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BackgroundPeople with osteoarthritis (OA) are at higher risk of developing a wide array of comorbidities. Whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) contributes to the increased risk of some incident comorbidities remains unknown.ObjectivesTo examine the contribution of NSAIDs in the development of a wide range of comorbidities in people with and without OA.MethodsThis observational cohort study used the UK primary care Clinical Practice Research Datalink (CPRD) GOLD containing data on 20+ million people covering 937 practices. We identified 259,000 people with incident OA and 259,000 age (±2 years), sex, and practice matched controls at 1:1 ratio. Controls were assigned the same index date (the date of first diagnosis of OA) as cases for the start of follow-up. Both cases and controls were further divided into two groups according to NSAID prescriptions at any time after the index date. This allowed us to examine both the main effect of each exposure and interaction between OA and NSAID exposure after the index date. People with an NSAID prescription before the index date were excluded from the study. NSAID exposure was defined as at least two prescriptions within 90 days. Exposure status of each participant was assessed every six months as yes/no until the end of the study/outcome of interests/death/last data available, whichever came first. Comorbidities were grouped into 9 categories as cancer, cardiovascular disease (CVD), endocrine, psychological, renal, gastrointestinal (GI), genitourinary, hepatic, and neurological conditions. Propensity scores for the prescription of NSAIDs were calculated using a logistic regression model including age, sex, body mass index (BMI), musculoskeletal and pain related conditions covariates. The propensity score adjusted time varying exposure analysis was undertaken using a multivariate COX model and hazard ratio (HR) and 95% confidence intervals were calculated. Proportional hazard assumption was tested using Schoenfeld test. Smoking, alcohol, ever prescription of proton pump inhibitors (PPIs) and other comorbidities were included in the adjusted model. The additional contribution of NSAIDs and OA towards the incident comorbidity was estimated using addictive interaction methods. We also investigated the individual risk across non-selective, and COX-2 selective NSAIDs.ResultsThe mean age was 59.4±12.8 years in people with OA and 60.2±12.8 years for controls with 57.7% being female. Nearly two thirds of people with OA were prescribed NSAIDs as defined, compared to one third in the control population. People with OA and exposed to NSAIDs had highest risk of developing psychological (1.51; 1.43,1.60), CVD (1.38; 1.33,1.43), cancer (1.34; 1.25,1.44), GI (1.25; 1.16,1.34) and renal (1.17; 1.11,1.24) comorbidities after adjusting for all the covariates and PPI drugs, compared to the non-OA and non-NSAID group. (Figure 1) Interaction between OA and NSAID was significant for cancer, GI, renal, hepatic, and neurological outcomes. Within people with OA, non-selective NSAIDs increased the risk of CVD (1.25; 1.20,1.30), cancer (1.11; 1.04,1.19), endocrine (1.15; 1.10,1.19), renal (1.19; 1.13,1.26) and psychological (1.21; 1.15,1.28) comorbidities, whereas COX-2 selective NSAIDs increased risk of incident CVD (1.34; 1.25,1.44), endocrine (1.13; 1.04,1.21), renal (1.25; 1.14,1.37), and psychological (1.21; 1.09,1.34) comorbidities.Figure 1.Hazard ratio of developing different comorbidities (reference group: no OA and no NSAIDs) OA- Osteoarthritis; NSAIDS- Non-steroidal anti-inflammatory drugs.ConclusionUse of NSAIDs among people with OA is associated with increased risk of a wide variety of comorbidities. Non-selective and COX-2 selective NSAIDs are both associated with increased risk of cardiovascular, renal, and psychological comorbidities.AcknowledgementsWe thank the Patient Research Participants (PRP) members Jenny Cockshull, Stevie Vanhegan, and Irene Pitsillidou for their involvement since the beginning of the project. We would like to thank the FOREUM for financially supporting the research.Disclosure of InterestsSubhashisa Swain: None declared, Anne Kamps: None declared, Jos Runhaar: None declared, Andrea Dell’Isola: None declared, Aleksandra Turkiewicz: None declared, Danielle E Robinson: None declared, Victoria Y Strauss: None declared, Christian Mallen: None declared, Chang-Fu Kuo: None declared, Carol Coupland: None declared, Michael Doherty Consultant of: Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Grant/research support from: Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Aliya Sarmanova: None declared, Daniel Prieto-Alhambra Speakers bureau: paid speaker services from Amgen and UCB Biopharma., Consultant of: His department has received advisory or consultancy fees from Amgen, Astellas, AstraZeneca, Johnson, and Johnson, and UCB Biopharma, Grant/research support from: Prof. Prieto-Alhambra’s research group has received grant support from Amgen, Chesi-Taylor, Novartis, and UCB Biopharma., Martin Englund: None declared, S.M.A. Bierma-Zeinstra: None declared, Weiya Zhang Speakers bureau: Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium, Consultant of: Consultant of: Grunenthal for advice on gout management

