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Background: Dupilumab, a human monoclonal anti-interleukin (IL)-4Ra antibody blocks the shared receptor component of IL-4 and IL-13, drivers of type 2 inflammation. Dupilumab is approved for severe/refractory asthma inadequately controlled by existing therapies, but knowledge of its effect on real-world disease burden is lacking. This study investigates real-world effects of dupilumab on asthma exacerbation risk and oral corticosteroid (OCS) use in Japanese individuals with asthma. Methods: This retrospective, cohort study used a Japanese insurance claims database to identify patients who started dupilumab between 26 March 2019–31 May 2020. Patients were followed for ±365 days from dupilumab initiation. The study primarily assessed the annual incidence rate of severe asthma exacerbations occurring simultaneously with hospitalizations or OCS bursts. Secondary and exploratory endpoints assessed OCS dosage and duration, and healthcare resource utilization (HRU), respectively. Results: At dupilumab initiation (N = 215), mean age was 57.2 years, 41.9% of patients were aged ≥65 years, and 59.5% were female. Dupilumab significantly reduced the annual incidence of severe asthma exacerbations from 1.29 to 0.74 (95% confidence interval, 0.44–0.76) per patient per year. Mean OCS dosage decreased from 10.4 to 7.2 mg/day in chronic OCS users; median frequency of OCS bursts decreased from 3 to 0. Both unscheduled outpatient visits (35.8% vs 29.8%) and hospitalizations (21.9% vs 12.1%) decreased. Mean (standard deviation) duration of hospitalization also decreased from 6.7 (27.6) to 2.2 (8.1) days. Conclusions: Japanese patients with asthma who received dupilumab had reduced incidence rates of severe asthma exacerbations, OCS use, and HRU over 12 months.

Among the numerous long COVID symptoms, olfactory dysfunction persists in ∼10 % of patients suffering from SARS-CoV-2 induced anosmia. Among the few potential therapies, corticoid treatment has been used for its anti-inflammatory effect with mixed success in patients. In this study, we explored its impact using hamster as an animal model. SARS-CoV-2 infected hamsters lose their smell abilities and this loss is correlated with damage of the olfactory epithelium and persistent presence of innate immunity cells. We started a dexamethasone treatment 2 days post infection, when olfaction was already impacted, until 11 days post infection when it started to recover. We observed an improvement of olfactory capacities in the animals treated with corticoid compared to those treated with vehicle. This recovery was not related to differences in the remaining damage to the olfactory epithelium, which was similar in both groups. This improvement was however correlated with a reduced inflammation in the olfactory epithelium with a local increase of the mature olfactory neuron population. Surprisingly, at 11 days post infection, we observed an increased and disorganized presence of immature olfactory neurons, especially in persistent inflammatory zones of the epithelium. This unusual population of immature olfactory neurons coincided with a strong increase of olfactory epithelium proliferation in both groups. Our results indicate that persistent inflammation of the olfactory epithelium following SARS-CoV-2 infection may alter the extent and speed of regeneration of the olfactory neuron population, and that corticoid treatment is effective to limit inflammation and improve olfaction recovery following SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Biologics are clinically available for patients with severe asthma, but changes in asthma control over time are unknown. We examined changes in disease burden and treatment in severe asthma patients., Methods: This retrospective study used a Japanese health insurance database (Cross Fact) and included patients aged ≥16 years treated continuously with an inhaled corticosteroid (ICS) for a diagnosis of asthma in each calendar year from 2015 to 2019. Severe asthma was defined as annual use of high-dose ICS plus one or more asthma controller medications four or more times, oral corticosteroids for ≥183 days, or biologics for ≥16 weeks. Changes in asthma exacerbations, prescriptions, and laboratory testing were examined., Results: Demographic characteristics were similar throughout the study. The number and proportion of patients with severe asthma among those with asthma increased (2724; 15.3% in 2015 vs 4485; 19.0% in 2019). The proportion of severe asthma patients with two or more asthma exacerbations decreased from 24.4% to 21.5%. Odds ratios (95% confidence interval) of ≥2 asthma exacerbations in each year compared with 2015 were 0.96 (0.85-1.08) in 2016 and 0.86 (0.76-0.97) in 2017, with significant reductions observed in subsequent years. Short-acting beta agonists and oral corticosteroid prescriptions for asthma exacerbations decreased and long-acting muscarinic antagonist and biologic prescriptions for maintenance treatment increased., Conclusions: This study showed improvements in disease burden and treatment in severe asthma patients. There remains an unmet medical need for patients with severe asthma, given the proportion who continue to have asthma exacerbations., Competing Interests: Declaration of competing interest HN has received honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kyorin Pharmaceutical, Novartis Pharma, and Sanofi; and research funding from GlaxoSmithKline. KM has received honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kyorin Pharmaceutical, Novartis Pharma, and Sanofi. HO, HU, YA, NM, and NT are employees of AstraZeneca. TH is an employee of AstraZeneca, and holds stock or stock options in Daiichi Sankyo., (Copyright © 2024. Published by Elsevier B.V.)

Background: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC)., Methods: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria., Results: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade., Conclusion: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Snakebite is a significant public health issue in which venom-induced consumption coagulopathy is a common and serious complication that results from the activation of the coagulation pathway by snake toxins. We report a male patient, 56 y old, who was thought to have been bitten by a snake on his left foot. He was transported to a nearby hospital where he received analgesics and 3 snake polyvalent antivenom vials, and then he was transported to our hospital after 12 h. He presented with 2 small puncture wounds, pain, blistering, and edema of the left foot. On the 2nd day, the patient developed gingival bleeding and hematuria. Laboratory investigations upon admission revealed prothrombin time (PT) of more than 3 min, prothrombin concentration (PC) of less than 2.5%, and an international normalized ratio (INR) of 23.43. Further investigation of urine showed more than 100 RBCs. Despite receiving 16 packs of plasma and 40 snake polyvalent antivenom vials manufactured by VACSERA over 3 days, hemoglobin concentration and platelet count decreased with the appearance of jaundice, lactate dehydrogenase was 520, and reticulocytes were 3.5%. PT was more than 300 s, and INR was still over range. Plasmapheresis and corticosteroids were provided, which improved the patient's general condition, PT, PC, and INR, and the patient was discharged after 6 days of hospital stay. This case report indicated that plasmapheresis and corticosteroids were clinically efficient approaches in the management of snake envenomation unresponsive to antivenom.

