The wearable cardioverter defibrillator (WCD) is used to protect patients at risk for sudden cardiac arrest. We examined defibrillation efficacy and safety of a biphasic truncated exponential ...waveform designed for use in a contemporary WCD in three animal studies and a human study.
Animal (swine) studies: #1: Efficacy comparison of a 170J BTE waveform (SHOCK A) to a 150J BTE waveform (SHOCK B) that approximates another commercially available waveform. Primary endpoint first shock success rate. #2: Efficacy comparison of the two waveforms at attenuated charge voltages in swine at three prespecified impedances. Primary endpoint first shock success rate. #3: Safety comparison of SHOCK A and SHOCK B in swine. Primary endpoint cardiac biomarker level changes baseline to 6 and 24 hours post-shock. Human Study: Efficacy comparison of SHOCK A to prespecified goal and safety evaluation. Primary endpoint cumulative first and second shock success rate. Safety endpoint adverse events.
Animal Studies #1: 120 VF episodes in six swine. First shock success rates for SHOCK A and SHOCK B were 100%; SHOCK A non-inferior to SHOCK B (entire 95% CI of rate difference above -10% margin, p < .001). #2: 2,160 VF episodes in thirty-six swine. Attenuated SHOCK A was non-inferior to attenuated SHOCK B at each impedance (entire 95% CI of rate difference above -10% margin, p < .001). #3: Ten swine, five shocked five times each with SHOCK A, five shocked five times each with SHOCK B. No significant difference in troponin I (p = 0.658) or creatine phosphokinase (p = 0.855) changes from baseline between SHOCK A and SHOCK B. Human Study: Thirteen patients, 100% VF conversion rate. Mild skin irritation from adhesive defibrillation pads in three patients.
The BTE waveform effectively and safely terminated induced VF in swine and a small sample in humans.
Human study clinical trial registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04132466.
Introduction
A wearable cardioverter defibrillator (WCD) is indicated in appropriate patients to reduce the risk for sudden cardiac death. Challenges for patients wearing a WCD have been frequent ...false shock alarms primarily due to electrocardiogram noise and wear discomfort. The objective of this study was to test a contemporary WCD designed for reduced false shock alarms and improved comfort.
Methods
One hundred and thirty patients with left ventricular ejection fraction ≤40% and an active implantable cardioverter defibrillator (ICD) were fitted with the ASSURE WCD (Kestra Medical Technologies) and followed for 30 days. WCD detection was enabled and shock alarm markers recorded, but shocks and shock alarms were disabled. All WCD episodes and ICD ventricular tachycardia/ventricular fibrillation (VT/VF) episodes were adjudicated. The primary endpoint was the false‐positive shock alarm rate with a performance goal of 1 every 3.4 days (0.29 per patient‐day).
Results
Of 163 WCD episodes, 4 were VT/VF and 159 non‐VT/VF (121 rhythms with noise, 32 uncertain with noise, 6 atrial flutter without noise). Only three false‐positive shock alarm markers were recorded; one false‐positive shock alarm every 1333 patient‐days (0.00075 per patient‐day, 95% confidence interval: 0.00015–0.00361; p < .001). No ICD recorded VT/VF episodes meeting WCD detection criteria (≥170 bpm for ≥20 s) were missed by the WCD during 3501 patient‐days of use. Median wear was 31.0 days (interquartile range IQR 2.0) and median daily use 23.0 h (IQR 1.7). Adverse events were mostly mild: skin irritation (19.4%) and musculoskeletal discomfort (8.5%).
Conclusion
The ASSURE WCD demonstrated a low false‐positive shock alarm rate, low patient‐reported discomfort, and no serious adverse events.
Use of participatory research methods is increasing in research trials. Once partnerships are established with end-users, there is less guidance about processes research teams can use to successfully ...incorporate end-user feedback. The current study describes the use of a brief reflections process to systematically examine and evaluate the impact of end-user feedback on study conduct.
The Comparative Effectiveness of Trauma-Focused and Non-Trauma- Focused Treatment Strategies for PTSD among those with Co-Occurring SUD (COMPASS) study was a randomized controlled trial to determine the effectiveness of trauma-focused psychotherapy versus non-trauma-focused psychotherapy for Veterans with co-occurring posttraumatic stress disorder and substance use disorder who were entering substance use treatment within the Department of Veterans Affairs. We developed and paired a process of "brief reflections" with our end-user engagement methods as part of a supplemental evaluation of the COMPASS study engagement plan. Brief reflections were 30-minute semi-structured discussions with the COMPASS Team following meetings with three study engagement panels about feedback received regarding study issues. To evaluate the impact of panel feedback, 16 reflections were audio-recorded, transcribed, rapidly analyzed, and integrated with other study data sources.
