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.

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.

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.

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.

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.

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.

Psychosocial impact of ocular surface allergic inflammatory disorders.

PURPOSE OF REVIEW: Allergic rhinoconjunctivitis is one of the most common ocular surface allergic inflammatory conditions seen in primary care that impacts patient's quality of life. Allergic conjunctivitis is increasingly being recognized as its own symptom complex that negatively impacts patient's quality of life separate from allergic rhinitis. This article reviews the psychosocial impact of ocular surface allergic inflammatory disorders (namely seasonal allergic conjunctivitis, ocular allergy, perennial allergic conjunctivitis, and atopic keratoconjunctivitis) on adult and pediatric populations. RECENT FINDINGS: Despite the perception that allergic conjunctivitis is a trivial condition, it imposes a burden on numerous psychosocial aspects of life for adolescents and adults. Several questionnaires specific to rhinoconjunctivitis have been found to be effective tools at gauging quality of life (QoL) and communicating impairments in specific behavioral domains for adult and pediatric populations. An emerging focus on the role of hormone fluctuations and age on ocular surface allergic inflammation underscores the importance of nuancing the physiologic effects on ocular allergy and QoL at every decade of life. SUMMARY: Further exploration and research of symptoms by age would greatly improve our understanding of age's impact on QoL in these patients and contribute to improved management of allergic conjunctivitis.

Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease.

PURPOSE OF REVIEW: To explore our current understanding of receptor profiles acted upon by medications used to treat dry eye disease (DED). RECENT FINDINGS: Research into histaminic and muscarinic receptor affinities for drugs targeting the ocular surface has not kept up with bench research pertaining to the receptor profile of the ocular surface. These insights are necessary for better evaluation of medications used in DED and other allergic disorders. SUMMARY: At the H1 receptor, Ketotifen (pKa = 9.2), pyrilamine (pKa = 9.0), and epinastine (pKa = 8.0) had the highest affinities, whereas ranitidine (pKa = 4.2) and cimetidine (pKa = 4.9) had the lowest. Ketotifen, a second-generation antihistamine, was found to have a pKa of 6.7 at muscarinic receptors which was higher than that of diphenhydramine (pKa = 6.4), a first-generation antihistamine. Additionally, second-generation antihistamines have higher affinity for H3 receptors, which have been linked to urticaria, compared to first-generation. Azelastine, a second-generation, demonstrated significant affinity (pKa = 7.1) at the H3 receptor compared to all other drugs. Antazoline (pKa = 4.4) and diphenhydramine (pKa = 4.6), both first-generation antihistamines, had the lowest affinities for the H3 receptor. These findings raise questions about the use of antihistamines in the treatment of DED and allergic disorders.

Comparison of structural components and functional mechanisms within the skin vs. the conjunctival surface.

PURPOSE OF REVIEW: The purpose of this review is to highlight and compare the structural and functional differences between the ocular surface and the skin. The goal is to further understand how these components interact from an immunobiological standpoint, which may inform future therapeutic uses. RECENT FINDINGS: Treatment agents, such as Dupilumab and Apremilast are traditionally indicated for integumentary conditions, such as atopic dermatitis and psoriasis, respectively. Both were also found to have potent effects on the conjunctival surface and ocular glands, which may be attributed to the similarities in structure. SUMMARY: Surfaces of the eyes and the skin are found to have similar composition in terms of immunohistology, steroidogenic properties, and allergic mechanisms. These translate directly into both the adverse effects and therapeutic benefits that overlap when treating these surfaces.

In vivo nuclear RNA structurome reveals RNA-structure regulation of mRNA processing in plants.

BACKGROUND: mRNA processing is critical for gene expression. A challenge in regulating mRNA processing is how to recognize the actual mRNA processing sites, such as splice and polyadenylation sites, when the sequence content is insufficient for this purpose. Previous studies suggested that RNA structure affects mRNA processing. However, the regulatory role of RNA structure in mRNA processing remains unclear. RESULTS: Here, we perform in vivo selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemical profiling on Arabidopsis and generate the in vivo nuclear RNA structure landscape. We find that nuclear mRNAs fold differently from cytosolic mRNAs across translation start and stop sites. Notably, we discover a two-nucleotide single-stranded RNA structure feature upstream of 5' splice sites that is strongly associated with splicing and the selection of alternative 5' splice sites. The regulatory role of this RNA structure feature is further confirmed by experimental validation. Moreover, we find the single-strandedness of branch sites is also associated with 3' splice site recognition. We also identify an RNA structure feature comprising two close-by single-stranded regions that is specifically associated with both polyadenylation and alternative polyadenylation events. CONCLUSIONS: We successfully identify pre-mRNA structure features associated with splicing and polyadenylation at whole-genome scale and validate an RNA structure feature which can regulate splicing. Our study unveils a new RNA structure regulatory mechanism for mRNA processing.

