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Tal Sigawi, Adir Israeli, Yaron Ilan Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, IsraelCorrespondence: Yaron Ilan, Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel, Email ilan@hadassah.org.ilAbstract: Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments.Keywords: immune system, variability, artificial intelligence, immunotherapy

Jiying Xiao,1 Lingyue Liu,1 Kamran Ali,2 Suling Wu,1 Junsong Chen1 1Department of Pulmonology, Hangzhou Children’s Hospital, Hangzhou, Zhejiang, 310015, People’s Republic of China; 2Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, People’s Republic of ChinaCorrespondence: Junsong Chen, Department of Pulmonology, Hangzhou Children’s Hospital, NO. 195 Wenhui Road, Gongshu Distract, Hangzhou, Zhejiang, 310015, People’s Republic of China, Tel +86-15990067220, Email doctorsong999@126.comObjective: We aimed to observe and analyze the differences in impulse oscillometry (IOS) and fractional expiratory nitric oxide (FeNO) in relation to asthma control among preschool children, and to explore the predictive value of IOS combined with FeNO for uncontrolled asthma.Methods: This study enrolled 171 preschool children with asthma and 30 healthy preschool children between June 2022 and June 2023. We categorized the asthmatic children as having controlled asthma (n=85) and uncontrolled asthma (n=86) after a 3-month follow-up. IOS and FeNO were collected on the first visit at baseline. Differences in metrics were compared between controlled asthma, uncontrolled asthma and healthy control groups. The area under the receiver operating characteristic curve (AUROC) was utilized to explore the discriminative ability of IOS and FeNO, alone or in combination, against uncontrolled asthma.Results: Compared to the controlled asthma group, the IOS values of R5, X5, R5-R20, and Fres were significantly higher in the uncontrolled asthma group, except for R20. R5 and R5-R20 had the highest area under the curve (AUC), which could reach 0.74 (95% CI 0.66– 0.82) and 0.72 (95% CI 0.64– 0.80). R20 had the lowest AUC of 0.59. The AUC for FeNO alone was 0.88 (95% CI 0.84– 0.93) with a cutoff value of 17.50 ppb, sensitivity and specificity of 0.73 and 0.89. The AUCs of all IOS metrics combined with FeNO were significantly higher, with the highest AUC of 0.92 (95% CI 0.87– 0.96) for R5-R20+FeNO, and with a sensitivity and specificity of 0.88 and 0.84.Conclusion: There were significant differences in IOS and FeNO in relation to asthma control among preschooler children. FeNO might be the best predictor of asthma control, and adding any of IOS metrics increased moderately the predictive value.Keywords: asthma control, impulse oscillometry, fractional expiratory nitric oxide, preschool children

Ziheng Chen,1 Jinxin Ma,1 Jiahui Lei,1 Yi Li,1 Ruijuan Zhao,1 Limin Zhao2 1Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Limin Zhao, Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of China, Email zhaolimin2002@126.comPurpose: This study aimed to identify environmental risk factors associated with asthmatic fixed airflow obstruction (FAO) and assess the relationship between small airway abnormalities defined by forced expiratory flow at 25– 75% (FEF25-75%) and FAO.Patients and Methods: We analyzed data from 312 han Chinese patients with stable asthma on standard treatment. Low FEF25-75% was defined as post-bronchodilator FEF25-75% z-score 10 years (2.01 [1.06– 3.86], P=0.035) and occupational exposure for > 20 years (2.67 [1.24– 5.91], P=0.013) were associated with asthmatic FAO. In cross-sectional analyses, compared with the normal FEF25-75%/ asthmatics without FAO (NON-FAO) group, the low FEF25-75%/ asthmatics with FAO (FAO) group had lower FEV1 z-scores and FEV1/FVC z-scores, more pack-years and years of biomass and occupational exposure, higher Asthma Control Questionnaire-5 and Chronic Obstructive Pulmonary Disease Assessment Test scores, and more frequent exacerbations. The low FEF25-75%/NON-FAO group showed the same trend, but to a lesser extent.Conclusion: Chronic airway inflammation is not the only driver of asthmatic FAO, and management and treatment targeting environmental risk factors (smoking and biomass and occupational exposures) may slow FAO progression in asthmatics. The FEF25-75% determined by the z-score is a reliable marker of small airway abnormalities, and patients with low FEF25-75% are at greater risk for FAO, requiring more frequent follow-up.Keywords: asthma, fixed airflow obstruction, environmental exposures, forced expiratory flow at 25-75%

Sumei Chen,1,* Lingrong Yang,2,* Bing Xia,3 Haitao Zhu,4 Zhenghao Piao,5 Youssef Jounaidi6 1Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 2Department of Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 3Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 4Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China; 5Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People’s Republic of China; 6Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA*These authors contributed equally to this workCorrespondence: Youssef Jounaidi, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA, Email yjounaidi@mgh.harvard.eduBackground: Enhancing NK cells’ antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.Results: NK92-expressing IL15RB (NK92IL15RB) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92IL5RB showed resistance to irradiation and IL-4. However, TGFβ 1 substantially reduced NK92IL5RB killing, suggesting the need to inhibit TGFβ 1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92IL15RB cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92IL15RB antitumor activity against leukemia and increased its STAT5 activation. NK92IL15RB anti-tumors activity was further enhanced by combination with anti-PD1.Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.Keywords: IL-15, IL2RB receptor, natural killer cells, cancer immunotherapy, IL15RB

Dennis K Ledford,1 Warner W Carr,2 Wendy C Moore,3 Njira L Lugogo,4 Arjun Mohan,4 Bradley Chipps,5 Alexander R Mackie,6 Andrew W Lindsley,7 Joseph Spahn,6 Christopher S Ambrose8 1Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 2Allergy & Asthma Associates of Southern California, Mission Viejo, CA, USA; 3Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 5Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 6BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 7US Medical Affairs, Amgen, Thousand Oaks, CA, USA; 8BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USACorrespondence: Christopher S Ambrose, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA, Tel +1 301-398-4454, Email chris.ambrose@astrazeneca.comPurpose: Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort.Patients and methods: CHRONICLE is an ongoing, real-world study of US adults with subspecialist-treated SA receiving biologics, maintenance corticosteroids, or who are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled between February 2018 and February 2022 who initiated a biologic for SA and had complete data for analysis were included. A locally estimated scatterplot smoothing (LOESS) analysis was used to plot the relationship between percentage exacerbation rate reduction and AAO by biologic class.Results: Of 578 patients with complete data, 198, 149, and 231 were diagnosed with asthma at age < 18, 18– 39, and ≥ 40 years, respectively. Across subgroups, patients were predominantly White (72– 78%), female (67– 73%), and commercially insured (54– 71%). In the LOESS analysis, exacerbation rate reductions were similar for anti-IgE and anti–IL-5/5R and anti–IL-4R subgroups with younger AAO, but the exacerbation rate reduction diminished for patients with older AAO receiving anti-IgE therapy, particularly with asthma onset age ≥ 40 years.Conclusion: Clinicians should consider age of onset in biologic treatment decisions, given reduced effectiveness of omalizumab in patients with asthma onset at age ≥ 40 years.Clinicaltrials.gov Identifier: NCT03373045.Keywords: Biologics, severe asthma, anti-interleukin therapy, anti-immunoglobulin E therapy, effectiveness, age of asthma onset

Monique da Silva Pinto,1 Caroline de Oliveira Ribeiro,1 Paula Morisco de Sá,2 Hermano Albuquerque Castro,3 Thiago Prudente Bártholo,4 Agnaldo José Lopes,4 Pedro Lopes Melo1,5 1Biomedical Instrumentation Laboratory, Institute of Biology and Faculty of Engineering, State University of Rio de Janeiro, Rio de Janeiro, Brazil; 2University of the Brazilian Air Force, Postgraduate Program in Operational Human Performance, Rio de Janeiro, Brazil; 3National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 4Pedro Ernesto University Hospital, Pulmonary Function Laboratory, State University of Rio de Janeiro, Rio de Janeiro, Brazil; 5State University of Rio de Janeiro, Laboratory of Clinical and Experimental Research in Vascular Biology, Rio de Janeiro, BrazilCorrespondence: Pedro Lopes Melo, Department of Physiology, State University of Rio de Janeiro, São Francisco Xavier Street, Maracanã, Rio de Janeiro, Brazil, Tel +55(21)2334-0705, Email plopes@uerj.brBackground: Asthma onset or worsening of the disease in adulthood may be associated with occupational asthma (OA) or work-exacerbated asthma (WEA). Oscillometry and respiratory modeling offer insight into the pathophysiology and contribute to the early diagnosis of respiratory abnormalities.Purpose: This study aims to compare the changes due to OA and WEA and evaluate the diagnostic accuracy of this method.Patients and Methods: Ninety-nine volunteers were evaluated: 33 in the control group, 33 in the OA group, and 33 in the WEA group. The area under the receiver operator characteristic curve (AUC) was used to describe diagnostic accuracy.Results: Oscillometric analysis showed increased resistance at 4 hz (R4, p< 0.001), 20 hz (R20, p< 0.05), R4-R20 (p< 0.0001), and respiratory work (p< 0.001). Similar analysis showed reductions in dynamic compliance (p< 0.001) and ventilation homogeneity, as evaluated by resonance frequency (Fr, p< 0.0001) and reactance area (p< 0.0001). Respiratory modeling showed increased peripheral resistance (p< 0.0001), hysteresivity (p< 0.0001), and damping (p< 0.0001). No significant changes were observed comparing OA with WEA in any parameter. For OA, the diagnostic accuracy analyses showed Fr as the most accurate among oscillometric parameters (AUC=0.938), while the most accurate from respiratory modeling was hysteresivity (AUC=0.991). A similar analysis for WEA also showed that Fr was the most accurate among traditional parameters (AUC=0.972), and hysteresivity was the most accurate from modeling (AUC=0.987). The evaluation of differential diagnosis showed low accuracy.Conclusion: Oscillometry and modeling have advanced our understanding of respiratory abnormalities in OA and WEA. Furthermore, our study presents evidence suggesting that these models could aid in the early diagnosis of these diseases. Respiratory oscillometry examinations necessitate only tidal breathing and are straightforward to conduct. Collectively, these practical considerations, coupled with the findings of our study, indicate that respiratory oscillometry in conjunction with respiratory modeling, may enhance lung function assessments in OA and WEA.Keywords: occupational asthma, work-exacerbated asthma, pulmonary function, forced oscillations, respiratory modeling, fractional order modeling

Jing He,1,&ast; Nan Lin,2,&ast; Ting Jin,2 Ming Lin,1 Zuowei Huang,1 Shuxian Li,1 Jinling Liu,1 Lin Su,1 Xian Ye,2 Lei Wu,1 Zhenghong Song,2 Hongzhen Xu,2 Zhimin Chen1 1Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhimin Chen, Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email zmchen@zju.edu.cn Hongzhen Xu, Master of nursing, Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email 6184020@zju.edu.cnBackground: Allergic conditions, identified as a significant global health challenge, are profoundly influenced by indoor allergens, especially house dust mites (HDM). Yet the relationship between mite sensitized components and respiratory allergies and asthma control remains poorly understood.Methods: A cohort of 96 children, either with allergic rhinitis (AR) or rhinitis with asthma syndrome (ARAS), was assessed. Protein microarray technology was deployed to quantify sIgE responses to the allergenic components of Der p and Der f.Results: The study cohort comprised 18 AR and 78 ARAS patients; with 43 mild and 53 moderate-to-severe AR; with 28 uncontrolled, 21 partially controlled, and 29 well-controlled asthma. Sensitization prevalence for HDM components was highest with Der p (97.9%), Der f 2 (97.9%), Der p 2 (94.8%), Der f 1(94.8%), Der p 1 (93.8%), Der p 23 (57.3%). Notably, sIgE concentrations for Der f and Der f 2 were significantly greater in the ARAS compared to AR (P < 0.05). While sIgE levels varied between mild and moderate-to-severe AR, the differences were not statistically significant (P > 0.05). However, Der p 23 sIgE levels demonstrated a significant fluctuation across the asthma control strata (P < 0.05), with the well-controlled group exhibiting the lowest readings.Conclusion: The sIgE levels to HDM allergens were higher in ARAS group compared to AR group, especially Der f and Der f 2, indicating an association between sIgE reactivity and the diagnosis of asthma. Reduced Der p 23 sIgE levels were indicative of enhanced asthma control.Keywords: house dust mite, allergic rhinitis, asthma, molecular sensitization, children

Thelma Satha Kamara,1 Amon Banturaki,1 Brian Ssenkumba,2 Theophilus Pius,3 Kingsley Akaba2,4 1Department of Internal Medicine Kampala International University, Western Campus, Ishaka, Uganda; 2Department of Pathology Kampala International University, Western Campus, Ishaka, Uganda; 3Department of Medical Laboratory Science, Kampala International University, Western Campus, Ishaka, Uganda; 4Department of Hematology, University of Calabar, Calabar, Cross River State, NigeriaCorrespondence: Thelma Satha Kamara, Email satha92@yahoo.co.ukAim: Sub-Saharan Africa bears the highest burden of HIV/AIDS infections and constitutes 72% and 69% of AIDS-related deaths and people living with HIV worldwide, respectively. Due to the relationship between pulmonary infections and HIV/AIDS, it is biologically plausible that the surge in morbidity and mortality among HIV/AIDS patients could be attributed to an increase in pulmonary infections among this cohort of patients. This study determined the bacterial profile, susceptibility patterns, and factors associated with culture-positive sputum among HIV patients presenting with cough at the Lira Infectious Disease Centre in Northern Uganda.Material and Methods: This prospective cross-sectional study recruited 180 participants. Culture and sensitivity of the sputum samples were done to determine the causative organism and its susceptibility. Blood agar, MacConkey’s agar, and Chocolate agar were deployed for the culture media. Antimicrobial susceptibility testing was done using the Kirby-Bauer disc diffusion test. Data were analyzed using SPSS version 26.Results: Out of the 180 enrolled patients, 113 were females with a mean age of 45. Bacterial growth was seen in 56 of the 180 samples. The most common isolate was Staphylococcus aureus at 35.7% of the 56 growths. The minority that accounted for 1.8% each were Citrobacter freundii, Salmonella species and Acinetobacter baumanii, respectively. A combination of ceftriaxone and gentamicin was effective against most organisms isolated in this study. At the multivariate level of analysis, an unsuppressed viral load and low peripheral oxygen saturation were independently associated with a sputum culture-positive cough.Conclusion: HIV patients at LIDC who present with productive cough with low oxygen saturation and an unsuppressed viral load may be screened for Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Klebsiella pneumonia, and Enterobacter species infection. A combination of ceftriaxone and gentamicin may be used as empiric therapy before the culture and sensitivity results are available.Keywords: HIV, susceptibility patterns, lira regional referral hospital, northern Uganda