Brief reflections revealed that the engagement panels made recommended changes in eight areas: enhancing recruitment; study assessment completion; creating uniformity across Study Coordinators; building Study Coordinator connection to Veteran participants; mismatch between study procedures and clinical practice; therapist skill with patients with active substance use; therapist burnout; and dissemination of study findings. Some recommendations positively impact study conduct while others had mixed impact. Reflections were iterative and led to emergent processes that included revisiting previously discussed topics, cross-pollination of ideas across panels, and sparking solutions amongst the Team when the panels did not make any recommendations or recommendations were not feasible.
When paired with end-user engagement methods, brief reflections can facilitate systematic examination of end-user input, particularly when the engagement strategy is robust. Reflections offer a forum of accountability for researchers to give careful thought to end-user recommendations and make timely improvements to the study conduct. Reflections can also facilitate evaluation of these recommendations and reveal end-user-driven strategies that can effectively improve study conduct.
ClinicalTrials.gov (NCT04581434) on October 9, 2020; https://clinicaltrials.gov/ct2/show/study/NCT04581434?term=NCT04581434&draw=2&rank=1 .
Uncovering the genetic underpinnings of musical ability and engagement is a foundational step for exploring their wide‐ranging associations with cognition, health, and neurodevelopment. Prior studies ...have focused on using twin and family designs, demonstrating moderate heritability of musical phenotypes. The current study used genome‐wide complex trait analysis and polygenic score (PGS) approaches utilizing genotype data to examine genetic influences on two musicality traits (rhythmic perception and music engagement) in N = 1792 unrelated adults in the Vanderbilt Online Musicality Study. Meta‐analyzed heritability estimates (including a replication sample of Swedish individuals) were 31% for rhythmic perception and 12% for self‐reported music engagement. A PGS derived from a recent study on beat synchronization ability predicted both rhythmic perception (β = 0.11) and music engagement (β = 0.19) in our sample, suggesting that genetic influences underlying self‐reported beat synchronization ability also influence individuals’ rhythmic discrimination aptitude and the degree to which they engage in music. Cross‐trait analyses revealed a modest contribution of PGSs from several nonmusical traits (from the cognitive, personality, and circadian chronotype domains) to individual differences in musicality (β = −0.06 to 0.07). This work sheds light on the complex relationship between the genetic architecture of musical rhythm processing, beat synchronization, music engagement, and other nonmusical traits.
The current study used genome‐wide complex trait analysis and polygenic score approaches to examine genetic influences on rhythmic perception and music engagement. Meta‐analyzed heritability estimates were 31% for rhythmic perception and 12% for self‐reported music engagement. A polygenic score on beat synchronization ability predicted both rhythmic perception and music engagement. Cross‐trait analyses revealed a modest contribution of polygenic scores from non‐musical traits to individual differences in musicality.
There are many nonpharmacologic interventions tested in randomized clinical trials that demonstrate significant benefits for people living with Alzheimer's disease (AD) and AD‐related dementia, their ...care partners, or professional care providers. Nevertheless, with few exceptions, proven interventions have not been translated for delivery in real‐world settings, such as home care, primary care, hospitals, community‐based services, adult day services, assisted living, nursing homes, or other healthcare systems (HCSs). Using embedded pragmatic clinical trial (ePCT) methods is one approach that can facilitate dissemination and implementation (D&I) of dementia care interventions. The science of D&I can inform the integration of evidence‐based dementia care in HCSs by offering theoretical frameworks that capture field complexities and guiding evaluation of implementation processes. Also, D&I science can suggest evidence‐based strategies for implementing dementia care in HCSs. Although D&I considerations can inform each stage of dementia care intervention development, it is particularly critical when designing ePCTs. This article examines fundamental considerations for implementing dementia‐specific interventions in HCSs and how best to prepare for successful dissemination upstream in the context of ePCTs, thereby illustrating the critical role of the D&I Core of the National Institute on Aging Imbedded Pragmatic Alzheimer's Disease and AD‐Related Dementias Clinical Trials Collaboratory. The scientific premise of the D&I Core is that having the “end” in mind, upfront in the design and testing of dementia care programs, can lead to decision‐making that optimizes the ultimate goal of wide‐scale D&I of evidence‐based dementia care programs in HCSs. J Am Geriatr Soc 68:S28–S36, 2020.