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes not only joint pain but also bone destruction resulting in impairment of quality of life. Tumor necrosis factor inhibitors have improved prognosis of patients with rheumatoid arthritis dramatically, especially in combination with methotrexate, however, the optimal dose of the concomitant methotrexate is unclear.ObjectivesTo evaluate the efficacy and safety of adalimumab in combination with reduced dose of methotrexate in patients with early RA with inadequate response to methotrexate.MethodsThe MIRACLE study was a multinational, randomized, open-label study in patients with RA with inadequate response to methotrexate conducted in Asia. It compared low dose and high dose methotrexate upon starting adalimumab. Methotrexate-naive patients with RA with a disease duration of less than two years started methotrexate at 6 to 8 mg/week and increased it to the maximum tolerable dose by week 12. Patients who have not achieved remission according to simplified disease activity index (SDAI) despite methotrexate ≥ 10 mg/week at week 24 were randomised to the maximum tolerable dose of methotrexate group (10 to 25 mg/week) or the reduced dose group (6 to 8 mg/week) and started to receive subcutaneous adalimumab 40 mg every other week. The primary endpoint was non-inferiority in the achievement of SDAI remission at week 48 in the reduced dose group compared with the maximum tolerable dose group with a non-inferiority margin of -15% based on two-sided 90% confidence interval. (NCT03505008)ResultsA total of 300 patients were enrolled in the study. Among them, 291 started methotrexate and were included in the analysis. The mean age was 57.7±15.2 years, female was 74.6%, and the mean disease duration from the diagnosis of RA was 21.1±56.2 days. Anti-CCP antibody was positive in 211 (73.0%) and the mean SDAI at study enrollment was 26.5±12.4. At week 24, with the mean dose of methotrexate of 12.6±2.9 mg/week, 108 patients (37.1%) achieved remission according to SDAI and continued MTX monotherapy. 134 patients (46.0%) were randomised and started adalimumab with 68 patients in the maximum tolerable dose group and 66 patients in the reduced dose group. At week 48, the remission achievement rates were 38.4 % and 44.8 %, respectively, with the adjusted risk difference of the reduced dose group to the maximum tolerable dose group of 6.4% (-7.0% to 19.8%, 90% CI), which met the criterion for noninferiority. No significant difference was found in health assessment questionnaire disability index ≤0.5 (59.1% vs 62.0%, respectively, p=0.72) and in radiological remission rates (Δmodified total Sharp score ≤0.5, 66.3% vs 62.0 %, respectively, p=0.59). Adverse drug reactions tended to be more frequent in the maximum tolerable dose group than in the reduced dose group (22.1% vs 9.1%, respectively, p=0.06).ConclusionThe MIRACLE randomised study demonstrated that, in patients with inadequate response to methotrexate, the efficacy of adalimumab with reduced dose of concomitant methotrexate was not inferior to that with maximum tolerable dose of methotrexate with better safety profile.Disclosure of InterestsHiroya Tamai Speakers bureau: Eisai, Grant/research support from: Eisai, Kei Ikeda Speakers bureau: AbbVie, Eisai, Eli Lilly, Novartis, Gilead, Asahi-Kasei, Grant/research support from: Mitsubishi-Tanabe, Toshiaki Miyamoto: None declared, Hiroaki Taguchi: None declared, Chang-Fu Kuo: None declared, Kichul Shin: None declared, Shintaro Hirata Speakers bureau: AbbVie, Asahi-Kasei, Astellas, Ayumi, Bristol Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Kyorin, Novartis, Pfizer, Sanofi, Tanabe-Mitsubishi, UCB, Paid instructor for: AbbVie, Mitsubishi-Tanabe, Consultant of: AbbVie, Astellas, Bristol Myers Squibb, Eisai, Gilead, Ily Lilly, Grant/research support from: AbbVie, Asahi-Kasei, Eisai, Otsuka, Sanofi, Shionogi, Chugai, Pfizer, Tanabe-Mitsubishi, Eli Lilly, UCB, yutaka okano: None declared, Shinji Sato Speakers bureau: AbbVie, Eisai, Grant/research support from: AbbVie, Eisai, Hidekata Yasuoka Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Daiichi-Sankyo, Eisai, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer-Ingelheim, Bayer, Glaxo Smith Kline, Paid instructor for: AbbVie, Consultant of: AbbVie, Asahi Kasei, Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, In Ah Choi Speakers bureau: Abbvie, Eisai, Sung-Hwan Park: None declared, Meng-Yu Weng Paid instructor for: Novartis, Eli Lilly, ChuGai, Abbvie, Consultant of: Abbvie, Masataka Kuwana Speakers bureau: Astellas, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Mitsubishi-Tanabe, Consultant of: Boehringer-Ingelheim, Kissei, Mochida, Grant/research support from: AbbVie, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, MBL, Nippon Shinyaku, Ono Pharmaceuticals, Mitsubishi-Tanabe, Yun Jong Lee Grant/research support from: Yuhan, Tomonori Ishii Speakers bureau: Chugai, Mitsubishi-Tanabe, Glaxo Smith Kline, Pfizer, Eli Lilly, Janssen, AbbVie, Eisai, Astellas, Jinhyun Kim: None declared, Hideto Kameda Speakers bureau: AbbVie, Pfizer, Consultant of: AbbVie, Grant/research support from: AbbVie, Eisai, Toshihisa Kojima Speakers bureau: AbbVie, Pfizer, Eisai, Grant/research support from: AbbVie, Han Joo Baek: None declared, Ping-Ning Hsu: None declared, Chun-Ming Huang Paid instructor for: Abbvie, Pfizer, Tien-Tsai Cheng Paid instructor for: Abbvie, Grant/research support from: Abbvie, Wan-Yu Sung: None declared, Takehiro Taninaga Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Masahiko Mori Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Hideaki Miyagishi Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Yasunori Sato Speakers bureau: Eisai Co., Ltd. Kowa Company, Ltd., Consultant of: MOCHIDA PHARMACEUTICAL CO., LTD, Tsutomu Takeuchi Speakers bureau: Astellas, AbbVie, Ayumi, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo Smith Kline, Janssen, Mitsubishi-Tanabe, Nippon-kayaku, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Asahi Kasei, AbbVie, Ayumi, Boehringer-Ingelheim, Chugai, Eisai, Eli Lilly, Mitsubishi-Tanabe, Sanofi, UCB, Yuko Kaneko Speakers bureau: Asahi Kasei, Astellas, Ayumi, Bristol Myers Squibb, Chugai, Eisai, Elli Lilly, Mitsubishi-Tanabe, Novartis, UCB, Grant/research support from: AbbVie, Chugai, Eisai, Mitsubishi-Tanabe, UCB.

