObjectiveCompare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.DesignProspective cohort study.SettingPrimary care (Australia and USA).Participants19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.MeasurementsBaseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.ResultsAt baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1–2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.LimitationsResidual confounding and reverse causality are possible. Assessment of dose or duration was not possible.ConclusionsHigh anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06550-2.KEY WORDS: anticholinergic burden, dementia, stroke, potentially inappropriate medication     

Eisenmenger's syndrome: current management

Eisenmenger's syndrome describes the elevation of pulmonary arterial pressure to the systemic level caused by increased pulmonary vascular resistance with reversal or bi-directional shunting through a large intracardiac or extracardiac congenital heart defect. This article reviews the natural history and pathophysiology of Eisenmenger's syndrome untreated and medical and surgical treatment options presently available. Although there is no cure for this condition at present, recent advances in management have improved the quality of life for many patients with Eisenmenger's syndrome.     

TEMPORALLY GRADED SEMANTIC MEMORY LOSS IN ALZHEIMER'S DISEASE: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

Abstract

Semantic knowledge of famous names and words that entered popular North American culture at different times in the 20th century was examined in 16 patients with mild-to-moderate Alzheimer's disease (AD), 12 of whom were re-tested 1 year later. All patients showed evidence of temporally graded memory loss, with names and words from the remote past being relatively better preserved than recent names and words. There was considerable between-patient variability with respect to severity of semantic impairment. Most patients exhibited losses extending back 30-40 years; however, two mildly impaired (MMSE >28) patients showed deficits restricted to the last 10-15 years. At the 1-year follow-up, patients not only exhibited more severe deficits overall, but the temporally graded period of loss extended further back in time, suggesting that this deficit reflects a loss of previously intact knowledge and not merely faulty encoding or lack of exposure to the material. The extensive period of graded semantic loss exhibited by most patients contrasts with the temporally limited retrograde semantic loss typical of medial temporal lobe amnesia. We propose that short periods of temporally graded semantic memory loss can be explained by damage to medial temporal structures, but that extensive periods of graded loss occur only with additional damage to neocortical tissue. This pattern contrasts with that of autobiographical memory loss, which is often ungraded and extends for the person's entire lifetime, even when damage is restricted to the medial temporal lobes.     

TLR ligands of ryegrass pollen microbial contaminants enhance Th1 and Th2 responses and decrease induction of Foxp3hi regulatory T cells

Microbial contamination of grass pollens could affect sensitization, subsequent allergic response, and efficacy of allergen‐specific immunotherapy. We investigated whether bacterial immunomodulatory substances can direct PBMC responses of allergic and nonatopic subjects against ryegrass pollen (RGP) toward Th1, Th2, or regulatory T (Treg) cells. Aqueous extracts of RGP with high or low LPS were fractionated into large and small molecular weight (MW) components by diafiltration. CFSE‐labeled PBMCs from allergic and nonatopic subjects were stimulated with RGP extracts (RGPEs) and analyzed for cytokine secretion and T‐cell responses. High LPS RGPE increased IFN‐γ⁺ Th1 and IL‐4⁺ Th2 effector cell induction and consistently decreased CD4⁺Foxp3^hi Treg‐cell induction. IL‐10‐producing T‐cell frequency was unaltered, but IL‐10 secretion was increased by high LPS RGPE. RGPE‐stimulation of TLR‐transfected cell lines revealed that high LPS pollen also contained a TLR2‐ligand, and both batches a TLR9‐ligand. Beta‐1,3‐glucans were detected in large and small MW fractions and were also T‐cell stimulatory. In conclusion, coexposure to allergen and proinflammatory microbial stimuli does not convert an established Th2‐ into a Th1‐response. Instead, proinflammatory responses are exacerbated and Foxp3^hi Treg‐cell induction is decreased. These findings show that adjuvants for specific immunotherapy should enhance Treg cells rather than target immune deviation from Th2 to Th1.     

Advances in allergen-specific immune cell measurements for improved detection of allergic sensitization and immunotherapy responses

Over the past two decades, precision medicine has advanced diagnostics and treatment of allergic diseases. Component-resolved analysis of allergen sensitization facilitates stratification of patients. Furthermore, new formulations of allergen immunotherapy (AIT) products can more effectively deliver the relevant components. Molecular insights from the identification of allergen component sensitization and clinical outcomes of treatment with new AIT formulations can now be utilized for a deeper understanding of the nature of the pathogenic immune response in allergy and how this can be corrected by AIT. Fundamental in these processes are the allergen-specific B and T cells. Within the large B- and T-cell compartments, only those that specifically recognize the allergen with their immunoglobulin (Ig) or T-cell receptor (TCR), respectively, are of clinical relevance. With peripheral blood allergen-specific B- and T-cell frequencies below 1%, bulk cell analysis is typically insufficiently sensitive. We here review the latest technologies to detect allergen-specific B and T cells, as well as new developments in utilizing these tools for diagnostics and therapy monitoring to advance precision medicine for allergic diseases.     

Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

BackgroundThe efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies.ObjectiveTo assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE.MethodsIn this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events.ResultsSixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH.ConclusionThe results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.Trial Registrationclinicaltrials.gov Identifier: NCT00225147