Pharmacokinetics/pharmacodynamics of benralizumab in chronic rhinosinusitis with nasal polyps: Phase III, randomized, placebo-controlled OSTRO trial.

AIMS: Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS: Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS: Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION: Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.

The Role of Inhalant Allergens on the Clinical Manifestations of Atopic Dermatitis.

BACKGROUND: Inhalant allergens provide a source of environmental factors that contribute to the development of clinical symptoms in patients with atopic dermatitis (AD). OBJECTIVE: To review the relationship between inhalant allergens and AD. METHODS: A literature review was conducted using three databases: PubMed/MEDLINE, ClinicalKey, and Web of Science. Search terms, including "atopic dermatitis," "atopic eczema," and "eczema," were used in combination with "inhalant allergen," "inhaled allergen," and "aeroallergen" to identify relevant published manuscripts that highlight the relationship between AD and exposures to inhalant allergens. RESULTS: Fifteen articles were suitable for review. The studies included in the review investigated the effect of inhalant allergens on the clinical manifestations of AD through bronchial provocation, direct skin contact, and allergen sensitization. CONCLUSION: There is a significant relationship between exposures to inhalant allergens and AD. Inhalant allergens may aggravate AD symptoms by either bronchial provocation or direct skin contact. Sensitization of inhalant allergens, mainly house dust mites, follows a specific age-related pattern.

Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs and enhances object location memory.

A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozyme's self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the Cpeb3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.

Stored within DNA are the instructions cells need to make proteins. In order for proteins to get made, the region of DNA that codes for the desired protein (known as the gene) must first be copied into a molecule called messenger RNA (or mRNA for short). Once transcribed, the mRNA undergoes further modifications, including removing redundant segments known as introns. It then travels to molecular machines that translate its genetic sequence into the building blocks of the protein. Following transcription, some RNAs can fold into catalytic segments known as self-cleaving ribozymes which promote the scission of their own genetic sequence. One such ribozyme resides in the intron of a gene for CPEB3, a protein which adds a poly(A) tail to various mRNAs, including some involved in learning and memory. Although this ribozyme is found in most mammals, its biological role is poorly understood. Previous studies suggested that the ribozyme cleaves itself at the same time as the mRNA for CPEB3 is transcribed. This led Chen et al. to hypothesize that the rate at which these two events occur impacts the amount of CPEB3 produced, resulting in changes in memory and learning. If the ribozyme cleaves quickly, the intron is disrupted and may not be properly removed, leading to less CPEB3 being made. However, if the ribozyme is inhibited, the intron remains intact and is efficiently excised, resulting in higher levels of CPEB3 protein. To test how the ribozyme impacts CPEB3 production, Chen et al. inhibited the enzyme from cutting itself with antisense oligonucleotides (ASOs). The ASOs were applied to in vitro transcription systems, neurons cultured in the laboratory and the brains of living mice in an area called the hippocampus. The in vitro and cell culture experiments led to higher levels of CPEB3 protein and the addition of more poly(A) tails to mRNAs involved in neuron communication. Injection of the ASOs into the brains of mice had the same effect, and also improved their memory and learning. The findings of Chen et al. show a new mechanism for controlling protein production, and suggest that ASOs could be used to increase the levels of CPEB3 and modulate neuronal activity. This is the first time a biological role for a self-cleaving ribozyme in mammals has been identified, and the approach used could be applied to investigate the function of two other self-cleaving ribozymes located in introns in humans.

Effects of past mating behavior versus past ejaculation on male mate choice and male attractiveness.

