Evaluation of vaccine allergy safety track program to assess potential COVID-19 vaccine allergy: a cost-effectiveness analysis.

BACKGROUND: Concerns about new COVID-19 vaccines played a key role in vaccine hesitancy and hampered population uptake. Hong Kong initiated a Vaccine Allergy Safety Track (VAS-Track) program to assess potential COVID-19 vaccine-associated allergies. A 'Hub-and-Spoke' model of predominately non-specialists supported by the allergist hub was established to meet overwhelming demand despite limited specialists. OBJECTIVE: To assess the cost-effectiveness of VAS-Track as a pre- and post-vaccination assessment service for individuals potentially at high risk of COVID-19 vaccine-related allergy. METHODS: An individual-level decision-analytical model was constructed using data from VAS-Track participants supplemented by published estimates. Analyses were from a health service provider perspective over 12 months. We calculated the incremental cost-effectiveness ratio (ICER) to estimate the cost per quality-adjusted life years (QALYs) gained. Willingness-to-pay threshold was based on local GDP per capita (US$ 49,590). Sensitivity analyses examined robustness of findings. RESULTS: Cost-effectiveness varied widely across age groups. VAS-Track was cost-saving for older adults (dominant strategy for age ≥ 50) compared with standard practice across a range of sensitivity analyses. VAS-Track was not cost-effective for younger groups (age 18-49: ICER: US$ 410,914/QALY for pre-vaccination and US$ 213,786/QALY for post-vaccination assessments). Infection rate, cost of treating severe infection, and vaccination rate were most influential on cost-effectiveness estimates. CONCLUSION: VAS-Track was cost-effective both as a pre- and post-vaccination assessment service for adults over 50. The 'Hub-and-Spoke' model using non-specialists with limited allergy specialist resources to provide vaccine allergy assessment services would provide high economic value compared with usual care for adults aged 50 and over.

Bibliometric analysis of the trends and evolution in ß-lactam allergy research.

Background: ß-Lactams remain the most reported drug allergy globally, with the volume and diversity of related drug allergy research continuing to accumulate. Recognizing evolving research trends can help inform future directions and encourage synergistic collaborations. Objective: We conducted a comprehensive bibliometric analysis of all publications relevant to ß-lactam allergy, with a focus on longitudinal publication rates, international collaborations, and key word/trend analysis. Methods: Meta-data from all original articles, letters, and reviews relevant to ß-lactam allergy on the Web of Science Core Collection up until December 31, 2023, were analyzed. Results: From 1966 to 2023, there were 4451 records (3536 articles, 631 reviews, and 284 letters) from 78 countries. There was an exponential increase in publications, especially during the past decade, with half of all publications on ß-lactam allergy published during this time (50.6% [2252 of 4452]). Overall, 18.1% of the publications (805 of 4452) involved international coauthorships, with a significant increase since the previous decade (12.7% vs 23.3% [P < .001]). The most frequent key words in the first published half of articles were skin testing (84 of 1919), IgE (57 of 1919), and anaphylaxis (49 of 1919); in contrast to the key word skin testing (137 of 3351), the key words drug provocation test (121 of 3351), antimicrobial resistance (120 of 3351), and antimicrobial stewardship (118 of 3351) were the most frequent key words in the latter half. Conclusion: There has been a surge in publications, international collaboration, and shifting paradigms in ß-lactam allergy research. The field has evolved beyond focusing on in vitro tests or desensitization toward antimicrobial stewardship. However, there still seems to be relatively fewer collaborations with non-Western countries. Further international collaborations to harmonize delabeling strategies against the threat of mislabeled ß-lactam allergy should be encouraged.

Impact of a drug allergy education course for non-specialists: Findings from ADAPT-A randomized crossover trial.

BACKGROUND: The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists. METHODS: A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts. RESULTS: Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively. CONCLUSIONS: ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact.

Validation and correlations of the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT) in Chinese patients with angioedema.