Yuan Yuan,1 Ze Wu,2 Xu Chen,3 Bin Xie2 1Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Pathology Center, First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Bin Xie, Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China, Email mrxiebin@163.comObjective: To assess the impact of rheumatoid arthritis (RA) on histopathological features and the risk of postoperative recurrence in chronic rhinosinusitis with nasal polyps (CRSwNP) patients.Methods: A retrospective cohort study of CRSwNP patients who underwent functional endoscopic sinus surgery was performed. Patients were followed up for more than two years, and classified into RA and Non-RA groups, recurrent and non-recurrent groups. The influence of RA on histopathological features and the risk of CRSwNP recurrence was explored.Results: A total of 517 CRSwNP patients were finally recruited, including 78 RA patients. The RA group exhibited a higher recurrence rate, tissue eosinophil counts and percentages compared to the non-RA group (P < 0.05). Tissue eosinophil count and percentage, and the prevalence of allergic rhinitis were significantly higher in the recurrent group in compared to the non-recurrent group (P < 0.05). Multivariate logistic regression analysis identified tissue eosinophil count and percentage, RA, and allergic rhinitis as significant predictors of increased recurrence risk (P < 0.05). Both adjusted and unadjusted models affirmed RA as an independent risk factor for CRSwNP postoperative recurrence (P < 0.05). Kaplan-Meier curves further indicated a higher recurrence risk in CRSwNP patients with RA than those without (P < 0.05).Conclusion: Our findings suggest that RA significantly exacerbates tissue eosinophilic inflammation and independently heightens the risk of postoperative recurrence in CRSwNP patients. These insights underscore the need for tailored therapeutic strategies addressing the complex interplay between CRSwNP and RA to mitigate recurrence risks and improve clinical outcomes.Keywords: rheumatoid arthritis, chronic rhinosinusitis with nasal polyps, endoscopic sinus surgery, recurrence

Victoria S Benson,1,&ast; James Siddall,2,&ast; Adam Haq,2 Mark Small,2 Rafael Alfonso-Cristancho,3 Zhiliu Tang,4 Peter Howarth,5 Tao Ye,6 Anna Richards7 1Epidemiology, Value Evidence & Outcomes, GSK, London, UK; 2Adelphi Real World, Bollington, UK; 3Value Evidence & Outcomes, GSK, Philadelphia, Pennsylvania, USA; 4Value Evidence & Outcomes, GSK, Shanghai, People’s Republic of China; 5Global Respiratory Franchise, GSK, Brentford, UK; 6Medical Affairs, Respiratory, GSK, Shanghai, People’s Republic of China; 7Value Evidence & Outcomes, GSK, Brentford, UK&ast;These authors contributed equally to this workCorrespondence: Tao Ye, Medical Affairs, Respiratory, GSK, 902 halei Road, Pudong, Shanghai, People’s Republic of China, Email ark.x.ye@gsk.comPurpose: To inform better asthma management in China, this study aimed to comprehensively investigate clinical characteristics, treatment patterns, asthma control status, exacerbations, and humanistic burden among adult patients seeking hospital-based asthma care by analyzing data from Adelphi Asthma Disease Specific Program conducted in China.Patients and Methods: All information was collected on survey date (August–December 2018) from medical records, physicians, or patients, without follow-up being conducted. Results are summarized descriptively for the overall population as well as subgroups defined by GINA 2018 treatment step.Results: Of the included 765 patients, 46.0%, 40.4%, and 29.2% had undergone lung function, blood eosinophil count, and specific immunoglobulin E/radioallergosorbent testing, and 17.2%, 24.1%, and 58.7% were managed at GINA Steps 1– 2, 3, and 4– 5, respectively. Asthma was not well controlled in 57.3% of patients based on definitions adapted from the ERS/ATS and 10.7% of patients had experienced ≥ 1 severe exacerbation in the preceding year. According to patient self-reporting (n=603), the mean (SD) was 0.9 (0.1) for utility on EQ-5D-3L and was 7.8% (10.4%), 36.9% (20.0%), 40.8% (22.2%), and 37.9% (22.3%) for absenteeism, presenteeism, work productivity loss, and activity impairment, respectively, on WPAI. Both asthma control and humanistic burden worsened with progressive GINA treatment steps.Conclusion: In patients seeking hospital-based asthma care in China, lung function and biomarker tests were underutilized, impairment in productivity and quality of life was observed, and more than half did not achieve well-controlled asthma despite approximately 60% being managed at GINA treatment Steps 4– 5. These findings highlight the urgent need for optimizing asthma management in China.Keywords: asthma control, exacerbation, treatment patterns, health care resource utilization, humanistic burden

Xiaoxue Liu,1 Jiawei Gao,2 Liuxin Yang,2 Xingxing Yuan2,3 1Department of Paediatrics, Harbin Hospital of Traditional Chinese Medicine, Harbin, 150010, People’s Republic of China; 2Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China; 3Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, 150006, People’s Republic of ChinaCorrespondence: Xingxing Yuan, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of China, Email yuanxingxing80@163.comAbstract: Asthma is a chronic inflammatory disorder of the airways, characterized by a complex interplay of genetic, environmental, and immunological factors that contribute to its onset and progression. Recent advances in researches have illuminated the critical role of exosomal microRNAs (miRNAs) in the pathogenesis and development of asthma. Exosomes are nano-sized extracellular vesicles that facilitate intercellular communication by transporting a variety of bioactive molecules, including miRNAs, and play a crucial role in regulating gene expression and immune responses, which are central to the inflammatory processes underlying asthma. Exosomal miRNAs are emerging as key players in asthma due to their involvement in various aspects of the disease, including the regulation of inflammation, airway hyperresponsiveness, and remodeling. Their ability to influence the behavior of target cells and tissues makes them valuable both as diagnostic biomarkers and as potential therapeutic targets. This review aims to provide a comprehensive overview of the biogenesis of exosomes, the functional roles of exosomal miRNAs in asthma, and their clinical potential. It will explore the mechanisms by which these miRNAs contribute to asthma pathophysiology, discuss their utility in diagnosing and monitoring the disease, and highlight ongoing research efforts to harness their therapeutic potential.Keywords: asthma, exosome, miRNA, biomarker, therapy

Tanazio Byamugisha,1 Fred Alinda,2 Samuel Lev Tushaboha,3 Godwin Kwemarira,4 Mahadih Kyambade4 1Kibaale District Civil Society Organization Network, Kagadi, Uganda; 2Institute Research and Innovation Centre, Uganda Management Institute, Kampala, Uganda; 3Infectious Diseases Institute, Hoima, Uganda; 4Department of Leadership and Governance, Faculty of Management, Makerere University Business School, Kampala, UgandaCorrespondence: Tanazio Byamugisha; Mahadih Kyambade, Email tbyamugisha@kcsonug.org; mahadkyambade@gmail.comBackground: - Despite the competence-building framework and interventions, the success of HIV/AIDS prevention and treatment programs remains unsatisfactory with scanty empirical evidence on the significance of professional competence to the success of HIV/AIDS control programs.Methods: - Using a triangulation of quantitative and qualitative data, from 40 health-care workers and 9 managers of the HIV/AIDS program in Kagadi District, this article analyzes the professional and cultural competencies among health-care workers and the significance of the competencies to the success of HIV/AIDS control programs. Descriptive statistics were generated to describe health-care workers’ opinions on their competence and success of HIV/AIDS control programs. In addition, a regression model was fitted to estimate the contribution of health-care workers’ competence to the success of HIV/AIDS control programs. This quantitative analysis was triangulated with a thematic analysis of key informants’ views.Results: - Findings indicate that health-care workers’ competence bears a positive statistically significant contribution to the success of HIV/AIDS control programs. Employee competence is necessary but not sufficient to foster the full realization of desired results from HIV/AIDS control programs.Conclusion: - Managers of HIV/AIDS control programs need to prioritize and continuously train health-care workers to boost their professional and cultural skills to effectively deliver interventional activities under HIV/AIDS control programs. Additionally, improving the working environment of health-care workers is critical to improve their motivation towards greater success of HIV/AIDS control programs.Keywords: health-care workers, employee competence, HIV/AIDS, programs, success

Hikmat Abdel-Razeq,1,2 Baha Sharaf,1 Suhaib Khater,1 Huda Jafar Baidoun,2 Hira Bani Hani,1 Ayat Taqash,3 Osama El Khatib,1 Sarah Edaily,1 Mahmoud Abunasser,1 Faris Tamimi,1 Yosra Nabeel Al-Masri,1 Tamer Moh’d Waleed Al-Batsh,1 Anas Zayed,1 Tala Ghatasheh,1 Tala Radaideh1 1Department of Internal Medicine, Section of Hematology and Medical Oncology, King Hussein Cancer Center, Amman, Jordan; 2School of Medicine, the University of Jordan, Amman, Jordan; 3Office of Scientific Affairs and Research. King Hussein Cancer Center, Amman, JordanCorrespondence: Hikmat Abdel-Razeq, Department of Internal Medicine, Section of Hematology and Medical OncologyKing Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan, Tel: +962-6 5300460, Email habdelrazeq@khcc.joBackground: Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment landscape of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2 −) metastatic breast cancer (MBC). Here, we present the real-world clinical outcomes and toxicity data of patients treated at a single cancer center.Methods: A retrospective analysis was conducted on patients with HR+/HER2− MBC treated with ribociclib plus endocrine therapy (ET). Outcomes measured included progression-free survival (PFS), overall survival (OS), and adverse events.Results: A total of 356 patients (median age 52, range 27– 91 years) were enrolled, all with metastatic disease; 204 (57.5%) had de novo metastasis, and 183 (51.4%) had visceral metastasis. Ribociclib was combined with aromatase inhibitors in 321 patients (90.2%) and with fulvestrant in 35 patients (9.8%). Dose reduction was needed in 101 patients (28.4%), primarily due to neutropenia (21.3%) and abnormal liver enzymes (5.9%). After a median follow-up of 36.3 months, median PFS was 27.3 months (95% CI: 21.3– 31.7). PFS was significantly better in patients receiving ribociclib as first-line therapy (32.1 months, 95% CI: 27.7– 42.1, p < 0.0001) and those with non-visceral metastasis (38.6 months, 95% CI: 29.8–NR, p < 0.0001). Similarly, OS was significantly better in first-line treatment (48.6 months, 95% CI: 39.1–NR) and non-visceral metastasis cases (NR, 95% CI: 40.6–NR, p < 0.0001). No significant differences in 3-year PFS and OS were found between patients with and without dose reductions.Conclusion: In real-world settings, and away from the stringency of controlled clinical trials, endocrine therapy in combination with ribociclib in patients with HR-positive/HER2-negative MBC is an effective and well-tolerated therapy with a manageable toxicity profile and a low drug discontinuation rate. Dose reduction due to toxicity did not worsen the outcome.Keywords: metastatic breast cancer, MBC, CDK4/6 inhibitors, ribociclib, aromatase inhibitors, fulvestrant

Kate Keenan,1 Sarah Walton,1 Kimberley Mbayiwa,1 Lara Akande,1 Anna Cherian,2 Christina Ciaccio,2 Ilaria Tare1 1Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA; 2Department of Pediatrics, The University of Chicago, Chicago, IL, USACorrespondence: Kate Keenan, Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, 5841 South Maryland Avenue, MC3077, Chicago, IL, 60637, USA, Tel +1-773-702-4449, Email kekeenan@uchicago.eduBackground: Black American children are at higher risk for developing asthma than White children. Identifying potential scalable preventive interventions that can reduce the racial disparities in asthma prevalence and associated morbidity and mortality are needed. We leveraged data from an RCT of prenatal supplementation with docosahexaenoic acid (DHA) in Black American women, to explore whether prenatal fatty acid supplementation is associated with offspring wheeze and asthma.Methods: Data were from the Nutrition and Pregnancy Study (NAPS), a double-blind RCT of prenatal DHA supplementation in Black women targeting stress regulation during pregnancy. A subset of mothers (n = 83) completed a standardized questionnaire on offspring wheeze and asthma when children were between 0.5 and 5.5 years of age. DHA levels were measured from venous blood and reported as percent of total fatty acids.Results: Of the 83 mothers providing data on child wheeze and asthma, 57 (68.7%) had been randomized to active DHA and 26 (31.3%) to placebo. Mothers and research staff were blind to group assignment. Comparison at the group assignment level yielded a relative reduction of 32% in the rate of wheeze or asthma among offspring of mothers assigned to active DHA compared to offspring of mothers assigned to placebo (OR = 1.6 [95% CI = 0.50– 5.09], p = 0.426). DHA levels measured at 25– 29 and 33– 37 weeks of gestation differed as a function of offspring wheeze or asthma (t = 2.21, p = 0.015 and t = 2.54, p = 0.007, respectively).Conclusion: These preliminary data suggest that increasing prenatal levels of DHA could be considered as a potential prevention for asthma in Black American children.Keywords: Asthma, omega-3 fatty acids, pregnancy, Black American

Helen Clare Ricketts,1 Varun Sharma,1 Femke Steffensen,2 Elaine Mackay,3 Gordon Wallace MacDonald,4 Duncan S Buchan,5 Michael Lean,6 Rekha Chaudhuri,7 Douglas C Cowan4 1College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 2Glasgow Clinical Research Facility, Glasgow Royal Infirmary, Glasgow, UK; 3Pulmonary Rehabilitation Team, Glasgow Royal Infirmary, Glasgow, UK; 4Respiratory Department, Glasgow Royal Infirmary, Glasgow, UK; 5Division of Sports and Exercise, University of the West of Scotland, Glasgow, UK; 6School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK; 7Respiratory Department, Gartnavel General Hospital, Glasgow, UKCorrespondence: Douglas C Cowan, Email douglas.cowan@ggc.scot.nhs.ukIntroduction: Management of difficult-to-treat asthma is particularly challenging in people with elevated body mass index (BMI). Our randomised controlled trial of pulmonary rehabilitation (PR) showed improved outcomes at 8 weeks. Here we assess immediate and one-year effects of asthma-tailored PR in participants with difficult-to-treat asthma and BMI ≥ 25 kg/m2, and identify response predictors.Methods: A prospective observational study of PR, tailored to asthma, comparing outcomes at baseline (V1), immediately after 8 weeks of PR (V2), and at 1 year (V3). Baseline characteristics were compared in responders/non-responders defined by achievement of minimum clinically important difference (MCID) for asthma control questionnaire (ACQ6) (0.5) at 8 weeks and 1 year.Results: Of 92 participants, 56 attended V2 and 45 attended V3. Mean age was 60 (SD 13) years, 60% were female, and median (IQR) BMI was 33.8 (29.5– 38.7) kg/m2. At V1, V2, and V3, respectively, there were significant differences in ACQ6 (mean (95% CI): 2.5 (2.1– 2.9), 2.2 (1.8– 2.5), and 2.3 (1.9– 2.7), p< 0.003), Borg breathlessness score post-6-minute walk test (median (IQR): 2 (0.5– 3), 1 (0– 2), and 1 (0.5– 2), p< 0.035), and annualised exacerbations requiring prednisolone (median (IQR): 3 (2– 5), 0 (0– 4.7), and 1.5 (0– 4.2), p< 0.003). A total of 27/56 (48%) had improvements >MCID for ACQ6 at V2 and 16 (33%) at V3. Participants with higher ACQ6 scores at baseline (suggesting poorer asthma control) were more likely to achieve MCID. Baseline BMI, within the range studied, was not predictive.Conclusion: Pulmonary rehabilitation induced improvements in asthma-related outcomes including perception of breathlessness, asthma control, and exacerbation frequency at 1 year. Those with poorer baseline asthma control were more likely to benefit.Keywords: asthma, difficult-to-treat asthma, obesity, pulmonary rehabilitation