Background & Aims: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours., Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure., Results: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96)., Conclusions: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes., Impact and Implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Antenatal steroid therapy is increasingly central to the obstetrical management of women at imminent risk of preterm birth. For women likely to deliver between 24 and 34 weeks' gestation, antenatal steroid therapy is the standard of care, conferring sizable benefits and few risks in high-resource environments when appropriately targeted. Recent studies have focused on antenatal steroid use in periviable and late preterm populations, and in term cesarean deliveries. As a result, antenatal steroid therapy has now been applied from 22 to 39 +6 weeks of estimated gestational age. There is also an increased appreciation that the vast majority of randomized control data informing the use of antenatal steroids are derived from predominantly high-resource, White populations. Accordingly, a sizable amount of work has recently been undertaken to test how to safely use antenatal steroids in low- and middle-resource environments, wherein the often high rates of preterm birth make these low-cost, easily administered interventions an attractive proposition. It is likely underappreciated by the obstetrical and neonatal communities that the overall efficacy of antenatal steroid therapy is highly variable (including when preterm risk is accurately assessed), the treatment regimens used are largely arbitrary, dosing is suprapharmacologic for effect, and the benefit-risk balance is significantly and differentially modified by gestation. It is also very likely that the patients consenting to receive these treatments are similarly unaware of the complex balance of potential benefits and harms. Although a small number of follow-up studies present a generally benign picture of long-term antenatal steroid risk, several large, population-based retrospective studies have identified associations between antenatal steroid use, childhood mental disease, and newborn infections that warrant urgent attention. Of particular contemporary importance are emergent efforts to optimize antenatal steroid regimens on the basis of the pharmacokinetics and pharmacodynamics of the agents themselves, the need for better targeting of these potent drugs, and clear articulation of the potential benefits and harms of antenatal steroid use at differing stages of pregnancy and in different delivery contexts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Chronic obstructive pulmonary disease (COPD) is a significant cause of mortality, with its prevalence projected to rise in Asia. The primary objective of this study was to describe clinical characteristics, maintenance treatment, and healthcare resource utilization (HCRU) among patients with COPD in Hong Kong. Secondary objectives were to assess patient demographics and clinical characteristics by eosinophil (EOS) levels, and compare the demographics, clinical characteristics, and treatment patterns of patients on multiple-inhaler triple therapy (MITT)., Methods: This study analyzed a cohort of patients with COPD who had entered a previously initiated prospective cohort study involving patients with COPD and/or asthma at the Prince of Wales Hospital between 2017 and 2019., Results: Patients with COPD were enrolled (N = 220, mean age 74.3 years, 97 % male). Twelve months prior to baseline assessment, 66 % of patients were on MITT, 17 % on long-acting muscarinic antagonists (LAMAs)/long-acting beta-agonists (LABAs), and 7 % on inhaled corticosteroids (ICS)/LABA. Compared with ICS/LABA or LAMA/LABA, more patients on MITT experienced ≥1 exacerbation (26.7 %, 10.5 %, 39.7 %, respectively). Patients on MITT also had a higher mean (SD) COPD Assessment Test score (9.4 [5.9]) and modified Medical Research Council Dyspnea Scale score (1.7 [0.7]) and incurred the most COPD-related and total HCRU costs. Compared with patients with EOS ≤300 cells/μL, those with EOS >300 cells/μL had a higher number of exacerbations., Conclusions: Patients with COPD in Hong Kong treated with MITT presented more severe disease profiles and incurred higher costs. These data can be used for decision making in patients with moderate-to-severe COPD in Hong Kong., Competing Interests: Declaration of competing interest FWSK conducted clinical research on asthma and COPD with funding from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis, with all fees paid direct to her institution. XX is an employee of GSK. CC is an employee of GSK. AN is an employee of GSK and owns shares in GSK. DSCH has no conflicts of interest. DM is an employee of GSK and owns shares in GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Physiotherapists in the United Kingdom (UK), who have received additional training can adopt injection therapy for the treatment of musculoskeletal (MSK) disorders., Objectives: The objective of this practice survey was to explore (i) the frequency of use of injection therapy by UK physiotherapists for MSK disorders; and (ii) the clinical reasoning for selection of injectate, dose and pre/post injection practice., Design: Cross-sectional online survey., Methods: The online survey was disseminated via social media and professional networks over a 3-month period. Responses to closed multiple choice survey questions were analysed with descriptive data, with reporting of confidence intervals at 95%. Open questions were analysed using content analysis., Results: The survey received 320 responses. The majority (86.6%, n = 277) used landmark guided approaches. The highest frequency of injections administered were for trigger digits, sub acromial pain and the knee joint. Corticosteroid drugs were widely used (99.7%, n = 319, CI 95% 98 to 100) with Triamcinolone (Kenalog) being the most frequently utilised for both joints (58.8%, n = 160, 53 to 65) and soft tissues (46.3%, n = 126, 40 to 52). Drug choice was largely based on availability in clinic (47.1%, n = 128, 41 to 53). Drug doses for common injection sites varied among the respondents with variation also evident in pre and post-injection practice., Conclusion: Marked variation across some elements of injection therapy practice was evident. Notable differences in corticosteroid preparation used, the doses of drug injected, and the use of local anaesthetic were reported by respondents. Injecting physiotherapists should endeavour to ensure practice is aligned to best available evidence., Competing Interests: Declaration of competing interest Nick Livadas is a tutor on a masters accredited injection therapy course at Teesside University and offers an online MSK Injection Therapy Update course. No other authors have competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: This study aimed to determine whether an increasing number of preoperative corticosteroid injections is associated with greater radiographic subsidence of the thumb