Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

Neglected but Clinically Relevant Allergens in Korea.

PURPOSE OF REVIEW: Allergy diagnostics and immunotherapeutics in Asia heavily rely on imported products from Western countries, raising concerns about the accuracy and efficacy of these products for the management of Asian allergy patients. RECENT FINDINGS: Recent advancements in allergen research have led to the identification and characterization of novel allergens from indigenous Korean species. While some allergens share homology with well-known allergens, others lack counterparts in imported allergen extracts. Classifying regional allergens in Asia into three categories based on their cross-reactivity with imported allergens offers valuable insights. Highly cross-reactive allergens, such as oak allergens Que m 1 from Quercus mongolica and Que ac 1 from Q. acutissima, can be effectively substituted with the imported allergens. Allergens with partial cross-reactivity, like the Asian needle ant allergen Pac c 3 (Antigen 5), permit limited diagnostic value by the currently available products. Unique allergens, including the Japanese hop allergen Hum j 6 (pectin methylesterase inhibitor) and the silkworm pupa allergen Bomb m 4 (30 kDa hemolymph lipoprotein) lack alternatives in the available product list. Greater attention is needed, particularly for species listed as ecologically invasive in Western regions. Additionally, allergens from domestic fruits and vegetables causing pollen food allergy syndrome require characterization for the development of improved diagnostics.

Risk of recurrence of nail unit melanoma after functional surgery versus amputation.

BACKGROUND: Minimally invasive nail unit melanoma (NUM) can be treated with functional surgery (FS) instead of amputation. OBJECTIVE: To determine risk factors associated with recurrence in NUM. METHODS: We retrospectively reviewed patients with NUM between 2008 and 2022 at a tertiary referral center. Multivariable Cox regression models adjusted for male sex and Breslow thickness (BT) were generated. Receiver operating characteristic analysis was performed to determine optimal cut-off points of the BT for stratifying recurrence risk. RESULTS: We evaluated 140 NUM cases (33 amputation and 107 FS). The mean BT values were 3.14 ± 2.62 mm (amputation) and 0.70 ± 1.36 mm (FS). Recurrence occurred in 10 (30.30%) patients with amputation and 23 (21.5%) with FS. Distant disease occurred in 10 (30.30%) patients with amputation and 8 (7.48%) with FS. Male sex, greater BT, amelanotic color, ulcers, and nodules were associated with greater risk for recurrence or distant disease. A BT of 0.8 mm was deemed the optimal cut-off for stratifying recurrence risk after surgery (odds ratio, 5.32; 95% CI, 2.04-13.85). LIMITATIONS: Small sample. CONCLUSION: FS can be considered for NUM with a BT < 0.8 mm, providing an amputation-sparing benefit. However, NUM with risk factors for recurrence requires patient counselling and close follow-ups.

A new index for distinguishing hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

BACKGROUND: It is difficult to differentiate between hypereosinophilic syndrome (HES) and antineutrophil cytoplasmic antibody (ANCA)-negative eosinophilic granulomatosis with polyangiitis (EGPA). OBJECTIVE: We compared laboratory data at diagnosis between Korean patients with HES and ANCA-negative EGPA and investigated independent laboratory predictors suggesting HES. METHODS: We reviewed the medical records of 41 HES patients and 16 ANCA-negative EGPA patients. The cut-offs were extrapolated by the receiver operator characteristic (ROC) curve. The odds ratio (OR) and relative risk (RR) were assessed using the multivariable logistic regression analysis and the chi-square test, respectively. We developed a new equation by assigning a weight to each variable according to the slopes (B) and expressed a decimal as the nearest integer. RESULTS: HES patients had a higher median WBC and eosinophil counts than ANCA-negative EGPA patients. The cutoffs of WBC and eosinophil counts for HES were set at 9,900.0/mm3 and 2,400.0/mm3. In the multivariable analysis, WBC count ≥ 9,900.0/mm3 (B 1.763) and eosinophil count ≥ 2,400.0/mm3 (B 1.515) were significantly associated with HES. An equation was as follows: HES-suggesting laboratory index (HSLI) = 2 × (WBC count ≥ 9,900.0/mm3 (1 = No or 2 = Yes)) + 1.5 × (eosinophil count ≥ 2,400.0/mm3 (1 = No or 2 = Yes)). The cut-off of HSLI for HES was 4.25. Patients with HSLI ≥ 4.25 exhibited a significantly high RR (51.429) for HES, compared to those without. CONCLUSIONS: In conclusion, the cut-off of HSLI derived from WBC and eosinophil counts could be an independent predictor of HES in patients suspected of both HES and ANCA-negative EGPA.

