Search

INTRODUCTION: The Alzheimers disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimers Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimers disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to screen out individuals who are less likely to have elevated brain amyloid, and to determine the participants eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

Coach education and development programmes are central to the professional development experiences of sport coaches. Typically, these programmes are structured and sequenced in a linear pathway, and present an opportunity for certification which can be a prerequisite to practice and/or employment. Increasingly, as learning becomes viewed as part of a coach's lifeworld, versus simply as a means to an end, education and development provision is beginning to reflect this. This article introduces and explores the Coach Development Institute Programme, part of the Premier League's Elite Coaching Plan, which seeks to improve the quality of football coaching in English boys'/men's football by engaging coaches in a 2-year work-based learning opportunity. Built around a core of project-based learning and assessment, coaches are supported as they examine a series of meaningful performance problems in their unique practice environments. Through this work, we demonstrate how theories, concepts, and principles from the adult education and assessment as learning literature might work as they are applied in a coach education and development context. With such sparsity of case-based examples like this within the peer-reviewed literature, we intend that our contribution could inform, promote dialogue, and raise questions about authentically supporting coaches beyond a minimum standard of practice. [ABSTRACT FROM AUTHOR]

Globally, preterm birth (PTB) is a primary cause of mortality and morbidity in infants, with PTB rates increasing worldwide over the last two decades. Biomarkers for accurate early prediction of PTB before the clinical event do not currently exist. Given their roles in the development and progression of many disease states, there has been increasing interest in the utility of microRNAs (miRNAs) as early biomarkers for pregnancy-related disorders, including PTB. The present study was designed to examine potential differences in miRNA abundances in maternal plasma from mothers with infants born following a moderate to late (28–36 weeks' gestation, n = 54) spontaneous PTB (SPTB) compared to mothers with matched term infants (n = 54). Maternal plasma collected at 15 weeks' gestation were utilised from the Auckland and Adelaide cohorts from the Screening for Pregnancy Endpoints (SCOPE) study. miRNAs in plasma were quantified using the NanoString nCounter expression panel (800 miRNAs). The top four most abundant miRNAs were significantly decreased in the plasma of mothers in the SPTB group with results consistent across both cohorts and pathway analysis was undertaken to examine the biological processes linked to the dysregulated miRNAs. The top candidate miRNAs (miRs-451a, −223-3p, let-7a-5p, and -126-3p) were linked to gene pathways associated with inflammation, apoptosis, and mitochondrial biogenesis. Moreover, miRNAs were consistently less abundant in the plasma of mothers of preterm infants across both sites, suggesting potential global dysregulation in miRNA biogenesis. This was supported by a significant downregulation in expression of key genes that are involved in miRNA biogenesis (DROSHA, DICER, and AGO2) across both sites in the SPTB group. In summary, the present study has identified miRNAs in maternal plasma that may provide predictive utility as early biomarkers for the risk of later SPTB. Importantly, these observations were conserved across two independent cohorts. Further, our data provide evidence for a persistent decrease in miRNA abundance in mothers who later experienced an SPTB, which is likely to have widespread consequences for gene regulation and epigenetic processes. [ABSTRACT FROM AUTHOR]

Background and Objective: COPD and bronchiectasis are common causes of morbidity, particularly around exacerbation. Colonisation with respiratory pathogens can increase the frequency and severity of exacerbations. However, bacterial and viral presence at exacerbation in people with airway colonisation has not been well studied. Methods: A 6‐month cohort study of participants (n = 30) with chronic bronchitis due to bronchiectasis (n = 26) and/or COPD (n = 13) and colonisation with Pseudomonas aeruginosa or Haemophilus influenzae was proven on two sputum cultures at exacerbation in the previous 12 months. Participants were provided self‐management education and collected sputum samples daily. Sputum samples at baseline (at least 14 days before or after an exacerbation) and at each exacerbation were examined for a panel of 34 respiratory pathogens using commercially available RT‐PCR kits and compared to results obtained using culture methods for the detection of bacteria. Results: Participants provided 29 baseline samples and 71 samples at exacerbation. In 17/29 baseline samples, RT‐PCR analysis confirmed the organism demonstrated by culture, while 12 samples showed a discrepancy from culture results. Most exacerbations (57.7%) were not associated with acquiring new bacteria or viruses, while 19.8% showed new bacteria, 15.7% new viruses and 7% both new viruses and bacteria. Conclusion: Over half of exacerbations were not associated with new organisms in this cohort of participants with chronic bronchitis and colonisation. However, 26.8% demonstrated a new bacterial species in sputum, which is relevant for antibiotic therapy. Baseline RT‐PCR and culture results were discordant in one‐third of participants. [ABSTRACT FROM AUTHOR]

Aims: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), in healthy participants. Methods: In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1–12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). Results: BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8–10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. Conclusion: The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. Clinical trial registration: NCT05347849. [ABSTRACT FROM AUTHOR]

Psychosocial well-being is key to living well after stroke, but often significantly affected by stroke. Existing understandings consider well-being comes from positive mood, social relationships, self-identity and engagement in meaningful activities. However, these understandings are socioculturally located and not necessarily universally applicable. This qualitative metasynthesis examined how people experience well-being after a stroke in Aotearoa New Zealand. This metasynthesis was underpinned by He Awa Whiria (Braided Rivers), a model which prompts researchers to uniquely engage with Māori and non-Māori knowledges. A systematic search identified 18 articles exploring experiences of people with stroke in Aotearoa. Articles were analysed using reflexive thematic analysis. We constructed three themes which reflect experiences of well-being: connection within a constellation of relationships, being grounded in one's enduring and evolving identities, and being at-home in the present whilst (re)visioning the future. Well-being is multi-faceted. In Aotearoa, it is inherently collective while also deeply personal. Well-being is collectively achieved through connections with self, others, community and culture, and embedded within personal and collective temporal worlds. These rich understandings of well-being can open up different considerations of how well-being is supported by and within stroke services. Psychosocial well-being is critical for people living with stroke. Well-being should be a priority in rehabilitation, however people with stroke indicate they do no consistently receive psychosocial support. It is clear that well-being has strong cultural elements, and understanding what supports well-being in individuals, whānau (those within wider networks who the person with stroke considers important), and wider cultural groups is important. Supporting whānau is crucial as whānau are core to well-being both during and beyond rehabilitation, and their own well-being is impacted by stroke. [ABSTRACT FROM AUTHOR]