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Objective: To determine if the choice of methodological elements affects the results in continuity of care studies., Design: This is a retrospective cohort study. The association between continuity of care and clinical outcome was investigated using the Continuity of Care Index. The association was explored in 12 scenarios based on four definitions of the relative timing of continuity and outcome measurements in three populations (three P s × four T s)., Setting: National Health Insurance claims from all primary and secondary care facilities in South Korea between 2007 and 2015., Participants: Participants were patients diagnosed with dyslipidaemia, made ≥2 ambulatory visits and were newly prescribed with ≥1 antihyperlipidaemic agent at an ambulatory setting in 2008. Three study populations were defined based on the number of ambulatory visits: 10 084 patients in population 1 (P1), 8454 in population 2 (P2) and 4754 in population 3 (P3)., Main Outcome Measure: Hospitalisation related to one of the four atherosclerotic cardiovascular diseases, including myocardial infarction, stable or unstable angina, ischaemic stroke and transient ischaemic attack., Results: Concurrent measure of continuity and outcome (T1) showed a significantly higher risk of hospitalisation (adjusted HRs: 2.73-3.07, p<0.0001) in the low continuity of care group, whereas T2, which measured continuity until the outcome occurred, showed no risk difference between the continuity of care groups. T3, which measured continuity as a time-varying variable, had adjusted HRs of 1.31-1.55 (p<0.05), and T4, measuring continuity for a predefined period and measuring outcomes in the remaining period, had adjusted HRs of 1.34-1.46 (p<0.05) in the low continuity of care. Within each temporal relationship, the effect estimates became more substantial as the inclusion criteria became stricter., Conclusions: The study design in continuity of care studies should be planned carefully because the results are sensitive to the temporal relationship between continuity and outcome and the population selection criteria., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB). Metformin, which is an essential anti-diabetic drug, has been shown to exhibit anti-TB effects in patients with DM. Its effect on preventing the development of TB among patients who are newly diagnosed with DM remains unclear., Methods: This was a retrospective cohort study using the claims database of the Korean Health Insurance Review and Assessment Service. The study population included patients who were newly diagnosed with type 2 DM and who were treated with anti-diabetic drugs between 1 January 2003 and 31 March 2011. A patient was defined as a metformin user if he/she had taken metformin for more than 28 days within 6 months since cohort entry, and as a metformin non-user if he/she had never been treated with metformin. The development of TB within 2 years after the index date was compared by Cox proportional hazard regression models between metformin users and 1:1 propensity score (PS)-matched non-users., Results: Among 76,973 patients who were newly diagnosed with type 2 DM, 13,396 were classified as metformin users, 52,736 were classified as metformin non-users, and 10,841 were excluded from the final analysis. PS-matched Cox proportional hazard regression models revealed that metformin use was not associated overall with the prevention of TB development (HR 1.17; 95% CI 0.75-1.83; P = 0.482). There was a trend, however, towards a reduction in the development of TB among patients taking a higher cumulative dose of metformin. Patients who were in the highest quartile (Q4) of cumulative metformin dose had only a 10% risk of developing TB compared to metformin non-users. In contrast, during the early phases of metformin treatment, patients in the second quartile (Q2) of cumulative metformin use had a higher risk of developing TB than patients in the first quartile (Q1)., Conclusions: Only the highest cumulative doses of metformin were protective against the development of TB among patients who were newly diagnosed with type 2 DM; lower cumulative doses of metformin did not appear to reduce the incidence of active TB infection., (© 2021. The Author(s).)

Objective: The impact of center case volume on mid-term postoperative outcome after coronary artery bypass grafting surgery (CABG) is still controversial and requires investigation. The aim of this study was to compare mid-term survival after CABG according to the institutional annual CABG case volume., Methods: Adult patients (≥ 18 years) who underwent CABG from 2009 to 2016 were identified by searching National Health Insurance database of Korea for CABG procedure codes. Hospitals were classified into three groups based on annual case volume; low-volume centers (< 20 cases/year), medium-volume centers (20-50 cases/year), and high-volume centers (> 50 cases/year)., Results: A total of 22,575 CABG were performed in 95 centers during the study period, and 14,697 (65.1%) cases performed at 15 high-volume centers, 5,262 (23.3%) cases at 26 medium-volume centers, and 2,616 (11.6%) cases at 54 low-volume centers. The overall 1-year mortality rate was the lowest in high-volume centers (6.5%), followed by medium-volume centers (10.6%) and low-volume centers (15.2%). Logistic regression identified medium-volume centers (adjusted OR 1.30 [95% CI 1.15-1.49], P < 0.01) and low-volume centers (adjusted OR 1.75 [95% CI 1.51-2.03], P < 0.01) as risk factors for 1-year mortality after CABG compared to high-volume centers. In the Cox proportional hazard model, low- and medium-volume centers were significantly risk factors for poor survival (adjusted HR 1.41 [95% CI 1.31-1.54], P < 0.01 and HR 1.26 [95% CI 1.17-1.35], P < 0.01 for low- and medium-volume centers, respectively)., Conclusions: Higher institutional case volume of CABG was associated with lower mid-term mortality., (© 2021. The Japanese Association for Thoracic Surgery.)