Allergenic characterization of Bomb m 4, a 30-kDa Bombyx mori lipoprotein 6 from silkworm pupa.

BACKGROUND: Silkworm pupa (SWP) food anaphylaxis has been described frequently in Asian countries. However, false-positive reactions by skin pricks and serum IgE (sIgE) tests to the extract complicate diagnosis, requiring identification of clinically relevant major allergens. OBJECTIVES: In this study, we characterized a novel SWP allergen, Bomb m 4, a 30-kDa lipoprotein, and evaluated its diagnostic sensitivity. METHODS: Bomb m 4 was identified by a proteomic analysis. This recombinant (r)Bomb m 4 was overexpressed in Escherichia coli, and the IgE reactivity by ELISA was compared with other reported allergenic proteins: Bomb m 1 (arginine kinase), 27-kDa glycoprotein, Bomb m 3 (tropomyosin) using the serum samples from 17 SWP allergic patients and 11 asymptomatic sensitized subjects. RESULTS: rBomb m 4-specific IgE was recognized by all 17 SWP allergic patients. The 27-kDa glycoprotein and Bomb m 1 sIgE were found in 35.3% and 0%, respectively, in the SWP allergic patients. ELISA sIgE reactivity increased significantly, when 4 M urea was added in serum samples. However, only 16% inhibition of sIgE reactivity to the whole SWP extract was exhibited by rBomb m 4, whereas more than 93% of self-inhibition of rBomb m 4 sIgE was obtained, possibly due to the low abundance of Bomb m 4 in the extract. Three linear epitopes (81-95, 191-205 and 224-238 residues) of rBomb m 4 were identified. These epitopes are shown to be released by pepsin digestion. Receiver operator characteristic (ROC) analysis showed the highest diagnostic value of Bomb m 4 followed by Bomb m 1, 27-kDa glycoprotein and Bomb m 3. CONCLUSION: Bomb m 4 is the major allergen of SWP allergic patients. It has cryptic epitopes which are exposed to IgE antibodies with digestive enzymes. This recombinant Bomb m 4 allergen permits exact diagnosis of SWP allergy.

Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.