Gaetana Pezzino,1 Alessia Calabrò,1 Fabiana Drommi,1 Stefania Campana,1 Riccardo Cavaliere,1,2 Irene Bonaccorsi,1 Paolo Carrega,1 Vincenzo Zammuto,3– 5 Maria Giovanna Rizzo,3 Concetta Gugliandolo,3,4 Guido Ferlazzo,6,7 Claudia De Pasquale1 1Laboratory of Immunology and Biotherapy, Department Human Pathology ”G. Barresi”, University of Messina, Messina, Italy; 2Division of Clinical Pathology, University Hospital Policlinico G. Martino, Messina, Italy; 3Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy; 4Research Centre for Extreme Environments and Extremophiles, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy; 5ATHENA Green Solutions S.r.l., Messina, Italy; 6Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy; 7Unit of Experimental Pathology and Immunology, IRCCS Ospedale Policlinico San Martino, Genova, ItalyCorrespondence: Guido Ferlazzo, Unit of Experimental Pathology and Immunology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, Email guido.ferlazzo@unige.itBackground: Respiratory viral infections are a leading cause of severe diseases and mortality; therefore, novel treatments effective for their prevention are highly requested. Here, we identified a broad-spectrum antiviral activity of a natural exopolysaccharide, EPS T14, purified from a marine thermotolerant strain of Bacillus licheniformis strain T14.Methods: The effects on human normal nasal epithelial cells (HNEpCs) following treatment with EPS T14 was evaluated at different time points and with increasing concentration of compound. To assess the antiviral properties, viability of HNEpCs treated with EPS T14 was analysed following infection with different respiratory viruses.Results: Neither toxicity nor pro-inflammatory properties were observed in vitro on HNEpCs treated with EPS T14 up to high concentrations, thus ensuring its safety. Cell culture-based assays revealed that treatment of HNEpCs with EPS T14 (used at 400ug/mL) results in efficient prevention of cell infection by different respiratory viruses through physically hindering the entry of the viruses via cell surface receptors. Interestingly, in addition to this prophylactic antiviral activity, EPS T14 also shows a long-lasting efficacy by inhibiting viral spread in the cell culture. Finally, combination of EPS T14 with a hypertonic saline solution shows a synergistic antiviral activity.Conclusion: EPS T14 can exert both prophylactic and therapeutic antiviral activity by blocking viral attachment to cellular receptors and could therefore represent a promising antiviral agent for preventing infections by different respiratory viruses. Keywords: exopolysaccharides, infection prophylaxis, nasal epithelium, respiratory virus, viral infection, EPSs

Abdelrahman Elsayed,1 Basant Elsayed,1 Mohamed Elmarasi,1 Ahmed Adel Elsabagh,1 Engy Elsayed,2 Ibrahim Elmakaty,1 Mohamed Yassin2,3 1Department of Medical Education, Hamad Medical Corporation, Doha, Qatar; 2College of Medicine, Qatar University, Doha, Qatar; 3Hematology Section, National Center for Cancer Care and Research (NCCCR), Doha, QatarCorrespondence: Ibrahim Elmakaty; Mohamed Yassin, Email ie1703006@qu.edu.qa; yassinmoha@gmail.comAbstract: Hematopoietic cell transplantation (HCT) is a well-established procedure that has become a therapeutic mainstay for various hematological conditions. Prolonged thrombocytopenia following HCT is associated with a significant risk of morbidity and mortality, yet no universally recognized treatment protocol exists for such a complication. First-generation thrombopoietin receptor (TpoR) agonists as well as second-generation agents are known for their role in enhancing platelet production, and their use is expanding across various thrombocytopenic conditions. Therefore, we conducted this comprehensive review of the literature to provide an updated evaluation of the use of TpoR agonists and explore their efficacy and safety in the treatment of extended post-HCT thrombocytopenia. The literature search was conducted using PubMed database from 1996 through December 2023, using a predefined strategy with medical subject headings terms. We identified 64 reports on the utility of TpoR agonists, five of them were randomized controlled trials and the rest were retrospective observational studies and case series, with a total number of 1730 patients. Second-generation TpoR agonists appear more convenient than subcutaneous recombinant human thrombopoietin (rhTpo) as they can be orally administered and exhibit similar efficacy in platelet recovery, as indicated by recent trial results. Among these agents, avatrombopag, unlike eltrombopag, does not require any dietary restrictions, which could be more favorable for patients. However, eltrombopag remains the most extensively studied agent. TpoR agonists had promising effects in the treatment of post-HCT thrombocytopenia with a good safety profile so far, highlighting the potential benefit of their use.Keywords: hematopoietic cell transplantation, thrombocytopenia, thrombopoietin receptor agonists, recombinant human thrombopoietin, romiplostim, eltrombopag

Alessandro Fiocchi,1 R Sharon Chinthrajah,2 Ignacio J Ansotegui,3 Panida Sriaroon,4 S Shahzad Mustafa,5 Pranil Raut,6 Briana Cameron,6 Sachin Gupta,1 David M Fleischer7 1Bambino Gesù Childrens’ Hospital IRCCS, Rome, Italy; 2Stanford University, Stanford, CA, USA; 3Hospital Quironsalud Bizkaia, Bilbao, Spain; 4University of South Florida, Tampa, FL, USA; 5Rochester Regional Health & University of Rochester, Rochester, NY, USA; 6Genentech Inc., South San Francisco, CA, USA; 7Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USACorrespondence: David M Fleischer, Section Head, Allergy & Immunology, University of Colorado School of Medicine and Children’s Hospital Colorado, 13123 East 16th Avenue, B518, Aurora, CO, 80045, USA, Tel +1-720-777-4393, Email David.Fleischer@childrenscolorado.orgBackground: The intrinsic link between food allergy and asthma is well-established, and comorbidity can exacerbate both conditions. Omalizumab, an anti-immunoglobulin E (IgE) antibody, has the biological plausibility to manage both conditions, but only a few small studies have assessed omalizumab in patients with comorbid asthma and food allergy.Patients and Methods: We conducted a post hoc analysis of placebo-controlled, randomized clinical trials (IA05 in children and 008/009 in adolescents/adults) and real-world observational studies (EXCELS and PROSPERO). For each study, patients with asthma were stratified by whether they had physician-reported food allergy, as per baseline characteristics data.Results: For patients with comorbid food allergy, there was evidence for increased atopy at baseline (numerically higher total IgE levels and atopic comorbidities). The collective body of evidence found that omalizumab consistently improved general and asthma-specific patient-centered outcomes (food allergy-specific outcomes were not available). For patients with asthma, omalizumab improved healthcare resource use (emergency room visits, hospitalizations, unscheduled doctor visits), quality of life (asthma-specific Asthma Quality of Life Questionnaire), productivity (missed work/school days and the Work Productivity and Activity Impairment: Asthma), and asthma outcomes (asthma exacerbations and Asthma Control Test score) regardless of comorbid food allergy.Conclusion: There was no loss of omalizumab efficacy even though patients with both asthma and food allergy appeared to be generally more atopic. Omalizumab may be a viable management option for patients with these comorbidities.Clinical trial registration: NCT00079937; NCT01922037; NCT00252135.Plain Language Summary: Food allergy and asthma are linked and if you have both conditions then you can feel worse. There is a treatment available, called omalizumab, that helps people with asthma and helps people with food allergy, but it’s not clear if it can help people with both conditions. Here, we look at whether omalizumab can help people with bad to very bad asthma (also called moderate to severe asthma) who also have food allergy. We found that omalizumab improved many aspects of a person’s life, including whether they visited the emergency room, were admitted to hospital, their quality of life, whether they missed school or work, and whether their asthma improved. These improvements occurred in all people with moderate to severe asthma, whether they had food allergy or did not have food allergy. This suggests that omalizumab can help people with both conditions.Keywords: asthma, food allergy, food hypersensitivity, healthcare resource use, omalizumab, productivity, quality of life

Miguel J Lanz,1 Michael Pollack,2 Ileen A Gilbert,2 Hitesh N Gandhi,2 Joseph P Tkacz,3 Njira L Lugogo4 1Allergy and Immunology Division, Nicklaus Children’s Hospital, Miami, FL, USA; 2BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 3Health Economics and Outcomes Research, IBM Watson Health, Bethesda, MD, USA; 4Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USACorrespondence: Ileen A Gilbert, BioPharmaceuticals, US Medical, AstraZeneca, 1800 Concord Pike, Wilmington, DE, 19803, USA, Tel +1 262-227-0686, Email ileen.gilbert@astrazeneca.comPurpose: To examine patterns of short-acting ß2-agonist (SABA) and maintenance therapy claims surrounding the subset of severe asthma exacerbations associated with outpatient, urgent care, or emergency department visits or hospitalization (termed serious exacerbations) in patients treated as intermittent or mild persistent asthma.Methods: This was a retrospective study of 2010– 2017 administrative claims from MerativeTM MarketScan® US databases for patients ≥ 12 years filling a SABA prescription for asthma (index). Patients had ≥ 12 months continuous insurance eligibility pre- and post-index and ≥ 1 additional SABA and/or maintenance medication fill appropriate for mild persistent asthma post-index. Prescription fills were assessed over 30 days before and after a serious exacerbation event.Results: Of 323,443 patients (mean [standard deviation] age: 34.9 [18.2] years; 62.0% female) treated as intermittent or mild persistent asthma, 51,690 (16.0%) experienced ≥ 1 serious exacerbation post-index. During the 30 days pre-event, a greater proportion of patients filled a SABA versus maintenance therapy (24.6% vs 19.0%; odds ratio [OR]: 1.39, 95% confidence interval [CI]: 1.35– 1.43; p < 0.001); during the 30 days post-event, patients were more likely to fill maintenance medication versus SABA (88.6% vs 67.0%; OR [95% CI]: 3.88 [3.75– 4.01]; p < 0.001). The closer in time prior to the event, the greater the likelihood of filling a SABA versus maintenance prescription (OR [95% CI]; 1– 7 days pre-event: 1.42 [1.36– 1.48]; 8– 14 days pre-event: 1.34 [1.27– 1.41]; 15– 30 days pre-event: 1.18 [1.12– 1.24]; all p < 0.001). Over 4.5 times more patients filled a maintenance therapy within 7 days post-event (45,014) versus all 30 days pre-event (9835) (OR [95% CI]: 28.7 [27.7– 29.7]; p < 0.001).Conclusion: These patterns of SABA rescue and maintenance fills suggest that a “window of opportunity” may exist to interrupt a serious exacerbation occurrence for patients treated as intermittent or mild persistent asthma if symptoms and inflammation are addressed concomitantly.Keywords: asthma, corticosteroid, inflammation, maintenance therapy, rescue therapy, short-acting ß2-agonist

Lorena Piñel Jimenez, Álvaro Martinez Mesa, Esther Sanchez Alvarez, Javier Lopez Garcia, Ana Aguilar Galvez, Nuria Reina Marfil, Belen Gómez Rodríguez, Eva Cabrera Cesar, Jose Luis Velasco Garrido Department of Pulmonology, Hospital Universitario Virgen de la Victoria, Málaga, SpainCorrespondence: Eva Cabrera Cesar, Department of Pulmonology, Hospital Universitario Virgen de la Victoria, Campus de Teatinos, S/N. 29010, Málaga, Spain, Tel +34 646905201, Email evacabreracesar@gmail.comObjective: To describe the clinical management of asthmatic patients and the level of compliance with the Guía Española para el Manejo del Asma (GEMA, Spanish Guidelines for Asthma Management) in the influential al area of Virgen de la Victoria University Hospital, Málaga (Spain).Materials and Methods: Descriptive, cross-sectional study in asthma patients from the Virgen de la Victoria University Hospital influential area, Málaga (Spain). Asthma Control Test (ACT) results, demographic and clinical characteristics, and GEMA indicators of quality asthma care were obtained from each participating patient.Results: Two hundred and eighty-eight patients (64.2% woman, mean age 48.6 years) were included in the study. The evaluation of the level of compliance with the GEMA quality indicators showed that in 20.8% of the patients the diagnosis of asthma was confirmed by spirometry and bronchodilator test, and 52.5% of the patients with suspicion of allergic asthma performed a sensitization test. Among the smoker patients, 76.3% were recommended to stop smoking; 14.2% of the patients received a paper-based educational plan. Regarding asthma treatment, 92.3% of patients with persistent asthma received inhaled glucocorticoids (IGC). IGC and LABA were the most common treatments for asthma, used in combination (ICG + LABA) in 139 (48.3%) patients; 32.6% discontinued SABA treatment during the study period. Asthma was well controlled in 54.9% of the patients (ACT score ≥ 20), and 13.9% of the patients registered exacerbations during the previous year with a mean (SD) of 1.38 (0.74) events.Conclusion: Most of the GEMA quality indicators of asthma care are not followed in real-world clinical practice. Specialists select the best option among the available treatments but there is an unmet need for training plans in other relevant aspects, such as diagnosis and/or disease monitoring.Keywords: asthma, asthma control, indicators of quality care, clinical guidelines, asthma management, compliance with guidelines

