Outcomes and baseline predictors of failure in primary standalone Xen45 gel stent vs trabeculectomy for glaucoma.

PURPOSE: To compare safety, effectiveness and baseline predictors of failure in standalone primary Xen45 gel stent (Xen) vs trabeculectomy (Trab) in glaucoma. DESIGN: Retrospective study SUBJECTS: Subjects that underwent primary Xen or Trab augmented by mitomycin-C with at least 12 months follow-up. METHODS: Multinational observational study of eyes in the Fight Glaucoma Blindness international registry MAIN OUTCOME MEASURES: The primary outcome was success at 12 months defined by IOP reduction ≥ 20% from baseline and ≤ threshold IOPs of 15mmHg, 18mmHg and 21mmHg with (qualified) or without (complete) medications and without secondary glaucoma surgery. Multivariable mixed effects cox regression models were used to identify risk factors for failure in each cohort. RESULTS: 701 eyes (Xen, 308; Trab, 393) of 596 subjects were included with baseline IOP being significantly higher (22.4 vs 19.9 mmHg, p < 0.001) and baseline medications significantly lower in the Xen vs the Trab group (2.9 vs 3.4, p <0.001). Baseline visual field (VF) mean deviation (MD) was less severe in the Xen group (-9.47 vs -13.04 dB, p < 0.001). The proportion of complete surgical success was significantly lower in the Xen vs Trab group across the three upper IOP limits at 12 months; 32% vs 52% at 15mmHg, 37% vs 54% at 18mmHg, and 39% vs 55% at 21mmHg (p < 0.001). The incidence of post-operative numerical and symptomatic hypotony was lower in the Xen vs Trab group. In the Xen cohort, a higher failure rate was associated with Asian ethnicity (HR, 1.97; 95% CI, 1.03-3.79) and use of oral acetazolamide at baseline (HR, 1.74; 1.13-2.70), while a lower failure rate was associated with diagnosis of ocular hypertension/open angle glaucoma suspect (HR, 0.52; 0.28-0.94) and secondary open angle glaucoma (HR, 0.45; 0.25-0.8). Exposure to prostaglandin analogue was associated with greater failure in the Trab group (HR, 2.66; 1.18-6.01). CONCLUSIONS: There was significantly greater complete success at 12 months across all complete success definitions for Trab compared to Xen, while the rate of post-operative hypotony was significantly lower in Xen group. Asian ethnicity and use of oral acetazolamide at baseline were associated with greater failure in Xen, while exposure to prostaglandin analogue was associated with greater failure in Trab patients. Such baseline predictors of success and failure may help guide patient selection for subconjunctival minimally invasive glaucoma surgery in patients undergoing surgical intervention.

Mast Cell Activation Syndrome: current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated. The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.

Chemical synthesis of grafted cyclotides using a "plug and play" approach.

Cyclotides are a diverse class of plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology. Their remarkable structural stability and resistance to proteolytic degradation can lead to improved pharmacokinetics and oral activity as well as selectivity and high enzymatic stability. Thus, cyclotides have emerged as powerful scaffold molecules for designing peptide-based therapeutics. The chemical engineering of cyclotides has generated novel peptide ligands of G protein-coupled receptors (GPCRs), today's most exploited drug targets. However key challenges potentially limit the widespread use of cyclotides in molecular grafting applications. Folding of cyclotides containing bioactive epitopes remains a major bottleneck in cyclotide synthesis. Here we present a modular 'plug and play' approach that effectively bypasses problems associated with the oxidative folding of cyclotides. By grafting onto a pre-formed acyclic cyclotide-like scaffold we show that difficult-to-graft sequences can be easily obtained and can target GPCRs with nanomolar affinities and potencies. We further show the suitability of this new method to graft other complex epitopes including structures with additional disulfide bonds that are not readily available via currently employed chemical methods, thus fully unlocking cyclotides to be used in drug design applications.