BackgroundOsteoarthritis (OA) patients are more likely to have other comorbidities (Swain, Sarmanova et al. 2020). Improving the understanding of comorbidity profiles of OA patients may lead to improvement in their clinical care.ObjectivesTo identify sub-groups in patients diagnosed with hip OA using patterns of comorbidity.MethodsRoutinely-collected data of individuals ≥18 years with an incident diagnosis of hip OA (baseline/time of diagnosis), with at least 1 year of follow-up in SIDIAP (Information System for Research in Primary Care, a primary case database from Spain) were collected from January 1st 2006 to June 31st 2020. Those with soft-tissue disorders or other bone/cartilage diseases at the same joint in the year prior/after baseline were excluded. Comorbidities associated with OA in the literature and present in ≥1% of the study population were included. Clusters of comorbidities were identified at baseline using latent class analysis (LCA), a soft clustering method that classifies individuals according to the distribution of their measured items. The number of clusters or sub-groups within the study population was decided by comparing goodness of fit parameters (CAIC, BIC, ABIC) and log-likelihood changes of models from 2 to 8 clusters. The selected model was externally evaluated by a survival analysis assessing 10 years mortality within each cluster, where the weight of the posterior probability was used as a probability of sampling weight.ResultsWe identified 94,720 individuals with an incident diagnosis of hip OA, 56.3% women and 43.7% men, with a mean age (SD) of 67.2 (13.1) years. We selected the LCA model with 5 clusters that could be described as: healthier (lower prevalence of all comorbidities than average in the cohort), multimorbidity (higher prevalence of all comorbidities, multiple comorbidities), back/neck pain plus mental health (B/N-mental), cardiovascular disease (CVD), and metabolic syndrome (MetS) (Figure 1). Cox regression (HR [95CI%]) showed higher mortality risk for multimorbidity (3.76 [3.70-3.83]), CVD (1.56 [1.53-1.59]) and MetS (4.56 [4.35-4.78]), compared to healthy. No difference was observed for B/N-mental cluster.Figure 1.Distribution of comorbidities within each cluster using latent class analysis. Clusters were described as Healthier, Multimorbidity, B/N-mental, CVD and MetS. Black horizontal lines represent the prevalence of the comorbidity before the clusterization. Abbreviations: Healthier, lower prevalence of all comorbidities; Multimorbidity, higher prevalence of all comorbidities; B/N-mental, back/neck pain plus mental health disorders; CVD, cardiovascular disease; Met, metabolic syndrome; Bhp, benign prostate hypertrophy; Chd, chronic heart disease; Chf, chronic heart failure; Ckd, chronic kidney disease; Copd, chronic obstructive pulmonary disease; Gbs, gall bladder stone; Gerd, gastroesophageal reflux disease; Ibd, inflammatory bowel disease; Ovd, other vessel diseases; Substance, substance abuse.ConclusionClustering of co-morbidities in hip OA patients at the time of diagnosis has the potential to detect sub-groups of hip OA patients who might require additional care.References[1]Swain, S., A. Sarmanova, C. Coupland, M. Doherty and W. Zhang (2020). “Comorbidities in Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies.” Arthritis Care Res (Hoboken) 72(7): 991-1000.AcknowledgementsWe thank the Patient Research Participants (PRP) members Jenny Cockshull, Stevie Vanhegan, and Irene Pitsillidou for their involvement since the beginning of the project. We would like to thank the FOREUM for financially supporting the research.Disclosure of InterestsNone declared

Background Burns are not only major personal catastrophic events but also constitute a national health problem due to its associated morbidity, rehabilitation, mortality and high cost medical services. Advances in care and treatment have increased survival from major burn injury. However, information on the epidemiology and risk factors of burn mortality in Taiwan is limited. The study aim was to determine the nationwide epidemiological characteristics, trends, and mortality risk factors of burn inpatients in Taiwan. Methods This nationwide population-based study evaluated data retrieved from the Taiwan National Health Insurance database. Patients hospitalized for burns (ICD-9-CM codes 940-949) between 2003 and 2013 were identified from hospitalization records. Results A total of 73,774 patients were included. The data showed increases in age, revised Baux score, and Charlson Comorbidity Index during the study period, but it was also accompanied by a continuing decrease in burn incidence and a significant shortening of the length of hospital stay. The average in-hospital mortality was 17.5/1000 in 2003 and 12.2/1000 in 2013 but did not showed significant change. Male gender, older age, higher Charlson Comorbidity Index, presence of inhalation injury, large total burn surface area (TBSA), and higher revised Baux score were significant predictors of mortality. Conclusion Population-based burn epidemiology data demonstrated ongoing improvement in hospital care during the past decade. Male gender, older age, higher Charlson Comorbidity Index, presence of inhalation injury, large TBSA, and higher revised Baux score were significant predictors of mortality.

