Digital interventions to improve adherence to maintenance medication in asthma

© 2018 The Cochrane Collaboration. This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the effectiveness of digital adherence interventions for improving adherence to maintenance treatments in asthma

Plastid Transcript Editing across Dinoflagellate Lineages Shows Lineage-Specific Application but Conserved Trends.

Dinoflagellates are a group of unicellular protists with immense ecological and evolutionary significance and cell biological diversity. Of the photosynthetic dinoflagellates, the majority possess a plastid containing the pigment peridinin, whereas some lineages have replaced this plastid by serial endosymbiosis with plastids of distinct evolutionary affiliations, including a fucoxanthin pigment-containing plastid of haptophyte origin. Previous studies have described the presence of widespread substitutional RNA editing in peridinin and fucoxanthin plastid genes. Because reports of this process have been limited to manual assessment of individual lineages, global trends concerning this RNA editing and its effect on the biological function of the plastid are largely unknown. Using novel bioinformatic methods, we examine the dynamics and evolution of RNA editing over a large multispecies data set of dinoflagellates, including novel sequence data from the peridinin dinoflagellate Pyrocystis lunula and the fucoxanthin dinoflagellate Karenia mikimotoi. We demonstrate that while most individual RNA editing events in dinoflagellate plastids are restricted to single species, global patterns, and functional consequences of editing are broadly conserved. We find that editing is biased toward specific codon positions and regions of genes, and generally corrects otherwise deleterious changes in the genome prior to translation, though this effect is more prevalent in peridinin than fucoxanthin lineages. Our results support a model for promiscuous editing application subsequently shaped by purifying selection, and suggest the presence of an underlying editing mechanism transferred from the peridinin-containing ancestor into fucoxanthin plastids postendosymbiosis, with remarkably conserved functional consequences in the new lineage

Progressive and biased divergent evolution underpins the origin and diversification of peridinin dinoflagellate plastids

Dinoflagellates are algae of tremendous importance to ecosystems and to public health. The cell biology and genome organization of dinoflagellate species is highly unusual. For example, the plastid genomes of peridinin-containing dinoflagellates encode only a minimal number of genes arranged on small elements termed "minicircles". Previous studies of peridinin plastid genes have found evidence for divergent sequence evolution, including extensive substitutions, novel insertions and deletions, and use of alternative translation initiation codons. Understanding the extent of this divergent evolution has been hampered by the lack of characterized peridinin plastid sequences. We have identified over 300 previously unannotated peridinin plastid mRNAs from published transcriptome projects, vastly increasing the number of sequences available. Using these data, we have produced a well-resolved phylogeny of peridinin plastid lineages, which uncovers several novel relationships within the dinoflagellates. This enables us to define changes to plastid sequences that occurred early in dinoflagellate evolution, and that have contributed to the subsequent diversification of individual dinoflagellate clades. We find that the origin of the peridinin dinoflagellates was specifically accompanied by elevations both in the overall number of substitutions that occurred on plastid sequences, and in the Ka/Ks ratio associated with plastid sequences, consistent with changes in selective pressure. These substitutions, alongside other changes, have accumulated progressively in individual peridinin plastid lineages. Throughout our entire dataset, we identify a persistent bias toward non-synonymous substitutions occurring on sequences encoding photosystem I subunits and stromal regions of peridinin plastid proteins, which may have underpinned the evolution of this unusual organelle.Wellcome Trus

Influence of age on the diagnosis of myocardial infarction

The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. METHODS: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50–74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. RESULTS: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5–82.9), 80.6% (95% CI, 79.2–82.1), and 81.6% (95% CI, 79.8–83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1–98.5) to 95.5% (95% CI, 95.2–95.8), and 82.6% (95% CI, 81.9–83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%–91.9%] versus 82.6% [95% CI, 81.9%–83.4%]) and positive predictive value (59.3% [57.0%–61.5%] versus 51.5% [49.9%–53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%–57.9%] versus 81.6% [79.8%–83.3%]. CONCLUSIONS: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population

strengthening agricultural decisions in countries at risk of food insecurity the geoglam crop monitor for early warning

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Implementation of high-sensitivity cardiac troponin and risk of myocardial infarction or death at 5 years: stepped-wedge, cluster-randomised controlled trial

