Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p

Implementation outcome instruments for use in physical healthcare settings: a systematic review

BACKGROUND: Implementation research aims to facilitate the timely and routine implementation and sustainment of evidence-based interventions and services. A glaring gap in this endeavour is the capability of researchers, healthcare practitioners and managers to quantitatively evaluate implementation efforts using psychometrically sound instruments. To encourage and support the use of precise and accurate implementation outcome measures, this systematic review aimed to identify and appraise studies that assess the measurement properties of quantitative implementation outcome instruments used in physical healthcare settings. METHOD: The following data sources were searched from inception to March 2019, with no language restrictions: MEDLINE, EMBASE, PsycINFO, HMIC, CINAHL and the Cochrane library. Studies that evaluated the measurement properties of implementation outcome instruments in physical healthcare settings were eligible for inclusion. Proctor et al.'s taxonomy of implementation outcomes was used to guide the inclusion of implementation outcomes: acceptability, appropriateness, feasibility, adoption, penetration, implementation cost and sustainability. Methodological quality of the included studies was assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Psychometric quality of the included instruments was assessed using the Contemporary Psychometrics checklist (ConPsy). Usability was determined by number of items per instrument. RESULTS: Fifty-eight publications reporting on the measurement properties of 55 implementation outcome instruments (65 scales) were identified. The majority of instruments assessed acceptability (n = 33), followed by appropriateness (n = 7), adoption (n = 4), feasibility (n = 4), penetration (n = 4) and sustainability (n = 3) of evidence-based practice. The methodological quality of individual scales was low, with few studies rated as 'excellent' for reliability (6/62) and validity (7/63), and both studies that assessed responsiveness rated as 'poor' (2/2). The psychometric quality of the scales was also low, with 12/65 scales scoring 7 or more out of 22, indicating greater psychometric strength. Six scales (6/65) rated as 'excellent' for usability. CONCLUSION: Investigators assessing implementation outcomes quantitatively should select instruments based on their methodological and psychometric quality to promote consistent and comparable implementation evaluations. Rather than developing ad hoc instruments, we encourage further psychometric testing of instruments with promising methodological and psychometric evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2017 CRD42017065348

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Time to focus on implementation: the need to re‐orient research on physical activity in childcare services

The case for promoting physical activity in childcare services is compelling. Physical activity in childhood provides a number of physical and developmental benefits and childcare services offer centralised access to large number of children each day. A number of childcare service policies and practices have been positively associated with increased child activity. Systematic reviews have also demonstrated that physical activity interventions in this setting are effective

Measuring implementation behaviour of menu guidelines in the childcare setting: confirmatory factor analysis of a theoretical domains framework questionnaire (TDFQ)

Abstract Background While there are number of frameworks which focus on supporting the implementation of evidence based approaches, few psychometrically valid measures exist to assess constructs within these frameworks. This study aimed to develop and psychometrically assess a scale measuring each domain of the Theoretical Domains Framework for use in assessing the implementation of dietary guidelines within a non-health care setting (childcare services). Methods A 75 item 14-domain Theoretical Domains Framework Questionnaire (TDFQ) was developed and administered via telephone interview to 202 centre based childcare service cooks who had a role in planning the service menu. Confirmatory factor analysis (CFA) was undertaken to assess the reliability, discriminant validity and goodness of fit of the 14-domain theoretical domain framework measure. Results For the CFA, five iterative processes of adjustment were undertaken where 14 items were removed, resulting in a final measure consisting of 14 domains and 61 items. For the final measure: the Chi-Square goodness of fit statistic was 3447.19; the Standardized Root Mean Square Residual (SRMR) was 0.070; the Root Mean Square Error of Approximation (RMSEA) was 0.072; and the Comparative Fit Index (CFI) had a value of 0.78. Conclusions While only one of the three indices support goodness of fit of the measurement model tested, a 14-domain model with 61 items showed good discriminant validity and internally consistent items. Future research should aim to assess the psychometric properties of the developed TDFQ in other community-based settings

Impact of scheduling multiple outdoor free-play periods in childcare on child moderate-to-vigorous physical activity: a cluster randomised trial

Abstract Background Increasing the frequency of periods of outdoor free-play in childcare may represent an opportunity to increase child physical activity. This study aimed to assess the efficacy of scheduling multiple periods of outdoor free-play in increasing the time children spend in moderate-to-vigorous physical activity (MVPA) while attending childcare. Methods The study employed a cluster randomised controlled trial design involving children aged 3 to 6 years, attending ten childcare services in the Hunter New England region of New South Wales, Australia. Five services were randomised to receive the intervention and five to a control condition. The intervention involved services scheduling three separate periods of outdoor free-play from 9 am to 3 pm per day, each at least 15 min in duration, with the total equivalent to their usual daily duration of outdoor play period. Control services implemented the usual single continuous period of outdoor free-play over this time. The primary outcome, children’s moderate-to-vigorous physical activity (MVPA) while in care per day, was measured over 5 days via accelerometers at baseline and at 3 months post baseline. Secondary outcomes included percentage of time spent in MVPA while in care per day, total physical activity while in care per day and documented child injury, a hypothesised potential unintended adverse event. Childcare services and data collectors were not blind to the experimental group allocation. Results Parents of 439 (71.6%) children attending participating childcare services consented for their child to participate in the trial. Of these, 316 (72.0%) children provided valid accelerometer data at both time points. Relative to children in control services, mean daily minutes of MVPA in care was significantly greater at follow-up among children attending intervention services (adjusted difference between groups 5.21 min, 95% CI 0.59–9.83 p = 0.03). Percentage of time spent in MVPA in care per day was also greater at follow-up among children in intervention services relative to control services (adjusted difference between groups 1.57, 95% CI 0.64–2.49 p < 0.001). Total physical activity while in care per day, assessed via counts per minute approached but did not reach significance (adjusted difference between groups 14.25, 95% CI 2.26–30.76 p = 0.09). There were no differences between groups in child injury nor subgroup interactions for the primary trial outcome by child age, sex, or baseline MVPA levels. Conclusion Scheduling multiple periods of outdoor free-play significantly increased the time children spent in MVPA while in attendance at childcare. This simple ecological intervention could be considered for broader dissemination as a strategy to increase child physical activity at a population level. Trial registration This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN1261000347460). Prospectively registered 17th March 2016