Background: Recent advances in esophageal cancer treatment require a reevaluation of the relationship between institutional case-volume and patient outcome. The aim of this study was to analyze and update the association between surgical case-volume and both in-hospital and long-term mortality after esophagectomy for esophageal cancer., Methods: Data of all adult patients who received esophageal cancer surgery in Korea between 2004 and 2017 were extracted from the database of the National Health Insurance Service. Hospitals were categorized into three groups according to the average annual number of esophageal cancer surgery: low-volume (<12 cases/year), medium-volume (12-48 cases/year), and high-volume centers (>48 cases/year). Postoperative in-hospital and 1-, 3-, and 5-year mortality were analyzed according to the categorized groups using logistic regression., Results: In total, 11, 346 esophageal cancer surgeries in 122 hospitals were analyzed. In-hospital mortality in the high-, medium-, and low-volume centers were 3.4%, 6.4%, and 11.1%, respectively. In-hospital mortality was significantly higher in low- volume (adjusted odds ratio, 3.91; confidence interval, 3.18-4.80; p < 0.001) and medium volume (adjusted odds ratio, 2.21; confidence interval, 1.80-2.74, p < 0.001) centers compared to high-volume centers. Patients who received esophageal cancer surgery in a low-or medium-volume center also had higher 1-, 3-, and 5-year mortality compared to patients who received the surgery in a high-volume center. Conclusions Centers with lower case-volume showed higher in-hospital mortality and long-term mortality after esophageal cancer surgery., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The relationship between institutional liver transplantation (LT) case volume and clinical outcomes after liver re-transplantation is yet to be determined., Methods: Patients who underwent liver re-transplantation between 2007 and 2016 were selected from the Korean National Healthcare Insurance Service database. Liver transplant centers were categorized to either high-volume centers (≥ 64 LTs/year) or low-volume centers (< 64 LTs/year) according to the annual LT case volume. In-hospital and long-term mortality after liver re-transplantation were compared., Results: A total of 258 liver re-transplantations were performed during the study period: 175 liver re-transplantations were performed in 3 high-volume centers and 83 were performed in 21 low-volume centers. In-hospital mortality after liver re-transplantation in high and low-volume centers were 25% and 36% (P = 0.069), respectively. Adjusted in-hospital mortality was not different between low and high-volume centers. Adjusted 1-year mortality was significantly higher in low-volume centers (OR 2.14, 95% CI 1.05-4.37, P = 0.037) compared to high-volume centers. Long-term survival for up to 9 years was also superior in high-volume centers (P = 0.005). Other risk factors of in-hospital mortality and 1-year mortality included female sex and higher Elixhauser comorbidity index., Conclusion: Centers with higher case volume (≥ 64 LTs/year) showed lower in-hospital and overall mortality after liver re-transplantation compared to low-volume centers., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Although the appendix has been suggested to play a role in maintaining the gut microbiome and immune system, the ramifications of appendectomy on the development inflammatory bowel disease, sepsis, and colorectal cancer are yet to be determined. The purpose of this study was to evaluate the potential long-term impacts of appendectomy, with a focus on inflammatory bowel disease, infection, and colorectal cancer, using the National Healthcare Insurance Service (NHIS) database of Korea., Methods: The National Healthcare Insurance Service database in Korea was used for analysis. Adult patients who received appendectomy between 2005 and 2013 were identified. The control group consisted of patients who did not receive appendectomy were matched by baseline characteristics including comorbidities and frequency of healthcare resource utilization. The primary outcome was the incidence-rate ratio (IRR) of Crohn's disease, ulcerative colitis, Clostridium difficile infection, sepsis, and colorectal cancer after appendectomy or the index date., Results: We identified 914,208 patients who underwent appendectomy, and after matching with control patients, a total of 486,844 patients were included for analysis. Patients who underwent appendectomy showed a significantly higher incidence of Crohn's disease (IRR 4.40, 95% confidence interval (CI) 3.78-5.13) and ulcerative colitis (IRR 1.78, 95% CI 1.63-1.93) compared to the control group during the 5-year follow-up period. The associations between appendectomy and Clostridium difficile infection, sepsis, and colorectal cancer were all found to be significant., Conclusion: Patients who underwent appendectomy may be at increased risk for developing Crohn's disease, ulcerative colitis, Clostridium difficile infection, sepsis, and colorectal cancer., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes.

Background: The association of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) with disease severity of patients with COVID-19 is still unclear. We conducted a systematic review and meta-analysis to investigate if ACEI/ARB use is associated with the risk of mortality and severe disease in patients with COVID-19., Methods: We searched all available clinical studies that included patients with confirmed COVID-19 who could be classified into an ACEI/ARB group and a non-ACEI/ARB group up until 4 May 2020. A meta-analysis was performed, and primary outcomes were all-cause mortality and severe disease., Results: ACEI/ARB use did not increase the risk of all-cause mortality both in meta-analysis for 11 studies with 12 601 patients reporting ORs (OR=0.52 (95% CI=0.37 to 0.72), moderate certainty of evidence) and in 2 studies with 8577 patients presenting HRs. For 12 848 patients in 13 studies, ACEI/ARB use was not related to an increased risk of severe disease in COVID-19 (OR=0.68 (95% CI=0.44 to 1.07); I 2 =95%, low certainty of evidence)., Conclusions: ACEI/ARB therapy was not associated with increased risk of all-cause mortality or severe manifestations in patients with COVID-19. ACEI/ARB therapy can be continued without concern of drug-related worsening in patients with COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of extracorporeal membrane oxygenation (ECMO) is increasing despite the limited evidence in survival benefit. This study aimed to analyze the changes of in-hospital mortality, medical costs, and other outcomes in ECMO therapy. We used 2004-2017 data from a nationwide healthcare administrative claims database in Korea. Overall, 14,775 ECMO procedures were performed in 14,689 patients at 112 hospitals. We found a 170-fold and a 334-fold increase in the number of ECMO procedures and related costs, respectively. For indications, the performance of ECMO for heart or lung transplantation and respiratory failure increased, whereas that for cardiovascular surgery decreased. The duration of ECMO increased from a median of 3 days (IQR, 2-5 days) in 2004 to 4 days (IQR, 2-9 days) in 2017. The overall in-hospital mortality rate was 68.6%, and this improved over time, especially for lung transplantation and respiratory failure patients. Bleeding-related complications and the transfusion amount also decreased. Hospitals with higher case volume showed better survival outcomes. The median cost per procedure and per day was 26,538 USD (IQR, 14,646-47,862 USD) and 1,560 USD (IQR, 903-2,929 USD), respectively, and increased with time. A trend toward greater resource use and better outcomes requires additional cost-effective analysis based on indications., Competing Interests: Hyun Joo Lee has supported the international fellowship grant from the Takeda foundation. Myo-Song Kim has supported by the Chung-Ang University Graduate Research Scholarship in 2019. The remaining authors have disclosed that they do not have any conflicts of interest., (Copyright © ASAIO 2020.)

