SMART - is it practical in the United States?

PURPOSE OF REVIEW: The 2020 focused updates to the asthma management guidelines by the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group advocate for inhaled corticosteroid (ICS)-formoterol combinations as single maintenance and reliever therapy (SMART) for patients with persistent asthma. We review the rationale, the evidence supporting SMART use in asthma, and barriers limiting its wide adoption in the United States. RECENT FINDINGS: A growing body of evidence supports the use of SMART over the conventional use of controller medicaments with an as-needed short-acting ß2 agonist for rescue therapy for the purpose of reducing the risk of asthma exacerbation and maintaining asthma control in adolescents and adults with persistent disease. Lack of US Food and Drug Administration approval, inconsistent insurance coverage, and limited options of ICS-formoterol combination available for use as SMART represent obstacles to wider integration of SMART in clinical practice. SUMMARY: SMART represents a paradigm shift in asthma management. By identifying and addressing the current and anticipated barriers to implementing SMART, its adoption by providers is likely to increase in the United States.

Intact RNA structurome reveals mRNA structure-mediated regulation of miRNA cleavage in vivo.

MicroRNA (miRNA)-mediated cleavage is involved in numerous essential cellular pathways. miRNAs recognize target RNAs via sequence complementarity. In addition to complementarity, in vitro and in silico studies have suggested that RNA structure may influence the accessibility of mRNAs to miRNA-induced silencing complexes (miRISCs), thereby affecting RNA silencing. However, the regulatory mechanism of mRNA structure in miRNA cleavage remains elusive. We investigated the role of in vivo RNA secondary structure in miRNA cleavage by developing the new CAP-STRUCTURE-seq method to capture the intact mRNA structurome in Arabidopsis thaliana. This approach revealed that miRNA target sites were not structurally accessible for miRISC binding prior to cleavage in vivo. Instead, we found that the unfolding of the target site structure plays a key role in miRISC activity in vivo. We found that the single-strandedness of the two nucleotides immediately downstream of the target site, named Target Adjacent nucleotide Motif, can promote miRNA cleavage but not miRNA binding, thus decoupling target site binding from cleavage. Our findings demonstrate that mRNA structure in vivo can modulate miRNA cleavage, providing evidence of mRNA structure-dependent regulation of biological processes.

Management of pediatric hereditary angioedema types 1 and 2: A search for international consensus.

Background: The management of hereditary angioedema has rapidly changed over the past decade. With these changes there has been increased recognition of the unique challenges of diagnosing and managing hereditary angioedema in pediatric populations. The objective of this review was to identify and compare recently published consensus guidelines for the management of hereditary angioedema types 1 and 2 to identify areas of agreement and conflict. Methods: A MEDLINE database search was performed to identify guidelines that offered guidance on diagnosing or managing hereditary angioedema in pediatric populations. A limitation was placed on guidelines published in the past 5 years to reflect the most recent literature. Results: Six clinical practice guidelines were included in the analysis. Early detection of disease status, coordination with specialists, and empowering patients with self-administered medications are emphasized, with use of plasma derived C1 esterase inhibitor as first line therapy for aborting attacks. The guidelines are shifting away from attenuated androgens and tranexamic acid for long-term prophylaxis toward medications such as subcutaneous C1 esterase inhibitor, lanadelumab, and berotralstat. Conclusion: Although some differences exist based on geographic region and health system where an included guideline was published, they have very minimal differences on close review.

FoldAtlas: a repository for genome-wide RNA structure probing data.

Most RNA molecules form internal base pairs, leading to a folded secondary structure. Some of these structures have been demonstrated to be functionally significant. High-throughput RNA structure chemical probing methods generate millions of sequencing reads to provide structural constraints for RNA secondary structure prediction. At present, processed data from these experiments are difficult to access without computational expertise. Here we present FoldAtlas, a web interface for accessing raw and processed structural data across thousands of transcripts. FoldAtlas allows a researcher to easily locate, view, and retrieve probing data for a given RNA molecule. We also provide in silico and in vivo secondary structure predictions for comparison, visualized in the browser as circle plots and topology diagrams. Data currently integrated into FoldAtlas are from a new high-depth Structure-seq data analysis in Arabidopsis thaliana, released with this work. AVAILABILITY AND IMPLEMENTATION: The FoldAtlas website can be accessed at www.foldatlas.com Source code is freely available at github.com/mnori/foldatlas under the MIT license. Raw reads data are available under the NCBI SRA accession SRP066985. CONTACT: yiliang.ding@jic.ac.uk or matthew.norris@jic.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.

Dysfunction in emotion processing underlies functional (psychogenic) dystonia.