BACKGROUND: The genetic test solely based on the clinical features of hereditary colorectal cancer has limitations in clinical practice. OBJECTIVE: This study aimed to analyze the results of comprehensive multigene panel tests based on clinical findings. DESIGN: This was a cross-sectional study based on a prospectively compiled database. SETTING: The study was conducted at a tertiary hospital. PATIENTS: A total of 381 patients with high risk for hereditary colorectal cancer syndromes were enrolled between March 2014 and December 2019. MAIN OUTCOME MEASURES: The primary outcome was to describe the mutational spectrum based on genotype-phenotype concordance and discordance. RESULTS: Germline mutations were identified in 89 patients for polyposis hereditary colorectal cancer genes (76 in APC; 4 in PTEN; 4 in STK11; 3 in BMPR1A; 1 in POLE; 1 in POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 in MLH1; 40 in MSH2; 6 in MSH6; and 2 in PMS2), and 12 patients for other cancer predisposition genes (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). If we had used direct sequencing tests of 1 or 2 major genes based on phenotype, 48 (25.3%) of 190 mutations would not have been detected due to technical differences (12.1%), less frequent genotype (4.2%), unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The genotype-phenotype discordance is probably linked to compound heterozygote, less distinctive phenotype, and insufficient information for colorectal cancer risk. LIMITATIONS: This study included a small number of patients with insufficient follow-up duration. CONCLUSIONS: A comprehensive multigene panel is expected to identify more genetic mutations than phenotype-based direct sequencing, with special utility for unclear phenotype or genotype-phenotype discordance. See Video Abstract at http://links.lww.com/DCR/B844. APLICACIN DE PRUEBAS DE PANEL MULTIGNICO EN PACIENTES CON ALTO RIESGO DE CNCER COLORRECTAL HEREDITARIO INFORME DESCRIPTIVO ENFOCADO EN LA CORRELACIN GENOTIPOFENOTIPO: ANTECEDENTES:La prueba genética basada únicamente en la característica clínica del cáncer colorrectal hereditario tiene limitaciones en la práctica clínica.OBJETIVO:Este estudio tuvo como objetivo analizar el resultado de pruebas integrales de panel multigénico basadas en hallazgos clínicos.DISEÑO:Este fue un estudio transversal basado en una base de datos recopilada prospectivamente.AJUSTE:El estudio se realizó en un hospital terciario.PACIENTES:Se inscribió un total de 381 pacientes con alto riesgo de síndromes de cáncer colorrectal hereditario entre marzo del 2014 y diciembre del 2019.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue describir el espectro mutacional basado en la concordancia y discordancia genotipo-fenotipo.RESULTADOS:Se identificaron mutaciones de la línea germinal en 89 pacientes para genes de cáncer colorrectal hereditario con poliposis (76 en APC; 4 en PTEN; 4 en STK11; 3 en BMPR1A; 1 en POLE; 1 en POLD1), 89 pacientes para genes de CCR hereditario sin poliposis (41 en MLH1; 40 en MSH2; 6 en MSH6; y 2 ​​en PMS2) y 12 pacientes por otro gen de predisposición al cáncer (1 en ATM; 2 en BRCA1; 1 en BRCA2; 1 en BRIP1; 1 en MLH3; 1 en NBN; 1 en PMS1; 1 en PTCH1; 1 en TP53; y 2 ​​en MUTYH monoalélico). Si hubiéramos utilizado pruebas de secuenciación directa de uno o dos genes principales basados ​​en el fenotipo, 48 (25,3%) de 190 mutaciones no se habrían detectado debido a diferencias técnicas (12,1%), genotipo menos frecuente (4,2%), fenotipo poco claro (3,7%) y discordancia genotipo-fenotipo (4,7%). La discordancia genotipo-fenotipo probablemente esté relacionada con el heterocigoto compuesto, el fenotipo menos distintivo y la información insuficiente para el riesgo de cáncer colorrectal.LIMITACIONES:Este estudio incluyó una pequeña cantidad de pacientes con una duración de seguimiento insuficiente.CONCLUSIONES:Se espera que un panel multigénico completo identifique más mutaciones genéticas que la secuenciación directa basada en el fenotipo, con especial utilidad para la discordancia de fenotipo o genotipo-fenotipo poco clara. Consulte Video Resumen en http://links.lww.com/DCR/B844. Traducción- Dr. Francisco M. Abarca-Rendon).

Association between obesity and lung function changes by sex and age in adults with asthma.

OBJECTIVE: The lung function changes presenting before and after asthma treatment in obese people remain largely unknown. This study aimed to investigate the association between obesity and lung function changes before and after treatment in adults with asthma. METHODS: We enrolled 937 newly diagnosed asthma patients from Cohort for Reality and Evolution of Adult Asthma in Korea cohort in 2015-2017, who performed follow-up spirometry after three months of asthma treatment. The percentage changes (Δ) between the spirometry results before and after treatment were calculated. Patients were categorized into four body mass index (BMI) groups; underweight (<18.5), normal (18.5-22.9), overweight (23.0-24.9), and obese (≥25.0). Association between percent change of pulmonary function and BMI was analyzed according to sex and/or age (< 45 yrs, 45-65 yrs, ≥ 65 yrs), which were statistically corrected for age, sex, smoking status, and medication history. RESULTS: There was no consistent correlation between BMI and each lung function parameter. However, there were significant differences between BMI and ΔFEV1/FVC before and after 3 months of controller treatment. The obese asthmatics showed significantly lower ΔFEV1/FVC (6.0 ± 13.5%) than the underweight (12.6 ± 21.4%, P = 0.044) or normal weight (9.1 ± 14.6%, P = 0.031). Middle-aged women had higher BMI (24.11 ± 3.60 vs. 22.39 ± 3.52) and lower ΔFEV1/FVC (5.7 ± 11.9% vs. 8.9 ± 14.3%, P = 0.012) than young women. CONCLUSIONS: Obesity is negatively correlated with the ΔFEV1/FVC before and after controller treatment. Sex and age differentially contribute to lung function changes in response to asthma medications in adult asthmatics, showing a significant decrease in the ΔFEV1/FVC in middle-aged women.

Clusters of Severe Eosinophilic Asthma in a Korean Asthma Cohort.