Objectives: To estimate risk of malignancy in patients with idiopathic inflammatory myositis (IIM) compared to patients with knee osteoarthritis (OA). Methods: Patients with IIM and knee OA aged over 50, who had no history of malignancy, were identified using Korean National claims database from January 2012 to December 2014. They had been observed until a malignancy was diagnosed or up to the end of the study, December 2015. The incidence rate (IR) of malignancy in IIM patients was calculated and compared with knee OA patients using standardized incidence ratio (SIR). Results: A total of 634 polymyositis (PM) and 556 dermatomyositis (DM) patients were included. Overall, 100 solid (IR 270.4/10,000 person-years (PY), 95% confidence interval (CI) 217.4-323.4) and 12 hematologic malignancies (IR 32.4/10,000 PY, 95% CI 14.1-50.8) occurred. Compared with knee OA, risk of overall (SIR 1.5, 95% CI 1.2-1.8), solid (SIR 1.4, 95% CI 1.1-1.6), and hematologic malignancy (SIR 5.7, 95% CI 2.5-9.0) were increased in IIM patients. This was due to increased incidence of malignancy in DM (hematologic malignancy, SIR 8.7, 95% CI 2.7-14.7, solid malignancy, SIR 1.5, 95% CI 1.1-1.9). Conclusion: Patients with IIM, especially DM, have an increased risk of malignancy compared to patients with knee OA.

Background: The inverse relationship between case volume and postoperative mortality following high-risk surgical procedures have been reported. Thoracic aorta surgery is associated with one of the highest postoperative mortality. The relationship between institutional case volume and postoperative mortality in patients undergoing thoracic aorta replacement surgery was evaluated., Methods: All thoracic aorta replacement surgeries performed in Korea between 2009 and 2016 in adult patients were analyzed using an administrative database. Hospitals were divided into low (< 30 cases/year), medium (30-60 cases/year), or high (> 60 cases/year) volume centers depending on the annual average number of thoracic aorta replacement surgeries performed. The impact of case volume on in-hospital mortality was assessed using the logistic regression., Results: Across 83 hospitals, 4867 cases of thoracic aorta replacement were performed. In-hospital mortality was 8.6% (191/2222), 10.7% (77/717), and 21.9% (422/1928) in high, medium, and low volume centers, respectively. The adjusted risk of in-hospital mortality was significantly higher in medium (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.16-2.11, P = 0.004) and low volume centers (OR, 3.12; 95% CI, 2.54-3.85, P < 0.001) compared to high volume centers., Conclusions: Patients who had underwent thoracic aorta replacement surgery in lower volume centers had increased risk of in-hospital mortality after surgery compared to those in higher volume centers. Our results may provide the basis for minimum case volume requirement or regionalization in thoracic aorta replacement surgery for optimal patient outcome.

Objectives: To estimate the prevalence, medical utilization, and recent changes in the economic burden of autoimmune rheumatic diseases (AIRDs) in Korea., Methods: Using a nationwide claims database that includes all medical claims made by approximately 50 million Korean residents, the prevalences of seropositive rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and others between 2012 and 2016 were calculated. Changes in medical utilization and the direct medical costs of each AIRD from 2012 to 2016 were also evaluated., Results: Based on the data for 2016, seropositive RA was the most common AIRD in Korea with 96,330 cases (188.5/100,000 population), followed by AS (30,006, 58.7/100,000 population), SLE (19,441, 38.0/100,000 population), Behçet's disease (BD, 14,943, 29.2/100,000 population), primary Sjögren syndrome (pSS, 12,018, 23.5/100,000 population), and systemic sclerosis (SSc, 3606, 7.1/100,000 population). In terms of medical utilization, patients with eosinophilic granulomatosis with polyangiitis visited outpatient clinics the most frequently (9.8 times/year/patient), while hospitalization was most frequent in microscopic polyangiitis patients (1.0 time/year/patient). Total medical costs for all AIRDs increased from $154,348,011 in 2012 to $262,481,974 in 2016. The annual medical cost per patient in 2016 was the highest in microscopic polyangiitis ($6223/year), followed by psoriatic arthritis ($3,362/year), and granulomatosis with polyangiitis ($2823/year)., Conclusions: In Korea, the most prevalent AIRD is seropositive RA, followed by AS, SLE, BD, pSS, and SSc. The economic burden of AIRDs has risen substantially in the last 5 years due not only to an increase in their prevalence but also to an increase in medical costs per patient., Competing Interests: Declaration of Competing Interests None of the authors have any conflicts of interest to declare., (Copyright © 2019. Published by Elsevier Inc.)

A fixed-dose combination of inhaled corticosteroid and long-acting beta agonist (ICS/LABA) may increase the risk of pneumonia in patients with chronic airway diseases including chronic obstructive pulmonary disease and asthma. Although lung deposition of ICS/LABA is dependent on the inhaler device and inhalation technique, there have been few studies comparing the risk for pneumonia according to the type of device used to deliver ICS/LABA in real-world practice. A retrospective cohort study was performed using the National Health Insurance Database of the Korean Health Insurance Review & Assessment Service. New users who began ICS/LABA were selected and followed-up 180 days after ICS/LABA initiation. The risk for pneumonia requiring emergency room (ER) visit or admission was compared according to inhaler device used-pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI)-after individual exact matching (1:5). Among the eligible cohort of 245,477 new ICS/LABA users, 7,942 patients who used pMDI only were matched with 39,690 patients who used DPI only. The incidence of pneumonia was higher in the pMDI group (1.6%) than the DPI group (1.1%); the adjusted hazard ratio (HR) for pneumonia was 1.6 (95% CI 1.3-2.0; p < 0.0001). In subgroup analyses, a significantly higher risk for pneumonia was found in the pMDI group compared with the DPI group regardless of the presence of history of pneumonia (HR 1.7 [95% CI 1.2-2.3]; p = 0.002), COPD (HR 1.6 [95% CI 1.2-2.0]; p = 0.0007), or asthma (HR 1.6 [95% CI 1.2-2.2]; p = 0.0008). In analyses of real-world data, pMDI users incurred a higher risk for pneumonia requiring hospitalization or ER visit compared with DPI users.