Yang Xi,1,&ast; Yu-Qin Deng,1,2,&ast; Han-Da Li,1 Wo-Er Jiao,1 Jin Chen,2 Jian-Jun Chen,3 Ze-Zhang Tao1,2 1Department of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Institute of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ze-Zhang Tao, Department of Otolaryngology, Head and Neck Surgery Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13907141892, Fax +86 27 88043958, Email taozezhang696@163.com Jian-Jun Chen, Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13659851719, +86 27 85726300, Email ylly80331@163.comPurpose: Up to now, there is no generally accepted biomarker to indicate the clinical response of immunotherapy. This study mainly analyzed the correlation between eosinophil cationic protein-myeloperoxidase (ECP-MPO) test papers and other immunotherapy indices in subcutaneous immunotherapy of dust mites and to explore whether the test paper can be used as an auxiliary index to quickly evaluate the efficacy of immunotherapy.Patients and methods: This study included 53 participants who received subcutaneous immunotherapy at the allergy clinic of Renmin Hospital of Wuhan University and 28 control participants. Six visits were conducted during a prospective study over one year. The results of the ECP-MPO test paper, nasal secretion eosinophil smear and count, nasal secretion ECP concentration, and clinical symptom scores were collected during five follow-up visits after the start of subcutaneous immunotherapy. Th1/Th2/Th17 cytokines, chemokines, IgE, IgG4 against dust mite components, and ECP concentrations were detected in the serum of participants at baseline, six months, and one year after subcutaneous immunotherapy.Results: The ECP test paper is not only easy to operate, but also can effectively and quickly detect the concentrations of ECP in the nasal secretion and diagnose allergic rhinitis. Symptom score is an important index for evaluating clinical immune efficacy, during subcutaneous immunotherapy, the ECP test paper showed a positive correlation with the symptom score. Simultaneously, during immunotherapy, the changes in the chromogenic grading of the test paper were synchronized with the changes in inflammatory cytokines and eosinophilic chemokines in Th2 cells of serum dust mite IgE. The sIgG4 against dust mites weakly negatively correlated with the concentration of ECP in nasal secretions and the color classification of the ECP test paper.Conclusion: The ECP-MPO test paper has a certain correlation with subcutaneous immunotherapy markers of allergic rhinitis, indicating that the ECP test paper may become an auxiliary biomarker to replace other complex laboratory tests.Keywords: dust mites, ECP-MPO test paper, subcutaneous immunotherapy, allergic rhinitis

Yuliana,1 Dewi Zakiawati2 1Oral Medicine Residency Program, Department of Oral Medicine, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Indonesia; 2Department of Oral Medicine, Faculty of Dentistry, Universitas Padjadjaran, Bandung, IndonesiaCorrespondence: Yuliana, Email yuliana21002@mail.unpad.ac.idIntroduction: Allergic stomatitis is an oral inflammatory disorder characterized by a painful, burning sensation, or itchiness in the oral cavity which clinically appears as erythematous plaques, vesiculation, ulceration, and/or hyperkeratosis. The causative agents include drugs, dental materials, and food ingredients. Allergic stomatitis might develop after a person eats, touches, or inhales food allergen which then triggers the hypersensitivity reaction. The most common types of food hypersensitivity generally involve type 1 and type 4 reactions or a combination of both.Purpose: This case report aims to discuss a case of allergic stomatitis caused by one of the staple food ingredients in Indonesia: cassava.Case: A 26-year-old woman came with complaints of burning pain from multiple ulcers on her right inner cheek. The ulcers appeared shortly after the patient ate boiled cassava, extending to the soft palate and causing pain when swallowing food. The patient has a history of asthma.Case Management: The patient was referred for a total IgE examination with a result of 271.41 KIU/L (normal < 150 KIU/L). She was prescribed an antiseptic mouthwash and topical corticosteroids for palliative therapy. Additionally, multivitamins were also prescribed to speed up the healing process.Conclusion: Allergic stomatitis can be caused by food ingredients, even those considered healthy or non-allergenic. A complete anamnesis, including the patient’s food history, along with supporting examinations, must be carried out to confirm the diagnosis and select appropriate therapy.Keywords: allergies, allergic stomatitis, hypersensitivity, cassava

Yue Yin,1,&ast; Yusen Hu,2,&ast; Yanning Li,1 Xia Peng,1 Huanjin Liao,1 Wei Shen,3 Li Li1 1Department of Laboratory Medicine, Shanghai General Hospital, Shanghai, People’s Republic of China; 2Department of Gastroenterology, Shanghai General Hospital, Shanghai, People’s Republic of China; 3Department of Laboratory Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Li, Department of Laboratory Medicine, Shanghai General Hospital, Shanghai, People’s Republic of China, Email annylish@126.com Wei Shen, Department of Laboratory Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, People’s Republic of China, Email applessw@163.comBackground: Mast cells can be activated in various ways and were shown to be involved in the development of Crohn’s disease (CD). The diagnosis of CD is still challenging, and seeking novel biomarkers is a worthwhile endeavor.Methods: An indirect enzyme-linked immunosorbent assay (ELISA) was successfully established for semi-quantitative detection of IgG anti-Fc&epsiv;RI in serum using human Fc&epsiv;RIα coated microplates and an enzyme-labeled anti-human IgG as secondary antibodies. The optimal working conditions were explored, followed by conducting the method evaluation. The serum samples and clinical data of 117 CD patients and 75 healthy controls were collected. IgE was measured by the rate turbidity turbidimetry; IgG anti-IgE and IgG anti-Fc&epsiv;RI were detected by ELISA. IgG anti-pancreatic antibody (PAB) and anti-Saccharomyces cerevisiae antibody (ASCA) were determined by indirect immunofluorescence assay. Data were analyzed concerning the clinical characteristics.Results: IgG anti-Fc&epsiv;RI was an effective marker for CD (P < 0.001), but IgE and IgG anti-IgE (P = 0.089, 0.219, respectively) were not. There was a positive correlation between anti-IgE and anti-Fc&epsiv;RI (R = 0.380, P < 0.001). Anti-Fc&epsiv;RI positive patients behaved with higher disease activity [OR: 1.478 (1.200~1.821), P < 0.001], but were less likely to be located in L4 among Montreal classification [OR: 0.253 (0.077~0.837), P = 0.024]. Existing indicators, PAB and ASCA, behaved with high specificity (both > 95%) with low sensitivity (both < 30%). The combination of anti-Fc&epsiv;RI with existing markers significantly improved the diagnostic efficiency [AUC: 0.879 (0.831~0.928)].Conclusion: An ELISA for the detection of anti-Fc&epsiv;RI was established and validated, which may contribute to facilitating research on Crohn’s diseases. Anti-Fc&epsiv;RI positive CD patients were associated with higher disease activity indices, suggesting its potential value in the diagnosis and management of CD.Keywords: Crohn’s disease, anti-Fc&epsiv;RI, biomarkers, autoantibodies, mast cells

Murong Wang,1,&ast; Qunfang Zhou,2,&ast; Hui Li,1 Mingyu Liu,3 Ruixia Li,4 Wei Wang,5 Xiaohui Wang,6 Jinhua Huang,1 Feng Duan2 1Department of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong province, People’s Republic of China; 2Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Minimally Invasive Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong province, People’s Republic of China; 4Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong province, People’s Republic of China; 5Department of General Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, People’s Republic of China; 6Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinhua Huang, Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, People’s Republic of China, Tel/Fax +86-020-87343272, Email huangjh@sysucc.org.cn Feng Duan, Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China, Tel/Fax +8610-66939123, Email duanfeng@vip.sina.comPurpose: The outcome between Lenvatinib plus programmed cell death protein-1 (PD-1) inhibitor and Lenvatinib in HCC beyond oligometastasis was unclear. In this multicenter, we compared the prognosis of Lenvatinib plus PD-1 inhibitor with Lenvatinib in HCC beyond oligometastasis.Patients and Methods: A total of 296 patients from six institutions were included. The patients were divided into two groups: (a) concurrent Lenvatinib plus PD-1 inhibitor treatment (Len+PD-1 group) and (b) Lenvatinib monotherapy (Len group). The primary endpoint was overall survival (OS), the second endpoint was progression-free survival (PFS) and efficacy.Results: The median OS was 20.1 ± 1.2 (17.7– 22.5) months and 15.7 ± 1.5 (12.8– 18.6) months in the Len+PD-1 and Len groups, respectively. The 12-, 24-, and 36-month OS rates were 79.1%, 39.4%, and 10.7% in the Len+PD-1 group, and 76.3%, 29.7%, and 0% in the Len group, respectively. The OS and PFS rates of the Len+PD-1 group were significantly longer compared with the Len group (hazard ratio [HR], 0.88; 95% confidence index [CI], 0.49– 0.94; P = 0.021) and (HR, 0.66; 95% CI, 0.50– 0.87; P = 0.003). A subgroup analysis revealed that OS (HR, 0.57; 95% CI, 0.36– 0.90; P = 0.016) was improved between the Len+PD-1 and Len groups with hepatic artery infusion chemotherapy (HAIC) treatment, whereas OS (HR, 1.11; 95% CI, 0.68– 1.80; P = 0.689) was similar between the Len and Len+PD-1 groups without HAIC.Conclusion: Lenvatinib combined with PD-1 inhibitor significantly improves the survival of HCC beyond oligometastasis. For patients with HAIC, there was obviously significance between Len and Len+PD-1 groups.Plain Language Summary: Lenvatinib as one of system therapy, is recommended treatment for HCC with multimetastases. The LEAP-002 trial, which evaluated Lenvatinib combined with Pembrolizumab exhibited improved progression-free survival (PFS) and overall survival (OS) compared with Lenvatinib alone. However, the combination efficacy on HCC beyond oligometastasis is unknown. In this multicenter study, we found that Lenvatinib combined with PD-1 inhibitor significantly improved both the OS and PFS and this combination could be recommended for HCC beyond oligometastases. OS and PFS were improved in the Len+PD-1 versus the Len group with hepatic artery infusion chemotherapy (HAIC) treatment, whereas the OS and PFS were similar between the Len and Len+PD-1 groups without HAIC. We provided clinical value that HAIC could be recommended as an effective local therapy to improve the prognosis for advanced HCC.Keywords: advanced hepatocellular carcinoma, Lenvatinib, beyond oligometastasis, prognosis, programmed death receptor-1 inhibitor

Li Wang, Li Liu, Jing Zhao, Xin Yu, Chunxia Su Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Chunxia Su, Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China, Email susu_mail@126.comBackground: Immunotherapy has become the standard treatment for driving gene-negative advanced non-small cell lung cancer (NSCLC). However, compared to PD-L1-positive patients, the efficacy of Anti-PD-(L)1 monotherapy is suboptimal in PD-L1-negative advanced NSCLC. In this study, we aim to analyze the optimal immunotherapy approach for PD-L1-negative NSCLC patients and develop a new nomogram to enhance the clinical predictability of immunotherapy for NSCLC patients.Methods: In this study, we retrieved clinical information and genomic data from cBioPortal for NSCLC patients undergoing immunotherapy. Cox regression analyses were utilized to screen the clinical information and genomic data that related to survival. The prognostic-relate genes function was studied by comprehensive bioinformatics analyses. The Kaplan-Meier plot method was employed for survival analysis.Results: A total of 199 PD-L1-negative NSCLC patients were included in this study. Among them, 165 patients received Anti-PD-(L)1 monotherapy, while 34 patients received Anti-PD-(L)1+Anti-CTLA-4 combination therapy. The Anti-PD-(L)1+Anti-CTLA-4 combination therapy demonstrated significantly higher PFS compared to the Anti-PD-(L)1 monotherapy. The mutation status of KRAS, ANO1, COL14A1, LTBP1. ERBB4 and PCSK5 were found to correlate with PFS. Utilizing the clinicopathological parameters and genomic data of the patients, a novel nomogram was developed to predict the prognosis of Anti-PD-(L)1+Anti-CTLA-4 combination therapy.Conclusion: Our study revealed that KRAS, ANO1, COL14A1, LTBP1. ERBB4 and PCSK5 mutation could serve as predictive biomarkers for patients with Anti-PD-(L)1+Anti-CTLA-4 combination therapy. Our systematic nomogram demonstrates significant potential in predicting the prognosis for NSCLC patients with responsive to dual PD-1/CTLA-4 blockade.Keywords: NSCLC, immunotherapy, immune checkpoint inhibitors, nomogram, cBioPortal

Semei Christopher Mukama,1 Jane Senyondo Nakawesi,1 Dedrix Stephenson Bindeeba,1 Simon Ezajobo,1 Andrew Mugisa,1 Catherine Senyimba,1 Eve Namitala,1 Robert Onzima DDM Anguyo,2 Simon Peter Katongole,3 Barbara Mukasa1 1Mildmay Uganda, Kampala, Uganda; 2Department of International Public Health, Liverpool School of Tropical Medicine (LSTM), Kampala, Uganda; 3Department of Public Health, Gudie University Project, Kampala, UgandaCorrespondence: Simon Peter Katongole, Email spkatongole@gmail.comBackground: This study evaluated the effectiveness and responsiveness of differentiated Human Immunodeficiency Virus (HIV)/Acquired Immuno-Deficiency Syndrome (AIDS) service delivery models (DSDMs) implemented to enhance antiretroviral therapy (ART) access and outcomes for patients while addressing Tuberculosis (TB)-HIV integration, focusing on four of the five DSDMs currently implemented in Uganda.Methodology: A descriptive cross-sectional survey was conducted in eight districts of central Uganda using Lot Quality Assurance Sampling approach from 7th to 23rd March 2023. We randomly sampled 2668 patients who have been on ART for at least 1 year in a Facility-Based Individual Management (FBIM) model or in a non-FBIM DSDM for at least one year. Data were collected through patient interviews and review of records in ART and DSDM registers as well as ART cards. We analyzed the data in proportions, comparing the selected ART outcome and responsiveness indicators between Community Client Led ART Distribution (CCLAD), Community Drugs Distribution Point (CDDP) and Fast-Track Drug Refill (FTDR) DSDMs with the standard care (FBIM) model. The ART outcome variables include patients retained in the 1st line of the ART regimen, patients in World Health Organization clinical stage 1 during the last facility visit, patients who had no CD4 request during the past 12 months, viral load suppression, ART adherence, and patients who reported that they did not experience HIV/AIDS-related symptoms in the past 6 months. The variables on TB care include screening for TB using the intensified case finding form and patients tested positive for TB. Responsiveness variables include the perceived; travel time for ART refill, travel distance for ART refill, convenience and flexibility during ART refill, cost of travel for ART refill, fear of being seen at ART refill point, waiting time before service, adequacy of service time, crowding and risk of infections, social support, ability to address ART treatment challenges, HIV status disclosure and barriers to access. Non-overlap in 95% confidence interval in indicator proportion between non-FBIM DSDM and FBIM means a statistically significant difference in proportion, or otherwise non-significant.Results: Higher proportions of ART patients in the CCLAD and CDDP DSDMs adhered to ART, had suppressed viral load, and a lower TB prevalence than those in FBIM model. Additionally, more CCLAD and CDDP clients reported shorter travel time and distance to access ART than their counterparts in the FBIM model. Compared to FBIM model, higher proportions of those in CCLAD and CDDP also reported flexibility in ART refill scheduling, reduced transport costs, fewer privacy concerns, less HIV/AIDS-related stigma, shorter waiting times, more efficient services, decreased congestion at ART pickup sites, enhanced peer support, improved problem-solving assistance, and increased HIV status disclosure. The FTDR model outperformed FBIM in proportions with fewer requests for CD4 testing, viral load suppression, as well as proportions of clients who reported; shorter travel time, lower transportation cost, decreased privacy concerns, shorter waiting time, and efficient service provision. Compared to both CDDP and FTDR, the FBIM had a higher proportion of clients remain on the first-line ART regimen.Conclusion: Community-based DSDMs show responsiveness to clients’ needs without compromising the effectiveness of ART care for patients. Although FTDR also demonstrates high effectiveness and responsiveness for clients on ART, there is potential for further improvement. Planners and implementers of ART programs should consider both demand- and supply-side innovations to sustain the continuation of DSDMs.Keywords: HIV/AIDS, TB-HIV, DSDM, LQAS