Background:Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). The concentrations of MTX-polyglutamates (PG) in erythrocytes, an active form of MTX, are useful markers for the optimal usage of MTX in patients with RA. The concentrations of MTX-PG have been reported to be different between Japanese and Caucasians. However, the difference among Asian ethnicity remains unclear.Objectives:To examine MTX-PG concentrations in association with MTX dose during the first 24 weeks after the initiation of MTX for newly diagnosed RA patients in Japan, Korea and Taiwan.Methods:MIRACLE study is a multicenter, open-label, randomized, 48 weeks interventional study conducted in Japan, Korea and Taiwan to evaluate non-inferiority of low dose to high dose of MTX as an add-on therapy to adalimumab in 300 patients with RA who do not achieve remission after 24 weeks MTX monotherapy in stipulated dosage. In the first 24 weeks, MTX was started at 6 to 8 mg/week for newly diagnosed RA patients, and promptly escalated to the maximum tolerable dose in 12 weeks in principle. This interim data evaluation was intended to investigate the differences among countries in the relationship between MTX dose, safety and MTX-PG concentrations in erythrocytes during the first 24 weeks. The efficacy of the treatment is not included at this point.Results:A total of 166 patients (106 in Japan, 35 in Korea, 25 in Taiwan) were included in this interim data. The age at treatment initiation was 57.2 years old on average and female was 79.5%. The time course changes in total and individual MTX-PG levels differed in the three countries. At 24 weeks, whereas the mean total MTX-PG concentrations were comparable (112.9 nmol/L in Japan, 104.4 nmol/L in Korea, and 115.7 nmol/L in Taiwan) with a dose of MTX of 12.3 mg/week, 14.1 mg/week, and 12.2 mg/week, respectively, the individual MTX-PG concentrations were different. The MTX-PG1 and MTX-PG2 concentrations were lower in Korea than Japan and Taiwan whereas MTX-PG3, MTX-PG4 and MTX-PG5 concentrations were the highest in Korea.Conclusion:The distribution of short-chain and long-chain MTX-PG concentrations were various among Asian countries despite similar dose of MTX administration: NCT03505008.Disclosure of Interests:Hiroya Tamai: None declared, Yuko Kaneko Speakers bureau: AbbVie, Astellas, Ayumi, Bristol–Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Kirin, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, and UCB., Grant/research support from: Sanofi, Hideto Kameda Speakers bureau: AbbVie, Pfizer, Consultant of: AbbVie, Grant/research support from: AbbVie, Eisai, Masataka Kuwana Speakers bureau: Astellas, Asahi Kasei Pharma, Boehringer- Ingelheim, Chugai, Eisai, Janssen, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Mitsubishi-Tanabe, Consultant of: Corbus, Grant/research support from: AbbVie, Asahi Kasei Pharma, Boehringer- Ingelheim, Chugai, Eisai, MBL, Nippon Shinyaku, Ono Pharmaceuticals, Mitsubishi-Tanabe, Yutaka Okano: None declared, Tomonori Ishii Speakers bureau: Chugai, Mitsubishi- Tanabe, Glaxo Smith Kline, Pfizer, Eli Lilly, Janssen, AbbVie, Eisai, Astellas, Kei Ikeda Speakers bureau: AbbVie, Eli Lilly, Novartis, Mitsubishi-Tanabe, Eisai, BMS, Grant/research support from: Mitsubishi-Tanabe, Hiroaki Taguchi: None declared, Shinji Sato: None declared, Toshiaki Miyamoto: None declared, Shintaro Hirata Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Ayumi, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Glaxo Smith Kline, Kissei, Pfizer, Sanofi, Mitsubishi- Tanabe, UCB, Paid instructor for: AbbVie, Mitsubishi- Tanabe, Consultant of: AbbVie, Eisai, Gilead, Grant/research support from: AbbVie, Chugai, Mitsubishi-Tanabe, UCB, Hidekata Yasuoka Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Daiichi- Sankyo, Eisai, Kissei, Takeda, Mitsubishi- Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer- Ingelheim, Bayer, Glaxo Smith Kline, Paid instructor for: AbbVie, Consultant of: AbbVie, Asahi Kasei, Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Toshihisa Kojima Speakers bureau: AbbVie, Pfizer, Eisai, Grant/research support from: AbbVie, Sung-Hwan Park: None declared, Kichul Shin: None declared, Han Joo Baek: None declared, Yun Jong Lee Grant/research support from: research fund, In Ah Choi Speakers bureau: Abbvie, Eizai, Grant/research support from: Abbvie, Eizai, Jinhyun Kim: None declared, Ping-Ning Hsu: None declared, Chang-Fu Kuo: None declared, Chun-Ming Huang Paid instructor for: AbbVie, Pfizer, Meng-Yu Weng Consultant of: AbbVie, Wan-Yu Sung: None declared, Wen-Chan Tsai: None declared, Tien-Tsai Cheng Paid instructor for: AbbVie, Grant/research support from: AbbVie, Takehiro Taninaga Shareholder of: Eisai Co., Ltd., Employee of: Eisai Co., Ltd., Masahiko Mori Shareholder of: Eisai Co., Ltd., Employee of: Eisai Co., Ltd., Hideaki Miyagishi Employee of: Eisai Co., Ltd., Yasunori Sato: None declared, Tsutomu Takeuchi Speakers bureau: Astellas, Abbvie, Daiichi Sankyo, Ayumi, Eisai, GlaxoSmithKline, Mitsubishi Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Bristol Myers Squibb, Janssen, UCB, TaishoToyama, Sanofi–Aventis, Nipponkayaku, Taiho, Gilead, Boehringer Ingelheim, Grant/research support from: Asahikasei, Astellas, Abbvie, Daiichi Sankyo, Ayumi, Eisai, Takeda, Mitsubishi Tanabe, Chugai, Eli Lilly, UCB, Sanofi–Aventis, Nipponkayaku, Boehringer Ingelheim

BACKGROUND AND PURPOSE We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. METHODS This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. RESULTS Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1-2, 3-4 or ≥5 was 131 [95% confidence interval (CI), 1.17-1.47], 1.65 (95% CI, 1.20-2.26) or 3.26 (95% CI, 1.58-6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00-1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81-2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. CONCLUSIONS Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival.