metacarpal at long-term follow-up after abductor pollicis longus suspensionplasty, secondary to steroid-induced pathologic weakening of capsuloligamentous restraints surrounding the thumb carpometacarpophalangeal joint and greater extension of the lunate, but neither affect patient-reported outcomes nor revision rates., Methods: A retrospective chart review was performed of patients who underwent primary trapeziectomy and abductor pollicis longus suspensionplasty by a single surgeon over a 10-year period. The number of preoperative corticosteroid injections in the trapeziometacarpal joint was documented, and patients were separated into 4 subgroups: 0, 1, 2, or 3 or more injections. Preoperative and final radiographs were evaluated for a change in the distance between the base of the thumb metacarpal and the distal pole of the scaphoid as a measure of thumb metacarpal subsidence and radiolunate angle as a measure of nondissociative carpal instability, which has been reported as a complication after basal joint arthroplasty. Additionally, the final patient-reported outcomes (Quick Disabilities of the Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation) and revision rates were also assessed., Results: Of a total of 60 patients with an average age of 64 years that were included in the study, 16 (26.7%) received 0, 19 (31.7%) received 1, 12 (20%) received 2, and 13 (21.7%) received 3+ preoperative injections. The median postoperative follow-up was 92 months. The mean distance between the base of the thumb metacarpal and the distal pole of the scaphoid decreased by 2 mm, and the mean radiolunate angle increased by 4° across the entire cohort. When comparing subgroups, no differences were observed in either parameter or the final Patient-Rated Wrist Evaluation and Quick Disabilities of the Arm, Shoulder, and Hand scores., Conclusions: This study demonstrates no apparent detrimental effect of an increased number of preoperative corticosteroid injections on radiographic thumb metacarpal subsidence, increase in extension of radiolunate angle (nondissociative carpal instability), patient-reported outcomes, or revision rates at an average of almost 8 years after trapeziectomy and abductor pollicis longus suspensionplasty., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Inflammatory pseudo tumor (IP) is an infrequent process with benign evolution in most cases whose etiology and pathogenesis are unknown. It usually affects young men and children, in whom the macroscopic lesion can mimic a malignant process, which is ruled out after biopsy. Therefore, the diagnosis of certainty is histological and treatment consists of corticosteroids, leaving resection for cases in which biopsy is not possible or in which it produces local complications. We present a case of an inflammatory pseudo tumor with special corticodependence that began as a long-term periodic fever and splenic focal lesion that required splenectomy for its diagnosis and that, after decreasing the corticosteroid regimen, presented recurrences at the cerebellar and systemic level requiring the association of various immunosuppressants and rituximab to achieve remission. As a result of this case, we have performed an analysis of all the pseudo tumors diagnosed in adults in the hospitals of the province of Malaga, and it has been compared with that described in the bibliography., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest. Regarding to this manuscript, the patient provided written and fully informed consent to publicatio, (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal., Research Question: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment?, Study Design and Methods: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV 1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment., Results: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy., Interpretation: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. H. reports speaker fees from AstraZeneca; M. B. S. reports speaker fees from GSK; A. v. B. reports consulting fees from Novartis, speaker fees from Novartis, GSK, and AstraZeneca, travel grants from AstraZeneca, and participation in advisory boards with AstraZeneca and Novartis; A.-S. B. reports lecture fees from AstraZeneca and GSK; L. M. R. has received lecture fees from AstraZeneca, GSK, and Teva, support for attending meetings and/or travel received from AstraZeneca and Chiesi, and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, GSK, and Teva; K. E. J. H. reports grants from SanofiGenzyme and AstraZeneca, lecture fees from AstraZeneca, GSK, Chiesi, TEVA, and SanofiGenzyme; O. H. reports support attending meetings from Sanofi, and participation in advisory boards with GSK, MSD, Sanofi, AstraZeneca, TEVA, and ALK; C. U. reports grants from Sanofi, Boehringer Ingelheim, AstraZeneca, and Novartis, consulting fees from Chiesi, Orion Pharma, AstraZeneca, GSK, Teva, Menarini, and Takeda, lecture fees from Orion Pharma, AstraZeneca, and TEVA, and participation in advisory boards with Novartis, GSK, AstraZeneca, Pfizer, Sanofi, Chiesi, and Boehringer Ingelheim; C. P. reports grants from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi, and ALK, consulting fees from AstraZeneca, GSK, Novartis, TEVA, Sanofi, Chiesi, and ALK, lecture fees from AstraZeneca, GSK, Novartis, TEVA, Sanofi, Chiesi, and ALK, participation in advisory boards with AstraZeneca, Novartis, TEVA, Sanofi, and ALK. None declared (J. S., C. R. J., T. I., S. L. J., M. B., K. D. A.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Status migrainosus is one of the recognized complications of migraine with or without aura, defined as a persistent debilitating migraine attack lasting for more than 72h with little reprieve, leading to functional disability. The individual impact of status migrainosus and the substantial healthcare burden are highlighted. Current case series which inform our understanding of this condition are examined with two groups emergent, those with classic status migrainosus and those with episodic status migrainosus. The question as to whether status migrainosus is a distinct biological state beyond the established migraine pathophysiology is examined. With the underlying pathophysiology not fully understood, attention is turned to therapeutic considerations and the available evidence informing practice. A practical approach to treatment of status migrainosus is presented. Given the severity and need for emergency care, options detailed are in line with recommendations for acute migraine care: with a staged approach initially combining subcutaneous sumatriptan with parenteral options including dopamine receptor antagonists, nonsteroidal anti-inflammatories and acetaminophen. The place of combination treatment with parenteral magnesium sulfate, dihydroergotamine, antiepileptics, corticosteroids, and anesthetic agents is outlined. With a paucity of high-quality evidence to consolidate current clinical approaches, consideration of future therapies and research questions is raised., (Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation., Methods: ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05-0·1 mg/kg before transplantation and 0·1-0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27)., Findings: Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15-0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 0·72 [95% CI 0·41-1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event., Interpretation: Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation., Funding: Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark., Competing Interests: Declaration of interests GD (sponsor of the study) reports receipt of a research grant from Astellas for the ScanCLAD study (partially but not fully funded by the company); a research grant from Abbott regarding an investigator-initiated destination therapy study on left-ventricular assist devices (the SweVAD study); and being a board member of XVIVO. Unrelated to the current study, JM discloses an unrestricted research grant from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Takeda Pharma, Vicore Pharma, and Mallinckrodt. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Asthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting β 2 -agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted., Methods: Searches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998-2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis., Results: The SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV 1 , smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs., Conclusion: A systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicolas Roche has received grants and personal fees from Boehringer Ingelheim, Novartis, Pfizer, GSK and personal fees from Austral, Biosency, MSD, AstraZeneca, Chiesi, Sanofi, Zambon. Arzu Yorgancıoğlu has received research grants from Novartis, MSD, AstraZeneca, and Sanofi, and has acted as a speaker/consultant for AstraZeneca, Abdi İbrahim, GSK, Novartis, Chiesi and Bilim. Alvaro Cruz has received personal fees from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Crossjet, Eurofarma, Abdi Ibrahim and Glennmark. Gabriel Garcia has received research grants from Novartis, GSK, Boehringer Ingelheim, AstraZeneca, and Sanofi, and for acting as a consultant/advisor/speaker for GSK, AstraZeneca, Novartis, and Sanofi. Kim L. Lavoie has received consulting fees/speaker fees from GSK, AbbVie, Boehringer Ingelheim, Janssen, Bausch, Astellas, Novartis, AstraZeneca, X-Facto, and Sojecci Inc. Abhijith PG was employed by GSK at the time of the study. Manish Verma, Anurita Majumdar and Swarnendu Chatterjee are full time employees of GSK and hold stocks/shares in GSK., (Copyright © 2023 GSK. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have improved the outcomes of cancer patients. However, ICIs often lead to colitis/diarrhea. This study aimed to assess the treatment of ICIs-associated colitis/diarrhea and outcomes., Methods: PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies which investigated the treatment and outcomes of colitis/diarrhea developing in patients who received ICIs. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea as well as the pooled rates of response to treatment, mortality, and ICIs permanent discontinuation and restarts in patients with ICIs-associated colitis/diarrhea were estimated using a random-effects model., Results: Among the 11,492 papers initially identified, 27 studies were included. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea were 17%, 3%, 17%, 13%, and 15%, respectively. The pooled rates of overall response, response to corticosteroid therapy, and response to biological agents were 88%, 50%, and 96%, respectively. The pooled short-term mortality in patients with ICIs-associated colitis/diarrhea was 2%. The pooled incidences of ICIs permanent discontinuation and restarts were 43% and 33%, respectively., Conclusion: ICIs-associated colitis/diarrhea is common, but rarely lethal. Half of them are responsive to corticosteroid therapy. There is a fairly high rate of response to biological agents in steroid-refractory colitis/diarrhea patients., Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Consequences of COVID-19 on olfactory functions remained unclear during the pandemic. We assessed the efficacy of local budesonide in addition to olfactory rehabilitation when managing non-severe COVID-19 patients with persistent hyposmia., Methods: A multicentric, randomized, superiority trial was conducted (ClinicalTrials.gov NCT04361474). The experimental group (EG) received budesonide and physiological saline nasal irrigations administered via three syringes of 20 ml in each nasal cavity in the morning and evening for 30 days. The control group (CG) received a similar protocol without budesonide. Patients were included if they were >18 years old, with a SARS-CoV-2 infection and presenting an isolated hyposmia persisting 30 days after symptom onset. The primary endpoint was the percentage of patients with improvement of more than two points on the ODORATEST score after 30 days of treatment., Results: In total, 123 patients were included and randomized (EG: 62 vs CG: 61). Two patients from the EG met the primary endpoint with no statistical difference between the two groups (P = 0.5)., Conclusion: To our knowledge, this is the first study evaluating local budesonide for COVID-19 related hyposmia treatment even though previous trials were performed with other local corticosteroids. Local budesonide efficacy was not demonstrated for persistent hyposmia related to COVID-19., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the cost-effectiveness of pharmacological treatment in maintenance therapy for adult heart transplant recipients from the Colombian health system perspective., Methods: We constructed a decision tree model with a 1-year time horizon. A review of the clinical literature was performed to extract probabilities of health events and acute rejections avoided were used as the health outcome. Costs were calculated from the base-case approximation and were obtained from administrative databases in Colombia (Sistema de Información de Precios de Medicamentos 2020 and Suficiencia 2012-2019), and the prices were adjusted to US dollar 2021., Results: Two evaluation results were presented. The first evaluates the tacrolimus + azathioprine + corticosteroid (TAC) scheme compared with cyclosporine + azathioprine + corticosteroid (CAC), in which the incremental cost-effectiveness ratio indicates that 1 additional rejection avoided has a cost of US dollar $5461.09 which, compared with the cost-effectiveness threshold in the base case, indicates that the TAC scheme is not a cost-effective (CE) strategy with respect to the CAC scheme. The second result shows the comparison of tacrolimus + mycophenolate mofetil + corticosteroid (TMC) with cyclosporine + mycophenolate mofetil + corticosteroid (CMC) in which TMC was found to be a dominant alternative to CMC., Conclusions: The tacrolimus-based immunosuppression scheme is not CE in its TAC scheme, versus CAC, and is dominant in its