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.     

Effect of Matrix Metalloproteinase Inhibition by Doxycycline on Myocardial Healing and Remodeling after Myocardial Infarction

Summary The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm² ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm², respectively; p < 0.05). Our work suggest that effective MMPs’ inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.     

CHADS2 and CHA2DS2-VASc scores as predictors of platelet reactivity in acute coronary syndrome

BackgroundPlatelet function testing (PFT) in patients treated with P2Y₁₂ inhibitors has been widely evaluated for the prediction of stent thrombosis, myocardial infarction, and bleeding events following percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). Thus, PFT-guided treatment could positively affect patient outcomes. Data regarding clinical parameters for predicting platelet reactivity in ACS patients are limited. Therefore, our study aims to evaluate CHADS2 and CHA2DS2-VASc scores as predictors for platelet reactivity in ACS patients.MethodsTwo hundred and ninety-one consecutive patients who underwent PCI and were treated with aspirin and clopidogrel due to ACS were tested for their CHADS2, CHA2DS2-VASc scores and platelet reactivity using adenosine diphosphate (ADP)-induced aggregation (conventional aggregometry). Patients were classified into groups according to their CHADS2 and CHA2DS2-VASc scores. Low-risk group (0–1 score) for CHADS2 and CHA2DS2-VASc scores and high-risk group (2–6, 2–9) for CHADS2 and CHA2DS2-VASc scores, respectively. Furthermore, platelet reactivity in each group were compared (low CHADS2 group vs high CHADS2 group, and low CHA2DS2-VASc vs high CHA2DS2-VASc). Platelet reactivity was defined as low platelet reactivity (<19 U), optimal platelet reactivity [(OPR); 19–46 U], and high on-treatment platelet reactivity [(HPR); >46 U]. Thereafter receiver operating characteristic curve analysis was conducted to verify whether CHADS2 and CHA2DS2-VASc scores could predict platelet reactivity.ResultsLow CHADS2 and CHA2DS2-VASc scores were significantly correlated with lower mean platelet ADP-induced aggregation as compared with high CHADS2 and CHA2DS2-VASc scores [45.5 U (± 16) vs. 54.8 U (±15) and 44.2 U (±16) vs. 51.0 U (±17), respectively, p = 0.01 for both].ConclusionIn ACS patients treated with clopidogrel following PCI, high CHADS2 and CHA2DS2-VASc scores correlated with HPR and lower scores correlated with OPR. Further studies are needed to evaluate our findings’ clinical implications.     

Association between electrical and mechanical remodeling after cardiac resynchronization therapy: systematic review and meta-analysis of observational studies

Heart Failure Reviews - Cardiac resynchronization therapy (CRT) may improve not only impaired left ventricular contractility but can also induce reverse remodeling of native conduction system....     

Gene and antisense delivery in alcoholism research

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. Drs. Yedy Israel and Fulton Crews were organizers and co-chairpersons. The presentations were (1) Introduction to the symposium, by Yedy Israel; (2) Gene delivery to the brain, by Fulton T. Crews; (3) Gene therapy in alcoholic liver injury, by Ronald Thurman; and (4) Antisense oligonucleotides and antisense-gene delivery, by Yedy Israel.     

Comparison of maximal midexpiratory flow rate and forced expiratory flow at 50% of vital capacity in children

BACKGROUND: The mid-portion of the maximal expiratory flow-volume (MEFV) curve is often described by values of the mean forced expired flow as lung volume decreases from 75% to 25% of vital capacity (ie, forced expiratory flow, midexpiratory phase [FEF(25-75)]). It is common practice to report also forced expired flow at 50% of vital capacity (FEF(50)). STUDY OBJECTIVE: To investigate whether FEF(50) and FEF(25-75) are highly correlated or whether the difference between them reflects a degree of airways obstruction. Also, we wanted to investigate the correlation between the two in cases of irregularly shaped MEFV curves (ie, "saw-toothing"). DESIGN: Analysis of the correlation between FEF(50) and FEF(25-75) in a single determination. We assessed the relationship between the FEF(50)/FEF(25-75) ratio and the degree of airways obstruction, as reflected by other traditional parameters such as FEV(1), FEV(1)/FVC ratio, and specific airway conductance (SGaw). PATIENTS: There were 1,350 forced expiratory maneuvers performed by children with a broad range of pulmonary abnormalities. RESULTS: FEF(50) correlated with FEF(25-75) as follows: FEF(50) (L/s) = 0.041 + 1.136*FEF(25-75)(L/s); r(2) = 0.956; standard error of the estimate = 0.013; p < 0.0001. The FEF(50)/FEF(25-75) ratio remained stable and did not correlate with FEV(1) (r = 0.12), FEV(1)/FVC ratio (r = 0.11), or SGaw (r = 0.02; difference not significant). The correlation between FEF(25-75) and FEF(50) was similar for both the smooth curve (r = 0.97) and the irregular curve (r = 0.96). CONCLUSIONS: Although not identical, FEF(25-75) and FEF(50) are highly correlated, and the ratio of the two is fairly constant. Therefore, the practice of reporting both of them is unnecessary. We suggest that it is reasonable to prefer FEF(50).     