BACKGROUND: Targeted therapies have broadened the available treatment options for patients with severe eosinophilic asthma (SEA). However, differences in the magnitude of treatment responses among patients indicate the presence of various underlying pathophysiological processes and patient subgroups. OBJECTIVES: We aimed to describe the characteristics of SEA and identify its patient subgroups. METHODS: Clinical data from the Cohort for Reality and Evolution of Adult Asthma in Korea were analyzed. Cluster analysis was performed among those with SEA using 5 variables, namely, prebronchodilator forced expiratory volume in 1 s, body mass index, age at symptom onset, smoking amount, and blood eosinophil counts. RESULTS: Patients with SEA showed prevalent sensitization to aeroallergens, decreased lung function, and poor asthma control status. Cluster analysis revealed 3 distinctive subgroups among patients with SEA. Cluster 1 (n = 177) consisted of patients reporting the lowest blood eosinophils (median, 346.8 cells/µL) and modest severe asthma with preserved lung function during the 12-month treatment period. Cluster 2 (n = 42) predominantly included smoking males with severe persistent airway obstruction and moderate eosinophilia (median, 451.8 cells/µL). Lastly, cluster 3 (n = 95) included patients with the most severe asthma, the highest eosinophil levels (median, 817.5 cells/µL), and good treatment response in terms of improved lung function and control status. CONCLUSIONS: Three subgroups were identified in SEA through the cluster analysis. The distinctive features of each cluster may help physicians predict patients who will respond to biologics with greater magnitude of clinical improvement. Further research regarding the underlying pathophysiology and clinical importance of each subgroup is warranted.

Association Between Clinical Burden and Blood Eosinophil Counts in Asthma: Findings From a Korean Adult Asthma Cohort.

BACKGROUND: Some reports have suggested that the clinical and economic burdens of asthma are associated with blood eosinophil levels. The association between clinical burden and blood eosinophil counts were evaluated in a Korean adult asthma cohort. METHODS: Clinical information including blood eosinophil counts that were not affected by systemic corticosteroids were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea database. Clinical burden was defined as 1) asthma control status, 2) medication demand and 3) acute exacerbation (AE) events during 1 consecutive year after enrollment. All patients were divided into atopic and non-atopic asthmatics. The associations between asthma outcomes and the blood eosinophil count were evaluated. RESULTS: In total, 302 patients (124 atopic and 178 non-atopic asthmatics) were enrolled. In all asthmatics, the risk of severe AE was higher in patients with blood eosinophil levels < 100 cells/µL than in patients with levels ≥ 100 cells/µL (odds ratio [OR], 5.406; 95% confidence interval [CI], 1.266-23.078; adjusted P = 0.023). Among atopic asthmatics, the risk of moderate AE was higher in patients with blood eosinophil levels ≥ 300 cells/µL than in patients with levels < 300 cells/µL (OR, 3.558; 95% CI, 1.083-11.686; adjusted P = 0.036). Among non-atopic asthmatics, the risk of medication of Global Initiative for Asthma (GINA) steps 4 or 5 was higher in patients with high blood eosinophil levels than in patients with low blood eosinophil levels at cutoffs of 100, 200, 300, 400, and 500 cells/µL. CONCLUSION: The baseline blood eosinophil count may predict the future clinical burden of asthma.

Comparison of sensitization patterns to dust mite allergens between atopic dermatitis patients and dogs, and non-specific reactivity of canine IgE to the storage mite Tyrophagus putrescentiae.

House dust mite is a common cause of atopic dermatitis (AD) both in humans and dogs. Detection of serum IgE to allergens is commonly used to diagnose allergic diseases. However, false-positive reactions due to cross-reactivity and non-specific reactivity may lead to misdiagnosis. We compared human and canine IgE reactivities to mite component allergens. Canine IgE-reactive components of Dermatophagoides farinae and Tyrophagus putrescentiae were identified by tandem mass spectrometry. Recombinant proteins were produced and IgE reactivities to component allergens were assessed by ELISA and inhibition assays using sera from AD patients and dogs. Canine IgE-reactive proteins (Der f 1, Der f 11, Tyr p 4, Tyr p 8, Tyr p 11, Tyr p 28) were identified by proteome analysis. Most patients were sensitized to Der f 1 (93.3%) and Der f 2 (86.7%). Dogs showed high sensitization to Der f 2 (94.1%) and Der f 18 (84.6%). Both patients and dogs showed low IgE binding frequency to Tyr p 8, 43.3% and 4%, respectively. The ELISA inhibition study indicated that canine IgE reactivity to T. putrescentiae is mostly due to non-specific reaction and cross-reaction with D. farinae. Different IgE sensitization patterns were shown between allergic humans and dogs with AD, especially to Der f 18, for the first time in Korea. Furthermore, non-specific canine IgE reactivity to storage mite indicates the possibility of misdiagnoses. Standardizations focused on the major canine allergen content of extracts should be developed. This will allow precision diagnosis and individuated treatments for each patient and atopic dog.