TMC scheme, versus CMC, sensitivity analyses show that tacrolimus could become a CE alternative in any scheme used against higher cost-effectiveness threshold., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Current treatment for moderate-severe asthma with inhaled corticosteroid (ICS)-based therapy can follow two strategies: a single inhaler maintenance and reliever therapy (MART) regimen, or regular dosing with ICS/long-acting β 2 -agonist used as maintenance therapy plus a separate short acting β 2 -agonist reliever inhaler. It would be clinically useful to understand the potential of patient traits to influence regular dosing or MART treatment outcomes., Objectives: A systematic literature review (SLR) and meta-analysis was conducted to identify specific patient traits that may predict improved clinical outcomes with regular dosing or MART., Results: The SLR identified 28 studies in patients with moderate-severe asthma assessing regular dosing or MART treatments and reporting the traits and outcomes of interest. Network meta-regressions found no significant difference in the relative efficacy of regular dosing as compared with MART on any of the clinical outcomes (exacerbation rate, time to first exacerbation, FEV 1 , reliever use and adherence) for any of the patient traits (baseline lung function, baseline ACQ, age, BMI, and smoking history) evaluated. However, some trends towards traits influencing treatment efficacy were identified. Inconsistent reporting of traits and outcomes was observed between trials., Conclusions: The analysed patient traits evaluated in this study were associated with similar efficacy for the analysed outcomes to either regular dosing or MART; however, trends from the data observed encourage future analyses for possible identification of additional traits, or a combination of traits, that may be of interest. More comparable reporting of clinically important traits and outcomes would improve future analyses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Arzu Yorgancıoğlu has received research grants from Novartis, MSD, AstraZeneca, and Sanofi, and has acted as a speaker/consultant for AstraZeneca, Abdi İbrahim, GSK, Novartis, Chiesi and Bilim. Alvaro Cruz has received personal fees from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Crossjet, Eurofarma, Abdi Ibrahim and Glennmark. Gabriel Garcia has received research grants from Novartis, GSK, Boehringer Ingelheim, AstraZeneca, and Sanofi, and for acting as a consultant/advisor/speaker for GSK, AstraZeneca, Novartis, and Sanofi. Kim L. Lavoie has received consulting fees/speaker fees from GSK, Abbvie, Boehringer Ingelheim, Janssen, Bausch, Astellas, Novartis, AstraZeneca, X-Facto and Sojecci Inc. Nicolas Roche has received grants and personal fees from Boehringer Ingelheim, Novartis, Pfizer, GSK and personal fees from Austral, Biosency, MSD, AstraZeneca, Chiesi, Sanofi, Zambon. Abhijith PG was employed by GSK at the time of the study. Manish Verma, Anurita Majumdar and Swarnendu Chatterjee are full time employees of GSK and hold stocks/shares in GSK., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Its symptoms range from mild to severe, with the latter often being life-threatening. This study aims to assess the effects of low-dose dexamethasone (DEX) in mild-to-severe COVID-19 pneumonia and examine the final clinical outcomes to identify the optimal therapeutic dose., Methods: Clinical data from 132 patients hospitalized for COVID-19 pneumonia between January and October 2021 at Yamato Municipal Hospital were retrospectively analyzed. Based on the ratio of peripheral arterial oxygen saturation (SpO 2 ) to inspired fraction of oxygen (FiO 2 ), patients were categorized into the mild (>450, n = 65), moderate (315-450, n = 55), and severe (<315, n = 12) pneumonia groups. The event of interest was defined as the worsening of the patient's condition during treatment (need to increase FiO 2  > 0.1). Patients were treated with low-dose DEX (6.6 mg/day) for 10 days., Results: The event-free survival rate decreased significantly in patients with severe pneumonia compared with in those with mild and moderate pneumonia (Bonferroni-adjusted p < 0.02). A total of 16 patients were treated with high-dose corticosteroids because of severe hypoxia. Recovery was observed in all discharged patients with respiratory condition improvement. Low SpO 2 /FiO 2 at admission was significantly associated with serum C-reactive protein levels., Conclusions: For Japanese patients with COVID-19, severe pneumonia, and SpO 2 /FiO 2 of <315, it may be necessary to administer a dose of corticosteroids of >6.6 mg DEX., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Dupilumab, a human monoclonal anti-interleukin (IL)-4Ra antibody blocks the shared receptor component of IL-4 and IL-13, drivers of type 2 inflammation. Dupilumab is approved for severe/refractory asthma inadequately controlled by existing therapies, but knowledge of its effect on real-world disease burden is lacking. This study investigates real-world effects of dupilumab on asthma exacerbation risk and oral corticosteroid (OCS) use in Japanese individuals with asthma., Methods: This retrospective, cohort study used a Japanese insurance claims database to identify patients who started dupilumab between 26 March 2019-31 May 2020. Patients were followed for ±365 days from dupilumab initiation. The study primarily assessed the annual incidence rate of severe asthma exacerbations occurring simultaneously with hospitalizations or OCS bursts. Secondary and exploratory endpoints assessed OCS dosage and duration, and healthcare resource utilization (HRU), respectively., Results: At dupilumab initiation (N = 215), mean age was 57.2 years, 41.9% of patients were aged ≥65 years, and 59.5% were female. Dupilumab significantly reduced the annual incidence of severe asthma exacerbations from 1.29 to 0.74 (95% confidence interval, 0.44-0.76) per patient per year. Mean OCS dosage decreased from 10.4 to 7.2 mg/day in chronic OCS users; median frequency of OCS bursts decreased from 3 to 0. Both unscheduled outpatient visits (35.8% vs 29.8%) and hospitalizations (21.9% vs 12.1%) decreased. Mean (standard deviation) duration of hospitalization also decreased from 6.7 (27.6) to 2.2 (8.1) days., Conclusions: Japanese patients with asthma who received dupilumab had reduced incidence rates of severe asthma exacerbations, OCS use, and HRU over 12 months., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Introduction: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. This study was designed to address this question., Methods: Eight patients with clinical indication for thermoplasty were studied. They were uncontrolled severe asthmatics despite optimal environmental control, treatment of comorbidities, and the use of high-dose inhaled corticosteroids and long-acting β 2 -agonists. Lung function measured by spirometry and respiratory mechanics measured by oscillometry were examined pre- and post-bronchodilator (salbutamol, 400 μg), both before and at least 1 year after