Past reproductive effort allows males to assess their ability to acquire mates, but it also consumes resources that can reduce their future competitive ability. Few studies have examined how a male's reproductive history affects his subsequent mate choice, and, to date, no study has determined the relative contribution of past mating behavior and past ejaculate production because these two forms of investment are naturally highly correlated. Here, we disentangled the relative effects of past mating behavior and past ejaculate production in mosquitofish (Gambusia holbrooki) by experimentally preventing some males from ejaculating when trying to mate. We assessed the effect of mating behavior on mate choice by comparing males that had previously been with or without access to females and male rivals for 8 and 16 weeks and assessed the effect of ejaculation on mate choice by comparing males that either could or could not ejaculate when they had access to females for 16 weeks. Reproductive treatment did not affect male attractiveness, but it did affect male mate choice. Somewhat surprisingly, in five of the six treatment-by-age at testing combinations, males preferred a female in the vicinity of a male rival over a solitary female. This preference was marginally stronger for males that had previously engaged in mating behavior but were unaffected by past ejaculate production. We discuss the potential benefits to males of associating with another male when seeking mates. This is the first study to quantify the relative influence of pre- and post-copulatory reproductive investment on male mate choice.

Risk for second primary cancers among pediatric and young adult melanoma survivors.

BACKGROUND/OBJECTIVES: Second primary cancers (SPCs) are a leading cause of morbidity and mortality among cancer survivors. In this study, we aimed to characterize the incidence of SPCs among pediatric and young adult survivors of CM. METHODS: Using the Surveillance, Epidemiology, and End Results Program data spanning 2000-2018, we calculated standardized incidence ratios (SIR) to assess SPC risk in all pediatric (0-18 years) and young adult (19-29 years) patients with a first primary cancer diagnosis of CM. RESULTS: Of 7,169 total CM survivors, 632 (8.82%) developed a SPC, corresponding to a 5-fold increased risk (standardized incidence ratio [SIR] 4.98; 95% confidence interval [CI] 4.60-5.38) compared to the general population. There was a highly elevated risk for second primary melanoma across all age groups (SIR 32.5; 95% CI 29.7-35.6), constituting the majority of SPC diagnoses (N = 485). Infants diagnosed with CM before 1 year of age had the highest risk for any SPC (SIR 164; 95% CI 19.8-592) and young adults diagnosed at 25-29 years had the lowest risk (SIR 4.64; 95% CI 4.19-5.13). SPC incidence was highest within the first year of CM diagnosis (SIR 27.5; 95% CI 23.7-31.6) and progressively decreased with time. CONCLUSIONS: Variation exists in the incidence and type of SPC according to age among pediatric and young adult survivors of CM.

Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up.

BACKGROUND: In the 52-week Phase III SYNAPSE study, mepolizumab given every 4 weeks (100 mg subcutaneously) reduced nasal polyp (NP) size, improved symptoms and quality of life (QoL), and reduced corticosteroid use and number of sinus surgeries in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), versus placebo. Because the durability of mepolizumab's efficacy after discontinuation is poorly understood in CRSwNP, the efficacy of mepolizumab after discontinuation was analyzed in severe CRSwNP, over a 24-week follow-up. METHODS: Changes from SYNAPSE baseline to end of treatment (week 52) and end of follow-up (week 76) were assessed for total endoscopic NP score, nasal obstruction and overall symptoms visual analog scale scores, and 22-item Sino-Nasal Outcome Test score. Time to first sinus surgery, time to first corticosteroid use, and geometric mean blood eosinophil counts (BECs) were also assessed. RESULTS: Among 134 follow-up patients, clinical improvements observed with mepolizumab versus placebo were partially evident 24 weeks after discontinuation despite BEC returning to baseline. The mean (95% confidence interval [CI]) change from baseline in NP score (week 52: -1.3 [1.8 to -0.9] vs. -0.3 [-0.6 to 0.1]; week 76: -1.2 [-1.6 to -0.7] vs. -0.1 [-0.5 to 0.3]) and the proportion of patients having sinus surgery (week 52: 4% vs. 25%; week 76: 9% vs. 31%) remained substantially improved with mepolizumab versus placebo. Mepolizumab-associated improvements in overall symptoms, quality of life, and corticosteroid use versus placebo were partially sustained at week 76. CONCLUSION: Fifty-two weeks of mepolizumab treatment is associated with sustained clinical benefits up to 24 weeks after discontinuation in patients with severe CRSwNP, which should be considered by physicians when making treatment decisions.

EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Purpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.

A worthwhile tool in evaluating worrisome lesions.

This study demonstrated the value of using electrical impedance spectroscopy in primary care to manage and diagnose pigmented skin lesions.

Remission: does it already exist in chronic rhinosinusitis with nasal polyposis?

BACKGROUND: Remission, defined as absence of symptoms and objective markers of disease, is emerging as the penultimate goal in the management of several chronic diseases. The concept of remission, well-established in Rheumatology as well as Gastroenterology, is currently emerging in Respiratory Medicine for asthma. It is interesting to consider whether the disease remission concept might successfully be applied to Otolaryngology-Head and Neck Surgery in the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). OBJECTIVE: The purpose of this letter is to explore the evidence supporting the concept of remission under continued medical therapy in chronic rhinosinusitis with nasal polyposis. METHODS: The authors reviewed the literature and summarized studies in chronic rhinosinusitis with nasal polyposis evaluating for evidence of clinical, biochemical, and endoscopic remission. RESULTS: Findings of the studies revealed that endoscopic sinus surgery with continued medical therapy achieved remission in approximately 50% of all patients. CRSwNP patients after primary endoscopic sinus surgery were able to achieve remission in 72% of instances, however this drops to 42% for patients having revision sinus surgery. For CRSwNP patients with co-morbidities such as asthma and aspirin exacerbated respiratory disease, remission rate drops to 23% and 23.5%, respectively compared to non-asthmatic CRSwNP patients who present a remission rate under continued medical therapy of 60%. CONCLUSION: Remission of symptoms and evidence of disease under medical therapy is indeed a concept achievable in patients with CRSwNP, as demonstrated by studies in the literature. Various co-morbidities, notably asthma, apparently influence rate of remission. Better defining this outcome through consensus-based definitions will allow for the development of strategies in CRSwNP care that can help affected patients attain complete relief from clinical, biochemical, and endoscopic markers of CRS with judicious use of medication and surgery. Future efforts will attempt to improve on these outcomes by achieving symptomatic and endoscopic control of disease following cessation of therapy, potentially paving the way towards clinical remission or a 'cure' in CRS.

Bortezomib-Induced Reticular Eruption in Patient with Multiple Myeloma.

Bortezomib is the first proteasome inhibitor to treat a variety of malignancies and is currently part of the standard of care regimen for the initial treatment of patients with newly diagnosed multiple myeloma. While bortezomib is generally well tolerated, it has been associated with various side effects, which have limited its use in some patients. Here, we describe a unique case with histological confirmation of a reticular eruption that appeared at the site of a subcutaneous administration of bortezomib in a 62-year-old male who was newly diagnosed with IgG kappa multiple myeloma. A skin biopsy was performed, which revealed superficial perivascular dermatitis predominantly composed of lymphocytes with rare eosinophils. The patient was successfully treated with betamethasone dipropionate 0.05% cream. When consulted, dermatologists should advise the oncology team of multiple myeloma patients treated with bortezomib to maintain a high threshold before discontinuing the drug when a patient experiences an atypical, reticular rash following subcutaneous administration. Additionally, potent topical corticosteroids, such as betamethasone dipropionate 0.05% cream, should be considered in managing the cutaneous reticular eruptions related to bortezomib administration, in order to maintain an optimal treatment regimen for patients with multiple myeloma.

Long-term environmental stability does not erode plasticity in nest building responses to changing ambient conditions.