Background:Precancerous lesions are pathologically atypical tissues which share part of abnormal features of cancerous tissue under microscopic examination but lack the ability of uninhibited growth and distant metastasis. Some of the measures to screen for precancerous tissues have gained popularity because supporting evidence indicates the beneficial effects on cancer incidence and mortality [1, 2]. However, the roles of these screenings and the risk of precancerous lesions in patients with autoimmune diseases have not been clarified. We aim to exam the risk of precancerous lesions among different autoimmune diseases.Objectives:To determine whether the Taiwanese autoimmune rheumatic diseases (ARDs) patients have a higher risk of precancerous lesions of the breast and cervix uteri.Methods:The Taiwan national breast cancer screening program provides biennially mammography for women above 45 years old or with a positive family history of breast cancer above 40 years old. The national cervical cancer screening program provides Pap smear test once every three years for women age above 30 years old. Using the National Health Insurance (NHI) database, we identified a cohort of 6 different groups of ARDs patients in Taiwan between 2004 and 2014. We linked the data from the national screening program of breast and cervical cancer and the NHI database to estimate the standardized incidence ratios (SIRs) of precancerous lesions (atypical lobular and ductal hyperplasia of the breast, carcinoma in situ of the breast, cervical intraepithelial neoplasia 1 to 3 of cervix uteri and carcinoma in situ of cervix uteri) in patients with ARDs compared with the general population.Results:From 2004-2014, we identified 64,904 patients with autoimmune diseases. Table 1 shows the number of patients receiving the screening programs. The standardized incidence ratio (SIR) of precancerous lesion of the breast was elevated in patients with rheumatoid arthritis (SIR, 2.21; 95% CI, 1.21-3.46) and Sjögren syndrome (SIR, 5.77; 95% CI, 2.63-9.85). The incidence of precancerous lesion of cervix uteri was elevated in patients with surveyed ARDs compared with the normal population, particularly for patients with systemic lupus erythematosus (SIR 28.94; 95% CI, 24.52-33.70) and inflammatory bowel disease (SIR, 27.50; 95% CI, 7.40-56.32) (Table 2).Table 1.Breast screen and Pap smear test in patients with autoimmune rheumatic diseasesRheumatoid arthritis (n=28289)Systemic lupus erythematosus (n=11609)Sjögren syndrome (n=17647)Systemic sclerosis (n=1489)Vasculitis(n=3050)Inflammatory bowel disease (n=2820)Female patients21199980815785104312251034Breast screening (n, %)6296 (29.70%)1382 (14.09%)4737 (30.01%)276 (26.46%)67 (5.47%)215 (20.79%)Pap smear (n, %)12827 (60.51%)6495 (66.22%)9961 (63.10%)670 (64.24%)1114 (90.94%)665 (64.31%)Table 2.Standardized incidence ratio (SIR) of precancerous lesion of the breast and cervix uteri in patients with autoimmune rheumatic diseasesPrecancerous lesion of BreastPrecancerous lesion of CervixSIR (95% CI)SIR (95% CI)Rheumatoid arthritis2.21 (1.21-3.46)5.32 (4.25-6.50)Systemic lupus erythematosus1.34 (0.27-2.93)28.94 (24.52-33.70)Sjögren syndrome5.77 (2.63-9.85)8.32(5.72-11.34)Systemic sclerosis6.45 (0.72-15.54)7.93 (2.90-14.80)Vasculitis0.007.68 (1.54-16.83)Inflammatory bowel diseases0.0027.50 (7.40-56.32)Conclusion:Precancerous lesions in the breast and cervix uteri were higher in female patients with ARDs and they should receive stringent screening program.References:[1]Tabar L, et al. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001, 91(9):1724-1731.[2]Peirson L, et al. Screening for cervical cancer: a systematic review and meta-analysis. Syst Rev 2013, 2:35.Disclosure of Interests:None declared

Objective The role of maxillofacial trauma in dementia risk is not well established. The aim of this study was to evaluate the association between craniofacial trauma, including facial bone fracture and traumatic brain injury (TBI), and dementia. Methods Using Taiwan's National Health Insurance Research Database, we identified 501,889 adults who had had ≥1 medical record of craniofacial trauma between 2000 and 2010 and did not have a dementia diagnosis at baseline. Diagnoses of craniofacial trauma, including facial bone fracture and TBI, and dementia were made using International Classification of Diseases, Ninth Revision codes. The standardized incidence ratio was used to determine whether craniofacial trauma was associated with a greater risk of incident dementia compared with the general population. The Cox proportional hazards model was used to predict the risk of dementia among the trauma cohort by comparing the patients with and without comorbidities. Results A total of 501,889 patients with craniofacial trauma were included, of which 1.5% (n = 7804) developed dementia. Facial bone fracture (standardized incidence ratio, 1.58; 95% confidence interval, 1.25–2.00) was shown to be associated with an increased dementia risk compared with the general population. In addition, craniofacial trauma accompanied with postinjury comorbidities was associated with an increased risk of dementia during follow-up periods compared with the group without comorbidities. Conclusions Craniofacial traumas, especially facial bone fracture, were associated with an increased risk of subsequent dementia. Maintaining a high index of suspicion for associated TBIs in all patients with facial trauma is crucial, even if no obvious initial signs and symptoms of brain injury are observed.

Background and purpose We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy. Methods We used the UK Clinical Practice Research Data-link to identify 2526 patients with incident MS and 9980 age-, sex- and index year-matched non-MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality. Results Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non-MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36-3.27) for pre-existing epilepsy. Among epilepsy-free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94-12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02-4.84) for all-cause mortality. Conclusions This population-based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non-MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without.

Background Preventable hospitalizations for specific conditions are considered preventable because appropriate outpatient care should potentially avoid hospitalisation for these conditions. Although not all of the hospitalizations can be prevented, to identify the rate of preventable hospitalizations among patients with systemic lupus erythematosus (SLE) can help us to understand the excess potential preventable hospitalizations and to provide an action to the SLE patients. Objectives To investigate the risk of preventable hospitalisation in patients with SLE before and after initial diagnosis of the disease. Methods We identified 4483 adult patients with incident SLE between 2005 and 2009 using the Taiwan National Health Insurance Database. Each SLE patients were matched to five controls without SLE during the same study period, by age and sex. The index date was the first date of SLE diagnosis and their matched controls. We estimated the incidence and incidence rate ratios (IRRs) of preventable hospitalisation by conditional Poisson regression, adjusted for age, sex, Elixhauser Comorbidity Index, number of outpatient visits and hospitalizations 1-y prior to index date, residence urbanisation, income levels, occupation and the number of physicians at the patients’ residence. Results The overall incidence of preventable hospitalisation was 1.88 (95% CI, 1.74 to 2.03) per 1000 person-months among SLE patients and 0.53 (95% CI, 0.49 to 0.56) per 1000 person-months among controls, giving an adjusted IRR of 3.57 (95% CI, 3.25 to 3.93). The IRRs especially higher in heart failure, bacterial pneumonia and urinary tract infection and the respective estimates were were 2.85 (95% CI, 2.14 to 3.80),4.67 (95% CI, 4.03 to 5.42) and 3.84 (95% CI,3.35 to 4.41). Conclusions Risk of preventable hospitalisation is higher in patients with SLE. Disclosure of Interest None declared