thermoplasty., Results: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two asthma questionnaires (ACQ-5 and ACT-5). The response to salbutamol was also not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (X rs5 ) and reactance area (Ax), showing an attenuated response to salbutamol after thermoplasty., Conclusions: Thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle., Competing Interests: Declaration of competing interest YB's laboratory received funds from Boston Scientific Inc (25800$) to conduct this project. AC is funded partially by GlaxoSmithKline, and has received consulting fees and honoraria for lectures from AstraZeneca, Sanofi, GlaxoSmithKline, Regeneron and Valeo pharma. CH, SB, MB, KG, JC and ML declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Suspended particulate matter (SPM) plays an important role in the geochemical behavior and fate of organic micropollutants in aquatic environments. However, the presence of trace emerging endocrine disruptors such as environmental corticosteroids (ECs) in SPM is less well understood. This study focused on the occurrence, distribution, and partitioning of SPM-associated ECs in the Pearl River system, China. Ubiquitous particulate ECs were found in the surface water of the rivers at average concentrations (dry weight) between 0.46 ng/g (flumethasone) and 8.83 ng/g (clobetasone butyrate). The total EC (∑ECs) concentrations of the 24 selected target compounds varied from <1.03 ng/g to 62.3 ng/g, with an average and median of 17.6 ng/g and 13.7 ng/g, respectively. Higher SPM-bound EC levels were commonly observed in winter (dry season), and spatially, their relatively high contamination in urban tributary networks decreased while flowing to mainstreams and then gradually attenuated from upstream to the estuary. Despite the approximately 90 % mass distribution of ∑ECs in the aqueous phase, approximately 50 % of their effect burden was derived from the suspended particulate fractions. For the first time, in situ SPM-water partitioning coefficients (K p ) and their organic carbon-normalized ones (K oc ) of ECs were determined in surface waters, and a field-derived preliminary linear equation was proposed to estimate K oc for ECs using basic physicochemical parameters n-octanol/water partitioning coefficient (K ow ), which is of importance with regard to the assessment of transport, fate, and risk of these emerging hazardous chemicals. Furthermore, the significant logK oc -logK ow relationship for ECs reveals that nonspecific hydrophobic partitioning is a major association mechanism between SPM and ECs. Moreover, hydrogen bonding is suggested to be a prevailing specific binding mechanism and provides more contribution to nonhydrophobic interactions between ECs and particulate organic matter than environmental estrogens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Dysregulation of adrenocortical steroid (corticosteroids) biosynthesis leads to pathological conditions such as Cushing's syndrome. Although several classes of steroid biosynthesis inhibitors have been developed to treat cortisol overproduction, limitations such as insufficient efficacy, adverse effects, and/or tolerability still remain. The present study aimed to develop a new class of small molecules that inhibit cortisol production, and investigated their putative modes of action., Main Methods: We screened an in-house chemical library with drug-like chemical scaffolds using human adrenocortical NCI-H295R cells. We then evaluated and validated the effects of the selected compounds at multiple regulatory steps of the adrenal steroidogenic pathway. Finally, genome-wide RNA expression analysis coupled with gene enrichment analysis was conducted to infer possible action mechanisms., Key Findings: A subset of benzimidazolylurea derivatives, including a representative compound (designated as CJ28), inhibited both basal and stimulated production of cortisol and related intermediate steroids. CJ28 attenuated the mRNA expression of multiple genes involved in steroidogenesis and cholesterol biosynthesis. Furthermore, CJ28 significantly attenuated de novo cholesterol biosynthesis, which contributed to its suppression of cortisol production., Significance: We identified a novel chemical scaffold that exerts inhibitory effects on cortisol and cholesterol biosynthesis via coordinated transcriptional silencing of gene expression networks. Our findings also reveal an additional adrenal-directed pharmacological strategy for hypercortisolism involving a combination of inhibitors targeting steroidogenesis and de novo cholesterol biosynthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Cough is a common and troublesome symptom in people with asthma and is often associated with poorer asthma control and exacerbations. Apart from asthma, other causes or comorbidities might underlie cough in asthma, such as rhinosinusitis and bronchiectasis. Eosinophilic inflammation and bronchoconstriction can lead to an acute episode of cough or worsen chronic cough. Cough hypersensitivity with laryngeal paraesthesia, allotussia, and hypertussia might underlie the cough of asthma through augmented sensory nerve excitability of upper-airway vagal sensory nerves. Cough associated with bronchoconstriction and type 2 inflammation should respond to inhaled corticosteroids and long-acting β-adrenoceptor agonist therapy. For cough hypersensitivity in adults, speech and language therapy and neuromodulators (eg, gabapentin) could be considered. In children, there is no consistent association of asthma with cough sensitivity or between cough and asthma severity. Further research is needed to realise the potential of cough as a measure of asthma control, to understand the mechanisms of cough in asthma, and to develop safe, effective treatments and a precision-medicine approach to the management of cough in asthma in children and adults., Competing Interests: Declaration of interests KL declares honoraria from AstraZeneca, Chiesi, Circassia, Daiichi Sankyo (China), GSK, Merck, Shionogi, and Novartis, and grant and other support from AstraZeneca, Chiesi, Circassia, Daiichi Sankyo (China), GSK, and Merck. IS is currently supported by the EJ Moran Campbell Early Career Award, Department of Medicine at McMaster University (Hamilton, ON, Canada). IS reports grants and personal fees from Merck, GSK, and Bellus; grants from Bayer; and personal fees from Respiplus, Genentech, and AstraZeneca, outside the submitted work. W-JS declares academic grants from MSD; consulting fees from MSD, GSK, AstraZeneca, and Novartis; and honoraria from MSD, GSK, AstraZeneca, and Novartis. AN declares honoraria for lectures and presentations for AstraZeneca, Kyorin, Novartis, GSK, and Sanofi, and for participating on Advisory Boards of AstraZeneca, MSD, Kyorin, and Bayer. ABC declares funds to her institution from the National Health Medical Research Council (Australia) and BMJ Best Practice and personal funds from UpToDate. PGG reports personal fees for lectures from AstraZeneca, GSK, and Novartis, and grants from AstraZeneca and GSK. KFC has