Background: The purpose of this study was to evaluate whether institutional case-volume affects clinical outcomes after pediatric liver transplantation., Methods: We conducted a nationwide retrospective cohort study using the database of Korean National Healthcare Insurance Service. Between January 2007 and December 2016, 521 pediatric liver transplantations were performed at 22 centers in Korea. Centers were categorized according to the average annual number of liver transplantations: >10, 1 to 10, and <1., Results: In-hospital mortality rates in the high-, medium-, and low-volume centers were 5.8%, 12.5%, and 32.1%, respectively. After adjustment, in-hospital mortality was significantly higher in low-volume centers (adjusted odds ratio, 9.693; 95% confidence interval, 4.636-20.268; P < 0.001) and medium-volume centers (adjusted odds ratio, 3.393; 95% confidence interval, 1.980-5.813; P < 0.001) compared to high-volume centers. Long-term survival for up to 9 years was better in high-volume centers., Conclusions: Centers with higher case volume (>10 pediatric liver transplantations/y) had better outcomes after pediatric liver transplantation, including in-hospital mortality and long-term mortality, compared to centers with lower case volume (≤10 liver transplantations/y).

Background and Objectives: Anti-tumor necrosis factor alpha (anti-TNFα) therapy is key to the treatment of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD). The objective of this study was to investigate prescribing patterns and non-persistence of anti-TNFα therapy for the treatment of IBD in a real-world scenario., Methods: Data from the Korean National Health Insurance claims database obtained between 2010 and 2014 were evaluated to identify patients with IBD who had received anti-TNFα therapy (infliximab or adalimumab). Patient characteristics and prescribing patterns were investigated. The non-persistence rate and associated reasons were determined in patients who initiated therapy between 2010 and 2012., Results: A total of 131,158 patients with UC and 57,286 with CD were identified. Of these 1747 UC (1.3%) and 3731 (6.5%) CD patients had received anti-TNFα therapy and were included in the analysis. Infliximab was prescribed more frequently than adalimumab (84.6% vs 15.4% in UC and 80.7% vs 19.4% in CD); 81.0% of UC and 72.0% of CD patients received anti-TNFα alone or in combination with 5-aminosalicylic acid. The non-persistence rate of anti-TNFα therapy was 72.6% and 80.4% in the UC and CD groups, respectively, with discontinuation of medication being the most common reason in both the UC and CD groups (63.9% and 73.3%, respectively)., Conclusion: The use of anti-TNFα therapy was seen to be low, with a high rate of non-persistence. Further research efforts are required to improve the response rate and, therefore, improve persistence in patients with IBD.

Background: The relationship between institutional case volume and clinical outcomes after living donor liver transplantation is not clarified., Methods: We conducted a nationwide retrospective cohort study using the database of Korean National Healthcare Insurance Service. Between January 2007 and December 2016, 7073 adult living donor liver transplantations were performed at 50 centers in Korea. Centers were categorized according to the average annual number of liver transplantations: >50, 10 to 50, and <10., Results: In-hospital mortality rates in the high-, medium-, and low-volume centers were 2.8%, 4.1%, and 6.7%, respectively. After adjustment, in-hospital mortality was significantly higher in low-volume centers (adjusted odds ratio, 2.287; 95% confidence interval, 1.471-3.557; P < 0.001) and medium-volume centers (adjusted odds ratio, 1.676; 95% confidence interval, 1.089-2.578; P = 0.019) compared with high-volume centers. Long-term survival for up to 9 years was better, and intensive care unit and hospital length of stay were shorter in high-volume centers., Conclusions: Centers with higher case volume (>50 liver transplantations/year) had better outcomes after living donor liver transplantation, including in-hospital mortality and long-term mortality compared with centers with lower case volume (≤50 liver transplantations/year).

Background: The inverse relationship between case-volume and surgical mortality has been reported in complex surgical procedures. The aim of this study was to evaluate the effect of case-volume on mortality after lung transplantation in Korea., Methods: The National Health Insurance Service data was used to analyse all adult lung transplantations in Korea between 2007 and 2016. Institutions were categorized into low-volume (< 5 lung transplantations/year) centers or high-volume (≥ 5 lung transplantations/year) centers. Risk-adjusted in-hospital mortality and long-term survival according to case-volume was evaluated., Results: A total of 315 adult recipients underwent lung transplantation at 7 centers. The odds ratio for in-hospital mortality in low-volume centers was similar to high-volume centers (OR, 1.496; 95% CI, 0.81-2.76; p = 0.197). Log-rank analysis of Kaplan-Meier curves according to case-volume also did not show a difference in long-term survival between high- and low-volume centers (p = 0.052)., Conclusions: There was no association between case-volume and in-hospital mortality after lung transplantation in Korea, although there was a tendency towards better long-term survival associated with high-volume centers.

Objectives: This study aimed to identify the prevalence and predictors of hypoglycemia in patients with type 2 diabetes (T2D) using South Korea's nationwide healthcare database., Study Design: Retrospective cohort and nested case-control analyses were conducted to estimate the prevalence and predictors of hypoglycemia, respectively., Methods: A cohort of 2,273,481 patients with T2D was followed to estimate the 1-year prevalence of hypoglycemia. Total hypoglycemia was identified using outpatient, inpatient, or emergency department visit data containing a diagnosis code for hypoglycemia. Severe hypoglycemia was defined as an event with inpatient admission or emergency care. Within the T2D cohort, cases with hypoglycemia were identified, and up to 4 controls were randomly selected after matching by sex, age, and cohort entry date. Possible predictive factors included insurance type, medical institution type, hypoglycemic history, antidiabetic drugs, Charlson Comorbidity Index score, and diabetic complications. We conducted conditional logistic regression analyses to estimate adjusted odds ratios (aORs) and 95% CIs to identify predictors of hypoglycemia., Results: The prevalences of total and severe hypoglycemia were 1.38% and 0.96%, respectively. Those with a history of hypoglycemia had the highest risk for a further hypoglycemic event (aOR, 16.71; 95% CI, 15.62-17.88). Use of combination therapy with insulin and sulfonylurea was highly associated with severe hypoglycemia (aOR, 15.09; 95% CI, 13.60-16.74). Among diabetic complications, the presence of nephropathy was the greatest predictive factor (aOR, 1.79; 95% CI, 1.73-1.85)., Conclusions: Patients with a history of hypoglycemia or receiving combined antidiabetic therapy must be appropriately managed to achieve optimal glycemic control without significant risk of hypoglycemia.

The objectives of this study are to identify the prevalence and incidence of rheumatoid arthritis (RA) and to investigate the patterns of medical care and drug utilization by RA patients in Korea. Korean National Health Insurance claims data were used for analysis. RA patients were defined as those having an RA code from 2009 to 2012 and using disease-modifying anti-rheumatic drugs (DMARDs) within 1 year after the code. RA patients identified in 2010 with a disease-free period for 12 months before the index date, and those who received continuous treatment in 2011-2013 were defined as incident cases. Patterns of medical care and drug utilization were compared among subgroups. The prevalence of RA increased yearly from 0.28% in 2009 to 0.32% in 2012. The incidence of RA in 2010 was 28.5 per 100,000 person-years. The use of biologic DMARDs (bDMARDs) increased from 2.31% in 2009 to 4.05% in 2012. Hydroxychloroquine (57.53-62.45%) was the most commonly used the conventional DMARDs, followed by methotrexate (49.99-51.87%). The use of bDMARDs (1.39 vs. 2.43%) was less frequent in EORA patients than YORA patients. Hydroxychloroquine (74.96 vs. 72.11%) was more frequently used, but methotrexate (55.24 vs. 59.25%) and sulfasalazine (27.96 vs. 32.72%) were used less frequently in EORA patients than in YORA patients. The prevalence of RA has increased in Korea. EORA patients used fewer bDMARDs, methotrexate, and sulfasalazine but more hydroxychloroquine than YORA patients.

Background: Panax ginseng is a well-known immune modulator, and there is concern that its immune-enhancing effects may negatively affect patients with rheumatoid arthritis (RA) by worsening symptoms or increasing the risk of adverse effects from other drugs. In this randomized, crossover clinical trial, we evaluated the impact of Korean Red Ginseng (KRG) on disease activity and safety in RA patients., Methods: A total of 80 female RA patients were randomly assigned to either the KRG (2 g/d, n  = 40) treatment or placebo ( n  = 40) groups for 8 wk, followed by crossover to the other treatment group for an additional 8 wk. The primary outcome was the disease flare rate, defined as worsening disease activity according to the disease activity score 28 joints-erythrocyte sedimentation rate (DAS28-ESR). The secondary outcomes were development of adverse events (AEs) and patient reported outcomes. Outcomes were evaluated at baseline and 8 wk and 16 wk. The outcomes were compared using the Chi-square test., Results: Of the 80 patients, 70 completed the full study. Their mean age was 51.9 yr, and most exhibited low disease activity (mean DAS28-ESR 3.5 ± 1.0) at enrollment. After intervention, the flare rate was 3.7% in each group. During KRG treatment, 10 AEs were reported, while five AEs were developed with placebo; however, this difference was not statistically significant ( p  = 0.16). Gastrointestinal- and nervous system-related symptoms were frequent in the KRG group., Conclusion: KRG is not significantly associated with either disease flare rate or the rate of AE development in RA patients.

Objectives: To estimate the incidence of cardiovascular disease (CVD) in Asian patients with rheumatoid arthritis (RA) and to evaluate the impact of anti-rheumatic treatment on the development of CVD., Methods: A retrospective cohort of Asian patients with RA was established to identify the incidence rate (IR) of CVD in RA patients. The cohort was generated using the Korean National Healthcare claims database, which contained claims from Jan 2009 to Dec 2013. A total of 137,512 RA patients were identified; individuals with a history of CVD for 6 months or more before the index date were excluded. Nested case-control samples were drawn from the full study population with a case:control ratio of 1:4 (n = 7102 cases; n = 27,018 controls without CVD). A conditional multivariate regression model was used to evaluate the impact of anti-rheumatic treatment on the development of CVD in RA patients after matching for age, sex, RA index date, comorbidities, and drug use (e.g., antiplatelet agents and cholesterol-lowering agents)., Results: The IR for development of overall CVD in RA patients was 182.1 (95% CI: 178.4-185.9) per 10,000 person-years. In models adjusted for other CVD risk factors, disease-modifying anti-rheumatic drugs (DMARDs) (OR = 0.79) were protective against CVD, and biologic DMARDs were not significantly associated with CVD risk (OR = 0.85). Corticosteroids (OR = 1.26) and NSAIDs (nonselective NSAIDs: OR = 1.32, Cox-2 inhibitors: OR = 1.31) were risk factors for CVD in RA patients., Conclusions: The use of DMARDs is protective against CVD, while corticosteroids and NSAIDs increased the risk of CVD in RA patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To estimate the incidence of tuberculosis (TB) in rheumatoid arthritis (RA) patients treated with tumor necrotizing factor inhibitor (TNFI) and evaluate the safety of resuming biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients who developed TB after anti-TNF treatment., Methods: We conducted an inception cohort study of RA patients in the Korean Healthcare Claims Database who started TNFI as the first biologic DMARD between January 2009 and December 2013. The incidence rate (IR) of TB was estimated among total TNFI starters and a nested case-control analysis was performed to compare the characteristics of patients who developed TB and those did not. Patients diagnosed with relapsed TB after resuming biologic DMARDs were identified and their features were described., Results: We included 4638 RA patients who started TNFI, contributing 8542 PYs of follow-up. The IR of TB in TNFI users was 1.10 (CI: 0.86-1.34) per 100 PYs. After the initial 6 months, the IR was highest at 1.56 (CI: 1.02-2.10) and decreased gradually over time. Among the 81 patients who developed TB, 30 patients (37.0%) resumed biologic DMARDs with a mean interval of 3.3 months after TB development. Two cases of TB were detected among 30 patients with an observational period of 45.7 PY., Conclusions: The IR of TB in RA patients who started TNFI was 1.10 per 100 PYs. This rate was highest during the first 6 months. Resumption of biologic DMARDs requires careful monitoring for TB relapse., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to compare the discontinuation rates of tofacitinib and biologics (tumour necrosis factor inhibitors (TNFi), abatacept, rituximab, and tocilizumab) in rheumatoid arthritis (RA) patients considering inadequate responses (IRs) to previous treatment(s)., Methods: Randomised controlled trials of tofacitinib and biologics - reporting at least one total discontinuation, discontinuation due to lack of efficacy (LOE), and discontinuation due to adverse events (AEs) - were identified through systematic review. The analyses were conducted for patients with IRs to conventional synthetic disease-modifying anti-rheumatic drugs (cDMARDs) and for patients with biologics-IR, separately. Bayesian network meta-analysis was used to estimate rate ratio (RR) of a biologic relative to tofacitinib with 95% credible interval (CrI), and probability of RR being <1 (P[RR<1])., Results: The analyses of 34 studies showed no significant differences in discontinuation rates between tofacitinib and biologics in the cDMARDs-IR group. In the biologics-IR group, however, TNFi (RR 0.17, 95% CrI 0.01-3.61, P[RR<1] 92.0%) and rituximab (RR 0.20, 95% CrI 0.01-2.91, P[RR<1] 92.3%) showed significantly lower total discontinuation rates than tofacitinib did. Despite the difference, discontinuation cases owing to LOE and AEs revealed that tofacitinib was comparable to the biologics., Conclusions: The comparability of discontinuation rate between tofacitinib and biologics was different based on previous treatments and discontinuation reasons: LOE, AEs, and total (due to other reasons). Therefore, those factors need to be considered to decide the optimal treatment strategy.

The microbiological safety, quality changes, and genotoxicity of chicken breasts treated with flexible thin-layer dielectric barrier discharge (FTDBD) plasma inside a sealed package were investigated. Following 10 min plasma treatment, the numbers of total aerobic bacteria, Listeria monocytogenes , Escherichia coli , and Salmonella Typhimurium were reduced by 3.36, 2.14, 2.73, and 2.71 Log CFU/g, respectively. Color L* and b* values increased whereas a* value decreased following plasma treatment with increasing exposure duration. Lipid oxidation was unaffected by plasma treatment. In sensory evaluation, flavor decreased and off-flavor increased with extended plasma exposure time, however, these changes had no effect on acceptability. Increased cohesiveness was the only texture profile analysis parameter that changed following plasma treatment. No genotoxicity was detected in plasma-treated chicken breast using the Salmonella mutagenicity assay. Therefore, FTDBD plasma is applicable since it is able to improve microbiological safety with minimal changes in sensory properties of the chicken breast.

Purpose: To elucidate and compare benefit-risk preferences among Korean patients and physicians concerning cyclooxygenase-2 (Cox-2) inhibitor treatments for arthritis., Materials and Methods: Subjects included 100 patients with arthritis and 60 board-certified orthopedic surgeon physicians in South Korea. Through a systematic review of the literature, beneficial attributes of using Cox-2 inhibitors were defined as a decrease in the Western Ontario and McMaster Universities Arthritis Index for pain score and improvement in physical function. Likewise, risk attributes included upper gastrointestinal (GI) complications and cardiovascular (CV) adverse events. Discrete choice experiments were used to determine preferences for these four attributes among Korean patients and physicians. Relative importance and maximum acceptable risk for improving beneficial attributes were assessed by analyzing the results of the discrete choice experiment by using a conditional logit model., Results: Patients ranked the relative importance of benefit-risk attributes as follows: pain reduction (35.2%); physical function improvement (30.0%); fewer CV adverse events (21.5%); fewer GI complications (13.4%). The physicians' ranking for the same attributes was as follows: fewer CV (33.5%); pain reduction (32.4%); fewer GI complications (18.1%); physical function improvement (16.0%). Patients were more willing than physicians to accept risks when pain improved from 20% or 45% to 55% and physical function improved from 15% or 35% to 45%., Conclusion: We confirmed that patients and physicians had different benefit-risk preferences regarding Cox-2 inhibitors. Patients with arthritis prioritized the benefits of Cox-2 inhibitors over the risks; moreover, in comparison with the physicians, arthritis patients were more willing to accept the trade-off between benefits and risks to achieve the best treatment level. To reduce the preference gap and achieve treatment goals, physicians must better understand their patients' preferences.