OBJECTIVE: We sought to determine whether abnormalities in emotion processing underlie functional (psychogenic) dystonia, one of the most common functional movement disorders. METHODS: Motor and emotion circuits were examined in 12 participants with functional dystonia, 12 with primary organic dystonia, and 25 healthy controls using functional magnetic resonance imaging at 4T and a finger-tapping task (motor task), a basic emotion-recognition task (emotional faces task), and an intense-emotion stimuli task. RESULTS: There were no differences in motor task activation between groups. In the faces task, when compared with the other groups, functional dystonia patients showed areas of decreased activation in the right middle temporal gyrus and bilateral precuneus and increased activation in the right inferior frontal gyrus, bilateral occipital cortex and fusiform gyrus, and bilateral cerebellum. In the intense-emotion task, when compared with the other groups, functional dystonia patients showed decreased activation in the left insular and left motor cortices (compared to organic dystonia, they showed an additional decrease in activation in the right opercular cortex and right motor cortex) and increased activation in the left fusiform gyrus. CONCLUSIONS: Functional dystonia patients exhibited stimulus-dependent altered activation in networks involved in motor preparation and execution, spatial cognition, and attentional control. These results support the presence of network dysfunction in functional dystonia. © 2017 International Parkinson and Movement Disorder Society.

Total synthesis and structural elucidation of spongosoritin A.

Two putative structures of spongosoritin A, with syn (6R,8R) and anti (6S,8R) configurations, were each synthesised in a total of 11 linear steps with only 8 purification procedures. The key steps in our strategy included Evans alkylation and olefin dihydroxylation to install the C8 and C6 stereocentres, a transacetalisation/dehydration cascade to construct the furanylidene core, and chromatographic separation of 9E- and 9Z-isomers of the final compounds with silver nitrate impregnated silica. Comparison of the 1H and 13C NMR data for the synthetic syn- and anti-isomers to that reported for the natural product revealed that the relative configuration of spongosoritin A is syn. The absolute stereochemistry was also confirmed as 6R,8R based on optical rotation measurements where the synthetic syn (6R,8R) and natural product had the same sign of optical rotation (negative).

A light-sensitive mutation in Arabidopsis LEW3 reveals the important role of N-glycosylation in root growth and development.

Plant roots have the potential capacity to grow almost indefinitely if meristematic and lateral branching is sustained. In a genetic screen we identified an Arabidopsis mutant showing limited root growth (lrg1) due to defects in cell division and elongation in the root meristem. Positional cloning determined that lrg1 affects an alpha-1,2-mannosyltransferase gene, LEW3, involved in protein N-glycosylation. The lrg1 mutation causes a synonymous substitution that alters the correct splicing of the fourth intron in LEW3, causing a mix of wild-type and truncated protein. LRG1 RNA missplicing in roots and short root phenotypes in lrg1 are light-intensity dependent. This mutation disrupts a GC-base pair in a three-base-pair stem with a four-nucleotide loop, which seems to be necessary for correct LEW3 RNA splicing. We found that the lrg1 short root phenotype correlates with high levels of reactive oxygen species and low pH in the apoplast. Proteomic analyses of N-glycosylated proteins identified GLU23/PYK10 and PRX34 as N-glycosylation targets of LRG1 activity. The lrg1 mutation reduces the positive interaction between Arabidopsis and Serendipita indica. A prx34 mutant showed a significant reduction in root growth, which is additive to lrg1. Taken together our work highlights the important role of N-glycosylation in root growth and development.

Prediction of lithium response in first-episode mania using the LITHium Intelligent Agent (LITHIA): Pilot data and proof-of-concept.

OBJECTIVES: Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first-episode bipolar mania. METHODS: We identified 20 subjects with first-episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1 H-MRS scans at baseline pre-treatment. We trained LITHIA using 18 1 H-MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods. RESULTS: LITHIA demonstrated nearly perfect classification accuracy and was able to predict post-treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting. CONCLUSIONS: The results provided proof-of-concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem-namely, prediction of the lithium response-in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment.

Structural diversity and chemical synthesis of peroxide and peroxide-derived polyketide metabolites from marine sponges.

Covering: up to early 2016Marine sponges are widely known as a rich source of natural products, especially of polyketide origin, with a wealth of chemical diversity. Within this vast collection, peroxide and peroxide-derived secondary metabolites have attracted significant interest in the fields of natural product isolation and chemical synthesis for their structural distinction and promising in vitro antimicrobial and anticancer properties. In this review, peroxide and peroxide-derived polyketide metabolites isolated from marine sponges in the past 35 years are summarised. Efforts toward their synthesis are detailed with a focus on methods that utilise or attempt to elucidate the complex biosynthetic interrelationships of these compounds beyond enzymatic polyketide synthesis. Recent isolations, advances in synthetic methodology and theories of biogenesis are highlighted and critically evaluated.

fMRI brain activation changes following treatment of a first bipolar manic episode.