Background Pregnancy involves adaptation to the immune system to prevent rejection of the foetus and this might have consequences on the activity of the rheumatoid arthritis (RA). Equally the aberrant immunity and disease activity of the RA might influence the pregnancy and foetal-neonatal outcomes. Objectives This study was designed to estimate the risk of adverse foetal-neonatal and maternal outcomes in pregnancies in women with RA. Methods We identified 2,350,339 singleton pregnancies using the Taiwan National Health Insurance database and birth registry between 2001 and 2012. Maternal history of RA, SLE, Sjogren’s syndrome, systemic sclerosis, vasculitis and poly/dermatomyositis were ascertained; among them, 845 individuals had RA. Odds ratios (ORs) and 95% confidence intervals (CIs) for pregnancy outcomes were estimated using an adjusted generalised estimating equation model. Results Pregnancies in women with RA were associated with an OR (95% CI) of 1.65 (1.37–1.98) for low birthweight ( Conclusions Pregnancies in women with RA were at a higher risk for multiple adverse foetal-neonatal outcomes, especially low birthweight ( References [1] Michet CJ Jr, McKenna CH, Elveback LR, Kaslow RA, Kurland LT. Epidemiology of systemic lupus erythematosus and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc1985;60(2):105–113. [2] Chiu YM, Lai CH. Nationwide population-based epidemiologic study of systemic lupus erythematosus in Taiwan. Lupus2010;19(10):1250–1255. [3] Rees F, Doherty M, Grainge M, Davenport G, Lanyon P, Zhang W. The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012. Ann Rheum Dis2016;75(1):136–141. [4] See LC, Kuo CF, Chou IJ, Chiou MJ, Yu KH. Sex- and age-specific incidence of autoimmune rheumatic diseases in the Chinese population: A Taiwan population-based study. Semin Arthritis Rheum2013;43(3):381–386. [5] Cutolo M, Matucci-Cerinic M, Lockshin M, Ostensen M. Introduction: New trends in pregnancy and rheumatic diseases. Rheumatology (Oxford)2008;47(Suppl 3):iii1. Acknowledgements The authors would like to thank Centre for Big Data Analytics and Statistics in Chang Gung Memorial Hospital for statistical consultation. The sponsors of the study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Disclosure of Interest None declared

Background Febuxostat is a new xanthine oxidase inhibitor which is effective in the treatment of hyperuricemia. Its use in people with different levels of renal function has not been thoroughly assessed. Objectives To assess the risk of renal function deterioration in gout patients using febuxostat and compare it with patients using allopurinol and other uricosuric agents. Methods We included 5882 adult patients with gout diagnosed between 2012 and 2015. We divided patients into three groups by usage of urate-lowering drugs used (allopurinol, febuxostat and uricosuric agents including benzbromarone, probenecid and sulfinpyrazone). The primary outcome was a progress of one chronic kidney disease (CKD) stage. The index date was the first date of urate-lowering drugs used. We follow each patient to the date of event, death, switch to other drug or the end of the study. The Cox proportional hazards model was used to estimate the adjusted hazard ratios (HRs), adjusted for age, sex, baseline eGFR, baseline serum urine acid, comorbidity, co-medication. Results The incident rate of the renal function deterioration was 2.37 (95% CI, 1.75–3.14) per 1000 person-days in allopurinol users, 1.54 (95% CI, 1.30–1.81) per 1000 person-days in febuxostat users and 1.43 (95% CI, 1.32–1.56) per 1000 person-days in uricosuric agent users. The HRs of progession of CKD stage in febuxostat and uricosuric agent users were 0.98 (95% CI, 0.70–1.38) and 0.80 (95% CI, 0.59–1.09) compared with allopurinol. Among febuxostat users, the HRs were 1.80 (95% CI, 0.85–3.98) in patients with an estimated glomerular filtration rate (eGFR) ≥90 ml/min/1.73 m2), 1.06 (95% CI, 0.56–2.03) for patients with an eGFR 60–89 ml/min/1.73 m2, 0.78 (95% CI, 0.45–1.42) for patients with an eGFR 30–59 ml/min/1.73 m2 and 0.73 (95% CI, 0.22–3.52) for patients with an eGFR 15–29 ml/min/1.73 m2. Among uricosutic agent users, the HRs were 0.94 (95% CI, 0.52–1.88) in patients with an eGFR ≥90 ml/min/1.73 m2, 0.88 (95% CI, 0.55–1.50) in patients with an eGFR 60–89 ml/min/1.73 m2, 0.71 (95% CI, 0.41–1.28) in patients with an eGFR 30–59 ml/min/1.73 m2 and 0.71 (95% CI, 0.19–3.62) in patients with an eGFR 15–29 ml/min/1.73 m2. Conclusions Renal function deterioration is not uncommon after initiation of urate-lowering treatment and febuxostat has a similar renal safety profile as allopurinols and uricosuric agents. Disclosure of Interest None declared

This paper describes the preparation and characterization of polymeric nanoparticles loaded with a potent anti-tumor metal chelator, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) for delivery to cancer cells. Metal chelators have been increasingly studied for their anti-cancer properties that rely on the high demand of neoplastic cells for iron. Dp44mT has previously shown great antiproliferative characteristics in several cancers including breast cancer and melanoma. To further expand the application of this highly cytotoxic agent for cancer treatment and to enable its specific delivery to malignant cells, here we apply nano-scale particles (NPs) of biodegradable poly(lactic-co-glycolide) (PLGA) for encapsulation of Dp44mT and evaluate its effectiveness in vitro. The results demonstrated that Dp44mT was efficiently encapsulated in PLGA particles. Resulting NPs were uniform in size and shape and had good colloidal stability. Moreover, Dp44mT encapsulation in PLGA enhanced the water solubility of this agent. Lastly, the present formulation showed high level of cytotoxicity in glioma cells. Together, these results show the potential of PLGA NPs as a nano-carrier for Dp44mT with no apparent impact on the anti-tumor activity of this compound.