Inhaled metaproterenol is superior to inhaled cromolyn in protecting against cold-air-induced bronchospasm

Eucapneic hyperventilation of cold air (EHCA) provokes bronchospasm in asthmatics. Although inhaled cromolyn powder and sympathomimetic solutions have attenuated the bronchospasm induced by EHCA, comparison of both drugs in solution has not been performed. We performed a prospective double-blind study comparing cromolyn solution, metaproterenol solution, and placebo (normal saline) given prior to EHCA. Eight asthmatics defined by a 20% reduction in forced expiratory volume in 1s (FEV1) after EHCA consented to the study. Patients were tested on 3 separate occasions at a similar time of day. Each session began with a determination of FEV1 followed by a randomized double-blind treatment. A repeat FEV1 (pre-EHCA) was performed 20 min after drug inhalation. Twelve minutes of EHCA was performed consisting of 4 min of tidal breathing, 4 min of eucapneic hyperventilation (60-70% of the predicted MVV) and a final 4 min of tidal breathing. FEV1 was performed immediately, 5 min, and 10 min after EHCA. The lowest value was defined as the post-EHCA FEV1. The pre-EHCA FEV1 was significantly larger after metaproterenol pretreatment compared to the pre-EHCA FEV1 following cromolyn (p = 0.01) and saline (p = 0.04). Metaproterenol pretreatment had a significant protective effect in comparison to placebo pretreatment (p less than 0.01). No other paired comparisons (cromolyn vs. placebo, cromolyn vs. metaproterenol) achieved statistical significance at a 0.05 level. In conclusion, metaproterenol is superior to cromolyn in protecting against cold-air-induced bronchospasm.     

The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.     

Screening for Problem Drinking and Counseling by the Primary Care Physician-Nurse Team

Present methods to screen for alcohol abuse are generally obtrusive and result in referral to services that deal mainly with alcoholics. These factors deter physicians from identifying alcohol abuse patients at an early stage. In the present study, 81% of all primary care physicians of a single city evaluated (i) the efficiency and the acceptability of a nonobtrusive screening method for the identification of problem drinkers and (ii) the effectiveness of brief cognitive behavioral counseling given by a nurse in a lifestyle context. Patients (n = 15,686) attending the private practices of 42 primary–care physicians were asked four alcohol–neutral trauma questions in the reception area. Physicians asked about alcohol use and alcohol-related problems only to patients with previous trauma. Problem drinkers by defined criteria were offered an appointment with a nurse who, by random assignment, gave either 3-hr of cognitive behavioral counseling over 1 year or simply advised patients to reduce their alcohol intake. The screening method identified 62–85% of expected number of problem drinkers in this population. Following the application of exclusion criteria, 105 problem drinkers were entered in the intervention part of the study. After 1 year, patients who received counseling showed significant reductions in reported alcohol consumption (-70%; p < 0.001), psychosocial problems (-85%; p < 0.001) and serum gamma glutamyl transferase (-32%h to -58%; p < 0.02). Physician visits were reduced (-34%; p < 0.02) following counseling. Patients receiving only advice showed neither reductions in psycho-social problems nor in serum gamma glutamyl transferase or physician visits, but reported a 46% reduction (p < 0.01) in alcohol consumption. Data indicate that asking patients about recent trauma is efficient and is well accepted as the first screening instrument in the identification of the problem drinker. Cost of screening per patient is under one dollar. Counseling of 3 hr given by a nurse is markedly superior (p < 0.05) to simple advice in reducing alcohol consumption, objective indicators of alcohol-related morbidity, and the frequency of physician visits.