Current Practice: Rationale for Screening Children with Hereditary Hemorrhagic Telangiectasia for Brain Vascular Malformations.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias, recurrent epistaxis, and organ vascular malformations including in the brain, which occur in about 10% of patients. These brain vascular malformations include high-flow AVMs and AVFs as well as low-flow capillary malformations. High-flow lesions can rupture, causing neurologic morbidity and mortality. STATE OF PRACTICE: International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia recommend screening children for brain vascular malformations with contrast enhanced MR imaging at hereditary hemorrhagic telangiectasia diagnosis. Screening has not been uniformly adopted by some practitioners who contend that screening is not justified. Arguments against screening include application of short-term data from the adult A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial of unruptured sporadic brain AVMs to children with hereditary hemorrhagic telangiectasia as well as concerns about administration of sedation or IV contrast and causing patients or families increased anxiety. ANALYSIS: In this article, a multidisciplinary group of experts on hereditary hemorrhagic telangiectasia reviewed data that support screening guidelines and counter arguments against screening. Children with hereditary hemorrhagic telangiectasia have a preponderance of high-flow lesions including AVFs, which have the highest rupture risk. The rupture risk among children is estimated at about 0.7% per lesion per year and is additive across lesions and during a lifetime. ARUBA, an adult clinical trial of expectant medical management versus treatment of unruptured brain AVMs, favored medical management at 5 years but is not applicable to pediatric patients with hereditary hemorrhagic telangiectasia given the life expectancy of a child. Additionally, interventional, radiosurgical, and surgical techniques have improved with time. Experienced neurovascular experts can prospectively determine the best treatment for each child on the basis of local resources. The "watch and wait" approach to imaging means that children with brain vascular malformations will not be identified until a potentially life-threatening and deficit-producing intracerebral hemorrhage occurs. This expert group does not deem this to be an acceptable trade-off.

Two-year outcomes of Xen 45 gel stent implantation in patients with open-angle glaucoma: real-world data from the Fight Glaucoma Blindness registry.

OBJECTIVE: To evaluate efficacy and safety outcomes of the Xen 45 gel stent implant over 24 months of follow-up. METHODS: A retrospective analysis of prospectively collected data from the Fight Glaucoma Blindness observational registry. Complete success (CS) was defined as intraocular pressure (IOP) reduction ≥20% from preoperative and an IOP ≤18 mm Hg and ≥6 mm Hg with no secondary procedure at 2 years and without IOP-lowering medications. Qualified success (QS) was defined similarly, allowing the use of IOP-lowering medications. RESULTS: The Xen 45 gel stent implant was implanted in 646 eyes of 515 patients. Preoperative IOP was 21.4±7.6 (mean±SD) mm Hg on 2.7±1.3 IOP-lowering medication and mean deviation was -10.2±8.4 dB. After 24-month follow-up, IOP was 16.8±7.3 mm Hg (mean reduction of 21.7%) on 1.2±1.4 IOP-lowering medications. CS and QS rates at 24 months were 26% and 48%, respectively. CS and QS were higher in the Xen stand-alone group (33% and 52%, respectively) than in the Xen+cataract group (16% and 42%, respectively). Bleb needling was performed in 28.4% of cases, and 18% underwent a secondary procedure. CONCLUSIONS: The Xen 45 gel stent implant offers acceptable long-term efficacy for the treatment of open-angle glaucoma. However, there is a significant rate of reoperation and needling, and outcomes are less effective if combined with cataract surgery.

Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.

Introduction: Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund's Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied. Methods: We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates. Results: We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens. Discussion: Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.

Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Molecular heterogeneity of quiescent melanocyte stem cells revealed by single-cell RNA-sequencing.

Melanocyte stem cells (McSCs) of the hair follicle are a rare cell population within the skin and are notably underrepresented in whole-skin, single-cell RNA sequencing (scRNA-seq) datasets. Using a cell enrichment strategy to isolate KIT+/CD45- cells from the telogen skin of adult female C57BL/6J mice, we evaluated the transcriptional landscape of quiescent McSCs (qMcSCs) at high resolution. Through this evaluation, we confirmed existing molecular signatures for qMcCS subpopulations (e.g., Kit+, Cd34+/-, Plp1+, Cd274+/-, Thy1+, Cdh3+/-) and identified novel qMcSC subpopulations, including two that differentially regulate their immune privilege status. Within qMcSC subpopulations, we also predicted melanocyte differentiation potential, neural crest potential, and quiescence depth. Taken together, the results demonstrate that the qMcSC population is heterogeneous and future studies focused on investigating changes in qMcSCs should consider changes in subpopulation composition.