Obesity-induced Vitamin D Deficiency Contributes to Lung Fibrosis and Airway Hyperresponsiveness.

Vitamin D (VitD) has pleiotropic effects. VitD deficiency is closely involved with obesity and may contribute to the development of lung fibrosis and aggravation of airway hyperresponsiveness (AHR). We evaluated the causal relationship between VitD deficiency and the lung pathologies associated with obesity. In vivo effects of VitD supplementation were analyzed using high-fat diet (HFD)-induced obese mice and TGF-ß1 (transforming growth factor-ß1) triple transgenic mice. Effects of VitD supplementation were also evaluated in both BEAS-2B and primary lung cells from the transgenic mice. Obese mice had decreased 25-OH VitD and VitD receptor expressions with increases of insulin resistance, renin and angiotensin-2 system (RAS) activity, and leptin. In addition, lung pathologies such as a modest increase in macrophages, enhanced TGF-ß1, IL-1ß, and IL-6 expression, lung fibrosis, and AHR were found. VitD supplementation to HFD-induced obese mice recovered these findings. TGF-ß1-overexpressing transgenic mice enhanced macrophages in BAL fluid, lung expression of RAS, epithelial-mesenchymal transition markers, AHR, and lung fibrosis. VitD supplementation also attenuated these findings in addition to the attenuation of the expressions of TGF-ß1, and phosphorylated Smad-2/3 in lung. Supplementing in vitro-stimulated BEAS-2B and primary lung cells with VitD inhibited TGF-ß1 expression, supporting the suppressive effect of VitD for TGF-ß1 expression. These results suggest that obesity leads to VitD deficiency and worsens insulin resistance while enhancing the expression of leptin, RAS, TGF-ß1, and proinflammatory cytokines. These changes may contribute to the development of lung fibrosis and AHR. VitD supplementation rescues these changes and may have therapeutic potential for asthma with obesity.

Effect of asthma and asthma medication on the prognosis of patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide rapidly. However, the effects of asthma, asthma medication and asthma severity on the clinical outcomes of COVID-19 have not yet been established. METHODS: The study included 7590 de-identified patients, who were confirmed to have COVID-19 using the severe acute respiratory syndrome coronavirus 2 RNA-PCR tests conducted up to May 15, 2020; we used the linked-medical claims data provided by the Health Insurance Review and Assessment Service. Asthma and asthma severity (steps suggested by the Global Initiative for Asthma) were defined using the diagnostic code and history of asthma medication usage. RESULTS: Among 7590 COVID-19 patients, 218 (2.9%) had underlying asthma. The total medical cost associated with COVID-19 patients with underlying asthma was significantly higher than that of other patients. Mortality rate for COVID-19 patients with underlying asthma (7.8%) was significantly higher than that of other patients (2.8%; p<0.001). However, asthma was not an independent risk factor for the clinical outcomes of COVID-19 after adjustment, nor did asthma medication use and asthma severity affect the clinical outcomes of COVID-19. However, use of oral short-acting ß2-agonists was an independent factor to increase the total medical cost burden. Patients with step 5 asthma showed significant prolonged duration of admission compared to those with step 1 asthma in both univariate and multivariate analysis. CONCLUSIONS: Asthma led to poor outcomes of COVID-19; however, underlying asthma, use of asthma medication and asthma severity were not independent factors for poor clinical outcomes of COVID-19, generally.

Influence of government-driven quality assessment program on patients with chronic obstructive pulmonary disease.