Objective: We investigated the effect of treatment with inhaled drugs on changes in mood, focusing on depression and anxiety during treatment in patients with newly diagnosed chronic obstructive pulmonary disease (COPD)., Methods: We prospectively selected new COPD patients from three Seoul National Hospitals. Participants underwent face-to-face interviews to evaluate clinical characteristics and drug use, and completed questionnaires using the Hospital Anxiety and Depression Scale (HADS) at the start of the project, the 4th week, and the 12th week. We compared changes in HADS scores both between inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) users and non-ICS/LABA users, as well as between long-acting muscarinic antagonist (LAMA) users and non-LAMA users. The general linear mixed model was applied for multivariate analysis., Results: Ninety new COPD patients participated in the study. Of these 90 patients, 84 completed face-to-face interviews. In the univariate analysis, those who were treated by ICS/LABA or LAMA showed a significant increase in HADS-A at the 4-week evaluation (0.73±2.56, P=0.038), but the statistical significance was lost in the multivariable analysis. No significant difference was found in the change in HADS scores between ICS/LABA users and non-ICS/LABA users, or between LAMA users and non-LAMA users in multivariate general linear mixed model analyses., Conclusion: In this prospective observational study, we found no significant effects of inhaled treatment on mood problems among new COPD patients. Further research should be conducted to identify the association between anxiety and depression and inhaled drugs for COPD treatment.

The aim of this study was to estimate the mapping model for EuroQol-5D (EQ-5D) utility values using the health assessment questionnaire disability index (HAQ-DI), pain visual analog scale (VAS), and disease activity score in 28 joints (DAS28) in a large, nationwide cohort of rheumatoid arthritis (RA) patients in Korea. The KORean Observational study Network for Arthritis (KORONA) registry data on 3557 patients with RA were used. Data were randomly divided into a modeling set (80 % of the data) and a validation set (20 % of the data). The ordinary least squares (OLS), Tobit, and two-part model methods were employed to construct a model to map to the EQ-5D index. Using a combination of HAQ-DI, pain VAS, and DAS28, four model versions were examined. To evaluate the predictive accuracy of the models, the root-mean-square error (RMSE) and mean absolute error (MAE) were calculated using the validation dataset. A model that included HAQ-DI, pain VAS, and DAS28 produced the highest adjusted R (2) as well as the lowest Akaike information criterion, RMSE, and MAE, regardless of the statistical methods used in modeling set. The mapping equation of the OLS method is given as EQ-5D = 0.95-0.21 × HAQ-DI-0.24 × pain VAS/100-0.01 × DAS28 (adjusted R (2) = 57.6 %, RMSE = 0.1654 and MAE = 0.1222). Also in the validation set, the RMSE and MAE were shown to be the smallest. The model with HAQ-DI, pain VAS, and DAS28 showed the best performance, and this mapping model enabled the estimation of an EQ-5D value for RA patients in whom utility values have not been measured.

Purpose: Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting β-agonists are frequently prescribed together, the efficacy of "triple therapy" has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy., Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models., Results: Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29-82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group., Conclusion: Triple therapy with TIO and ICSs/long-acting β-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed.

Background/objectives: There have been controversies about whether inhaled bronchodilators could increase the risk of clinically important tachyarrhythmias. We investigated the association between inhaled bronchodilators and the development of tachyarrhythmias, including atrial fibrillation and other paroxysmal tachyarrhythmias in real practice., Methods: We conducted a nested case-control study with the use of the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea). Overall, 3312 cases with newly developed tachyarrhythmias including atrial fibrillation and other paroxysmal tachyarrhythmias and 9732 matched (up to 1:5) controls were identified from 545,508 subjects without acute major cardiovascular events in the past year between January 1, 2011 and December 31, 2011. Conditional logistic regression analysis adjusted by comorbidities, cardiovascular drugs and healthcare utilization was performed., Results: In various multivariate models, the use of inhaled long-acting muscarinic antagonists (LAMAs) or long-acting inhaled β2 agonists (LABAs) was significantly associated with tachyarrhythmias. Statistically significant effects of LAMAs on tachyarrhythmias were found only in the non-users of β-blockers. We did not find a statistically significant difference in the impact of a LABA without a LAMA vs a LAMA without a LABA (aOR, 0.93; 95% CI, 0.74-1.18), or a multiplicative or additive interaction between a LABA and a LAMA., Conclusions: Inhaled LAMAs and LABAs were significantly and comparably associated with an increased risk of tachyarrhythmias., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Baicalein is one of the major flavonoids in Scutellaria baicalensis Georgi, which has long been used in Asia as herbal medicine. Several biological effects of baicalein, such as antiviral, anti-inflammatiom, anti-hepatotoxicity, and anti-tumour properties, have been reported., Objective and Design: In this study, the antibacterial activities of baicalein were investigated in combination with ampicillin and/or gentamicin against oral bacteria., Results: Baicalein was determined with MIC and MBC values ranging from 80 to 320 and 160 to 640 μg/mL against oral bacteria. The range of MIC₅₀ and MIC₉₀ were 20-160 μg/mL and 80-320 μg/mL, respectively. The combination effects of baicalein with antibiotics were synergistic (FIC index <0.375-0.5 and FBCI <0.5) against oral bacteria. Furthermore, a time-kill study showed that the growth of the tested bacteria was completely attenuated after 1-6 h of treatment with the MIC₅₀ of baicalein, regardless of whether it was administered alone or with ampicillin or gentamicin., Conclusion: These results suggest that baicalein combined with other antibiotics may be microbiologically beneficial and not antagonistic., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Inhaled corticosteroid (ICS) use could decrease local immunity of the lung. Concerns have been raised regarding the risk of tuberculosis (TB) development among ICS users. The aim of this study was to elucidate the association between ICS use and development of TB among patients with various respiratory diseases in South Korea, an intermediate-TB-burden country., Methods: A nested case-control study based on the Korean national claims database was performed. The eligible cohort consisted of 853 439 new adult users of inhaled respiratory medications between 1 January 2007 and 31 December 2010. Patients diagnosed as having TB after initiation of inhaled medication were included as cases. For each case individual, up to five control individuals matched for age, sex, diagnosis of asthma or chronic obstructive pulmonary disease (COPD) and initiation date of inhaler use were selected., Results: From the cohort population, we matched 4139 individuals diagnosed as having TB with 20 583 controls. ICS use was associated with increased rate of TB diagnosis (adjusted OR (aOR), 1.20; 95% CI 1.08 to 1.34). The association was dose dependent (p for trend <0.001). A subgroup analysis revealed that ICS use increased the risk of TB development among non-users of oral corticosteroid (OCS) but not among OCS users., Conclusions: ICS use increases the risk of TB in an intermediate-TB-burden country. Clinicians should be aware of the possibility of TB development among patients who are long-term high-dose ICS users.