Friedreich's ataxia is the most common inherited ataxia. Ninety‐six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining ...cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy‐terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino‐terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early‐onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele. Ann Neurol 1999;45:200–206
There are 200+ tested interventions for care partners (family, friends, and fictive kin) of people living with dementia (PLWD). But these interventions do not systematically cover relevant settings. ...Nor do these interventions affect all relevant outcomes that matter to people and healthcare systems. We present an evidence map of settings and outcomes from translated interventions to identify gaps. Of 190 studies identified, 31 unique interventions were retained in the evidence map. Identified setting gaps included studies set solely in hospitals/medical centers or set in multiple settings. Identified outcome gaps included interventions that improved care partner beliefs about providing care, care partner negative coping strategies, PLWD resources (e.g., social support), and PLWD coping strategies. Armed with an understanding of present gaps, we call on researchers to fill the identified gaps to ensure systematic coverage of settings and evaluation of outcomes that matter to people and healthcare systems.
The pipeline from discovery to testing and then implementing evidence-based innovations in real-world contexts may take 2 decades or more to achieve. Implementation science innovations, such as ...hybrid studies that combine effectiveness and implementation research questions, may help to bridge the chasm between intervention testing and implementation in dementia care. This paper describes hybrid effectiveness studies and presents 3 examples of dementia care interventions conducted in various community-based settings. Studies that focus on outcomes and implementation processes simultaneously may result in a truncated and more efficient implementation pipeline, thereby providing older persons, their families, health care providers, and communities with the best evidence to improve quality of life and care more rapidly. We offer post-acute and long-term care researchers considerations related to study design, sampling, data collection, and analysis that they can apply to their own dementia and other chronic disease care investigations.
Thiazolyl peptide antibiotics, nocathiacin I, II and III, were identified in a culture of Nocardia sp. WW-12651 (ATCC 202099). They exhibit potent in vitro activity (ng/ml) against a wide spectrum of ...Gram-positive bacteria, including multiple-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus infection mice model.
Background
The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate ...specificity with CYP3A4 and the multidrug efflux pump P‐glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial.
Objective
Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR‐1 (which encodes P‐glycoprotein) influence the drug levels of ABT‐773, a ketolide antibiotic that is a substrate for both CYP3A and P‐glycoprotein.
Methods
Healthy volunteers given 3 different oral dose levels of ABT‐773 were genotyped at 2 common CYP3A5 and 7 common MDR‐1 polymorphisms. Individuals were categorized as CYP3A5‐positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5‐negative if they did not. Area under the plasma concentration–time curves (AUCs) from 0 to 6 hours (AUCt) and maximum postdose plasma concentration (Cmax) after a single dose and on day 5 of a twice‐daily regimen were calculated and correlated with genotypes.
Results
ABT‐773 AUCt and Cmax were, on average, higher in CYP3A5‐negative subjects given 450 mg ABT‐773 (n = 9) than in CYP3A5‐positive subjects with identical doses (n = 8). The relationship for AUCt was statistically significant both after a single dose (geometric mean and 95% confidence interval CI, 5.0 μg · h/mL 3.9–6.4 μg · h/mL versus 2.8 μg · h/mL 1.8–4.3 μg · h/mL; P = .03) and on the fifth day of twice‐daily dosing (12.4 μg · h/mL 8.7–17.6 μg · h/mL versus 7.4 μg · h/mL 5.5–9.8 μg · h/mL, P = .04). The relationship for Cmax was statistically significant after a single dose (1220 μg/mL 867–1167 μg/mL versus 727 μg/mL 506–1044 μg/mL, P = .04) and showed a trend in the same direction on the fifth day of twice‐daily dosing (2566 μg/mL 1813–3631 μg/mL versus 1621 μg/mL 1122–2343 μg/mL, P = .07). In contrast, AUCt and Cmax were not significantly different between CYP3A5‐positive and CYP3A5‐negative individuals given 150 mg or 300 mg ABT‐773. ABT‐773 plasma levels did not trend with MDR‐1 genotypes.
Conclusions
These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose‐dependent.
Clinical Pharmacology & Therapeutics (2004) 75, 516–528; doi: 10.1016/j.clpt.2004.01.013
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