Andrew Marvin Kanyike,1,2,&ast; Ashley Winfred Nakawuki,3 Gabriel Madut Akech,1 Raymond Bernard Kihumuro,4 Timothy Mwanje Kintu,5 Racheal Nalunkuma,2 Rachael Mukisa Nakandi,2 Joshua Mugabi,1 Nicholas Twijukye,1 Denis Bwayo,1 Richard Katuramu1,&ast; 1Department of Internal Medicine, Faculty of Health Sciences, Busitema University, Mbale, Uganda; 2Department of Internal Medicine, Mengo Hospital, Kampala, Uganda; 3Department of Nursing, Faculty of Health Sciences, Busitema University, Mbale, Uganda; 4Way Forward Youth Africa Limited, Kampala, Uganda; 5Department of Internal Medicine, Mulago National Referral Hospital, Kampala, Uganda&ast;These authors contributed equally to this workCorrespondence: Andrew Marvin Kanyike, Department of Internal Medicine, Mengo Hospital, Kampala, Uganda, Email andrewmarvinkanyike@gmail.comIntroduction: Despite advancements in Antiretroviral Therapy (ART), people living with HIV (PLHIV) face increasing risks of HTN, leading to significant morbidity and premature mortality, undermining the hard-earned gains of fighting HIV. The prevalence of hypertension among HIV patients and associated risk factors has not been extensively studied in the rural parts of Uganda.Objective: We assessed the prevalence, awareness, and factors associated with hypertension among PLHIV at two health facilities in Eastern Uganda.Methods: A cross-sectional study was conducted at Mbale Regional Referral Hospital and Bugobero Health Center IV HIV clinics from May to July 2023. We recruited patients with HIV above the age of 18 years and willing to consent. Participants were interviewed using a structured questionnaire adapted from the WHO STEPwise approach to noncommunicable disease risk factor surveillance (STEPS) and the AIDS Clinical Trials Group. Anthropometric measurements and blood pressure were taken. Bivariate and multivariable logistic regression were performed. A P value < 0.2 in the bivariate analysis was transferred to the multivariable logistic regression model. A P value < 0.05 was statistically significant.Results: The study surveyed 400 PLHIV with a mean age of 46.5 (SD: 12.4) years; most were female (n=261, 65.3%). Hypertension prevalence was at 37.5%, with 20.5% in stage 2 and 68% ((n=102) of hypertensive participants were unaware. Hypertension was associated with age ≥ 50 years (aOR: 2.11, 95% CI: 1.33– 3.37, p = 0.002), a suppressed viral load (aOR: 3.71, 95% CI: 1.02– 5.13, p = 0.046) and BMI ≥ 25 Kg/m2 (aOR: 1.64, 95% CI: 1.01– 2.66, p = 0.044).Conclusion: Hypertension is a significant burden among PLHIV in Eastern Uganda, influenced by HIV and lifestyle-related risk factors. Improved screening and diagnosis are needed with close monitoring for patients with viral load suppression due to the possible negative effects of ART on blood pressure.Plain Language Summary: This study explored the prevalence, awareness, and risk factors linked to high blood pressure among people living with HIV (PLHIV) at two health facilities in Eastern Uganda. We found that 37.5% of the participants had high blood pressure, yet the majority (68%) were unaware of their condition. We identified older age ≥ 50 years, a higher body mass index (BMI) ≥ 25 kg/m2, and having a suppressed viral load as significant risk factors for high blood pressure among PLHIV. These results reveal the urgent need for improved health strategies that integrate the management of HIV and hypertension and preventive care to enhance the overall health outcomes for PLHIV in rural areas.Keywords: human immunodeficiency syndrome, antiretroviral therapy, hypertension, body mass index

Jianqun Yin,&ast; Jiawei Chen,&ast; Ting Wang, Huiming Sun, Yongdong Yan, Canhong Zhu, Li Huang, Zhengrong Chen Respiratory Department, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengrong Chen; Li Huang, Respiratory Department, Children’s Hospital of Soochow University, No. 303 Jingde Road, Gusu District, Suzhou City, Jiangsu Province, People’s Republic of China, Tel +86-13771721180 ; +86-18962183510, Email chenzhengrong@suda.edu.cn; huanglilcy@163.comObjective: To investigate the significance of VISTA in bronchial asthma and its impact on the disease.Methods: Human peripheral blood of asthma children was gathered. The expression concentrations of VISTA, IL-4, IL-6, CD25, CD40L, and PD-L2 in peripheral blood plasma were detected by ELISA. We established the mouse model of asthma and intervened with agonistic anti-VISTA mAb (4C11) and VISTA fusion protein. ELISA, flow cytometry, and Western blotting were performed to detect the expression levels of Th1, Th2, and Th17 cell subsets and related characteristic cytokines, as well as the protein levels of MAPKs, NF-κB, and TRAF6 in lung tissues. In addition, the infiltration of eosinophils and inflammatory cells, airway mucus secretion, and VISTA protein expression in lung histopathological sections of different groups of mice were analyzed.Results: The concentration of VISTA in human asthma group decreased significantly (p < 0.05); A positive correlation was observed between VISTA and CD40L. The intervention of 4C11 mAb and fusion protein respectively during the induction period increase the differentiation of Th1 cells and the secretion of IFN-γ, and inhibit the differentiation of Th2 and Th17 cells, as well as the secretion of IL-4, IL-5, IL-13 and IL-17, partially reduce the pathological changes of asthma in mouse lungs and correct the progress of asthma. The MAPK, NF-κB, and TRAF6 protein levels were the middle range in the 4C11 mAb and fusion protein groups (p < 0.05).Conclusion: The findings suggest VISTA may play a negative regulatory role in the occurrence and development of bronchial asthma.Keywords: VISTA, bronchial asthma, Th2 cells, cytokines, anti-VISTA mAb, VISTA fusion protein

Craig LaForce,1 Frank C Albers,2 Mark Cooper,3 Anna Danilewicz,4 Lynn Dunsire,3 Robert Rees,4 Christy Cappelletti5 1North Carolina Clinical Research, Chapel Hill, NC, USA; 2Avillion, Northbrook, IL, USA; 3BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, UK; 4Avillion, London, UK; 5BioPharmaceuticals Research and Development, AstraZeneca, Durham, NC, USACorrespondence: Mark Cooper, BioPharmaceuticals Reseach and Development, AstraZeneca, Cambridge, UK, Email mark.cooper1@astrazeneca.comPurpose: Decentralized clinical trials, where trial-related activities occur at locations other than traditional clinical sites(eg participant homes, local healthcare facilities), have the potential to improve trial access for people for whom time and/or distance constraints may impede participation. Albuterol–budesonide 180/160 μg pressurized metered-dose inhaler (pMDI) is FDA approved for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years or older. BATURA (NCT05505734) is a fully decentralized study, investigating as-needed albuterol–budesonide in participants with mild asthma.Methods: BATURA is a fully decentralized, phase 3b, randomized, double-blind, event-driven exacerbation study conducted in the United States. Participants aged ≥ 12 years using as-needed short-acting β2-agonist (SABA), alone or with low-dose inhaled corticosteroid or leukotriene receptor antagonist maintenance, are randomized 1:1 to as-needed albuterol–budesonide 180/160 μg or albuterol 180 μg pMDI for up to 52 weeks (minimum 12 weeks). Participants continue their current maintenance therapy, if applicable. Participants must have used SABA for ≥ 2 days in the 2 weeks pre-enrollment and have an Asthma Impairment Risk Questionnaire score ≥ 2 at screening and randomization. All trial-related visits, including screening and consent, are conducted virtually, with study medication shipped directly to each participant’s residence. The primary objective is to evaluate the efficacy of as-needed albuterol–budesonide versus albuterol on severe asthma exacerbation risk, measured by time-to-first severe asthma exacerbation (primary endpoint). Secondary endpoints include annualized rate of severe asthma exacerbation and total systemic corticosteroid exposure. Study medication use is captured via a Hailie sensor attached to the study medication pMDI. The intended sample size is 2500 participants.Conclusion: BATURA evaluates as-needed albuterol–budesonide in participants with mild asthma. The decentralized study model enables the trial to move out of research sites into participant homes, reducing participant burden and improving access.Keywords: decentralized clinical trials, trial design, albuterol–budesonide, SABA–ICS

Shivani Srivastava,1,&ast; Anuradha Tyagi,2,&ast; Vishakha Anand Pawar,3,&ast; Nawaid Hussain Khan,4,&ast; Kavita Arora,5,6 Chaitenya Verma,7,8 Vinay Kumar9 1Department of Pathology, School of Medicine, Yale University, New Haven, CT, USA; 2Department of cBRN, Institute of Nuclear Medicine and Allied Science, Delhi, India; 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Faculty of Medicine, Ala-Too International University, Bishkek, Kyrgyz Republic; 5Advanced Instrumentation Research Facility, Jawaharlal Nehru University, New Delhi, India; 6School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India; 7Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, USA; 8Department of Biotechnology, SSET, Sharda University, Greater Noida, 201306, India; 9Pennsylvania State University Hershey Medical Center, 500 University Dr, Heshey, PA, USA&ast;These authors contributed equally to this workCorrespondence: Chaitenya Verma; Vinay Kumar, Email chaitenya999@gmail.com; vinayktyagi07@gmail.comAbstract: The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.Keywords: CAR-T cells, immune checkpoint inhibitors, gene therapies, gene editing, predictive biomarkers

Anderson Bendera,1 Deogratias Mugisha Baryomuntebe,2 Nwanna Uchechukwu Kevin,3 Miisa Nanyingi,4 Patience Bemanya Kinengyere,5 Salaam Mujeeb,6 Esther Jachi Sulle7 1Department of Radiology and Medical Imaging, Monduli District Hospital, Arusha, Tanzania; 2Faculty of Nursing, Fins Medical University, Kampala, Uganda; 3Department of Community Health, University of Rwanda, Kigali, Rwanda; 4Department of Health Sciences, Uganda Martyrs University, Kampala, Uganda; 5AiKA Health Consults, Kampala, Uganda; 6Department of Pathology, Islamic University in Uganda, Kampala, Uganda; 7Credit Department, WEDAC Microfinance Institution Ltd, Arusha, TanzaniaCorrespondence: Anderson Bendera, Department of Radiology and Medical Imaging, Monduli District Hospital, P. O. Box 12, Arusha, Tanzania, Email andybendera@gmail.comBackground: About half of people infected with Human Immunodeficiency Virus (HIV) often present late for care, resulting in higher healthcare costs, undesired treatment outcomes, and ongoing HIV transmission. This study aimed to assess the prevalence and determinants of late HIV diagnosis and advanced HIV disease (AHD) in Tanzania.Methods: Data were obtained from the 2016– 17 Tanzania HIV impact survey. We included 677 newly diagnosed people living with HIV. Late HIV diagnosis and AHD were defined as having a CD4 cell count below 350 cells/μL or 200 cells/μL at diagnosis, respectively. Bivariate and multivariable logistic regression models were fitted to identify the determinants of late HIV diagnosis or AHD.Results: The mean age of the participants was 37.8 years (SD, 12.4). About two-thirds were women (62.6%). The prevalence of late HIV diagnosis was 42.4%, whereas the prevalence of AHD was 17.7%. Factors associated with late HIV diagnosis included age 31– 40 years (adjusted odds ratio [aOR] = 1.72, 95% confidence interval [CI]: 1.14– 2.60), age ≥ 41 years (aOR = 1.79, 95% CI: 1.16– 2.76), male sex (aOR = 1.88, 95% CI: 1.29– 2.73), and active syphilis infection (aOR=2.63, 95% CI: 1.20– 5.76). Factors associated with AHD were age 31– 40 years (aOR = 2.12, 95% CI: 1.18– 3.81), age ≥ 41 years (aOR = 2.42, 95% CI: 1.32– 4.41), male sex (aOR = 1.77, 95% CI: 1.09– 2.87), formal education (aOR = 0.49, 95% CI: 0.30– 0.81) and active syphilis infection (aOR = 2.49, 95% CI: 1.07– 5.77).Conclusion: Late HIV diagnosis and AHD are prevalent among newly diagnosed people living with HIV in Tanzania. Specific subgroups are more likely to present late for HIV care, including middle-aged and older adults, men, illiterate individuals, and those with active syphilis and HIV co-infection. Therefore, we recommend expanding HIV testing services and implementing targeted interventions to improve early access and enrollment in HIV care.Keywords: advanced HIV disease, HIV/AIDS, HIV care, late presentation, Tanzania

Luca Potestio,1,&ast; Cataldo Patruno,2,&ast; Stefano Dastoli,2 Claudio Brescia,1 Maddalena Napolitano1 1Section of Dermatology Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; 2Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy&ast;These authors contributed equally to this workCorrespondence: Luca Potestio, Section of Dermatology Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, Napoli, 80131, Italy, Tel +39 081 7462457 ; Fax +39 081 7462442, Email potestioluca@gmail.comIntroduction: Even if mild forms of atopic dermatitis (AD) are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging, especially in special populations (SPs). These patients include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials. As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. In this context, the aim of our study was to retrospectively investigate the effectiveness and safety of tralokinumab in the management of AD in SPs.Methods: A 24-weeks retrospective, dual-center study was performed enrolling patients with a diagnosis of moderate-to-severe AD undergoing treatment with tralokinumab at labelled dosage. Disease severity was assessed using Eczema Area Severity Index (EASI), Pruritus–Numerical Rating Scale (P-NRS), and Dermatology Life Quality Index (DLQI) score at baseline and after 4 weeks (W4), W16, and W24. Adverse events (AEs) were monitored at the same timepoints. Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student’s t-test, considering significant a p-value < 0.05.Results: Our study enrolling 27 SPs patients showed a significant improvement in EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decreases at each timepoint as compared with baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease.Discussion: Our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.Keywords: atopic dermatitis, special populations, treatment, tralokinumab, biologics