BACKGROUND: The Korean Health Insurance Review and Assessment Service (HIRA) has launched the Chronic Obstructive Pulmonary Disease (COPD) Quality Assessment Program (CQAP) since 2014. We aimed to reveal the influence of this national program on clinical outcomes and the burden of COPD in Korea. METHODS: The CQAP is conducted annually. We used healthcare claims data linked with the results of the program provided by HIRA between May 2014 and April 2017. Patients were considered to have COPD if they visited a hospital for COPD management during the assessment term. Those who visited a medical institution for COPD and were prescribed COPD medications at least twice were assessed by the CQAP (assessed subjects, AS; not-assessed subjects, NAS). CQAP evaluated the pulmonary function test conduction rate, regular visitation rate, and prescription rates of COPD medications. RESULTS: Among the 560,000 patients with COPD, about 140,000 were assessed by the CQAP annually. In both groups, the pulmonary function test conduction rate and inhaled bronchodilator prescription rate improved since 2014. Compared to the NAS group, the risk of admission and all-cause mortality rate in the AS group were significantly reduced by 21.2% and 40.7%, respectively. In patients who were assessed for 3 consecutive years, all of the above variables were high at baseline and were not improved much from implementation of CQAP. In matching analysis, we observed this improvement to be limited in the COPD quality assessment year. CONCLUSIONS: The CQAP by the health insurance bureau has improved the management protocol and prognosis of COPD.

C-reactive protein is associated with postoperative outcomes in patients with intestinal Behçet's disease.

BACKGROUND: Patients with intestinal Behçet's disease (BD) frequently undergo intestinal resections, which significantly affects postoperative morbidity and mortality. The aim of this study was to identify the association between C-reactive protein (CRP) levels and postoperative outcomes in patients with intestinal BD who underwent surgical bowel resection. METHODS: Patients who were diagnosed with intestinal BD and underwent intestinal surgery due to BD at Severance Hospital between November 2005 and April 2018 were retrospectively investigated. Clinical relapse was defined as a disease activity index of BD (DAIBD) > 40, existence of newly added medications, re-hospitalization, or re-operation related to intestinal BD. The relationship between CRP level and postoperative outcomes was analyzed, and a receiver operating characteristic (ROC) curve was drawn to specify a cut-off value. RESULTS: Ninety patients with intestinal BD were included. Among them, 44 were male (48.9%), and the median age at diagnosis was 38 years (range, 11-69 years). The median total disease follow-up duration was 130 months (range, 3-460 months). Forty patients (44.4%) underwent laparoscopic surgery. A higher CRP level immediately after surgery was significantly associated with postoperative complications (OR 1.01, 95% CI 1.004-1.018, p < 0.01), re-operation (hazard ratio [HR] 1.01, 95% CI 1.005-1.020, p < 0.01), and re-admission (HR 1.01, 95% CI 1.006-1.017 p < 0.01). The ROC curve showed that CRP predicts the risk of postoperative complications (p < 0.01) at a cut-off value of 41.9% with a sensitivity of 60.0% and specificity of 67.7%. CONCLUSIONS: Postoperative CRP levels in patients with intestinal BD undergoing surgical resection were associated with postoperative outcomes.

Prevalence of cerebrovascular diseases that can cause hemorrhagic stroke in liver transplantation recipients: a 6-year comparative study with 24,681 healthy adults.

BACKGROUND AND PURPOSE: Cerebrovascular diseases are a leading cause of mortality after liver transplantation (LT). The prevalence of potentially hemorrhagic cerebrovascular diseases (HCVDs) that could cause a hemorrhagic stroke in patients with severe liver diseases has not been reported. We aimed to analyze the underlying prevalence of HCVDs that could lead to hemorrhagic strokes in LT recipients compared with that in previously healthy controls. METHODS: A retrospective study with 1,920 consecutive LT recipients and 24,681 adults who underwent a health checkup during the same period was conducted (January 2011-December 2016). The prevalence of cerebral aneurysms (CA), cerebral arteriovenous malformation (AVM), and cavernous malformation (CM) was evaluated using brain imaging, including computed tomography angiography, magnetic resonance imaging, magnetic resonance angiography, and digital subtraction angiography. RESULTS: The prevalence of CA and CM were 3.1% and 0.5%, respectively, in the LT group and 3.8% and 0.4%, respectively, in the control group. According to the location of the cerebral artery, paraclinoid internal carotid artery aneurysms (odds ratio [OR] 0.440; P = 0.009) had a lower prevalence in LT recipients than in healthy controls. Anterior communicating artery (OR 3.080; P = 0.002) and superior cerebellar artery (OR 8.767; P = 0.017) aneurysms had a higher prevalence in the LT group than in the control. The prevalence of AVM was significantly higher in LT recipients (0.26%) than in healthy controls (0.06%). CONCLUSION: LT recipients showed a different distribution of CA prevalence according to the locations of the cerebral artery and had a higher overall prevalence of AVM than previously healthy controls.