OBJECTIVES: We tested the hypothesis that, with treatment, functional magnetic resonance imaging (fMRI) regional brain activation in first-episode mania would normalize - i.e., that differences from healthy subjects would diminish over time, and would be associated with clinical remission status, potentially identifying neuroanatomic treatment response markers. METHODS: Forty-two participants with bipolar I disorder were recruited during their first manic episode, pseudo-randomized to open-label lithium or quetiapine, and followed for 8 weeks. fMRI scans were obtained at baseline and then after 1 and 8 weeks of treatment, while participants performed a continuous performance task with emotional distracters. Healthy participants received fMRI scans at these same intervals. Specific region-of-interest (ROI) activations within prefrontal emotional networks were assessed as potential measures of treatment response. RESULTS: ROI data were reduced using exploratory factor analysis, which identified five factors that were organizationally consistent with functional anatomic models of human emotion modulation. Half of the participants with bipolar disorder achieved remission by Week 8 and were contrasted with the other half that did not. Analyses demonstrated that, in the bipolar disorder group in general, treatment led to decreases in activation across brain regions toward healthy subject values. However, differences in activation changes were observed between subjects with bipolar disorder who did or did not achieve remission in subcortical and amygdala factors. CONCLUSIONS: These findings provide evidence for potential neuroanatomic treatment response markers in first-episode bipolar disorder.

Total Synthesis of Plakilactones C, B and des-Hydroxyplakilactone B by the Oxidative Cleavage of Gracilioether Furanylidenes.

A chemoselective oxidative cleavage of synthetic gracilioether B, 11-epi-gracilioether C benzoate, and des-hydroxygracilioether C with pyridinium chlorochromate, which proceeds with loss of the furanyl acetate, has enabled total synthesis and stereochemical elucidation of the marine sponge metabolites (4R,6R)-plakilactone C, (4R,6R,9R)-plakilactone B, and (4R,6R)-des-hydroxyplakilactone B. des-Hydroxygracilioether C, the putative biosynthetic precursor to hippolachnin A, was also found to undergo a facile ene cyclization on treatment with SnCl4.

Artificial Intelligence-Generated Scientific Literature: A Critical Appraisal.

BACKGROUND: Review articles play a critical role in informing medical decisions and identifying avenues for future research. With the introduction of artificial intelligence (AI), there has been a growing interest in the potential of this technology to transform the synthesis of medical literature. Open AI's Generative Pre-trained Transformer (GPT-4) (Open AI Inc, San Francisco, CA) tool provides access to advanced AI that is able to quickly produce medical literature following only simple prompts. The accuracy of the generated articles requires review, especially in subspecialty fields like Allergy/Immunology. OBJECTIVE: To critically appraise AI-synthesized allergy-focused minireviews. METHODS: We tasked the GPT-4 Chatbot with generating 2 1,000-word reviews on the topics of hereditary angioedema and eosinophilic esophagitis. Authors critically appraised these articles using the Joanna Briggs Institute (JBI) tool for text and opinion and additionally evaluated domains of interest such as language, reference quality, and accuracy of the content. RESULTS: The language of the AI-generated minireviews was carefully articulated and logically focused on the topic of interest; however, reviewers of the AI-generated articles indicated that the AI-generated content lacked depth, did not appear to be the result of an analytical process, missed critical information, and contained inaccurate information. Despite being provided instruction to utilize scientific references, the AI chatbot relied mainly on freely available resources, and the AI chatbot fabricated references. CONCLUSIONS: The AI holds the potential to change the landscape of synthesizing medical literature; however, apparent inaccurate and fabricated information calls for rigorous evaluation and validation of AI tools in generating medical literature, especially on subjects associated with limited resources.

Comparative Impact of Asthma Biologics: A Nationwide US Claim-Based Analysis.