Vinylic C-H Activation of Styrenes by an Iron-Aluminum Complex.

The oxidative addition of sp2 C-H bonds of alkenes to single-site transition-metal complexes is complicated by the competing π-coordination of the C═C double bond, limiting the examples of this type of reactivity and onward applications. Here, we report the C-H activation of styrenes by a well-defined bimetallic Fe-Al complex. These reactions are highly selective, resulting in the (E)-ß-metalation of the alkene. For this bimetallic system, alkene binding appears to be essential for the reaction to occur. Experimental and computational insights suggest an unusual reaction pathway in which a (2 + 2) cycloaddition intermediate is directly converted into the hydrido vinyl product via an intramolecular sp2 C-H bond activation across the two metals. The key C-H cleavage step proceeds through a highly asynchronous transition state near the boundary between a concerted and a stepwise mechanism influenced by the resonance stabilization ability of the aryl substituent. The metalated alkenes can be further functionalized, which has been demonstrated by the (E)-selective phosphination of the employed styrenes.

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

Efficacy of EDS-FLU for Chronic Rhinosinusitis: Two Randomized Controlled Trials (ReOpen1 and ReOpen2).

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. OBJECTIVE: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). METHODS: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24. RESULTS: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids. CONCLUSIONS: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.

Should Biologics Be Used Before Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease?

There has been a paradigm shift in the management of aspirin-exacerbated respiratory disease (AERD). It started in 2015 when the first biologic was Food and Drug Administration (FDA) approved for severe eosinophilic asthma. Thus, there emerged a new era in the treatment of patients with type 2-mediated airway diseases. This has led to an increasing number of options for patients, undoubtably a great thing, but has left clinicians without a clear answer for how to balance the therapies that exist for AERD, what to recommend for treatment, and how to best assess the benefits and risks of each therapy. This paper aims to explore these benefits and risks, and to provide a roadmap for future studies.

Healthcare costs following falls and cataract surgery in older adults using Australian linked health data from 2012-2019.

OBJECTIVES: To investigate publicly funded healthcare costs according to faller status and the periods pre- and post-cataract surgeries, and identify factors associated with higher monthly costs in older people with bilateral cataract. METHODS: This prospective cohort study included community-dwelling older people aged 65 and over (between 2012 and 2019); at baseline participants had bilateral cataract and were waiting for cataract surgery in New South Wales (NSW) public hospitals. Participants were followed for 24 months. The study used self-reported and linked data (Medicare Benefits Schedule, Pharmaceutical Benefits Scheme, NSW Admitted Patient and Emergency Department Data Collections) to identify falls, cataract surgeries and healthcare costs incurred by the Australian and NSW Governments, all costs were inflated to 2018-19 Australian dollars (AUD). Median monthly healthcare costs were calculated for faller status (non-faller, non-medically treated faller, medically treated faller) and surgery periods (pre-surgery, post-first surgery, post-second surgery). Costs in the 30 days following a medically treated fall were estimated. A generalised linear model was used to investigate predictors of healthcare costs. RESULTS: During the median follow-up period of 24 months, 274 participants suffered 448 falls, with 95 falls requiring medical treatment. For medically treated falls, the mean cost in the 30 days after treatment was A$3779 (95% confidence interval $2485, $5074). Higher monthly healthcare costs were associated with a higher number of medications, being of the male sex, having one or more medically treated falls and having bilateral cataract surgery. After excluding the cost of cataract surgery, there were no significant differences in healthcare costs between the pre-cataract surgery, post-first eye cataract surgery and post-second eye cataract surgery periods. CONCLUSIONS: To our knowledge, this is the first study investigating publicly funded costs related to falls and cataract surgery in older people with bilateral cataract. This information enhances our understanding of healthcare costs in this group. The patterns in costs associated with falls can guide future government healthcare expenditure on falls treatment and prevention, including timely cataract surgery.