Sensitization profile to sawtooth oak component allergens and their clinical implications.

OBJECTIVE: The component allergens from sawtooth oak, which is a main cause of tree pollinosis in Korea, have not been extensively characterized except Que ac 1. This study was undertaken to characterize the allergenic components from sawtooth oak pollen and investigate the diagnostic values of each component allergen. METHODS: Transcriptomic analysis was performed to identify the birch pollen allergen homologues from sawtooth oak pollen. Recombinant Que ac 1, 2, 3, 6, 7, and 8 were produced in an E. coli expression system. IgE reactivity to each allergen was examined by ImmunoCAP and ELISA using the sera of 50 Korean tree pollinosis patients. RESULTS: Six birch pollen allergen homologues were identified using transcriptome analysis, as follows: Que ac 1 (54.8% identity to Bet v 1), Que ac 2 (79.7% to Bet v 2), Que ac 3 (24.9% to Bet v 3), 6 (71.3% to Bet v 6), Que ac 7 (80.9% to Bet v 7), and Que ac 8 (78.9% to Bet v 8). Que ac 1 sIgE was the most frequently recognized (84.0%), followed by Que ac 2 (12.0%), Que ac 3 (6.0%), and three other allergens (2.0% each). Que ac 1 was a dominant allergen affecting 83.7% of patients suffering from allergic rhinoconjunctivitis, and 92.9% of pollen food allergy syndrome patients. CONCLUSION: Five novel IgE reactive components of sawtooth oak were characterized using transcriptome analysis. Que ac 1 is the single most important component allergen of sawtooth oak pollen.

Efficacy of transdermal immunotherapy with biodegradable microneedle patches in a murine asthma model.

BACKGROUND: House dust mite (HDM) is a well-known cause of asthma. Allergen-specific immunotherapy (AIT) can only modify the natural course of the disease. Conventional routes of HDM AIT are subcutaneous or sublingual. Subcutaneous immunotherapy (SCIT) has a disadvantage of systemic hypersensitive reaction, and the sublingual immunotherapy has a disadvantage of local allergic reaction and low drug adherence. OBJECTIVE: To overcome the weak points of conventional AIT, we developed a HDM loaded biodegradable microneedle patch (MNP) for transdermal immunotherapy (TDIT). We aim to demonstrate the efficacy of TDIT in murine asthma model triggered by HDM compared with conventional SCIT. METHODS: To make HDM asthma mouse model, 5-week-old BALB/c female mice were sensitized and challenged by intranasal administration of HDM. The mice were divided into 5 groups: sham, asthma, low (10 µg) and high dose (100 µg) SCIT, and TDIT (10 µg). To make HDM loaded MNP, droplet-born air blowing method was used. Airway hyperresponsiveness and allergic inflammation markers were analysed by bronchoalveolar lavage fluid, immunohistochemistry, serum immunoglobulin (Ig) analysis, and lung cytokine assays. RESULTS: Airway hyperresponsiveness was ameliorated by TDIT. Eosinophilic inflammation in bronchoalveolar lavage was improved without adverse reactions. Reduction of Th2 (IL-4, IL-5, and IL-13) cytokines, and HDM-specific IgE, induction of Treg (IL-10, TGF-ß), Th1 (IFN-γ) cytokines were observed. Eosinophilic infiltration, goblet cell hyperplasia, and subepithelial fibrosis were also alleviated by TDIT. These changes were more significant in the TDIT group than in subcutaneous AIT group. CONCLUSION: In conclusion, HDM loaded biodegradable TDIT is a novel treatment option to treat asthma which showed more effectiveness and may have better safety profiles than conventional SCIT.

Survival Benefit for Metformin Through Better Tumor Response by Neoadjuvant Concurrent Chemoradiotherapy in Rectal Cancer.

BACKGROUND: Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies. OBJECTIVE: This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer. DESIGN: This is a retrospective study. SETTING: This study was conducted at a single institution in the Republic of Korea. PATIENTS: Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed. MAIN OUTCOME MEASURES: Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured. RESULTS: Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1-2), ypN stage (1-2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082-0.794), p = 0.018; HR, 0.147 (95% CI, 0.031-0.697), p = 0.016; HR, 3.693 (95% CI, 1.283-10.635), p = 0.015; HR, 3.181 (95% CI, 1.155-8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040-0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077-0.639); p = 0.005). LIMITATIONS: This was a small retrospective study conducted at a single institution. CONCLUSIONS: Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at http://links.lww.com/DCR/B185. BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL: La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.Estudio retrospectivo.Institución única en la República de Corea.Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1-2), el estadio ypN (1-2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082-0.794], p = 0.018; 0.147 [0.031-0.697], p = 0.016; 3.693 [1.283-10.635], p = 0.015; 3.181 [1.155-8.759], p = 0.025 y 0.175 [0.040-0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077-0.639]; p = 0.005).Este fue un estudio retrospectivo pequeño realizado en un solo instituto.El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en http://links.lww.com/DCR/B185. (Traducción-Dr. Jorge Silva Velazco).

Intradermal Testing With Radiocontrast Media to Prevent Recurrent Adverse Reactions.

OBJECTIVE. Adverse drug reactions (ADRs) to radiocontrast media are a significant social and economic burden and are difficult to predict. Because some ADRs to radiocontrast media may be immunologically induced, a skin test with diluted 1:10 radiocontrast media has been used to predict ADRs. However, using this test in clinical practice is difficult because of its low sensitivity. SUBJECTS AND METHODS. This study enrolled 36 patients with a history of immediate ADR to radiocontrast media who visited the Allergy and Asthma Clinic of Severance Hospital from 2017 to 2018. Patients underwent intradermal testing (IDT) with five types of diluted (1:10) and undiluted radiocontrast media (iohexol, iobitridol, iopamidol, iopromide, and iodixanol). The IDT result was regarded as positive if at least one radiocontrast medium elicited a positive reaction. Positivity of IDT and sensitivity to the culprit radiocontrast medium were calculated and compared. For subsequent CT examinations with a radiocontrast medium, the contrast agent eliciting a negative skin reaction in IDT was selected, excluding the previous culprit radiocontrast medium. RESULTS. IDT positivity and sensitivity for the culprit radiocontrast medium at 1:10 dilution were 47.2% and 47.2%, respectively, whereas the positivity and sensitivity for the undiluted radiocontrast medium were 86.1% and 75.0%, respectively. The positivity and sensitivity were higher with frequent radiocontrast medium use or with severe reaction. Of 22 patients who underwent another CT examination with the contrast medium selected on the basis of IDT results, 21 (95.5%) did not experience an ADR. CONCLUSION. IDT to prevent ADR should be performed with undiluted radiocontrast medium. Selecting an alternative radiocontrast agent on the basis of IDT results can be clinically useful to prevent recurrent ADRs to radiocontrast media.

Variation of clinical manifestations according to culprit drugs in DRESS syndrome.

PURPOSE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious condition that systematically damages various internal organs through T-cell-mediated immunological drug reactions. We aimed to investigate whether clinical manifestations of DRESS syndrome differ according to culprit drugs. METHODS: We retrospectively analyzed data from 123 patients with probable/definite DRESS syndrome based on the RegiSCAR criteria (January 2011 to July 2016). The data were obtained from the Korean Severe Cutaneous Adverse Reaction Registry. Causality was assessed using the World Health Organization-Uppsala Monitoring Centre criteria. The culprit drugs were categorized as allopurinol, carbamazepine, anti-tuberculosis drug, vancomycin, cephalosporins, dapsone, and nonsteroidal anti-inflammatory drugs. RESULTS: Differences were observed among culprit drugs regarding the frequencies of hepatitis (P < 0.01), renal dysfunction (P < 0.0001), lymphadenopathy (P < 0.01), and atypical lymphocyte (P < 0.01). Latency period differed among culprit drugs (P < 0.0001), being shorter in vancomycin and cephalosporin. In terms of clinical severity, admission duration (P < 0.01) and treatment duration (P < 0.05) differed among culprit drugs, being longer in vancomycin and anti-tuberculosis drugs, respectively. CONCLUSIONS: Based on the findings, clinical manifestations, including latency period and clinical severity, may differ according to culprit drugs in DRESS syndrome.