BACKGROUND: Biologic modifiers targeting type 2 (T2) airway inflammation are effective in reducing asthma exacerbation. However, real-world and comparative effectiveness studies remain limited. OBJECTIVE: To examine and compare the real-world impact of anti-T2 asthma biologics. METHODS: In this retrospective, new user cohort study, we used the MarketScan, a Commercial Claims and Encounters Database, to identify adult patients with asthma who began to receive an anti-T2 biologic agent (anti-IL-5s, dupilumab, or omalizumab). We examined the influence of the biologic class on asthma exacerbation by comparing the average number of asthma exacerbation 1 year before and after biologic initiation. We conducted multivariable regression analyses to compare the effectiveness of these asthma biologics on reducing the incidence of asthma exacerbations within 18 months of the initial administration of biologics while controlling for demographic variables, comorbidities, and asthma severity. RESULTS: We identified 5,538 asthma patients who were new to taking an anti-T2 biologic [mean age [±SD], 45.6 (12.78) years; 65.8% female). Asthma biologics reduced asthma exacerbation by 11% to 47%, particularly among patients with two or more asthma exacerbations in the year preceding biologic initiation (31% to 65% reduction). Biologics were especially effective in reducing asthma-related hospitalizations (44.6% to 60%). After adjusting for baseline demographics, asthma medication, and comorbidities, dupilumab was associated with a lower estimated mean number of asthma exacerbation per year and lower adjusted odds ratio for developing an asthma exacerbation relative to other biologics (50% to 80% less likely). CONCLUSIONS: Anti-T2 asthma biologics reduced asthma exacerbation in real-word settings. Evidence supports growing literature reporting that dupilumab might have a more favorable impact on asthma exacerbation relative to other asthma biologics.

A pilot study of anterior cingulate cortex neurochemistry in adolescents with generalized anxiety disorder.

BACKGROUND/AIMS: This study used proton magnetic resonance spectroscopy (¹H MRS) to evaluate the neurochemistry of the anterior cingulate cortex (ACC) in adolescents with generalized anxiety disorder (GAD). METHODS: Adolescents with GAD (n = 10) and healthy subjects (n = 10) underwent a ¹H MRS scan at 4 T. Glutamate (Glu), N-acetyl aspartate, creatine (Cr) and myo-inositol concentrations were measured in the ACC and were compared between untreated adolescents with GAD and age- and sex-matched healthy subjects. RESULTS: Glu/Cr ratios in the ACC correlated with the severity of both generalized anxiety symptoms on the Pediatric Anxiety Rating Scale and with total anxiety symptom severity as measured by the Hamilton Anxiety Rating Scale, but did not differ between adolescents with GAD and healthy subjects. In addition, no differences in N-acetyl aspartate, Cr, or myo-inositol were detected between groups. CONCLUSION: These findings suggest that Glu/Cr in untreated adolescents with GAD may relate to the severity of anxiety symptoms and raise the possibility that dysregulation of Glu within the ACC may be linked to the pathophysiology of pediatric GAD.

Racial and Ethnic Disparities in Allergen Immunotherapy Prescription for Allergic Rhinitis.

BACKGROUND: Racial and ethnic differences exist in the severity of various atopic diseases including allergic rhinitis (AR). Patients of under-represented races and ethnicities may be subjected to disparate subcutaneous allergen immunotherapy (SCIT) prescription practices. OBJECTIVE: To explore the racial and ethnic disparities in the use of SCIT among patients with AR. METHODS: In this retrospective matched cohort study, we used the TriNetX US Collaborative Network, a multicenter electronic health record-based database to identify patients with AR 18 years and older. Patients were grouped according to their racial and ethnic identification. Study groups were matched for baseline demographics, atopic comorbidities, heart diseases and utilization of ß-blockers, and angiotensin-converting enzyme inhibitors. The proportion of patients of under-represented racial and ethnic groups started on SCIT was contrasted to the non-Hispanic White cohort. RESULTS: We identified 1,038,000 patients with AR; the mean age (±standard deviation) at the index was 49.7 (±16.1) years, and 64.6% were female. Ethnicity information was available from 87.3% of patients, and the majority (92.3%) were non-Hispanic. Over a 3-year observation period, fewer Black patients (relative risk [RR], 0.40; 95% confidence interval [CI], 0.33-0.48) and Hispanic patients (RR, 0.80; 95% CI, 0.64-0.99) were started on SCIT compared with non-Hispanic White patients. The proportions of Asian patients who were initiated on SCIT tended to be lower when compared with non-Hispanic White patients (RR, 0.69; 95% CI, 0.47-1.009). CONCLUSIONS: In the United States, differences in SCIT prescription exist between Black and Hispanic patients relative to White patients. Barriers to treatment should be explored and mitigated.

A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis.

Background and aims: With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. Methods: We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Results: Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores >70% in the "Scope and Purpose" and "Rigour of Development" domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the "Applicability" domain were generally low, and only 3 CPGs rated highly in the "Implementability" domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. Conclusion: The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders' preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. PROSPERO registration number: CRD42021265689.