AbstractObjective: To evaluate the impact of implementing a high-sensitivity cardiac troponin I assay on long-term outcomes in patients with suspected acute coronary syndromeDesign: Secondary observational analysis of a stepped-wedge cluster-randomised controlled trial.Setting: Ten secondary and tertiary care centresParticipants: Consecutive patients with suspected acute coronary syndrome (n=48,282; 47% women) were included in this trial. Myocardial injury was defined as any high-sensitivity cardiac troponin I concentration &gt;99th centile of 16 ng/L in women and 34 ng/L in men.Intervention: Hospital sites were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation of a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds.Main Outcome Measures: Subsequent myocardial infarction or death at 5 years.Results: Overall, 10,360 patients had cardiac troponin concentrations greater than the 99th centile of whom 1,771 (17%) were reclassified by the high-sensitivity assay. The 5-year incidence of subsequent myocardial infarction or death before and after implementation of the high-sensitivity assay was 29% (5,588/18,978) versus 26% (7,591/29,304), respectively, in all patients (adjusted hazard ratio [aHR] 0.97 [95% CI 0.93 to 1.01]), and 63% (456/720) versus 54% (567/1,051) in those reclassified by the high-sensitivity assay (aHR 0.82 [0.72-0.94]). Following implementation, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischemic myocardial injury (aHR 0·83 [0·75-0·91]), but not in those with type 1 or type 2 myocardial infarction (aHR 0·92 [0·83-1·01] and 0·98 [0·84-1·14]).Conclusions: In patients with suspected acute coronary syndrome, implementation of a high-sensitivity cardiac troponin assay reduced the risk of subsequent myocardial infarction or death at 5 years in those reclassified by the high-sensitivity assay. Improvements in outcome were greatest in patients with non-ischemic myocardial injury suggesting a broader benefit beyond the identification of myocardial infarction.<br/

Implementation of a high sensitivity cardiac troponin i assay and risk of myocardial infarction or death at five years:Observational analysis of a stepped wedge, cluster randomised controlled trial

Abstract:Objective: To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. Design: Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. Setting: 10 secondary and tertiary care centres in Scotland, UK. Participants: 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I &gt;99th centile of 16 ng/L in women and 34 ng/L in men. Intervention: Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. Main outcome measure: The main outcome was myocardial infarction or death at five years. Results: 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). Conclusions: Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. Trial registration: ClinicalTrials.gov NCT01852123.</p

The Implementation of Recommender Systems for Mental Health Recovery Narratives: Evaluation of Use and Performance

Background:Recommender systems help narrow down a large range of items to a smaller, personalized set. NarraGive is a first-in-field hybrid recommender system for mental health recovery narratives, recommending narratives based on their content and narrator characteristics (using content-based filtering) and on narratives beneficially impacting other similar users (using collaborative filtering). NarraGive is integrated into the Narrative Experiences Online (NEON) intervention, a web application providing access to the NEON Collection of recovery narratives.Objective:This study aims to analyze the 3 recommender system algorithms used in NarraGive to inform future interventions using recommender systems for lived experience narratives.Methods:Using a recently published framework for evaluating recommender systems to structure the analysis, we compared the content-based filtering algorithm and collaborative filtering algorithms by evaluating the accuracy (how close the predicted ratings are to the true ratings), precision (the proportion of the recommended narratives that are relevant), diversity (how diverse the recommended narratives are), coverage (the proportion of all available narratives that can be recommended), and unfairness (whether the algorithms produce less accurate predictions for disadvantaged participants) across gender and ethnicity. We used data from all participants in 2 parallel-group, waitlist control clinical trials of the NEON intervention (NEON trial: N=739; NEON for other [eg, nonpsychosis] mental health problems [NEON-O] trial: N=1023). Both trials included people with self-reported mental health problems who had and had not used statutory mental health services. In addition, NEON trial participants had experienced self-reported psychosis in the previous 5 years. Our evaluation used a database of Likert-scale narrative ratings provided by trial participants in response to validated narrative feedback questions.Results:Participants from the NEON and NEON-O trials provided 2288 and 1896 narrative ratings, respectively. Each rated narrative had a median of 3 ratings and 2 ratings, respectively. For the NEON trial, the content-based filtering algorithm performed better for coverage; the collaborative filtering algorithms performed better for accuracy, diversity, and unfairness across both gender and ethnicity; and neither algorithm performed better for precision. For the NEON-O trial, the content-based filtering algorithm did not perform better on any metric; the collaborative filtering algorithms performed better on accuracy and unfairness across both gender and ethnicity; and neither algorithm performed better for precision, diversity, or coverage.Conclusions:Clinical population may be associated with recommender system performance. Recommender systems are susceptible to a wide range of undesirable biases. Approaches to mitigating these include providing enough initial data for the recommender system (to prevent overfitting), ensuring that items can be accessed outside the recommender system (to prevent a feedback loop between accessed items and recommended items), and encouraging participants to provide feedback on every narrative they interact with (to prevent participants from only providing feedback when they have strong opinions)

Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI