Meta-analysis of Epstein-Barr virus genomes in Southern Chinese identifies genetic variants and high risk viral lineage associated with nasopharyngeal carcinoma.

Genetic variants in Epstein-Barr virus (EBV) have been strongly associated with nasopharyngeal carcinoma (NPC) in South China. However, different results regarding the most significant viral variants, with polymorphisms in EBER2 and BALF2 loci, have been reported in separate studies. In this study, we newly sequenced 100 EBV genomes derived from 61 NPC cases and 39 population controls. Comprehensive genomic analyses of EBV sequences from both NPC patients and healthy carriers in South China were conducted, totaling 279 cases and 227 controls. Meta-analysis of genome-wide association study revealed a 4-bp deletion downstream of EBER2 (coordinates, 7188-7191; EBER-del) as the most significant variant associated with NPC. Furthermore, multiple viral variants were found to be genetically linked to EBER-del forming a risk haplotype, suggesting that multiple viral variants might be associated with NPC pathogenesis. Population structure and phylogenetic analyses further characterized a high risk EBV lineage for NPC revealing a panel of 38 single nucleotide polymorphisms (SNPs), including those in the EBER2 and BALF2 loci. With linkage disequilibrium clumping and feature selection algorithm, the 38 SNPs could be narrowed down to 9 SNPs which can be used to accurately detect the high risk EBV lineage. In summary, our study provides novel insight into the role of EBV genetic variation in NPC pathogenesis by defining a risk haplotype of EBV for downstream functional studies and identifying a single high risk EBV lineage characterized by 9 SNPs for potential application in population screening of NPC.

Long-term prophylaxis for hereditary angioedema: Initial experiences with garadacimab and lanadelumab.

Background: With no approved long-term prophylaxis (LTP) for the prevention of hereditary angioedema (HAE) attacks in Hong Kong, patients rely on compassionate use programs and drug trials. Moreover, studies regarding the use and efficacy of LTP in Asia are lacking. Objectives: Our aim was to assess 2 LTP medications for HAE in Hong Kong: lanadelumab and garadacimab. Methods: A prospective study was performed. Adult patients with a diagnosis of type I or type II HAE with 1 or more expert-confirmed attacks per month were consecutively recruited. The patients had been receiving treatment for at least 6 months. Clinical data were obtained, and questionnaires were administered before treatment periodically for at least 6 months following initiation of LTP. Results: Almost one-third of the patients with HAE experienced frequent attacks and began receiving LTP (8 of the 11 received garadacimab and 3 of the 11 received lanadelumab). At baseline, the time-normalized number of HAE attacks was 2.5 plus or minus 1.3 per month. At month 6, there was an overall reduction of time-normalized number of attacks per month of -2.4 attacks per month (95% CI = -3.3 to -1.5. [P < .01]). The time-normalized number of HAE attacks at month 6 was 0.1 plus or minus 0.1 per month. More than 70% of the patients (8 of 11) were completely attack-free during the 6-month period while receiving LTP, and no patients required hospitalization. LTP improved patients' scores of the Angioedema Quality-of-Life Questionnaire (P < .001) and reduced activity impairment due to health (P = .008). Patients experienced significant improvement across all dimensions of the Treatment Satisfaction for Medication Questionnaire (54.5%-76.8% [P = .002]), and no adverse events were reported. Conclusion: The patients receiving LTP with garadacimab and lanadelumab experienced a significant reduction in number of HAE attacks and improvement in quality of life, and they were satisfied with treatment.

Incidence and Risk Factors for Eosinophilia and Lung Disease in Biologic-Exposed Children With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Although interleukin-1 (IL-1)/IL-6 inhibitors are effective therapies for systemic juvenile idiopathic arthritis (JIA), some patients develop eosinophilia and lung disease during treatment. This study was undertaken to retrospectively evaluate incidence and risk factors for eosinophilia and describe lung disease outcomes in IL-1/IL-6 inhibitor-exposed patients with systemic JIA. METHODS: Among JIA patients at our institution exposed to interleukin-1 (IL-1)/IL-6 inhibitors (1995-2022), we compared incidence rate of eosinophilia in systemic JIA compared to other JIA, stratified by medication class (IL-1/IL-6 inhibitors, other cytokine inhibitors, methotrexate). We used Cox models to identify predictors of eosinophilia during IL-1/IL-6 inhibitor use and summarized treatment changes and outcomes after eosinophilia, including lung disease. HLA typing was performed on a clinical or research basis. RESULTS: There were 264 new medication exposures in 75 patients with systemic JIA and 41 patients with other JIA. A total of 49% of patients with systemic JIA with HLA typing (n = 45) were positive for HLA-DRB1*15 alleles. Eosinophilia was common during IL-1/IL-6 inhibitor use and did not differ by systemic JIA compared to other JIA (0.08 and 0.07 per person-year, respectively; P = 0.30). Among systemic JIA patients, pretreatment macrophage activation syndrome (MAS) was associated with a higher rate of subsequent eosinophilia on biologic therapy (unadjusted hazard ratio 3.2 [95% confidence interval 1.2-8.3]). A total of 4 of 5 patients who switched therapy within 10 weeks of eosinophilia experienced disease flare compared to none of the patients who continued the original therapy. A total of 8 of 25 patients with pulmonary evaluations had lung disease, and all had severe manifestations of systemic JIA (MAS, intensive care unit stay). One death was attributed to systemic JIA-lung disease. CONCLUSION: Eosinophilia is common in JIA patients using IL-1/IL-6 inhibitors. Severe disease may be associated with eosinophilia and lung disease in systemic JIA.

A case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis.

BACKGROUND: Although most immunoglobulin E (IgE)-mediated penicillin allergy wanes with time, sensitisation may occasionally persist for many years. Previous reports on the loss of penicillin-specific IgE sensitisation were based on non-anaphylaxis cases and, although uncommon, persistent sensitisation may still be possible in the minority of cases. OBJECTIVE: This case highlights that irrespective of the elapsed duration since the index reaction, it is important to remain vigilant when approaching patients with a history of severe reactions. MATERIAL AND METHODS: We described a case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis. RESULTS: A 78-year-old male with a history of perioperative penicillin anaphylaxis in 2003 was referred for allergy workup in 2022 before his knee joint replacement surgery. The patient had strictly avoided all beta-lactams since the index reaction. However, his penicillin-specific sensitisation persisted, evidenced by positive skin tests (with generalised urticaria after intradermal testing) and basophil activation tests. CONCLUSION: To our knowledge, this was the first case of positive BAT tested around two decades following the index reaction. This case illustrates that a cautious approach may still be warranted in patients with a history of severe reaction to penicillin regardless of the duration since the reported index reaction.

A case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis

Background: Although most immunoglobulin E (IgE)-mediated penicillin allergy wanes with time, sensitisation may occasionally persist for many years. Previous reports on the loss of penicillin-specific IgE sensitisation were based on non-anaphylaxis cases and, although uncommon, persistent sensitisation may still be possible in the minority of cases. Objective: This case highlights that irrespective of the elapsed duration since the index reaction, it is important to remain vigilant when approaching patients with a history of severe reactions. Material and Methods: We described a case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis. Results: A 78-year-old male with a history of perioperative penicillin anaphylaxis in 2003 was referred for allergy workup in 2022 before his knee joint replacement surgery. The patient had strictly avoided all beta-lactams since the index reaction. However, his penicillin-specific sensitisation persisted, evidenced by positive skin tests (with generalised urticaria after intradermal testing) and basophil activation tests. Conclusion: To our knowledge, this was the first case of positive BAT tested around two decades following the index reaction. This case illustrates that a cautious approach may still be warranted in patients with a history of severe reaction to penicillin regardless of the duration since the reported index reaction (AU)

Ten-year outcomes of Perioperative Anaphylaxis Workup Study in Hong Kong (PAWS-HK): Performance of diagnostic modalities.

BACKGROUND: Studies on perioperative anaphylaxis (PA) in Asia are lacking. Furthermore, allergy workup for PA has largely been limited to the "silver standard" of skin tests (ST). Using in vitro tests as an adjunct to ST may improve and overcome these diagnostic challenges. OBJECTIVE: To evaluate the clinical characteristics and diagnostic tests of patients with suspected PA through the Perioperative Anaphylaxis Workup Study in Hong Kong cohort. METHODS: Patients with a diagnosis of PA over a 10-year period were recruited into the Perioperative Anaphylaxis Workup Study in Hong Kong. We reviewed the medical records, tryptase elevation, and diagnostic tests including ST, specific immunoglobulin E, and basophil activation tests (BAT). RESULTS: In 151 patients with PA, diagnosis was reached in three-fourths of the cases (113/151, 74.8%). The most common culprits identified were neuromuscular blocking agents (25.8%), ß lactams (17.2%) and chlorhexidine (13.9%). Severe anaphylaxis was associated with female sex, older age, elevated acute tryptase levels, and more cardiovascular manifestations during induction. Skin tests remained the most sensitive diagnostic modality overall (66.2%). BAT showed better performance for chlorhexidine and gelofusine anaphylaxis, with sensitivity of 80.0% and 79.6%, respectively. Specific Immunoglobulin E indicated even higher sensitivity (95.2%) than did ST (85.0%) and BAT (80.0%) for chlorhexidine anaphylaxis but performed poorly for other drugs. CONCLUSION: Neuromuscular blocking agents remain the most common culprit in PA. There was a higher prevalence of gelofusine anaphylaxis in our cohort than was seen in the literature. Skin tests remain the most sensitive testing modality. In vitro tests for chlorhexidine and gelofusine showed promising results, but more studies to further elucidate its use are warranted.

SARS-CoV-2-specific T cell responses in patients with multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vß skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vß11-2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.

Prospective Study on the Efficacy and Impact of Cascade Screening and Evaluation of Hereditary Angioedema (CaSE-HAE).

BACKGROUND: Recommendations regarding family screening for hereditary angioedema (HAE) remain variable and mostly based on expert opinion. Studies evaluating its implementation and efficacy are lacking. OBJECTIVES: A novel HAE screening program was established to evaluate the efficacy and impact of cascade family screening (CFS) for at-risk relatives. METHODS: Potential HAE relatives were screened through the CFS approach. Prospective data on clinical, psychological, and HAE-related outcomes were collected at baseline and 1-year follow-up. Longitudinal outcomes were analyzed and compared between index patients and those given a diagnosis through CFS. RESULTS: Of 179 relatives, 53% were contactable, 67% of whom consented to screening. Twenty-nine patients (46%) were newly given the diagnosis of HAE; half were symptomatic at baseline (52%). There was a stronger trend toward higher diagnostic yield among first-degree families, although this did not meet statistical significance (57.6% vs 33.3%; P = .077). Among symptomatic patients, there was a higher proportion with complete annual HAE remission (15% vs 46%; P = .021) and a reduction in annual HAE-related hospital admissions (1 vs 0; P = .016) and length of stay (3 vs 2 days; P = .001) after 1 year. Among all patients, there were reduced Hospital Anxiety and Depression Scale-anxiety (14.35 ± 6.32 vs 6.47 ± 4.14; P = .001) and improved Angioedema Quality of Life scores (55% vs 35%; P < .001). By extrapolation, CFS led to a reduction of at least HK $1,200 (US $153) in HAE-related costs per patient per year. Screening using a greater than suggested C4 cutoff of 22.9 mg/dL yielded superior sensitivity (100%) and specificity (77%). CONCLUSION: Cascade family screening is an effective approach to family screening in HAE, improving clinical and psychological outcomes, and reducing disease-related costs.

Light-responsive polyurethanes: classification of light-responsive moieties, light-responsive reactions, and their applications.

Stimuli responsiveness has been an attractive feature of smart material design, wherein the chemical and physical properties of the material can be varied in response to small environmental change. Polyurethane (PU), a widely used synthetic polymer can be upgraded into a light-responsive smart polymer by introducing a light-sensitive moiety into the polymer matrix. For instance, azobenzene, spiropyran, and coumarin result in reversible light-induced reactions, while o-nitrobenzyl can result in irreversible light-induced reactions. These variations of light-stimulus properties endow PU with wide ranges of physical, mechanical, and chemical changes upon exposure to different wavelengths of light. PU responsiveness has rarely been reviewed even though it is known to be one of the most versatile polymers with diverse ranges of applications in household, automotive, electronic, construction, medical, and biomedical industries. This review focuses on the classes of light-responsive moieties used in PU systems, their synthesis, and the response mechanism of light-responsive PU-based materials, which also include dual- or multi-responsive light-responsive PU systems. The advantages and limitations of light-responsive PU are reviewed and challenges in the development of light-responsive PU are discussed.

PH Responsive Polyurethane for the Advancement of Biomedical and Drug Delivery.

Due to the specific physiological pH throughout the human body, pH-responsive polymers have been considered for aiding drug delivery systems. Depending on the surrounding pH conditions, the polymers can undergo swelling or contraction behaviors, and a degradation mechanism can release incorporated substances. Additionally, polyurethane, a highly versatile polymer, has been reported for its biocompatibility properties, in which it demonstrates good biological response and sustainability in biomedical applications. In this review, we focus on summarizing the applications of pH-responsive polyurethane in the biomedical and drug delivery fields in recent years. In recent studies, there have been great developments in pH-responsive polyurethanes used as controlled drug delivery systems for oral administration, intravaginal administration, and targeted drug delivery systems for chemotherapy treatment. Other applications such as surface biomaterials, sensors, and optical imaging probes are also discussed in this review.