received honoraria for participating in advisory board meetings for Roche, Merck, Novartis, GSK, Nocion, Shionogi, and Rickett-Beckinson, and has also been renumerated for speaking engagements for Novartis and AstraZeneca. KFC organised the 12th International Cough Symposium in July, 2022, which received an educational grant from Merck. KFC has received research funding from GSK and Merck. GW and PP declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Glucocorticoids are considered the main treatment option for nasal polyps, but their effect is only recently being understood. AIM: To evaluate whether fluticasone propionate (FP) inhibits the inflammatory process induced by TNF-alpha in vitro, and to assess if NF-kappaB is associated to this inhibition. STUDY DESIGN: Experimental in vitro study. MATERIALS AND METHODS: Nasal polyp fibroblasts were cultured during 24 hours. Three different concentrations of FP (1, 10 and 100 nM, added to TNF-alpha) were compared to negative (without additive) and positive (TNF-alpha) controls. Gene expression (RTQ-PCR) and protein concentration (ELISA) of VCAM-1, ICAM-1, eotaxin and RANTES were measured, as well as the nuclear translocation of NF-kappaB. RESULTS: TNF-alpha significantly increased protein concentration and RNA expression of all the studied molecules, as well as the nuclear translocation of NF-kappaB, when compared to the negative control. FP decreased these parameters in a dose-dependent manner, statistically different from positive control up to 100nM. CONCLUSIONS: FP extensively inhibited inflammatory recruiters, at both protein and RNA levels, confirming the ability of glucocorticoids to modulate the inflammatory process in nasal polyps. This inhibition was associated to decreased NF-kappaB nuclear translocation, demonstrating that this is an important mechanism of glucocorticoids action for nasal polyps.Glicocorticoides são considerados a principal opção terapêutica para polipose nasossinusal, mas seus efeitos estão sendo descobertos apenas recentemente. OBJETIVO: Avaliar se proprionato de fluticasona (FP) inibe in vitro o processo inflamatório induzido por TNF-alfa, e se NF-kappaB está associado a esta inibição. FORMA DE ESTUDO: Experimental in vitro. MATERIAIS E MÉTODOS: Fibroblastos de pólipos nasais foram cultivados por 24 horas. Três concentrações diferentes de FP (1, 10 e 100nM, além do TNF-alfa) foram comparados a controles negativo (sem aditivo) e positivo (TNF-alfa). Expressão gênica (RTQ-PCR) concentração proteica (ELISA) de VCAM-1, ICAM-1, eotaxin e RANTES foram medidos, assim como a translocação nuclear de NF-kappaB. RESULTADOS: TNF-alfa aumentou significativamente a concentração proteica e expressão gênica de todas molé¬culas estudadas, assim como a translocação nuclear de NF-kappaB, quando comparado ao controle negativo. O FP diminuiu estes parâmetros numa forma dose-dependente, diferente estatisticamente do controle positivo até 100nM. CONCLUSÕES: O FP extensivamente inibiu os recrutadores inflamatórios, em níveis proteicos e gênicos, confirmando a habilidade dos glicocorticoides em modular o processo inflamatório na polipose nasossinusal. Esta inibição esteve associada à diminuição da translocação nuclear de NF-kappaB, demonstrando que este é um importante mecanismo de ação dos glicocorticoide na polipose nasossinusal.

The management of asthma has changed fundamentally during the past two decades. Precise assessment and phenotyping are now required to establish individually targeted treatment with disease-modifying anti-asthmatic drugs (DMAADs). Patients with asthma are often managed by primary care doctors or non-respiratory specialists in secondary care. However, the implementation of complex asthma guidelines in non-specialised care remains a challenge. There is a need for easy-to-understand, concise guides for general practice. In this Viewpoint, we propose a one-page practical guide for asthma management, titled A 2 BCD, with four components: dual assessment (A 2 ) of asthma (ie, diagnosis and phenotype, plus asthma control and future risks); basic measures (B; eg, education, self-management skills, regular physical activity, and avoidance of asthma triggers); identification and treatment of comorbidities (C) of asthma (eg, chronic rhinosinusitis, obesity, or sleep apnoea); and phenotype-specific, individually targeted treatment with DMAADs (D), including individual inhalation schemes based on inhaled corticosteroids, leukotriene modifiers, biologics, and allergen immunotherapy., Competing Interests: Declaration of interests ML has received grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft, and GlaxoSmithKline. He has received consulting fees or honoraria for lectures from ALK; Allergopharma; AstraZeneca; Berlin-Chemie; Boehringer Ingelheim; Chiesi; GlaxoSmithKline; HAL Allergy; Leti; Novartis; Merck, Sharp & Dohme; Sanofi; and Teva. He has received travel expenses from AstraZeneca and Novartis. GGB has received research funding, paid to his institution, from Merck, Sharp & Dohme and fees for advisory board membership and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi. MLL has received consultancy fees from Chiesi, Clement Clarke International, Respiri (Australia), SmartRespiratory, and Teva; fees for advisory board participation from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Orion Pharmaceuticals, and Trudel Pharmaceuticals; fees from Chiesi for data safety monitoring board participation; lecture fees from AstraZeneca, Chiesi, Menarini, Novartis, Orion Pharmaceuticals, Soar Beyond, and Teva; conference sponsorship from Chiesi, Orion Pharmaceuticals, and Napp; travel expenses and accommodation support from Orion and the Global Initiative for Asthma; an educational grant from Consorzio Futuro in Ricerca for work as a member of the ADMIT group; accommodation support from NAPP and Chiesi; fees for clinical leadership and mentorship and for assessment and reporting of outcomes from the National Services for Health Improvement; and fees as lead for asthma in developing dashboards for clinical care from Whole Systems Integrated Care, North West London. GWC has received consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, HAL Allergy, Menarini, Novartis, Regeneron, Sanofi, and Stallergenes; and honoraria for lectures from AstraZeneca, Chiesi, GlaxoSmithKline, HAL Allergy Menarini, Novartis, and Stallergens. IDP has received a research grant from Chiesi. He has received consultancy fees from Almirall; AstraZeneca; Boehringer Ingelheim; Chiesi; Circassia; Dey Pharma; Genentech; GlaxoSmithKline; Knopp Biosciences; Merck; Merck, Sharp & Dohme; Napp Pharmaceuticals; Novartis; Regeneron; RespiVert; Sanofi; Schering-Plough; and Teva. He has received payments to support US Food and Drug Administration approval meetings from GlaxoSmithKline; speaker's fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi, and Teva; scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Napp Pharmaceuticals, Regeneron, Sanofi, and Teva; and payment for the organisation of educational events from