Background Total joint replacement (TJR) is a major surgical procedure aiming to replace damaged natural joints with artificial prosthesis to restore function and alleviate pain. Total knee replacement (TKR) and total hip replacement (THR) are two common replacement procedures, mainly as a result of osteoarthritis, rheumatoid arthritis, trauma, fracture and infection. Whether gout associates with a greater risk of TJR independent of these primary risk factors is controversial, despite tophaceous or chronic deforming gouty arthritis may lead to joint destruction and subsequent TJR Objectives We carried out a case control study using the National Health Insurance (NHI) database with full coverage of the general population of Taiwan to investigate the burden of TJR in gout patients at diagnosis compared to matched controls. We further followed incident gout patients and their matched controls after diagnosis to compare their subsequent risk for TJR. Methods The Taiwan National Health Insurance database was used to identify 74,729 new diagnosis gout patients in 2005. These were matched 1:1 to 74,729 controls by birth year and sex with people who did not have gout diagnosis or urate-lowering treatment prescription. Odds ratios (ORs) of total hip or knee replacement (THR or TJR) at diagnosis and hazards ratios (HRs) after diagnosis were estimated adjusted for gender, age at diagnosis, comorbidities, co-medications, place of residence, income and occupation. Results Gout was associated with adjusted ORs (95% CIs) of 0.87 (0.54 to 1.40), 1.01 (0.57 to 1.79), 0.93 (0.64 to 1.35) for the THR, TKR and TJR at diagnosis, respectively. The incidence rate of THR or TKR in the patients with gout was 1.60 and 1.76 (per 1,000 person-years) which was higher than matched controls (0.99 and 0.98, respectively). Gout was also associated with an adjusted HR (95% CI) of 1.41 (1.19 to 1.68), 1.37 (1.16 to 1.61) and 1.37 (1.22 to 1.56) for developing THR, TKR and TJR. Conclusions Compared to matched controls people with gout did not have an increased risk of TJR at diagnosis but the risk increased substantially after diagnosis. Whether adequate urate-lowering treatment reduces the risk requires further study. References Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nature reviews. Rheumatology 2015;11:649–62. Roddy E, Zhang W, Doherty M. Are joints affected by gout also affected by osteoarthritis? Ann Rheum Dis 2007;66:1374–7. Disclosure of Interest None declared

Background There is emerging evidence suggesting that offspring born to patients with rheumatic diseases has higher risk of neuropsychiatric diseases. Previous data from Quebec showed children born to women with SLE have an increased risk of autism spectrum disorder (ASD) but data regarding risk of ASD in offspring of mothers with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) mothers have not been reported in other population. Objectives We aimed to examine whether offspring of mothers with SLE and RA in Taiwan has a higher risk of developing ASD using data from a linkage between National Health Insurance (NHI) database and National Birth Registry in Taiwan. Methods We established a birth cohort of all live-births between 2001 and 2012 in Taiwan established using the National Health Insurance database and the National Birth Registry. Children born to mothers with SLE or RA were identified and matched up to 8 controls by maternal age, 1-minute Apgar score, 5-minute Apgar score, mode of delivery, sex of child, gestational age, birth weight, socioeconomic status (place of residence, income level, occupation). A marginal Cox proportional hazard models were used to estimate the relative risk (RR; 95% confidence interval [CI]) for ASD in newborns with affected mothers. Results Of 1,893,244 newborns, 0.08% (n=1,594) were born to mothers with SLE (mean age 30.43±4.37 years old) and 0.04% (n=673) were born to mothers with RA (31.97±4.51 years old). Overall, 5 of 673 (0.74%) RA offspring developed ASD, 7 of 1594 (0.44%) SLE offspring developed ASD and 10,631 of 1,893,244 (0.56%) all infants developed ASD. The incidence of ASD was 140.39 (95% CI, 45.58–327.62) per 100,000 person-years for RA group, 76.19 (95% CI, 30.63–156.97) per 100,000 person-years for SLE group, 89.85 (95% CI, 88.15–91.57) per 100,000 person-years for non-RA group and 89.87 (95% CI, 88.17–91.60) per 100,000 person-years for non-SLE group. The children born to RA and SLE mothers did not have higher risk of ASD with a HR (95% CI) of 1.42 (0.60–3.40) and 0.76 (0.36–1.59) for ASD, respectively. Conclusions Children born to women with SLE and RA do not have higher risk of developing ASD. References Lahita, R.G., Systemic lupus erythematosus: learning disability in the male offspring of female patients and relationship to laterality. Psychoneuroendocrinology, 1988. 13(5): p. 385–96. Vinet, E., et al., Increased Risk of Autism Spectrum Disorders in Children Born to Women With Systemic Lupus Erythematosus: Results From a Large Population-Based Cohort. Arthritis Rheumatol, 2015. 67(12): p. 3201–8. Disclosure of Interest None declared

Background A higher risk of urolithiasis has been reported in gout patients. However, whether urate-lowering treatments, including both xanthine oxidase inhibotors and uricosuric agents, are beneficial to reduce the risk or urolithiasis in gout patients has not been examined. Objectives To investigate the independent associations between urate-lowering treatment (ULT) and the risk of urolithiasis in incident gout patients. Methods We conducted a nested case-control study based on the Taiwan National Health Insurance Research Database (NHIRD), which was used to identify 473,858 newly diagnosis gout patients during the period from January 1, 2000 through December 31, 2004. All these patients were followed until December 31, 2013. We considered patients who first diagnose incident urolithiasis after the date of entry cohort (gout onset) as cases and the diagnostic date was defined as index date. Each case was matched up to five eligible controls whose follow-up period included the case9s index date by sex, birth of year and gout diagnosis year. And the index date of case was assigned to the matched controls. Odds ratios (ORs) and 95% confidence interval (CI) of urolithiasis associated with cumulative defined daily dose (cDDD) of xanthine oxidase inhibitor and uricosuric agents were main ourcome measures. Results Gout patients with incident urolithiasis (n=32,654) occurring after the initial diagnosis of gout aged 20–79 were age- and sex-matched 1:5 to 163,270 gout patients without urolithiasis. After adjusting for age, sex, urbanization status, income, occupation, and pertinent drugs and comorbidities, the OR of urolithiasis associated with use of ULT among gout patients were 1.04 (95% CI 1.00 to 1.07) for those with 28–90 cDDD, 0.95 (95% confidence interval 0.91–0.99) for 91–365 cDDD and 0.77 (95% confidence interval 0.73–0.82) for >365 cDDD, compared with those with a cDDD 365 cDDD. For uriscouric agents, the OR (95% CI) for urolithiasis among those with 28–91, 91–365 and Conclusions Higher ULT consumption was associated with a lower risk of urolithiasis. Xanthine oxidase inhibitors associated with reduced urolithiasis risk consistently across the range of consumption studied but for uricosuric agents inadequate cumulative dose results in a higher risk despite the risk reduced gradually with a higher cumulative dose. Disclosure of Interest None declared

The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.