The primary function of animal nests is to protect developing offspring from hostile and fluctuating environments. Animal builders have been shown to adjust nest construction in response to changes in their environment. However, the extent of this plasticity, and its dependence on an evolutionary history of environmental variability, is not well understood. To test whether an evolutionary history with flowing water impacts male ability to adjust nests in response to flow regime, we collected three-spined sticklebacks (Gasterosteus aculeatus) from three lakes and three rivers, and brought them into reproductive condition in controlled laboratory aquaria. Males were then allowed to nest under both flowing and static conditions. Nest building behaviour, nest structure and nest composition were all recorded. In comparison to males building nests under static conditions, males building in flowing water took longer to construct their nests and invested more in nesting behaviour. Moreover, nests built in flowing water contained less material, were smaller, more compact, neater and more elongated than nests built under static conditions. Whether males came from rivers or lakes had little impact on nesting activities, or male capacity to adjust behaviours in response to flow treatment. Our findings suggest that aquatic animals which have experienced a stable environment over a long period of time retain plasticity in nest-building behaviours that allow them to adjust nests to ambient flow conditions. This ability may prove crucial in coping with the increasingly unpredictable flow regimes found in anthropogenically altered waterways and those resulting from global climate change. This article is part of the theme issue 'The evolutionary ecology of nests: a cross-taxon approach'.

Inhibition of CPEB3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory.

A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element binding protein 3 (CPEB3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozyme's self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the CPEB3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.

Effects of Mesoporosity and Conductivity of Hierarchically Porous Carbon Supports on the Deposition of Pt Nanoparticles and Their Performance as Electrocatalysts for Oxygen Reduction Reaction in Alkaline Media.

The structural characteristics of supports, such as surface area and type of porosity, affect the deposition of electrocatalysts and greatly influence their electrochemical performance in fuel cells. In this work, we use a series of high surface area hierarchical porous carbons (HPCs) with defined mesoporosity as model supports to study the deposition mechanism of Pt nanoparticles. The resulting electrocatalysts are characterized by several analytical techniques, and their electrochemical performance is compared to a state-of-the-art, commercial Pt/C system. Despite the similar chemical composition and surface area of the supports, as well as similar amounts of Pt precursor used, the size of the deposited Pt nanoparticles varies, and it is inversely proportional to the mesopore size of the system. In addition, we show that an increase in the size of the catalyst particles can increase the specific activity of the oxygen reduction reaction. We also report on our efforts to improve the overall performance of the above electrocatalyst systems and show that increasing the electronic conductivity of the carbon support by the addition of highly conductive graphene sheets improves the overall performance of an alkaline fuel cell.

Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy.

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

Image guided dilation of sinus ostium in revision sinus surgery.

PURPOSE: Assess if a rigid, image-guided balloon could be used effectively and safely in revision sinus surgery. MATERIALS AND METHODS: A prospective, non-randomized, single-arm, multicenter study to assess the safety and device performance of the NuVent™ EM Balloon Sinus Dilation System. Adults with CRS in need of revision sinus surgery were enrolled for balloon sinus dilation of a frontal, sphenoid, or maxillary sinus. The primary device performance endpoint was the ability of the device to (1) navigate to; and (2) dilate tissue in subjects with scarred, granulated, or previously surgically-altered tissue (revision). Safety outcomes included the assessment of any operative adverse events (AEs) directly attributable to the device or for which direct cause could not be determined. A follow-up endoscopy was conducted at 14 days post-treatment for assessment of any AEs. Performance outcomes included the surgeon's ability to reach the target sinus (es) and dilate the ostia. Endoscopic photos were captured for each treated sinus pre- and post-dilation. RESULTS: At 6 US clinical sites, 51 subjects were enrolled; 1 subject withdrew before treatment due to a cardiac complication from anesthesia. 121 sinuses were treated in 50 subjects. The device performed as expected in 100 % of the 121 treated sinuses, with investigators able to navigate to the treatment area and dilate the sinus ostium without difficulty. Ten AEs were seen in 9 subjects, with 0 related to the device. CONCLUSION: The targeted frontal, maxillary or sphenoid sinus ostium were safely dilated in every revision subject treated, with no AEs directly attributed to the device.

Effective Use of Medical Chaperones: Practical Strategies and Perspectives.

This Viewpoint examines the use of medical chaperones in the context of sensitive dermatologic examinations and provides recommendations on improving safety and satisfaction for patients and medicolegal protection and cost-saving strategies for clinicians.