Wei Wang,1,&ast; Ruixia Li,2,&ast; Hui Li,3 Murong Wang,3 Juncheng Wang,4 Xiaohui Wang,5 Qunfang Zhou6 1Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, People’s Republic of China; 2Department of Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 4Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 5Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan, People’s Republic of China; 6Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohui Wang, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province, 410005, People’s Republic of China, Tel +86-0731-83928052, Email xiaohuiwang21@163.com Qunfang Zhou, Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China, Tel +86-010-66939123, Email zhouqun988509@163.comPurpose: The prognosis of infiltrative hepatocellular carcinoma (HCC) is dismal. Hepatic arterial infusion chemotherapy (HAIC) plus Lenvatinib (Len) and immune checkpoint inhibitor (ICI) have shown promising results for HCC. However, this three combination therapy on infiltrative HCC is unknown. In this study, we compared HAIC plus lenvatinib (Len) and programmed cell death protein-1 (PD-1) inhibitor with HAIC plus Len for infiltrative HCC.Patients and Methods: This multi-center cohort study included patients with infiltrative HCC who received HAIC combined with Len (HAIC+Len group, n = 173) or HAIC combined with Len and PD-1 inhibitor (HAIC+Len+ICI group, n = 128) as the first-line treatment from January 2019 to December 2021. To balance any intergroup differences, one-to-one propensity score matching (PSM) was applied. Overall survival (OS) and progression-free survival (PFS) were compared between the two groups.Results: After PSM, the median OS was 14.1 ± 1.0 and 16.1 ± 1.4 months in the HAIC+Len and HAIC+Len+ICI groups, respectively. The median PFS was 4.6 ± 0.4 months in the HAIC+Len group and 7.5 ± 0.8 months in the HAIC+Len+ICI group. The HAIC+Len+ICI group showed significantly better OS (hazard ratio [HR], 0.66; 95% CI, 0.49– 0.90; P = 0.008) and PFS (HR, 0.53; 95% confident index [CI], 0.40– 0.70; P < 0.001) compared with the HAIC+Len group. Subgroup analysis revealed that for OS in HCC without metastasis, the addition of PD-1 inhibitor was not significant (HR, 0.68; 95% CI, 0.43– 1.07; P = 0.091). No difference was observed in OS between low (2– 3 cycles) and high (4– 6 cycles) level of HAIC cycles (HR, 0.99; 95% CI, 0.67– 1.44; P = 0.938).Conclusion: The HAIC+Len+ICI group had a longer PFS and OS compared with the HAIC+Len group, demonstrating an acceptable safety profile. This triple combination strategy may be an alternative treatment for infiltrative HCC management.Plain language summary: The evidence of HAIC plus Len and PD-1 inhibitors for infiltrative HCC is limited. There was no study to evaluate the efficacy of HAIC combined with Len and PD-1 inhibitors for infiltrative HCC. In this study, we found that HAIC plus Len and PD-1 inhibitor (HAIC+Len+ICI) was associated with longer progression-free survival and overall survival than HAIC plus Len combination (HAIC+Len) for patient with infiltrative HCC. In addition, OS in patients with metastasis was improved with HAIC+Len+ICI treatment. OS in patients without metastasis, addition of PD-1 inhibitor after HAIC and Len was not beneficial. What’s more, three cycles of HAIC are adequate, especially for patients with high tumor burden, especially with main branch portal vein tumor thrombus (PVTT). Our research provides new evidence that HAIC+Len+ICI treatment significantly improved the OS and PFS of infiltrative HCC patients compared with those who received HAIC+Len treatment. It provides a strong reference for clinical treatment.Keywords: Infiltrative hepatocellular carcinoma, hepatic arterial infusion chemotherapy, Len, PD-1 inhibitor, Prognosis

Joon Young Choi,1 Chin Kook Rhee2 1Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Chin Kook Rhee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea, Tel +82 2 2258 6067, Fax +82 2 599 3589, Email chinkook77@gmail.comAbstract: Asthma is a chronic inflammatory airway disease with significant burden; exacerbations can severely affect quality of life and healthcare costs. Advances in big data analysis and artificial intelligence have made it easier to predict future exacerbations more accurately. This study used an integrated dataset of Korean National Health Insurance, meteorological, air pollution, and viral data from national public databases to develop a model to predict asthma exacerbations on a daily basis in South Korea. We merged these sources and applied random forest, AdaBoost, XGBoost, and LightGBM machine learning models to compare their performances at predicting future exacerbations. Of the models, XGBoost (AUROC of 0.68 and accuracy of 0.96) and LightGBM (AUROC of 0.67 and accuracy of 0.96) were the most promising. Common important variables were the number of visits and exacerbations per year, and medical resource utilization, including the prescription of asthma medications. Comorbid diabetes, hypertension, gastroesophageal reflux, arthritis, metabolic syndrome, osteoporosis, and ischemic heart disease were also associated with elevated exacerbation risk. The models examined in this study highlight the importance of previous exacerbations, use of medical resources, and comorbidities in the prediction of future exacerbations in patients with asthma.Keywords: asthma, machine learning, big data analysis, South Korea, XGBoost, LightGBM

Liu Yang,1 Kaijie Gao,1 Weihua Gong,1 Ci Li,1 Nan Chen,1 Tiewei Li,1 Shan Wang,1 Jiajia Ni,2,3 Junmei Yang1 1Department of Clinical Laboratory, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou Key Laboratory of Children’s Infection and Immunity, Zhengzhou, Henan, People’s Republic of China; 2Research and Development Center, Guangdong Meilikang Bio-Science Ltd, Foshan, Guangdong People’s Republic of China; 3Department of Detection and Diagnosis Technology Research, Guangzhou National Laboratory, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Junmei Yang, Email yangjunmei7683@163.comPurpose: Although allergic diseases in children are on the rise, there has been no comprehensive investigation of the allergens affecting children with allergic diseases in central China. Therefore, we aimed to analyze the distribution of serum allergen species among children with allergic conditions in central China to inform the prevention, diagnosis, and treatment of childhood allergies.Patients and Methods: A total of 9213 children (5543 males with 2.88 ± 0.04 years old and 3670 females with 2.91 ± 0.05 years old) underwent allergen screening, and serum allergen-specific IgE (sIgE) antibodies were detected using an automated fluorescent enzyme immunoassay system.Results: Our findings revealed a total sIgE-positive rate (sIgE-PR) of 57.83%, with mixed food (42.10%), egg whites (30.83%), milk (28.97%), mixed dust mites (24.57%), and mixed molds (23.20%) being the most prevalent source of allergens. The sIgE-PR for common sources of allergens exhibited significant sex-based differences, with males having greater susceptibility than females (p< 0.05). Dust mites were the primary source of inhaled allergens, whereas egg white was the predominant source of food allergens. Sources of food allergens were most dominant among infants (0– 3 years old); sIgE-PRs for most source of food allergens decreased with age, whereas those for most source of inhaled allergens increased. The autumn sIgE-PRs for mixed molds, weed pollen combinations, and tree pollen combinations were significantly higher than those found in other seasons (p< 0.05).Conclusion: Our findings suggest that sources of allergens profiles in children with allergies vary across age groups and seasons. Understanding these patterns can improve the effective prevention of childhood allergies.Keywords: allergen, childhood allergies, IgE antibodies, source of food allergens, allergy prevention

Jingxuan Zhang,1,&ast; Yun Yan,1,&ast; Feifei Jiang,2,&ast; Jingguo Chen,3,&ast; Yuhui Ouyang,1,4,5 Luo Zhang1,4,5 1Department of Allergy, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi ‘an Jiaotong University, Xi’an, People’s Republic of China; 4Beijing Laboratory of Allergic Diseases, Municipal Education Commission and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, People’s Republic of China; 5Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuhui Ouyang; Luo Zhang, Department of Allergy, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +8610 58268375 ; +8610 65141136, Fax +8610 85115988, Email oyyuhui@sina.com; dr.luozhang@139.comBackground: Pollen allergies have a high prevalence in northern China, whereas, the types of pollen allergens and population characteristics among different regions remain unclear.Objective: To study the species and temporal distribution of the main allergenic pollen, as well as the characteristics of patients with pollen-related allergic rhinitis (AR) in different cities in northern China.Methods: Pollen data were obtained from pollen-monitoring stations in 13 cities of northern China between 2020 and 2021. Questionnaire surveys and allergen testing were conducted in 494 patients with pollen-related allergies from Beijing in Central, Shenyang in Northeast, and Xi’an in Northwest China.Results: In 13 cities of northern China, the main sources of pollen were cypress, poplar, elm, pine, birch and ash in spring, and mugwort, goosefoot, hop and ragweed in autumn. In Northwest China, the spring and autumn pollen periods started earlier and lasted longer than that in Central and Northeast China, and the pollen counts in autumn in was significantly higher than that in Central and Northeast China. Furthermore, the nasal, ocular and respiratory symptom and quality of life scores of AR patients in Northwest China were significantly higher than that in Central and Northeast China. 69.32– 73.28% of patients had annual cost of anti-allergic medication between 500– 5000 yuan. However, 40.93– 48.86% of patients reported minor control of symptoms.Conclusion: Our results can be used as a basis for developing effective prevention and management measures for patients with pollen-related allergy in these regions, including timely pollen monitoring, patient guidance on protective measures, early intervention, and specific immunotherapy, to improve pollen-related allergy management.Keywords: allergic rhinitis, pollen monitoring, Northern China, questionnaire survey, symptom scores

Ping Wu,1 Yijing Hu,2 Xiaoxia Yan3 1School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Respiratory Medicine, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of ChinaCorrespondence: Xiaoxia Yan, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of China, Tel +86 13761286006, Email xiaoxia.yan@qq.com Yijing Hu, Department of Respiratory Medicine, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86 18917180737, Email huyijing@shchildren.com.cnAbstract: Asthma is the most common chronic respiratory disease in children. It has a serious impact on children’s physical and mental health. Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention for patients with chronic respiratory disease, whose major components include breathing training, inspiratory muscle training and exercise training. Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention for patients with chronic respiratory diseases, the main components of which are breathing training, inspiratory muscle training and exercise training. Pulmonary rehabilitation can improve the physical and mental condition of patients with chronic respiratory diseases and promote healthy behaviors. However, there is little research on pulmonary rehabilitation in children with asthma. This review comprehensively evaluated the effect of pulmonary rehabilitation in children with asthma at home and abroad, aiming to provide reference for clinical research on pulmonary rehabilitation in children with asthma.Keywords: bronchial asthma, pulmonary rehabilitation, breathing training, inspiratory muscle training, exercise training

Bradley E Chipps,1 Robert S Zeiger,2 David A Beuther,3 Robert A Wise,4 William McCann,5 Joan Reibman,6 Maureen George,7 Ileen Gilbert,8 James M Eudicone,8 Karin S Coyne,9 Gale Harding,9 Kevin R Murphy10 1Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 2Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA; 3Department of Medicine, National Jewish Health, Denver, CO, USA; 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Allergy Partners, Asheville, NC, USA; 6Department of Medicine, New York University School of Medicine, New York, NY, USA; 7Columbia University School of Nursing, New York, NY, USA; 8BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 9Evidera, Bethesda, MD, USA; 10Boys Town National Research Hospital, Boys Town, NE, USACorrespondence: Bradley E Chipps, Capital Allergy & Respiratory Disease Center, 5609 J Street, Suite C, Sacramento, CA, 95819, USA, Tel +1 916-453-1454, Email bchipps@capitalallergy.com

Désirée Larenas-Linnemann,1 Blanca María Morfín-Maciel,2 Victor Gonzalez-Uribe,3 Claudia Ivonne Gallego-Corella,4 Germán Agustín Rico-Solís,5 Luiana Hernández-Velázquez,6 Daniel García-Imperial,7 Chrystopherson Gengyny Caballero-Lopez,8 Ondina Marlene Garibay-Vargas,9 José Luis Gálvez-Romero,10 Daniela García Fajardo,11 Joel Barroso-Santos,12 Herberth de Jesús Pérez-Áviles,13 Jorge Agustín Luna-Pech,14 Cecilia Yvonne García-Cobas,15 Kareli Guadalupe Coronado-Hernández,16 Margarita Ortega-Cisneros,17 Carlos Humberto González-Gutiérrez,18 Daniela Rivero-Yeverino,8 Elsy Maureen Navarrete-Rodríguez,19 Leticia Lezama-Vázquez,20 Karen Lilian Rivera-Alvarado,21 Georgina Guadalupe Ochoa-López,22 Sara Elizabeth Covarrubias-Ramírez,23 Claudia Patricia Reyes-Galindo,24 Beatriz Bayardo-Gutiérrez,25 María del Carmen Calderón-Ezquerro26 1Centro de Excelencia en Asma y Alergia Larenas, Hospital Médica Sur, Mexico City, DF, Mexico; 2Private practice, Mexico City, DF, Mexico; 3AlergiaMx, Mexico City, DF, Mexico; 4Centro de Alergia y Asma de Tijuana, Tijuana, BCN, Mexico; 5Hospital Regional Valentín Gómez Farías, Department of Allergy and Clinical Immunology, Colima, COL, Mexico; 6IMSS Hospital General de Zona Número 8, Ensenada, BCN, Mexico; 7Private Practice, Querétaro, QRO, Mexico; 8Hospital Universitario de Puebla, Benemérita Universidad Autónoma de Puebla, Puebla, PUE, Mexico; 9Private practice, Uruapan, MICH, Mexico; 10Jefatura de investigación, Hospital Regional ISSSTE, Puebla, PUE, Mexico; 11Private Practice, San Luis Potosí, SLP, Mexico; 12Private practice, Pachuca, HGO, Mexico; 13Private Practice, Mérida, YUC, Mexico; 14Departamento de Disciplinas Filosófico, Metodológico e Instrumentales, CUCS, Universidad de Guadalajara, JAL, Mexico; 15Alergia e Inmunología, HGR 46, Instituto Mexicano del Seguro Social, Guadalajara, JAL, Mexico; 16Centro Médico Nacional del Occidente Pediatrics, Guadalajara, JAL, Mexico; 17Centro Médico Nacional de Occidente UMAE Hospital de Especialidades, Department of clinical immunology and allergy, Guadalajara, JAL, Mexico; 18HGZ &num; 1 IMSS, Zacatecas, ZAC, Mexico; 19Hospital Infantil de México ‘Federico Gómez’, Mexico City, DF, Mexico; 20Private practice, Tuxtla-Gutiérrez, CHIS, Mexico; 21IMSS UMAE 14, Veracruz, VER, Mexico; 22Private practice, Ciudad Juárez, CHIH, Mexico; 23Plebitos, Especialidades Pediátricas, Mazatlán, SIN, Mexico; 24ISSSTE, Ciudad Victoria, TAMPS, Mexico; 25Centro Médico Nacional de Occidente UMAE Hospital de Especialidades, Departamento de Inmunología Clínica y Alergia, Hospital Regional ISSSTE, Puebla, PUE, Mexico; 26Instituto de Ciencias de la Atmósfera y Cambio Climático, Universidad Autónoma de México, Mexico City, DF, MexicoCorrespondence: Désirée Larenas-Linnemann, Centro de Excelencia en Asma y Alergia Larenas, Hospital Médica Sur, Torre 2 cons. 602, Puente de Piedra 150, Col. Toriello Guerra, Del. Tlalpan, Ciudad de México, 14050, Mexico, Tel +52-55-5171-2248 ; +5606-6222 Ext.4372 ; +52-55-8509-5950, Email marlar1@prodigy.net.mxIntroduction: Aeroallergen exposure has an intra- and extra-domiciliary component and varies according to climatological zones. Mexico is a large country with a great variety of climates. A previous study (2009) evaluated skin prick test results (SPT) in different regions. In this study, we compare previous sensitization patterns from 14y ago with current ones and compare them between different climatological zones.Methods: Mexican allergists were asked to share their last 100 SPT results in patients with respiratory allergy. Clinics were grouped in (semi)humid vs (semi)dry zones. Results were analyzed nationwide and compared to the 2009 results, calculating odds ratio (OR) and 95% confidence intervals (95% CIs), with p < 0.05 as cut-off. Similarly, we compared (semi)humid versus dry zones.Results: We collected 2915 SPT results from 28 clinics (19 cities). Dermatophagoides was the most frequently sensitizing allergen. There was a significant increase in SPT positivity from 2009 to 2023 in both in- and outdoor aeroallergens (OR 1.26– 2.65, 95% CI from 1.06– 1.50 to 1.99– 3.52). Comparing dry-humid zones, sensitization to pollen from Oleaceae, Fagaceae (p < 0.0001 all) and most weeds is more frequent in humid zones, as are Dermatophagoides and cockroach (both p < 0.0001). Eucalyptus, mesquite, and all grass pollen sensitizations predominate in dry zones (p < 0.05– 0.0001). There are no differences in sensitization to cat or dog between zones.Conclusion: We found a general increase in SPT sensitization over the past fourteen years, suggesting that this is probably not only due to climate change. The different sensitization profile throughout the country was mainly related to humidity. Repeating epidemiologic SPT studies over the years could help tracking changes in allergen sensitization over time.Keywords: allergy, diagnosis, skin prick testing, aeroallergen, climate change, pollen allergy, allergic rhinitis, allergic asthma