Background: The impact of recurrent angioedema can be severely debilitating and remains difficult to quantify. Several standardized patient-reported outcome measures (PROMs), including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT), have been developed and translated into different languages. However, these PROMs have yet to be validated in Chinese individuals, and their correlations in the Chinese population remain unknown. Objective: Our aim was to validate the Chinese versions of the AAS, AE-QoL questionnaire, and AECT and assess their intercorrelations. Methods: A prospective cohort of 118 Chinese patients with recurrent angioedema at the Angioedema and Urticaria Centre of Reference and Excellence in Hong Kong completed the traditional Chinese versions of the AAS, AE-QoL questionnaire, and AECT. We analyzed the reliability and validity of these PROMs and their correlations with each other as well as with generic PROMs. Results: The Chinese AAS, AE-QoL questionnaire, and AECT demonstrated excellent internal consistency (Cronbach α = 0.920, 0.976, and 0.832, respectively; McDonald ω = 0.972, 0.977, and 0.901, respectively). Confirmatory factor analysis for the AE-QoL questionnaire showed an acceptable fit with the 4-dimensional model (comparative fit index = 0.869; Tucker-Lewis index = 0.842). The AECT showed significant correlations with both the AAS and AE-QoL questionnaire (ρ = -0.750 and -0.456 respectively [both P < .05]). The AE-QoL questionnaire was moderately correlated with certain domains of generic PROMs such as the Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0, and the Short Form 12-Item Health Survey, version 2 (all ρ < 0.60). Conclusion: The Chinese AE-QoL questionnaire, AAS, and AECT are valid and reliable tools for use with Chinese patients. More validated tools should be made available to improve patient care and research for all patients with angioedema globally.

Extending the role of tryptase in perioperative anaphylaxis: Predicting positive results in basophil activation tests.

Background: Basophil activation tests (BATs) are useful in identifying culprits of perioperative anaphylaxis (PA), but their utility remains limited due to technical limitations, cost, and availability. Being able to prioritize patients with likely higher yields for BAT would be useful in reducing costs and manpower. Objective: We sought to investigate whether tryptase levels and clinical parameters may be useful for selecting patients for BATs. Methods: We performed a 10-year retrospective study in Hong Kong to investigate the performance of BATs associated with tryptase levels (taking during PA) and other clinical parameters. Results: Of 90 patients, 70 (77.8%) showed significant tryptase level elevation and 37 (41.1%) had a positive BAT result. BAT-positive patients presented with significantly higher absolute levels (15.9 µg/L vs 9.1 µg/L; P = .018), absolute elevation (12.8 µg/L vs 7.1 µg/L; P = .012), and fold elevation (5.6- vs 4.1-fold; P = .014) of acute tryptase than did BAT-negative patients. Among patients with positive BAT result, 94.6% (35 of 37) demonstrated elevated acute tryptase, significantly more than the BAT-negative group (66.0%; P < .001). In regression analysis, tryptase elevation was the sole significant factor correlated to BAT positivity (odds ratio, 10.14; 95% CI, 2.15-47.85; P = .003). Overall, elevated acute tryptase demonstrated a sensitivity of 94.7% and a negative predictive value of 90.0% in predicting positive results with BATs. Conclusions: We observed that tryptase elevation is a very sensitive predictor of BAT positivity among patients with identified culprits of PA. Acute elevation of tryptase would not only aid in confirming anaphylaxis but may also help guide the decision toward selecting labor-intensive and costly in vitro tests such as BATs.

Penicillin Allergy in China: Consequences of Inappropriate Skin Testing Practices and Policies.

Penicillins are the most frequently prescribed class of medications worldwide and first-line antibiotic of choice for most bacterial infections. They are also commonly labelled as the culprit of drug 'allergy'; leading to obligatory use of second-line antibiotics, suboptimal antibiotic therapy and increased antimicrobial resistance. However, the majority of reported penicillin 'allergy' labels are found to be incorrect after allergy testing, emphasising the importance of proper drug allergy testing and evaluation. Penicillin skin testing (PST) remains an important component of drug allergy diagnosis; however, its practice and policies significantly differ across the world. Inappropriate and non-evidence-based PST practices can lead to consequences associated with allergy mislabelling. Even within different regions of China, with a population exceeding 1.4 billion, there are marked differences in the implementation, execution and interpretation of PST. This review aims to examine the differences in PST between Mainland China, Hong Kong and the rest of the world. We critically analyse the current practice of 'pre-emptive' PST in Mainland China, which has a significant false-positive rate leading to high levels of penicillin allergy mislabelling. Non-evidence-based practices further compound the high false-positive rates of indiscriminatory PST. We postulate that inappropriate PST policies and practices may exacerbate the mislabelling of penicillin allergy, leading to unnecessary overuse of inappropriate second-line antibiotics, increasing antimicrobial resistance and healthcare costs. We advocate for the importance of more collaborative research to improve the contemporary workflow of penicillin allergy diagnosis, reduce mislabelling and promote the dissemination of evidence-based methods for allergy diagnosis.