AstraZeneca, GlaxoSmithKline, Regeneron, Sanofi, and Teva. MS has received research funding, paid to his institution, from ALK; and royalties for educational contributions from UpToDate. MS is Editor-in-Chief of the Journal of Allergy and Clinical Immunology: In Practice and Principal Investigator for the Vaccines and Medications in Pregnancy Surveillance System. JCV has received grants for research from Deutsche Forschungsgemeinschaft; GlaxoSmithKline; and Merck, Sharp & Dohme. He has received consulting fees from Avontec; Boehringer Ingelheim; Chiesi; Essex, Schering-Plough; GlaxoSmithKline; Janssen-Cilag; MEDA; Merck, Sharp & Dohme; Mundipharma; Novartis; Regeneron; Revotar; Roche; Sandoz-Hexal; Sanofi-Aventis; Teva; and UCB, Schwarz-Pharma. He has received honoraria for lectures from AstraZeneca; Avontec; Bayer; Bencard; Bionorica; Boehringer Ingelheim; Chiesi; Essex, Schering-Plough; GlaxoSmithKline; Janssen-Cilag; Leti; MEDA; Merck; Merck, Sharp & Dohme; Mundipharma; Novartis; Nycomed, Altana; Pfizer; Revotar; Sandoz-Hexal; Stallergens; Teva; UCB, Schwarz-Pharma; and Zydus, Cadila. He has received fees for data safety monitoring board participation from Chiesi; and travel support from Sanofi and Boehringer Ingelheim., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Data on the potential benefits and risks of induction therapy in pediatric liver transplantation (LT) are limited. This was a retrospective cohort study of 2748 pediatric LT recipients at 26 children's hospitals between January 1, 2006 to May 31, 2017 using data from the pediatric health information system linked to the United Network for Organ Sharing database. The induction regimen was obtained from the pediatric health information system day-by-day pharmacy resource utilization. Cox proportional hazards evaluated the association of induction regimen (none/corticosteroid-only, nondepleting, and depleting) on patient and graft survival. Additional outcomes, including opportunistic infections and posttransplant lymphoproliferative disorder, were studied using multivariable logistic regression. Overall, 64.9% received none/corticosteroid-only induction, whereas 28.1% received nondepleting, 8.3% received depleting, and 2.5% other antibody regimens. Differences in patient characteristics were small, but center practices were heterogeneous. Compared with none/corticosteroid-only induction, nondepleting induction was associated with reduced acute rejection (odd ratio [OR], 0.53; P <.001) but with the increased posttransplant lymphoproliferative disorder (OR, 1.75; P =.021). Depleting induction was associated with improved graft survival (hazard ratio [HR], 0.64; P =.028) but with increased noncytomegalovirus opportunistic infections (OR, 1.46; P =.046). Depleting induction is underused yet may offer long-term benefits in this large multicenter cohort. Greater consensus guidance in this aspect of pediatric LT care is warranted., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Frozen shoulder is a disabling condition characterised by severe pain and loss of shoulder movement and may affect up to 5% of the population. Qualitative research documents debilitating pain and how treatment to reduce pain is a priority for people diagnosed with frozen shoulder. Corticosteroid injections are a principal treatment to reduce the pain of frozen shoulder, however little is known about the patient experience., Objectives: This study aims to address this gap in the knowledge by exploring the lived experience of people with frozen shoulder who have undergone an injection and to highlight other novel findings., Design: This is a qualitative study using interpretative phenomenological analysis. One-to-one, semi-structured interviews were conducted with seven people diagnosed with frozen shoulder who had received a corticosteroid injection as part of their management., Methodology: A purposive sample of participants were interviewed via MSTeams™ due to Covid-19 restrictions. Data was collected through semi-structured interviews and analysed in accordance with interpretive phenomenological analysis methods., Results: Three group experiential themes were identified: the dilemma surrounding injections; the challenges of understanding the causes of frozen shoulder; the impact on self and others., Conclusion: Participants conveyed a strong desire in seeking a corticosteroid injection whilst seemingly dismissing the risks. A novel concept was illuminated as frozen shoulder seemed inextricably linked with the ageing process, which negatively impacted body-image. The impact on others is driven by a sense of the unfamiliar nature of illness and it is incumbent on healthcare professionals to seek opportunities to explore the individual's beliefs., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Some patients with severe asthma do not achieve sufficient symptom control despite guideline-based treatment, and therefore receive oral (OCS) and systemic corticosteroids (SCS) on regular basis. The side effects of corticosteroid use negatively impact patients' health-related quality of life (HRQoL) and increase the disease burden. Biologics have shown promise in asthma therapy; however, identifying patients who might benefit from biologic therapy is complex due to the heterogeneous pathophysiology of the disease., Methods: The European, non-interventional, multicentre RECOGNISE study (NCT03629782) assessed patient characteristics, asthma medication and control, HRQoL as assessed by St. George's Respiratory Questionnaire (SGRQ), and health care resource use in patients with severe asthma, as well as their eligibility for biologic treatment. Here, data from the Greek cohort (N = 97) are reported., Results: In Greece, patients with severe asthma were more often female (71%) and never smokers (68%). 87% of patients were assessed as eligible for biologic treatment by investigator's judgement (per label criteria: 76%). Most patients had been previously treated with SCS (82% eligible vs 85% non-eligible), with OCS use being more common in non-eligible patients (23.1% vs 11.9%). More eligible patients had poorly controlled asthma (76% vs 54%), and more impaired HRQoL (mean total SGRQ score: 46% vs 39%); symptom burden was significantly higher (mean symptom score: 60% vs. 44%, p: 0.0389)., Conclusions: A high proportion of Greek patients with severe asthma are eligible for biologic therapy; however, individual risk factors and differences between asthma types must be considered before the introduction of targeted therapy., Competing Interests: Declaration of competing interest BP reports honoraria for presentations, participation fees in advisory boards and support for attending meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, MSD, Novartis and Specialty. Therapeutics. TS reports honoraria for presentations, participation fess in advisory boards from AstraZeneca, Chiesi, Elpen and Menarini. PA has nothing to disclose. NM is an employee of AstraZeneca Greece, Athens, Greece. PG is an employee of AstraZeneca Greece, Athens, Greece., (Copyright © 2023 Elsevier Ltd. All rights reserved.)