Hong Ding,1 Xiaofan Lu,2 Huimin Wang,3 Wenming Chen,3 Bing Niu4 1Otolaryngology Department, The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 2Respiratory Department, The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 3Otolaryngology Department, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 4Stomatology Department, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Hong Ding; Bing Niu, Henan University of Chinese Medicine, The Second Clinical Medical College, 6 Dongfeng Road, Jinshui District, Zhengzhou City, Henan Province, 450002, People’s Republic of China, Email superding@hactcm.edu.cn; 13838061768@163.comPurpose: Accumulating evidence indicates that oxidative stress and inflammation are the pathological basis of allergic diseases. Inhibition of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome could ameliorate allergic rhinitis (AR). Here, we explored the effects and mechanisms that underlie NLRP3 inhibition on oxidative stress and inflammation in AR.Methods: Ovalbumin (OVA)-induced AR murine model was established using wild-type (WT) and NLRP3-deficient mice. HNEpCs were stimulated with interleukin (IL)-13 with MCC950 pretreatment or PTEN-induced putative kinase 1 (PINK1) siRNA. The indicators of oxidative stress, inflammation, apoptosis, and mitophagy were determined both in vivo and in vitro.Results: NLRP3 knockout (KO) reduced the frequency of nasal rubbing and sneezing, the infiltration of eosinophils, the number of mast cells, and the accumulation of goblet cells in AR mice after OVA stimulation. The NLRP3 KO AR mice exhibited the increased concentrations of OVA-specific immunoglobulin E (OVA-sIgE), IL-1β, IL-4, IL-13, IL-6, TNF-α, and the upregulated level of IFN-γ. NLRP3 KO significantly inhibited oxidative stress, and also markedly decreased apoptosis in the nasal mucosa of AR mice. Moreover, evaluated protein expressions of PINK1, enzyme 3 (E3) ubiquitin ligase PRKN (Parkin), and LC3 II, decreased expression of TOM20, as well as the increased colocalization of LC3 with mitochondria were observed in NLRP3 KO AR mice. In vitro, IL-13 exposure increased the levels of NLRP3 and IL-1β. Inhibition of NLRP3 using MCC950 enhanced PINK1/Parkin-mediated mitophagy but attenuated inflammation, oxidative stress, and apoptosis. However, PINK1 knockdown abrogated mitophagy and also reversed the protective effects of MCC950 on inflammation, oxidative stress, and apoptosis in HNEpCs stimulated with IL-13.Conclusion: Inhibition of NLRP3 inflammasome exerts the protective effects on AR by facilitating mitophagy regulated by PINK1/Parkin signaling pathway.Keywords: NLRP3, mitophagy, inflammation, oxidative stress, PINK1/Parkin

Godfrey L Sambayi,1,&ast; George M Bwire,2,3,&ast; Mary Spicar Kilapilo,3 David T Myemba,4 Idda H Mosha,5 Manase Kilonzi,6 Renatus B Magati,7 Maryam Amour,8 Rogers Mwakalukwa,1 Ally Nassoro Mangara,9 Muhammad Bakari,10 Christopher R Sudfeld,11 Mecky IN Matee,12 Raphael Z Sangeda,3 Lisa V Adams,13 Japhet Killewo14 1Department of Pharmacognosy, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65013, Tanzania; 2Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research Clinical and Epidemiological Virology, Institute for the Future, KU Leuven, Leuven, 3000, Belgium; 3Department of Pharmaceutical Microbiology, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65013, Tanzania; 4Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65013, Tanzania; 5Department of Behavioural Sciences, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65015, Tanzania; 6Department of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65013, Tanzania; 7Department of Clinical Nursing, Catholic University of Health and Allied Sciences, Mwanza, P.O. Box 1464, Tanzania; 8Department of Community Health, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65015, Tanzania; 9Dar Es Salaam Urban Cohort Study, Department of Epidemiology and Biostatistics, School of Public Health and Social Sciences, Dar es Salaam, 65013, Tanzania; 10Department of Internal Medicine, School of Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, P.O. Box 65001, Tanzania; 11Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 12Department of Microbiology and Immunology, School of Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65013, Tanzania; 13Department of Medicine, Center for Global Health Equity, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 14Department of Epidemiology and Biostatistics, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Salaam, 65015, Tanzania&ast;These authors contributed equally to this workCorrespondence: Godfrey L Sambayi, Department of Pharmacognosy, Sciences, School of Pharmacy, Muhimbili University of Health and Allied, Dar es Salaam, P. O. Box 65013, Tanzania, Email godfreysambayi08@gmail.comPurpose: To explore the enabling factors, barriers, and strategies to improve retention in HIV care and adherence to antiretroviral therapy (ART) among adults (18 years and above) living with HIV in Dar es Salaam, Tanzania.Methods: We conducted a descriptive qualitative study to better understand and explore enablers, barriers, and strategies to improve retention in HIV care and adherence to antiretroviral therapy (ART) among PLHIV in Dar es Salaam, Tanzania. Focus group discussions (FGD) were conducted with a semi-structured discussion guide between December 2021 and June 2022. A non-random purposive sampling technique was used to select PLHIV and people involved in provision of healthcare and socioeconomic support to PLHIV. Thematic analysis was used to identify and interpret the themes.Results: Three major themes with 10 sub-themes emerged. Participants indicated that family and partner support, peer-support group/adherence clubs, and healthcare provider counselling on medication adherence facilitated retention and adherence to ART. In contrast, stigma and discrimination, financial constraints, disease outbreaks such as the COVID-19 pandemic, myths and misconceptions about HIV, and side effects of antiretrovirals were mentioned as barriers. Strengthening community and patient education about HIV and ART through peer support groups and financial support for poor PLHIV were the proposed mitigation.Conclusion: Addressing the challenges to ART adherence may require a more holistic approach. We recommend the implementation of peer support groups and financial support through small microfinance groups as interventions to increase retention in HIV care and adherence to ART in the study area.Keywords: people living with HIV, peer support group, stigma, SDG 3.3

Ayu Permatasanti,1 Irna Sufiawati2 1Oral Medicine Residency Program, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Indoenesia; 2Department of Oral Medicine, Faculty of Dentistry, Universitas Padjadjaran, Bandung, IndonesiaCorrespondence: Irna Sufiawati, Department of Oral Medicine, Faculty of Dentistry, Universitas Padjadjaran, Jalan Sekeloa Selatan I, Bandung, 40132, Indonesia, Tel +62-22-2504985, Fax +62-22-2532805, Email irna.sufiawati@fkg.unpad.ac.idIntroduction: Human immunodeficiency virus (HIV) impairs immune function leading to oral mucosal lesions. While highly active antiretroviral therapy (HAART) has reduced the incidence of HIV-associated oral lesions (HIV-OLs), these lesions can still manifest across all HIV stages due to various patient-related factors.Purpose: To evaluate the occurrence of HIV-OLs and clinical characteristics across all HIV stages in people living with HIV (PLWH).Patients and Methods: Five patients aged 7 to 60 with canker sores visited the Oral Medicine Clinic. One newly diagnosed patient with stage II HIV had not yet started ART, while others in stages I, III, and IV were already receiving ART. Diagnosed oral lesions included recurrent intraoral herpes (RIH) in patients with stages I, II, and III; linear gingival erythema (LGE) in stages I; acute pseudomembranous candidiasis (APC) and oral hairy leukoplakia (OHL) in stages II; traumatic ulcers in stages III; erythema multiforme (EM) and angular cheilitis (AC) in stages IV. Potential risk factors for these oral lesions included poor oral hygiene, low CD4+ T-cell counts, detectable viral load, non-adherence to ART, smoking, medication use for systemic diseases, nutritional deficiency, and comorbidities.Results: Treatment included antiviral for RIH; antifungal for APC and AC; topical corticosteroid and antiseptic mouthwash for oral ulcers and improving oral hygiene; application of normal saline-soaked gauze dressing followed by topical steroid for EM; petroleum jelly for dry lips; and multivitamins. Lesions improved over 5– 15 days. Addressing risk factors involved improving oral hygiene, treating comorbidities, promoting weight gain, smoking cessation, and starting ART for those untreated.Conclusion: Oral lesions are prevalent throughout the stages of HIV and are influenced by immune status, medication adherence, and overall health, underscoring the need for holistic care to enhance the quality of life, potentially alter HIV progression, and reduce morbidity through integrated oral health assessments in routine care.Keywords: Antiretroviral, HIV, oral mucosa lesion, risk factors, clinical stages

Pierfrancesco Visaggi,1,&ast; Matteo Ghisa,2,&ast; Edoardo Vespa,3 Alberto Barchi,3 Amir Mari,4 Andrea Pasta,5 Elisa Marabotto,5,6 Nicola de Bortoli,1 Edoardo Vincenzo Savarino2 1Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 2Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 3Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, 20132, Italy; 4Gastroenterology Unit, Nazareth Hospital EMMS, Azrieli Faculty of Medicine, Bar Ilan University, Ramat Gan, Israel; 5Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; 6IRCCS Policlinico San Martino, Genoa, Italy&ast;These authors contributed equally to this workCorrespondence: Edoardo Vincenzo Savarino, Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, Padua, 35128, Italy, Tel +39-049-8217749, Email edoardo.savarino@unipd.itAbstract: Eosinophilic esophagitis (EoE) is a chronic type 2 inflammation-mediated disease characterized by an eosinophil-predominant inflammation of the esophagus and symptoms of esophageal dysfunction. Relevant treatment outcomes in the setting of EoE include the improvement of histology, symptoms, and endoscopy findings, quality of life (QoL), and the psychological burden of the disease. Established validated tools for the assessment of EoE include questionnaires on dysphagia and QoL (ie, DSQ, EEsAI, and EoE-IQ). More recently, esophageal symptom-specific anxiety and hypervigilance, assessed using the esophageal hypervigilance and anxiety scale (EHAS), have emerged as contributors to disease burden, confirming the importance of psychological aspects in EoE patients. The EoE endoscopic reference score (EREFS) is the only validated endoscopy score in EoE and can quantify mucosal disease burden. However, esophageal panometry using the functional lumen imaging probe (FLIP) and high-resolution manometry (HRM) have shown potential to optimize the assessment of fibrostenotic features of EoE, providing novel insights into the pathophysiology of symptoms. There is a growing number of licenced and off-label therapeutic options in EoE, with various randomized controlled trials demonstrating the efficacy of proton pump inhibitors, topical steroids, food elimination diets, biological drugs, and esophageal dilatation. However, standardized optimal management strategies of EoE are currently lacking. In this review, we provide an overview of established and novel assessment tools in EoE including patient reported outcomes, FLIP panometry, HRM, endoscopy, and histology outcome measures to improve the outcomes of EoE patients. In addition, we summarize available therapeutic options for EoE based on the most recent evidence.Keywords: eosinophilic esophagitis, treatment, monitoring

Yan Pan, Wei Dong Chen, Lei Liu, Huijuan Yang, Baochao Chang, Caixia Cui Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, People’s Republic of ChinaCorrespondence: Wei Dong Chen, Email cwd2012@163.comObjective: Serum-specific antibodies as a non-invasive means to effectively diagnose idiopathic membranous nephropathy and assess clinicopathology.Methods: Immunofluorescence of anti-PLA2R and THSD7A antibodies and kidney tissue PLA2R, THSD7A and IgG4 expression in IMN and non-IMN (2020– 2021) was detected to assess the efficacy of diagnosing IMN. IMN patients were divided into two groups, anti-PLA2R antibody positive (161 cases) and negative (26 cases), and two groups, kidney tissue PLA2R (40 cases) and PLA2R+THSD7A (6 cases), to compare the clinical and pathological features, and to carry out a prognostic analysis of THSD7A-positive patients, with a focus on correlation with malignancy.Results: The positive rate of anti-PLA2R antibodies was significantly higher in IMN (P< 0.05); anti-PLA2R antibodies, kidney tissue PLA2R and IgG4 and THSD7A had some diagnostic value. Anti-PLA2R antibodies correlated with proteinuria levels in IMN patients, and their levels were negatively correlated with blood albumin (r=− 0.146, P=0.042); correlated with pathological stage and C3 and IgG4 immunodeposition; there was no significant difference in clinical pathology between kidney tissue THSD7A+PLA2R positive compared to kidney tissue PLA2R positive patients, but the probability of achieving complete remission was low and time longer, and no malignancy events were detected during follow-up.Conclusion: Anti-PLA2R antibodies, kidney tissue PLA2R, THSD7A and IgG4 have high diagnostic efficacy for IMN; anti-PLA2R antibodies can be used as diagnostic markers to assist in the assessment of clinical and pathological features; co-expression of kidney tissue PLA2R and THSD7A is not significantly different from kidney tissue PLA2R in assessing the clinical features, pathological manifestations and prognosis, but requires long-term. However, long-term follow-up is needed to monitor the potential risk, and a larger multicentre study with long-term follow-up is expected to be conducted to comprehensively assess IMN characteristics.Keywords: Idiopathic membranous nephropathy, PLA2R, THSD7A, clinical features and pathology