Validity, reliability, and sensitivity to change of the traditional Chinese Urticaria Control Test (UCT) in Hong Kong.

Background: Uncontrolled chronic urticaria (CU) can severely affect physical and psychosocial health as well as quality of life. Patient-reported outcome measures are crucial for measuring disease control. The Urticaria Control Test (UCT) is recommended by guidelines to monitor CU and guide clinical management. However, the traditional Chinese version of the UCT has not yet been validated. Objective: We sought to validate the traditional Chinese UCT among Chinese CU patients in Hong Kong. Methods: Patients with CU were enrolled at a Urticaria Centre of Reference and Excellence (aka UCARE) in Hong Kong and completed the traditional Chinese UCT. The internal consistency, test-retest reliability, construct validity, convergent validity, known-group validity, and sensitivity to change of the traditional Chinese UCT were evaluated. Results: We recruited 162 CU patients (80.9% female; age 50 ± 14 years) with a mean (median) ± standard deviation baseline UCT score of 8.8 (8) ± 4.7. Overall, Chinese UCT showed excellent internal consistency (Cronbach α and McDonald ω = 0.948), as well as test-retest reliability (intraclass correlation coefficient = 0.916 [95% confidence interval = 0.866-0.953]). Exploratory factor analysis revealed a unidimensional structure and confirmed its construct validity. Strong correlation between UCT and the 7-day urticaria activity score (UAS7) attested to its convergent validity (ρ = -0.699, P < .001). Its known-group validity was supported by significantly different UCT scores among patient subgroups with different disease activity. The Chinese UCT also demonstrated good sensitivity to change, as reflected by the significant correlation between changes in UCT and UAS7 scores (ρ = 0.491, P < .001). Conclusion: The traditional Chinese UCT is a valid, reliable, and sensitive-to-change instrument among Hong Kong Chinese with CU.

Beyond the classic players: Mas-related G protein-coupled receptor member X2 role in pruritus and skin diseases.

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas-related G protein-coupled receptor X2 (MRGPRX2) has emerged as a promising non-IgE-mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro-inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin-14, LL37, PAMP-12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Comparison of the penile microbiome in infant male circumcision: Mogen clamp versus Shangring.

BACKGROUND: This study aimed to characterise the infant penile (coronal sulcus) microbiome and the effects of early infant male circumcision (EIMC), following a standard surgical method (Mogen Clamp) and a non-surgical alternative (ShangRing). METHODS: We collected coronal sulcus swabs at baseline and on days 7 and 14 post-circumcision from infants assigned to receive EIMC by Mogen Clamp (n = 15) or ShangRing (n = 15), in a randomised trial in Rakai and Kakuuto, Uganda. We used 16S rRNA gene-based sequencing and broad-coverage qPCR to characterise the infant penile microbiome and assess the effects of EIMC in both study arms. FINDINGS: Prior to EIMC, the infant penile microbiome had a mixture of facultative and strict anaerobes. In both study arms, EIMC caused penile microbiome proportional abundance changes characterised by decreases in penile anaerobes [ShangRing Prevotella: -15.0%, (SD = 19.1); Mogen clamp Prevotella: -3.6% (11.2); ShangRing Veillonella: -11.3% (17.2); Mogen clamp Veillonella: -2.6% (11.8)] and increases in skin-associated facultative anaerobes [ShangRing Corynebacterium: 24.9%, (22.4); Mogen clamp Corynebacterium: 4.7% (21.3); ShangRing Staphylococcus: 21.1% (20.5); Mogen clamp Staphylococcus: 18.1% (20.1)]. Clostridium tetani was not detected during the study. INTERPRETATION: Mogen Clamp and ShangRing EIMC both changed the composition of the infant penile microbiome by reducing the proportional abundances of anaerobes and uropathogens, which is consistent with medical male circumcision findings in adults. C. tetani was not increased by either EIMC method. FUNDING: Bill and Melinda Gates Foundation.

Frailty in patients on dialysis.

Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive state, leading to a combination of symptoms, such as weight loss, exhaustion, low physical activity level, weakness, and slow walking speed. Frail patients not only experience a poor quality of life, but also are at higher risk of hospitalization, infection, cardiovascular events, dialysis-associated complications, and death. Frailty occurs as a result of a combination and interaction of various medical issues in patients who are on dialysis. Unfortunately, frailty has no cure. To address frailty, a multifaceted approach is necessary, involving coordinated efforts from nephrologists, geriatricians, nurses, allied health practitioners, and family members. Strategies such as optimizing nutrition and chronic kidney disease-related complications, reducing polypharmacy by deprescription, personalizing dialysis prescription, and considering home-based or assisted dialysis may help slow the decline of physical function over time in subjects with frailty. This review discusses the underlying causes of frailty in patients on dialysis and examines the methods and difficulties involved in managing frailty among this group.