Background: Chronic inflammation has been implicated in the pathogenesis of several cancers, including lung and laryngeal cancer. The objective of the study is to elucidate the association between ICS use and diagnosis of lung and laryngeal cancer., Methods: A nested case-control study based on the Korean national claims database included new adult users of inhaled medications between January 1, 2007, and December 31, 2010. Patients diagnosed with lung cancer or laryngeal cancer after enrollment were identified as cases and up to five control individuals matched for age, sex, diagnosis of asthma or COPD, Charlson Comorbidity Index scores, number of health care visits, and initiation date were selected., Results: From the 792,687 eligible cohort, 9177 individuals diagnosed with lung cancer were matched with 37,048 controls. Additionally, 408 laryngeal cancer patients and 1651 controls were matched. ICS use was associated with a decreased rate of lung cancer diagnosis [adjusted odds ratio (aOR), 0.79; 95% confidence interval (CI), 0.69-0.90]. The inverse association between ICS use and lung cancer risk was dose dependent (P < 0.0001 for the trend). However, no reduction in the risk of laryngeal cancer among ICS users was identified (aOR, 1.06; 95% CI, 0.62-1.18)., Conclusion: The use of ICS is associated with a reduced risk of lung cancer but not of laryngeal cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It is of interest to investigate whether synthetic thioflavonoids have vasorelaxant actions as natural flavonoids. We tested the hypothesis that 3',4'-dimethoxythioflavone induces endothelium-dependent vasorelaxation through activation of epidermal growth factor (EGF) receptor. Rat aortic rings were mounted in organ baths and subjected to relaxation upon contraction. 3',4'-Dimethoxythioflavone induced endothelium-dependent vasorelaxation, which was attenuated by pretreatment with either L-N (ω)-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. 3',4'-Dimethoxythioflavone-induced vasorelaxation was not affected by pretreatment with a general estrogen receptor antagonist ICI 182,780, a selective estrogen receptor-α antagonist methyl-piperidino-pyrazole dihydrochloride, or a G protein-coupled receptor 30 antagonist G15. However, pretreatment with EGF receptor blockers AG1478 or DAPH, but not with a phosphatidylinositol-3 kinase inhibitor LY294002 or an Akt1/2 kinase inhibitor Akt inhibitor VIII, attenuated 3',4'-dimethoxythioflavone-induced vasorelaxation. In addition, pretreatment with a Src inhibitor PP2 or an ERK inhibitor U0126 also attenuated vascular relaxation induced by the cumulative addition of 3',4'-dimethoxythioflavone. However, neither a mitochondrial electron transport inhibitor rotenone, an NADPH oxidase inhibitor apocynin, nor a superoxide dismutase mimetic MnTMPyP affected the vascular relaxation induced by the cumulative addition of 3',4'-dimethoxythioflavone. In conclusion, 3',4'-dimethoxythioflavone induces endothelium-dependent vasorelaxation through activation of EGF receptor and Src/ERK pathway in rat aorta.

17β-Estradiol (E2) exerts rapid non-genomic vascular effects through activation of its plasma membrane receptors. We tested the hypothesis that E2 induces vasorelaxation through activation of the G-protein-coupled receptor 30 (GPR30) in rat aorta. Rat aortic rings were mounted in organ baths and subjected to contraction followed by relaxation. Whether endothelium was intact or denuded, both E2 and G1, a GPR30 agonist, induced vasorelaxation in concentration-dependent manners. Although G15, a specific GPR30 antagonist, blocked G1-induced vasorelaxation, it did not block E2-induced vasorelaxation. In conclusion, 17β-estradiol induces vasorelaxation in a GPR30-independent manner in rat aorta.

This article reports the cloning and expression of 2 fragments of the P97 adhesin of Mycoplasma hyopneumoniae for use in serodiagnosis: a 50-kDa fragment (including the N-terminal cleavage site) and a 30-kDa fragment (including the C-terminal R1 and R2 repeats, which are essential for adherence). The genes encoding the fragments were amplified, cloned, and expressed in the Escherichia coli expression system BL21 (DE3)pLysS. Antiserum against the purified recombinant proteins reacted with the mycoplasmal 97-kDa intact protein and the 66-kDa major cleavage fragment, confirming that both cloned fragments could induce antigen-specific antibodies in mice. Of 70 serum samples from nonvaccinated pigs, 26 (37%) were seropositive when the 30-kDa fragment was used as an antigen for enzyme-linked immunosorbent assay, suggesting that natural mycoplasmal infection is quite common in Korea. However, only 4 samples were seropositive when the 50-kDa fragment was used; this fragment was therefore deemed unsuitable for serodiagnosis. The 30-kDa fragment protein might be useful for measuring antibody response to vaccination and for detecting mycoplasmal infection.

The immunological role of the Pasteurella multocida toxin (PMT) in mice was examined using a PMT mutant strain. After a nasal inoculation, the mutant strain failed to induce interstitial pneumonia. Moreover, PMT had no significant effect on the populations of CD4+, CD8+, CD3+, and CD19+ immunocytes in blood or on the populations of CD4+ and CD8+ splenocytes (P<0.01). However, there was a significant increase in the total number of cells in the BAL samples obtained from the wild-type P. multocida-inoculated mice. On the other hand, the level of IL-1 expression decreased when the macrophages from the bronchio-alveolar lavage were stimulated with PMT. Overall, PMT appears to play some role (stimulating and/or inhibiting) in the immunological responses but further studies will be required to confirm this.