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The New England Journal of Medicine Jun 2024Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear.
METHODS
In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24.
RESULTS
A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events.
CONCLUSIONS
In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).
Topics: Humans; Eosinophilic Esophagitis; Antibodies, Monoclonal, Humanized; Male; Double-Blind Method; Eosinophils; Female; Adolescent; Middle Aged; Adult; Child; Young Adult; Aged; Deglutition Disorders; Leukocyte Count; Interleukin-5 Receptor alpha Subunit
PubMed: 38924732
DOI: 10.1056/NEJMoa2313318 -
The New England Journal of Medicine Jun 2024Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents.
METHODS
In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically.
RESULTS
In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B.
CONCLUSIONS
Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).
Topics: Humans; Eosinophilic Esophagitis; Antibodies, Monoclonal, Humanized; Male; Female; Child; Double-Blind Method; Child, Preschool; Infant; Eosinophils; Injections, Subcutaneous; Dose-Response Relationship, Drug; Esophagus; Interleukin-13; Remission Induction; Interleukin-4
PubMed: 38924731
DOI: 10.1056/NEJMoa2312282 -
Journal Der Deutschen Dermatologischen... Jun 2024Tinea incognita (TI) can mimic other dermatoses, presenting a diagnostic challenge for dermatologists. In some uncertain cases, it is crucial to accurately identify the...
Tinea incognita (TI) can mimic other dermatoses, presenting a diagnostic challenge for dermatologists. In some uncertain cases, it is crucial to accurately identify the causative agent using internal transcribed spacer (ITS) sequencing. The global issue of drug-resistant dermatophytosis is increasing, with Trichophyton (T.) indotineae being the main cause. This study presents four cases of TI (diagnosed as eczema) by terbinafine-resistant T. indotineae strains and reviews the current global TI epidemiology based on geographical continent and related conditions. Furthermore, squalene epoxidase (SQLE)-associated resistance mechanisms are evaluated. Lesions caused by terbinafine-resistant T. indotineae strains do not respond to allylamine antifungals, thus allowing the infection to spread. Among T. indotineae isolates, the SQLE F397L substitution is the most prevalent mutation contributing to azole resistance. F397L and L393F replacements in SQLE were detected in all isolates that exhibited high-level resistance. L393S was seen in isolates with low-resistant strains. Interestingly, and for the first time, an L393F amino acid substitution in the SQLE gene product was detected in the Iranian clinical T. indotineae strain. Also, a genomics-based update on terbinafine resistance that focuses on T. indotineae is discussed in this study.
PubMed: 38924688
DOI: 10.1111/ddg.15440 -
Pediatric Transplantation Aug 2024Varicella-zoster virus (VZV) reactivation is the most common infectious complication in the late posthematopoietic stem cell transplantation (HSCT) period and is...
BACKGROUND
Varicella-zoster virus (VZV) reactivation is the most common infectious complication in the late posthematopoietic stem cell transplantation (HSCT) period and is reported as 16%-41%. Acyclovir prophylaxis is recommended for at least 1 year after HSCT to prevent VZV infections. However, studies on the most appropriate prophylaxis are ongoing in pediatric patients.
METHODS
Patients who underwent allogeneic HSCT between January 1, 1996 and January 1, 2020 were retrospectively analyzed to outline the characteristics of VZV reactivation after allogeneic HSCT in pediatric patients using 6 months acyclovir prophylaxis.
RESULTS
There were 260 patients and 273 HSCTs. Median age was 10.43 (0.47-18.38), and 56% was male. Median follow-up was 2325 days (18-7579 days). VZV reactivation occurred in 21.2% (n = 58) at a median of 354 (55-3433) days post-HSCT. The peak incidence was 6-12 months post-HSCT (43.1%). Older age at HSCT, female gender, history of varicella infection, lack of varicella vaccination, low lymphocyte, CD4 count, and CD4/CD8 ratio at 9 and 12 months post-HSCT was found as a significant risk for herpes zoster (HZ) in univariate analysis, whereas history of varicella infection and low CD4/CD8 ratio at 12 months post-HSCT was an independent risk factor in multivariate analysis.
CONCLUSIONS
Tailoring acyclovir prophylaxis according to pre-HCT varicella history, posttransplant CD4 T lymphocyte counts and functions, and ongoing immunosuppression may help to reduce HZ-related morbidity and mortality.
Topics: Humans; Acyclovir; Male; Female; Child; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Child, Preschool; Adolescent; Antiviral Agents; Infant; Virus Activation; Herpesvirus 3, Human; Herpes Zoster; Varicella Zoster Virus Infection; Transplantation, Homologous; Risk Factors
PubMed: 38924278
DOI: 10.1111/petr.14819 -
Clinical and Experimental Allergy :... Jun 2024There has been limited data regarding the incidence of anaphylaxis in Asia. We aim to describe patterns in patient characteristics, triggers and clinical presentation of...