Helper T cell subsets: Development, function and clinical role in hypersensitivity reactions in the modern perspective.

Helper T cells are traditionally classified into T helper 1 (TH1) and T helper 2 (TH2). The more recent discoveries of T helper 17 (TH17), follicular helper T cells (TFH) and regulatory T cells (Treg) enhanced our understanding on the mechanisms of immune function and hypersensitivity reactions, which shaped the modern perspective on the function and role of these different subsets of helper T cells in hypersensitivity reactions. Each subset of helper T cells has characteristic roles in different types of hypersensitivity reactions, hence giving rise to the respective characteristic clinical manifestations. The roles of helper T cells in allergic contact dermatitis (TH1-mediated), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome (TH2-mediated), and acute generalised exanthematous pustulosis (AGEP) (TH17-mediated) are summarised in this article, demonstrating the correlation between the type of helper T cell involved and the clinical features. TFH plays crucial roles in antibody class-switch recombination; they may be implicated in antibody-mediated hypersensitivity reactions, but further research is warranted to delineate their exact pathogenic roles. The helper T cell subsets and their specific cytokine profiles implicated in different hypersensitivity reactions could be potential treatment targets by biologics, but more clinical trials are warranted to establish their clinical effectiveness.

Organization and Structures for Detection and Monitoring of CKD Across World Countries and Regions: Observational Data From a Global Survey.

RATIONALE & OBJECTIVE: Established therapeutic interventions effectively mitigate the risk and progression of chronic kidney disease (CKD). Countries and regions have a compelling need for organizational structures that enable early identification of people with CKD who can benefit from these proven interventions. We report the current global status of CKD detection programs. STUDY DESIGN: A multinational cross-sectional survey. SETTING & PARTICIPANTS: Stakeholders, including nephrologist leaders, policymakers, and patient advocates from 167 countries, participating in the International Society of Nephrology (ISN) survey from June to September 2022. OUTCOME: Structures for the detection and monitoring of CKD, including CKD surveillance systems in the form of registries, community-based detection programs, case-finding practices, and availability of measurement tools for risk identification. ANALYTICAL APPROACH: Descriptive statistics. RESULTS: Of all participating countries, 19% (n=31) reported CKD registries, and 25% (n=40) reported implementing CKD detection programs as part of their national policies. There were variations in CKD detection program, with 50% (n=20) using a reactive approach (managing cases as identified) and 50% (n=20) actively pursuing case-finding in at-risk populations. Routine case-finding for CKD in high-risk populations was widespread, particularly for diabetes (n=152; 91%) and hypertension (n=148; 89%). Access to diagnostic tools, estimated glomerular filtration rate (eGFR), and urine albumin-creatinine ratio (UACR) was limited, especially in low-income (LICs) and lower-middle-income (LMICs) countries, at primary (eGFR: LICs 22%, LMICs 39%, UACR: LICs 28%, LMICs 39%) and secondary/tertiary health care levels (eGFR: LICs 39%, LMICs 73%, UACR: LICs 44%, LMICs 70%), potentially hindering CKD detection. LIMITATIONS: A lack of detailed data prevented an in-depth analysis. CONCLUSIONS: This comprehensive survey highlights a global heterogeneity in the organization and structures (surveillance systems and detection programs and tools) for early identification of CKD. Ongoing efforts should be geared toward bridging such disparities to optimally prevent the onset and progression of CKD and its complications. PLAIN-LANGUAGE SUMMARY: Early detection and management of chronic kidney disease (CKD) is crucial to prevent progression to kidney failure. A multinational survey across 167 countries revealed disparities in CKD detection programs. Only 19% reported CKD registries, and 25% implemented detection programs as part of their national policy. Half used a reactive approach while others actively pursued case-finding in at-risk populations. Routine case-finding was common for individuals with diabetes and hypertension. However, limited access to gold standard tools such as estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), especially in low-income and lower-middle income countries, may hinder CKD detection. A global effort to bridge these disparities is needed to optimally prevent the onset and progression of CKD and its complications.

MRGPRX2 antagonist GE1111 attenuated DNFB-induced atopic dermatitis in mice by reducing inflammatory cytokines and restoring skin integrity.