Use of allergen immunotherapy for treatment of allergic conjunctivitis.

PURPOSE OF REVIEW: The purpose of this article is to provide an overview of the literature pertaining to the use of allergen immunotherapy for treatment of allergic conjunctivitis with an emphasis on recent developments. RECENT FINDINGS: Both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy continue to show efficacy in treating allergic conjunctival disease, subcutaneous more than sublingual. Adverse effects of sublingual therapy continue to be reported since the FDA's approval of SLIT tablets in 2014. Initial SLIT studies reported high rates of adherence, while real use reports identify rates of nonadherence/discontinuation ranging between 50 and 80%. Studies in polyallergic patients evaluating the efficacy of SLIT combination therapy report encouraging results. SUMMARY: Both SCIT and SLIT offers improvement in allergic conjunctival symptom scores and decrease medication utilization. Although SCIT has a higher likelihood of systemic reaction, SLIT has a very high rate of mild-to-moderate adverse events - especially in the first month. Cost-benefit analyses tend to favor SCIT (greater efficacy and less impacted by discontinuation rates).

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.

Scalable Syntheses of Methoxyaspartate and Preparation of the Antibiotic Cystobactamid 861-2 and Highly Potent Derivatives.

An improved scalable synthesis of orthogonally functionalized methoxyaspartate, the chiral hinge region element in cystobactamids, is reported. This improvement sets the stage for the total synthesis of four new cystobactamids along with cystobactamid 861-2, whose antibacterial properties are determined and compared. The cyano derivative of cystobactamide 861-2 shows superior antibacterial activity against Gram-negative bacteria to any natural cystobactamide tested so far.

Cystobactamids 920-1 and 920-2: Assignment of the Constitution and Relative Configuration by Total Synthesis.

Total synthesis of cystobactamid 920-1 and its epimer has allowed an unambiguous assignment of the relative and absolute configuration of the natural product. A careful structural analysis of each isomer using both NMR and computational techniques also prompted a constitutional revision of the structures originally reported for cystobactamids 920-1 and 920-2, and has provided further insight into the unique conformational preferences of the cystobactamid family.

Cosmetics and ocular allergy.

PURPOSE OF REVIEW: The purpose of this review was to explore recent developments in the study of ocular cosmetics, as they pertain to adverse reactions that can be attributed to them. RECENT FINDINGS: Immunologically mediated adverse reactions to cosmetics are most commonly the result of sensitization to preservatives, fragrances and dyes used in these products. Metals such as nickel, cobalt, chromium and lead are used in products such as eye shadows and eye liners as well as toy makeup sets in amounts greater than the recommended amount of 1 ppm. Cosmetics make up the majority of fragrance-induced contact dermatitis. Recently, a free smartphone app was developed by American Contact Dermatitis Society that holds promise in better enabling patients to utilize their patch test data while shopping for cosmetics. SUMMARY: Both immediate and delayed hypersensitivity reactions linked to cosmetics are often the result of sensitization to preservatives, fragrances and additives in the products themselves. Despite significant advances in our understanding of these reactions, further research will be necessary to elucidate the mechanisms behind these reactions and bring this knowledge to the bedside as to improve patient care with potential cosmetic-based related allergic disorders.

Seasonal ocular allergy and pollen counts.

PURPOSE OF REVIEW: The purpose of the article is to provide a historical overview of literature regarding pollen sensitization and ocular allergy with an emphasis on developments that have occurred over the past 5 years. RECENT FINDINGS: Currently, pollen studies have examined the molecular and cellular pathways involved in initiating allergic conjunctivitis to find targets for therapeutics. Studies have also documented the threshold, linear increase and plateau point in the relationship between pollen levels and allergic conjunctivitis symptoms. SUMMARY: Traditionally, intact pollen grains are counted as a means of correlating patient symptoms to allergen exposure. However, establishing a dose-response relationship between pollen grain exposure and allergic conjunctivitis has proven to be difficult. It has been observed that ocular allergies induce a two-fold response including early-phase and late-phase IgE-mediated reactions. Sensitization itself is a combination of pollen exposure over time in genetically predisposed individual. However, symptoms appear to reach an asymptotic point at which clinical severity plateaus. More studies are needed to clearly define differences in pollen sensitization by plant species.