ROS1 rearrangements in lung adenocarcinomas are defined by diffuse strong immunohistochemical expression of ROS1.

A small subset of lung adenocarcinomas harbour ROS1 gene arrangements and are amenable to tyrosine kinase inhibitor therapy. Current practice in Australia involves screening for ROS1 rearrangements in adenocarcinomas using ROS1 immunohistochemistry (IHC) followed by confirmatory molecular testing such as fluorescence in situ hybridisation (FISH), if other known genetic driver alterations are absent. The best threshold to determine ROS1 IHC positivity is not well defined, however, and this study aims to determine the optimal threshold for ROS1 IHC screening to identify ROS1-rearranged lung adenocarcinomas. A total of 177 lung adenocarcinomas tested for a ROS1 rearrangement by FISH at our institution between 2017 and 2020 due to presence of ROS1 IHC staining were included in the study. ROS1 IHC staining was assessed by scoring the staining intensity (0, 1, 2, or 3+) and multiplying by the percentage of positive cells to generate an H-score. IHC H-scores were compared with FISH. Of 177 cases, 32 (18%) were ROS1 FISH-positive and 145 (82%) were negative. FISH-positive cases had a median H-score of 300 (range 200-300; mean 290.3) and negative cases had a median H-score of 40 (range 0-300; mean 63). All FISH-positive cases showed strong and diffuse IHC positivity. Using a threshold H-score of 200, the sensitivity of identifying ROS1 rearrangements was 100% and the specificity was 95% amongst cases referred with ROS1 IHC positivity. Adenocarcinomas with a FISH-confirmed ROS1 rearrangement demonstrate diffuse, strong (2-3+) IHC staining. Cases with weak, patchy ROS1 IHC staining are not associated with ROS1 rearrangements and in these cases FISH testing is of little to no utility.

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients. Single-cell transcriptomics enabled further definition of the Tph gene signature in inflamed tissues and showed that Tph cells from ANA-positive patients upregulated genes associated with B cell help to a greater extent than patients without autoantibodies. T cells that co-expressed regulatory T and B cell-help factors were identified. The phenotype of these Tph-like Treg cells suggests an ability to restrain T cell-B cell interactions in tissues. Our findings support the central role of disordered T cell-help to B cells in autoantibody-positive arthritides.

Perioperative anaphylaxis and investigations: a local study in Hong Kong.

INTRODUCTION: Data on local intraoperative anaphylaxis in Hong Kong is scarce, with few reviews available. We aimed to study the characteristics, presentations and workup results of cases referred to a local allergy clinic. METHODS: A retrospective review was performed of patient referrals and workup results for suspected intraoperative anaphylaxis at Queen Mary Hospital drug allergy clinic in 2012-2016. RESULTS: Tryptase was checked in only 81.7% (49/60) of the cases, most of which showed elevation (71.4%, 35/49). Among the 59 patients who received a workup, 47 (79.7%) showed positive findings, with a particularly high yield in the tryptase-positive subgroup (88.6%, 31/35). Among the 54 patients who consented to skin tests (the most sensitive investigation), 43 (79.6%) cases were positive. Overall, neuromuscular blockers were the commonest cause (25.0%, 15/60) of intraoperative anaphylaxis, while antibiotics ranked second (23.3%, 14/60). The timing of reactions was an important indication of potential allergens. For example, the majority of the neuromuscular blocker allergies occurred during the induction phase, while all gelofusine allergic events were in the maintenance phase of anaesthesia. 13 (21.7%) out of 60 cases received subsequent general anaesthesia procedures, with no recurrence of allergic reactions. CONCLUSION: Proper workup after an intraoperative anaphylactic event has a fairly good chance of identifying the causative allergen. These results are useful for patient management and the planning of subsequent anaesthetic procedures.

High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma.

Whether certain variants of Epstein-Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case-control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A-C and 2A-B amongst the population carriers in contrast to the predominance of 1A and -B in the majority of NPC. Genome-wide association study (GWAS) identified a panel of NPC-associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four-base-deletion polymorphism downstream of EBER2 (EBER-del) from coordinates 7188-7191 (p = 1.91 × 10-7 ). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV-associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC-EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV-associated cancers is warranted.