BACKGROUND
There has been limited data regarding the incidence of anaphylaxis in Asia. We aim to describe patterns in patient characteristics, triggers and clinical presentation of childhood anaphylaxis in Singapore.
METHODS
This was a retrospective review of emergency electronic medical records of children with anaphylaxis. Patients with the allergy-related diagnoses of anaphylaxis, angioedema, allergy and urticaria based on ICD-9 codes were screened. Cases fulfilling the World Allergy Organization criteria for anaphylaxis were included.
RESULTS
A total of 1188 cases of anaphylaxis were identified with a median age of 6.3 years. Extrapolating data from the study sites, from 2015 to 2022, the incidence rate of childhood anaphylaxis emergency visits in Singapore doubled from 18.9 to 38.8 per 100,000 person-years, with an incidence rate ratio (IRR) of 2.06 (95% confidence interval [CI] 1.70-2.49). In 2022, the incidence rate of food anaphylaxis was 30.1 per 100,000 person-years, IRR 2.39 (95% CI 1.90-3.01) and drug anaphylaxis was 4.6 per 100,000 person-years, IRR 1.89 (95% CI 1.11-3.25). The incidence rate in children aged 0-4 years quadrupled during the study period. Common triggers were egg (10.4%), peanut (9.3%), tree nut (8.8%), milk (8%), shellfish (7.8%) and non-steroidal anti-inflammatory drug (4.4%). The majority (88.6%) of patients were treated with intramuscular adrenaline. Total number of allergy-related visits did not increase over time between 2015 and 2019. Rates of severe anaphylaxis, namely anaphylactic shock and admission to high-dependency and intensive care, did not increase over time, with a mean incidence of 1.6, IRR 0.85 (95% CI 0.40-1.83) and 0.7, IRR 1.77 (95% CI 0.54-5.76) per 100,000 person-years, respectively.
CONCLUSION
While the number of emergency visits due to childhood anaphylaxis has increased, the number of cases of allergy-related visits, anaphylactic shock and anaphylaxis requiring high-dependency and intensive care did not rise.
PubMed: 38923779
DOI: 10.1111/cea.14528 -
Contact Dermatitis Jun 2024
PubMed: 38923570
DOI: 10.1111/cod.14624 -
Physiologia Plantarum 2024During microspore embryogenesis, microspores are induced to develop into haploid embryos. In Brassica napus, microspore embryogenesis is induced by a heat shock (HS),...
The different response of Brassica napus genotypes to microspore embryogenesis induced by heat shock and trichostatin A is not determined by changes in cell wall structure and composition but by different stress tolerance.
During microspore embryogenesis, microspores are induced to develop into haploid embryos. In Brassica napus, microspore embryogenesis is induced by a heat shock (HS), which initially produces embryogenic structures with different cell wall architectures and compositions, and with different potentials to develop into embryos. The B. napus DH4079 and DH12075 genotypes have high and very low embryo yields, respectively. In DH12075, embryo yield is greatly increased by combining HS and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). However, we show that HS + TSA inhibits embryogenesis in the highly embryogenic DH4079 line. To ascertain why TSA has such different effects in these lines, we treated DH4079 and DH12075 microspore cultures with TSA and compared the cell wall structure and composition of the different embryogenic structures in both lines, specifically the in situ levels and distribution of callose, cellulose, arabinogalactan proteins and high and low methyl-esterified pectin. For both lines, HS + TSA led to the formation of cell walls unfavorable for embryogenesis progression, with reduced levels of arabinogalactan proteins, reduced cell adhesion of inner walls and altered pectin composition. Thus, TSA effects on cell walls cannot explain their different embryogenic response to TSA. We also applied TSA to DH4079 cultures at different times and concentrations before HS application, with no negative effects on embryogenic induction. These results indicate that DH4079 microspores are hypersensitive to combined TSA and HS treatments, and open up new hypotheses about the causes of such hypersensitivity.
Topics: Brassica napus; Cell Wall; Hydroxamic Acids; Heat-Shock Response; Genotype; Pollen; Stress, Physiological
PubMed: 38923567
DOI: 10.1111/ppl.14405 -
Addiction (Abingdon, England) Jun 2024Opioid use disorder (OUD) and opioid dependence lead to significant morbidity and mortality, yet treatment retention, crucial for the effectiveness of medications like...