Omima Mohammed Ali Omima Mohammed,1 Omaima Abdel Majeed Mohamed Salih,2 Islamia Ibrahim Ahmed Omer,3 Yousra Ibrahim Abdallah Mohammed,4 Omer A Mohammed,4 Ammar Elgadi,4 Lina Hemmeda,4 Walaa Elnaiem,4 Malaz Tarig Abdalla Mohamed,4 Areeba Ahsan,5 Khabab Abbasher Hussien Mohamed Ahmed4 1Department of Pediatrics and Child Health, Mohamed Alamin Hamid Tertiary Pediatric Hospital, Omdurman, Sudan; 2Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Omdurman Islamic University, Omdurman, Sudan; 3Pediatrics and Child Health Department, College of Medicine, Sulaiman Al Rajhi University, Al-Bukayriyah, Qassim Province, Saudi Arabia; 4Faculty of Medicine, University of Khartoum, Khartoum, Sudan; 5School of Health Sciences, Foundation University, Islamabad, PakistanCorrespondence: Khabab Abbasher Hussien Mohamed Ahmed, Email khabab9722@gmail.comBackground: Asthma is one of the most common non-communicable diseases. Childhood asthma has been increasing in Sudan, with a 13– 16% prevalence among Khartoum school children. To achieve and maintain good asthma control, proper diagnosis, assessment of severity, and appropriate medication administration are crucial, with phenotyping being a key factor in determining patients’ specific treatment.Objective: To study the frequency of severe asthma and the distribution of its different phenotypes and to investigate associations between age and gender and different phenotypes of asthma.Methodology: This descriptive cross-sectional hospital-based study was conducted in the Asthma Clinic of Mohamed Al-Amin Hamid Pediatrics Hospital. It included 229 patients who were presented to the clinic from September 2021 to April 2022. Data were collected from the patients and/or their caregivers using a modified validated standard questionnaire and were analyzed using SPSS version 26.0. A p-value of 0.05 or less was considered statistically significant.Results: In this study of 229 participants, 14.4% had severe asthma, with 44.5% and 41% exhibiting mild and moderate asthma, respectively. Most were effectively managed in steps 2 or 3. The cohort, primarily aged 5 or younger (40.2%) with a male majority (62%), showed a mean diagnosis age of 2.9 ± 2.8 years. Impressively, 90% maintained well-controlled asthma. Within severe asthma cases (87% atopic), 39.4% represented a severe allergic asthma phenotype. Elevated eosinophil counts were noted in 45.5% (serum) and 78.8% (sputum cytology), while 57.6% had normal serum IgE levels. The predominant symptom pattern in severe asthma was episodic multi-trigger wheezing (48.5%). Age and gender displayed no significant association with severe asthma phenotype.Conclusion: This study reveals a concerning rise in childhood asthma prevalence in Sudan, emphasizing the importance of tailored treatment strategies. Severe asthma, characterized by atopic eosinophilic involvement, necessitates targeted interventions in pediatric asthma care for specific phenotypes.Keywords: asthma, pediatrics, respiratory system, chronic obstructive pulmonary diseases, Sudan

Xiufeng Chen, Yong hong Jiang, Xiaoqin Fei, Mingjing Wang, Anqi Liu, Xuejun Li, Zhiyan Jiang Department of Pediatrics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Zhiyan Jiang, Email jiangzhiyan@shutcm.edu.cnBackground: Asthma severely interferes with people’s lives through coughing, wheezing and inflammation of the lungs. Herbacetin is a class of natural compounds that inhibit the development of inflammation. However, whether Herbacetin inhibits asthma has not been definitively studied.Methods: Lipopolysaccharides (LPS)-induced lung epithelial (BASE-2B) cells injury model was established, and then the relief of damaged BASE-2B cells with different concentrations of Herbacetin was examined. The cell counting kit (CCK8) was used to detect the effect of Herbacetin on the proliferation ability in ovalbumin (OVA)-induced asthma mice model, and Western Blot and flow cytometry were used to detect the effect of Herbacetin on the apoptosis in OVA-induced asthma mice model. Additionally, pulmonary pathology was detected by HE and Masson staining, and serum inflammatory factors were detected by alveolar lavage fluid.Results: Herbacetin reduces BESA-2B cells induced by LPS level of inflammation, and reactive oxygen species (ROS) generation, inhibits cell apoptosis, promotes cell proliferation, OVA-induced mice lung histopathology test HE staining, serum inflammatory factors show the same results. Western Blot shows that Herbacetin regulates the expression of Caspase-3, Bax, and Bcl-2. SGK1 overexpression increased the rate of apoptosis, and Herbacetin reversed this phenomenon. By silencing the expression of SGK1, it was found that Herbacetin was an inhibitor of SGK1, which could inhibit the NF-κB/p-P65 pathway in asthmatic airway inflammation.Conclusion: Herbacetin reduces pro-inflammatory cytokine levels by inhibiting the SGK1/NF-κB pathway. Our data suggest that Herbacetin has a significant anti-inflammatory effect on asthma and can be used as a potential therapeutic agent.Keywords: asthma, herbacetin, SGK1, NF-κB, anti-inflammatory

Josefine Persson,1 Juhani Aakko,2 Saara Kaijala,2 Mariann I Lassenius,2 Arja Viinanen,3 Hannu Kankaanranta,4 Lauri Lehtimäki5 1AstraZeneca, Nordic, Mölndal, Sweden; 2Medaffcon Oy, Espoo, Finland; 3Turku University Hospital, Division of Medicine, Department of Pulmonary Diseases and the University of Turku, Department of Pulmonary Diseases and Clinical Allergology, Turku, Finland; 4Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland, Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland; 5Allergy Centre, Tampere University Hospital; Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandCorrespondence: Josefine Persson, AstraZeneca AB, Pepparedsleden 1, Mölndal, 431 83, Sweden, Email josefine.persson1@astrazeneca.comPurpose: Patients with asthma and low levels of type 2 inflammatory biomarkers (T2 low) have limited effective treatment options. Such biomarkers include eg blood eosinophils (b-eos) and fractional exhaled nitric oxide (FeNO). The healthcare resource utilisation (HCRU) of severe uncontrolled T2 low asthma remains unexplored. Thus, this study aimed to estimate the HCRU of T2 low and non-T2 low severe uncontrolled asthma patients using real-world data in Finland.Patients and Methods: Adult patients with an asthma diagnosis during baseline (2012– 2017) at the pulmonary department of Turku University Hospital were included and followed during 2018– 2021, or until death. Total HCRU costs and respiratory-related HCRU costs were evaluated. The main drivers for the HCRU and costs were assessed with gamma and negative binomial regression models.Results: Of the severe uncontrolled asthma patients with T2 status available, 40% (N=66) were identified with T2 low and 60% (N=103) with non-T2 low asthma. The average cumulative cost per patient was similar in patients with T2 low compared with non-T2 low, with all-cause costs cumulating in four years of follow-up to 37,524€ (95% CI: 27,160, 47,888) in T2 low compared to 34,712€ (25,484, 43,940) in non-T2 low. The corresponding average cumulative respiratory-related costs were 5178€ (3150, 7205) in T2 low compared to 5209€ (4104, 6313) in non-T2 low. Regression modelling identified no differences between the T2-status groups when assessing all-cause healthcare costs per patient-year (PPY). On the other hand, the regression modelling predicted more inpatient days PPY for severe uncontrolled patients with T2 low status compared to the patients with non-T2 low status.Conclusion: Patients with uncontrolled severe T2 low asthma use equal healthcare resources as corresponding non-T2 low patients. This study brought new insights into the HCRU of severe uncontrolled asthma patients per T2 status, which has not previously been investigated.Keywords: severe uncontrolled asthma, phenotypes, healthcare resource utilisation, economic burden, real-world evidence

Gang Xu,1,2,&ast; Tao Pan,2,&ast; Si Li,2,3,&ast; Jing Guo,2 Ya Zhang,2 Qi Xu,2 Renwei Chen,4 Yanlin Ma,2 Yongsheng Li2,3 1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China, Harbin, 150081, People’s Republic of China; 2Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Reproductive Medical Center, National Center for International Research, The First Affiliated Hospital of Hainan Medical University, College of Biomedical Information and Engineering, Hainan Medical University, Haikou, Hainan, 571199, People’s Republic of China; 3School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 4Hainan Women and Children’s Medical Center, Hainan Medical University, Haikou, Hainan, 571199, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongsheng Li; Yanlin Ma, Email liyongsheng@ems.hrbmu.edu.cn; mayanlinma@hotmail.comBackground: The heterogeneity and dynamic changes of endometrial cells have a significant impact on health as they determine the normal function of the endometrium during the menstrual cycle. Dysfunction of the endometrium can lead to the occurrence of various gynecological diseases. Therefore, deconvolution of immune microenvironment that drives transcriptional programs throughout the menstrual cycle is key to understand regulatory biology of endometrium.Methods: Herein, we comprehensively analyzed single-cell transcriptome of 59,397 cells across ten human endometrium samples and revealed the dynamic cellular heterogeneity throughout the menstrual cycle.Results: We identified two perivascular cell subtypes, four epithelial subtypes and four fibroblast cell types in endometrium. Moreover, we inferred the cell type-specific transcription factor (TF) activities and linked critical TFs to transcriptional output of diverse immune cell types, highlighting the importance of transcriptional regulation in endometrium. Dynamic interactions between various types of cells in endometrium contribute to a range of biological pathways regulating differentiation of secretory. Integration of the molecular biomarkers identified in endometrium and bulk transcriptome of 535 endometrial cancers (EC), we revealed five RNA-based molecular subtypes of EC with highly intratumoral heterogeneity and different clinical manifestations. Mechanism analysis uncovered clinically relevant pathways for pathogenesis of EC.Conclusion: In summary, our results revealed the dynamic immune microenvironment of endometrium and provided novel insights into future development of RNA-based treatments for endometriosis and endometrial carcinoma.Keywords: single-cell sequencing, cell–cell interaction, biological pathways, molecular subtypes, RNA biomarkers

Pongsakorn Tantilipikorn,1 Virat Kirtsreesakul,2 Chaweewan Bunnag,3 Mukda Vangveeravong,4 Sanguansak Thanaviratananich,5 Supinda Chusakul6 1Center of Research Excellence in Allergy & Immunology, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand; 2Department of Otolaryngology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand; 3Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 4Queen Sirikit National Institute of Child Health, Bangkok, Thailand; 5Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University, Khonkaen, Thailand; 6Department of Otolaryngology, Chulalongkorn University, Bangkok, ThailandCorrespondence: Virat Kirtsreesakul, Division of Allergy and Rhinology, Department of Otolaryngology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand, Tel/Fax +6674 429-620, Email kvirat2002@hotmail.comAbstract: The incidence of allergic rhinitis (AR) in Asia and the world is steadily rising. Patients experience incomplete symptom relief despite existing treatment options, which warrants the need for new therapeutic regimes. Azelastine hydrochloride/fluticasone propionate (MP-AzeFlu), a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate has been indicated in the treatment of AR. The current review discusses the effects of MP-AzeFlu versus conventional therapies in achieving superior clinical improvement with a very rapid onset of action (5 minutes). The superiority of MP-AzeFlu in offering complete symptom control with sustained relief in patients with AR compared to the existing therapeutic options is also discussed. MP-AzeFlu has been shown to improve the quality of life for patients with AR, thereby enhancing patient adherence to therapy and establishing its preference for the treatment of AR. Currently, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend the use of a combination of intranasal corticosteroids and intranasal antihistamines as first-line treatment in patients with persistent AR with visual analog scores ≥ 5 or when prior treatment with single agents has been ineffective. Widely published data on the efficacy and safety of its prolonged use in adults and children have validated that effective treatment of AR can be achieved with MP-AzeFlu.Keywords: fixed-dose combination, intranasal, MP-AzeFlu, corticosteroids, antihistamines

Leila S Matoy,1– 3 Felista S Tarimo,2,4 Efraim M Kosia,2 Josephine J Mkunda,2 Maja Weisser,1,3,5– 7 Sally Mtenga8 1Interventions and Clinical Trials, Ifakara Health Institute, Morogoro, Tanzania; 2The Nelson Mandela, African Institution of Science and Technology, Tengeru, Arusha, Tanzania; 3Chronic Diseases Clinic of Ifakara, St. Francis Referral Hospital, Morogoro, Tanzania; 4Environmental Health and Ecological Sciences, Ifakara Health Institute, Dar-es-Salaam, Tanzania; 5Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, 4031, Switzerland; 6University of Basel, Basel, 4002, Switzerland; 7Swiss Tropical and Public Health Institute, Allschwil, 4123, Switzerland; 8Health System Impact Evaluation and Policy, Ifakara Health Institute, Dar-es-Salaam, TanzaniaCorrespondence: Leila S Matoy, Ifakara Health Institute, P.O. Box 53, off Mlabani Passage, Ifakara, Morogoro, Tanzania, Tel +255 718 410 774, Email lsamson@ihi.or.tzIntroduction: Healthcare workers (HCW) play an important role in managing women living with HIV (WLHIV) with gender-based violence (GBV) experience, but little is known about their experience in screening and managing GBV among WLHIV. This study explored the perceptions and experience of the HCWs on screening and managing GBV cases among WLHIV.Patients and Methods: We performed a descriptive phenomenological qualitative study to elicit the views and experience of HCW on GBV screening and management for WLHIV. The study was conducted in the semi-urban setting in Morogoro Region, Tanzania. Ten in-depth interviews (IDIs) were administered to HCW selected purposefully based on their roles at an HIV care and treatment center. Data were transcribed using patterns matching study aim and then merged into relevant themes for analysis and interpretation. NVIVO software version 12 was used for data coding and analysis.Results: We found that HCW experienced multiple challenges in GBV screening and management, including limited capacity for GBV screening and management; inadequate training on assessment and handling GBV cases, limited resources (time, GBV guidelines and screening tools), inadequate GBV referral and monitoring systems; referral forms for GBV survivors to social support centers and follow-up mechanisms to trace survivors, mental aspects; HCWs’ fear of being stressed by listening to women’s’ GBV traumatic experiences, HCWs’ fear of causing problems to the women’s families and HCW biased notions on women disclosure of GBV; the believes that women will not report their GBV experiences.Conclusion: We identified context-specific challenges preventing HCW to deliver optimal services of GBV to WLHIV, stressing the necessity to strengthen HCW capacity and resources for GBV services and to integrate psychosocial services into HIV care. Policy and programs should be developed to support GBV screening and management for WLHIV.Keywords: healthcare provider, intimate partner violence, women living with HIV, gender-based violence