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterised by itching, erythema, and epidermal barrier dysfunction. The pathogenesis of AD is complex and multifactorial; however,mast cell (MC) activation has been reported to be one of the crucial mechanisms in the pathogenesis of AD. The MC receptor Mas related G protein-coupled receptor-X2 (MRGPRX2) has been identified as a prominent alternative receptor to the IgE receptor in causing MC activation and the subsequent release of inflammatory mediators. The current study aimed to evaluate the therapeutic effect of a novel small molecule MRGPRX2 antagonist GE1111 in AD using in vitro and in vivo approaches. Methods: We developed an in vitro cell culture disease model by using LAD-2 MC, HaCaT keratinocytes and RAW 264.7 macrophage cell lines. We challenged keratinocytes and macrophage cells with CST-14 treated MC supernatant in the presence and absence of GE1111 and measured the expression of tight junction protein claudin 1, inflammatory cytokines and macrophage phagocytosis activity through immunohistochemistry, western blotting, RT-qPCR and fluorescence imaging techniques. In addition to this, we developed a DFNB-induced AD model in mice and evaluated the protective effect and underlying mechanism of GE1111. Results and Discussion: Our in vitro findings demonstrated a potential therapeutic effect of GE1111, which inhibits the expression of TSLP, IL-13, MCP-1, TNF-a, and IL-1ß in MC and keratinocytes. In addition to this, GE1111 was able to preserve the expression of claudin 1 in keratinocytes and the phagocytotic activity of macrophage cells. The in vivo results demonstrated that GE1111 treatment significantly reduced phenotypic changes associated with AD (skin thickening, scaling, erythema and epidermal thickness). Furthermore, immunohistochemical analysis demonstrated that GE1111 treatment preserved the expression of the tight junction protein Involucrin and reduced the expression of the inflammatory mediator periostin in the mouse model of AD. These findings were supported by gene and protein expression analysis, where GE1111 treatment reduced the expression of TSLP, IL-13, and IL-1ß, as well as downstream signalling pathways of MRGPRX2 in AD skin lesions. In conclusion, our findings provide compelling in vitro and in vivo evidence supporting the contribution of MRGPRX2-MC interaction with keratinocytes and macrophages in the pathogenesis of AD.

Prospective, Multicenter, Head-to-Head Comparison Between Allergists Versus Nonallergists in Low-Risk Penicillin Allergy Delabeling: Effectiveness, Safety, and Quality of Life (HK-DADI2).

BACKGROUND: Penicillin "allergy" labels are prevalent but frequently misdiagnosed. Mislabelled allergies are associated with adverse outcomes and increased antimicrobial resistance. With an urgent need to delabel the overwhelming number of mislabeled allergies, nonallergist evaluations have been advocated for low-risk individuals. Despite growing interest in non-allergist-led initiatives, evidence on their effectiveness, safety, and impact by direct comparisons is lacking. OBJECTIVE: To assess the comparative outcomes of penicillin allergy evaluations conducted by allergists versus nonallergists. METHODS: A prospective, multicenter, pragmatic study was conducted at 4 tertiary hospitals (1 allergist- vs 3 non-allergist-led) for low-risk penicillin allergy patients in Hong Kong-the Hong Kong Drug Allergy Delabelling Initiative 2 (HK-DADI2). RESULTS: Among 228 low-risk patients who underwent testing (32.9% by allergists, 67.1% by nonallergists), only 14 (6.1%) had positive penicillin allergy testing results. Delabeling rates (94.1% vs 93.3%; P = .777), positive skin test results (2.6% vs 2.7%; P > .99), and drug provocation test results (3.3% vs 2.7%; P = 1.000) were similar between allergists and nonallergists. There were no systemic reactions in either cohort. All patients had significant improvements in health-related quality of life (Drug Hypersensitivity Quality of Life Questionnaire scores -5.00 vs -8.33; P = .072). Nonallergist evaluations had shorter waiting times (0.57 vs 15.7 months; P < .001), whereas allergists required fewer consultations with higher rate of completing evaluations within a single visit (odds ratio, 0.04; P < .001). CONCLUSIONS: With training and support, nonallergists can independently evaluate low-risk penicillin allergies. Compared with allergists, evaluation of low-risk penicillin allergy by nonallergists can be comparably effective, safe, and impactful on quality of life. More multidisciplinary partnerships to empower nonallergists to conduct allergy evaluations should be encouraged.