BACKGROUND AND AIMS
Opioid use disorder (OUD) and opioid dependence lead to significant morbidity and mortality, yet treatment retention, crucial for the effectiveness of medications like buprenorphine-naloxone, remains unpredictable. Our objective was to determine the predictability of 6-month retention in buprenorphine-naloxone treatment using electronic health record (EHR) data from diverse clinical settings and to identify key predictors.
DESIGN
This retrospective observational study developed and validated machine learning-based clinical risk prediction models using EHR data.
SETTING AND CASES
Data were sourced from Stanford University's healthcare system and Holmusk's NeuroBlu database, reflecting a wide range of healthcare settings. The study analyzed 1800 Stanford and 7957 NeuroBlu treatment encounters from 2008 to 2023 and from 2003 to 2023, respectively.
MEASUREMENTS
Predict continuous prescription of buprenorphine-naloxone for at least 6 months, without a gap of more than 30 days. The performance of machine learning prediction models was assessed by area under receiver operating characteristic (ROC-AUC) analysis as well as precision, recall and calibration. To further validate our approach's clinical applicability, we conducted two secondary analyses: a time-to-event analysis on a single site to estimate the duration of buprenorphine-naloxone treatment continuity evaluated by the C-index and a comparative evaluation against predictions made by three human clinical experts.
FINDINGS
Attrition rates at 6 months were 58% (NeuroBlu) and 61% (Stanford). Prediction models trained and internally validated on NeuroBlu data achieved ROC-AUCs up to 75.8 (95% confidence interval [CI] = 73.6-78.0). Addiction medicine specialists' predictions show a ROC-AUC of 67.8 (95% CI = 50.4-85.2). Time-to-event analysis on Stanford data indicated a median treatment retention time of 65 days, with random survival forest model achieving an average C-index of 65.9. The top predictor of treatment retention identified included the diagnosis of opioid dependence.
CONCLUSIONS
US patients with opioid use disorder or opioid dependence treated with buprenorphine-naloxone prescriptions appear to have a high (∼60%) treatment attrition by 6 months. Machine learning models trained on diverse electronic health record datasets appear to be able to predict treatment continuity with accuracy comparable to that of clinical experts.
PubMed: 38923168
DOI: 10.1111/add.16587 -
Brazilian Dental Journal 2024The aim of this clinical, prospective, randomized, and parallel study was to evaluate different in-office treatments for dentin hypersensitivity (DH). One hundred... (Randomized Controlled Trial)
Randomized Controlled Trial
The aim of this clinical, prospective, randomized, and parallel study was to evaluate different in-office treatments for dentin hypersensitivity (DH). One hundred ninety-two teeth with non-cavitated root exposures were treated using different desensitizers: fluoride varnish (Duraphat - FLU); bioactive ceramic solution (Biosilicate - BIOS); universal self-etching adhesive (Single Bond Universal - SBU); bioactive photoactivated varnish (PRG filler - SPRG). The degree of DH was analyzed using a visual analog scale (VAS) and computerized visual scale (CoVAS), before treatments and after 7, 15, and 30 days from the first session. Comparisons among desensitizers were performed using the Kruskal-Wallis and Dunn's tests. Friedman test was used to compare between times (p ≤ 0.05). Comparing desensitizers FLU presented a higher value of DH than BIOS using VAS at 7 days, however, no differences were found using CoVAS analysis. Comparing times, BIOS and SBU showed a reduction in DH after 7 days and SBU showed a reduction at 30 days compared to 7 days using VAS. FLU and SPRG groups reduced DH from 15 days to 30 days using VAS. There was a reduction in DH for FLU, BIOS, and SBU after 7 days and for BIOS this reduction also occurred at 30 days when compared to 15 days using CoVAS. SPRG group showed a reduction from 15 to 30 days. All desensitizers tested were able to reduce the initial sensitivity. The bioactive ceramic solution reduced the DH gradually after 30 days using computerized analysis.
Topics: Humans; Dentin Sensitivity; Dentin Desensitizing Agents; Male; Female; Prospective Studies; Adult; Treatment Outcome; Middle Aged; Fluorides, Topical
PubMed: 38922247
DOI: 10.1590/0103-6440202405487 -
Arthritis Research & Therapy Jun 2024To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc).
BACKGROUND
To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc).
METHODS
SSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated.
RESULTS
GORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively).
CONCLUSION
GORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.
Topics: Humans; Gastroesophageal Reflux; Lung Diseases, Interstitial; Female; Male; Middle Aged; Scleroderma, Systemic; Proton Pump Inhibitors; Aged; Histamine H2 Antagonists; Adult; Cohort Studies; Treatment Outcome; Australia
PubMed: 38918847
DOI: 10.1186/s13075-024-03355-0