Mechanical disorders of the cervicocerebral circulation in children and young adults.

Mechanical disorders of the cervicocerebral circulation (MDCC) are conditions in which neurological symptoms result from a disturbance of cerebral blood flow attributable to external mechanical forces exerted on extracranial blood vessels by adjacent musculoskeletal structures during head movement that is presumably within a physiological range. The disease spectrum includes bow hunter's syndrome, carotid-type Eagle syndrome, and various dynamic venous compression syndromes. These conditions have distinct phenotypes in children which differ from those expressed in older adults. In contemporary practice, recognition and diagnostic evaluation is the domain of the neuroendovascular specialist. The diagnostic evaluation of MDCC involves significant technical nuance that can be critical to directing appropriate management, particularly in children. This report aims to provide a comprehensive overview of the pathophysiology, anatomical patterns, diagnosis, and treatment for the full spectrum of MDCC that is commonly encountered in clinical practice.

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy.

BACKGROUND: Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. METHODS: A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb-IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. RESULTS: The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFß2, a marker of the N2 neutrophils with immunosuppressive activity. CONCLUSIONS: These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

Diabetic Retinopathy Screening at the Point of Care (DR SPOC): detecting undiagnosed and vision-threatening retinopathy by integrating portable technologies within existing services.

INTRODUCTION: The aim of this study was to determine the prevalence of diabetic retinopathy (DR) in a low socioeconomic region of a high-income country, as well as determine the diagnostic utility of point-of-care screening for high-risk populations in tertiary care settings. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of patients with diabetes attending foot ulcer or integrated care diabetes clinics at two Western Sydney hospitals (n=273). DR was assessed using portable, two-field, non-mydriatic fundus photography and combined electroretinogram/ pupillometry (ERG). With mydriatic photographs used as the reference standard, sensitivity and specificity of the devices were determined. Prevalence of DR and vision-threatening diabetic retinopathy (VTDR) were reported, with multivariate logistic regression used to identify predictors of DR. RESULTS: Among 273 patients, 39.6% had any DR, while 15.8% had VTDR, of whom 59.3% and 62.8% were previously undiagnosed, respectively. Non-mydriatic photography demonstrated 20.2% sensitivity and 99.5% specificity for any DR, with a 56.7% screening failure rate. Meanwhile, mydriatic photography produced high-quality images with a 7.6% failure rate. ERG demonstrated 72.5% sensitivity and 70.1% specificity, with a 15.0% failure rate. The RETeval ERG was noted to have an optimal DR cut-off score at 22. Multivariate logistic regression identified an eGFR of ≤29 mL/min/1.73 m2, HbA1c of ≥7.0%, pupil size of <4 mm diameter, diabetes duration of 5-24 years and RETeval score of ≥22 as strong predictors of DR. CONCLUSION: There is a high prevalence of vision-threatening and undiagnosed DR among patients attending high-risk tertiary clinics in Western Sydney. Point-of-care DR screening using portable, mydriatic photography demonstrates potential as a model of care which is easily accessible, targeted for high-risk populations and substantially enhances DR detection.

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

Development of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples.

The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are promising drug candidates for the treatment of neuropsychiatric disorders. Hitherto, the vast majority of selective drug leads that have been developed for KOR are small molecules. In this study, novel peptide probes were designed by using an endogenous dynorphin A1-13 sequence as a template for peptide stapling via late-stage cysteine functionalization. Leveraging this strategy, we developed a stable and potent KOR antagonist, CSD-CH2(1,8)-NH2, with approximately 1000-fold improved selectivity for KOR over µ- and δ-opioid receptors. Its potent competitive KOR antagonism was verified in KOR-expressing cells, peripheral dorsal root ganglion neurons, and using the tail-flick and rotarod tests in mice. This work highlights the value of cysteine stapling to develop selective peptide probes to modulate central KOR function, as innovative peptide drug candidates for the treatment of KOR-related illnesses.