Clustered regularly interspaced short palindromic repeats (CRISPR) are composed of numerous repeat-spacer units and are considered a prokaryotic defence system against foreign nucleic acids. Since antibiotic-resistant genes are frequently encoded in foreign nucleic acids, the aim of this study was to test whether erythromycin susceptibility in group A streptococcus (

Summary Klebsiella pneumoniae is a well-known Gram-negative pyogenic pathogen that can cause various types of infection. Liver abscesses caused by community-acquired K. pneumoniae infection are commonly reported in Taiwan, especially in people with diabetes mellitus. Meningococcal bacteraemia can present as disseminated pustules and leucocytoclastic vasculitis, but it has rarely been seen in patients with K. pneumoniae infection. To date, there are only two reports in the English literature about K. pneumoniae bacteraemia presenting as generalized pustulosis. We report a third case, occurring in a Taiwanese woman with a community-acquired K. pneumoniae liver abscess leading to sepsis and generalized pustules, complicated by cutaneous leucocytoclastic vasculitis.

Summary Background Whether environmental exposures may modulate the effect of the skin barrier gene on atopic dermatitis (AD) remains to be elucidated. Objectives To determine whether filaggrin (FLG) variants can serve as a predictor for atopic disorders in Chinese individuals and if allergen exposures may modify the effect of FLG variants on AD by total IgE levels. Methods In total, 116 children aged 2–5 years with AD and 212 control subjects were analysed for the FLG variants using DNA sequencing. Multiple logistic regression models were performed to estimate the association among FLG polymorphisms and atopic phenotypes. Serum total IgE level, standing for the degree of allergen exposures, was later stratified to determine the effects of FLG polymorphisms on AD. Results A significant difference in genotype frequency was found among AD cases and controls in FLG P478S polymorphism. FLG P478S GG genotype significantly increased the risk of AD [odds ratio (OR) 4·60, 95% confidence interval (CI) 1·88–11·24]. In addition, among subjects with AD, GG genotypes also significantly increased the risk of developing asthma (OR 4·68, 95% CI 1·37–16·03). Further, a similar result was obtained for allergic rhinitis (OR 3·23, 95% CI 1·01–10·30). Interestingly, the P478S GG genotype was significantly related to AD (OR 5·67, 95% CI 1·93–16·60) in children with IgE level ≥ 100 kU L−1. However, the association was not evident when IgE level was

ZnO epitaxial layers were successfully grown on nitridated Si(1 0 0) substrate with high-temperature (HT) GaN and low-temperature ZnO double buffer layers by molecular beam epitaxy. It was found that the HT-GaN buffer was crystalline with both hexagonal and cubic phases. It was also found that numerous cone-shaped nano-islands were formed on the ZnO epitaxial layers with density, average diameter and average height of 1.25×109 cm−2, 300 nm and 150 nm, respectively. X-ray diffraction and photoluminescence results both indicate that quality of our ZnO epitaxial layers was good.

The optical and electrical characteristics of zinc oxide (ZnO) films grown by molecular-beam epitaxy (MBE) on Si substrates were investigated. ZnO epitaxial layer was successfully grown on nitridated Si(100) substrate initially covered with high-temperature GaN and low-temperature ZnO double buffer layers using MBE. X-ray diffraction and photoluminescence results both indicated that a reasonable quality of ZnO epitaxial layer was obtained. As the CV measurement had indicated, the carrier concentration was reduced virtually in a linear fashion from ZnO surface down to GaN buffer layer. A reduction in electron concentration was caused by the carrier depletion due to the presence of the Schottky barrier of Ni/ZnO. The large density of electron accumulated at the ZnO/GaN interface was due to the large conduction band discontinuity and offset.

We report the fabrication of ZnO photoconductive sensors epitaxially grown on sapphire substrates with interdigitated Ni/Au electrodes. It was found that there exists an electric field-dependent photoconductive gain in the fabricated sensors. With an applied electric field of 500 V/cm, it was found that maximum quantum efficiency was around 2.8% while time constant of the decay transient was τ ∼ 0.556 ms. © 2007 Elsevier B.V. All rights reserved.

In this paper, we report the fabrication of vertically well-aligned ZnO nanowire ultraviolet (UV) photodetectors on ZnO:Ga/glass templates. With 1 V applied bias, it was found that dark current density of the device was only 1.37times10-7 A/cm2. It was also found that UV-to-visible rejection ratio of the fabricated photodetector was around 1000 with a maximum quantum efficiency of 12.6%. It was also found that noise equivalent power and normalized detectivity of the ZnO nanowire photodetector were 5.73times10-11 W and 6.17times109 cmHz0.5W-1, respectively.

Adipocyte determination and differentiation-dependent factor 1 (ADD1) drives the expression of several lipogenic genes in mammals. Polyunsaturated fatty acids decrease ADD1 mRNA abundance in differentiating porcine adipocytes. The current study was designed to explore the mechanisms by which PUFA inhibit the expression of ADD1 in porcine adipocytes. Porcine preadipocytes were differentiated for 24 h with 0 or 100 microM of docosahexaenoic acid (DHA) and mixtures of different concentrations of antioxidants to investigate the effect of DHA and antioxidants on the ADD1 mRNA abundance. We found the relative mRNA abundance was decreased by the addition of 100 microM DHA to the medium for porcine differentiating adipocytes, and adding an antioxidant mixture to the medium prevented part of the decrease in ADD1 mRNA abundance. These data suggest that DHA decreased the steady-state transcription factor ADD1 mRNA through a mechanism related to fatty acid peroxidation. Indeed, adding 7.5 microM vitamin E (a natural antioxidant) also restored the concentrations of ADD1 and fatty acid synthase mRNA, which were decreased by DHA treatment; however, the DHA or the antioxidant treatment did not change the expression of antioxidation genes (superoxide dismutase 1 and glutathione peroxidase 1) in porcine stromal vascular cells. When supplemented with the eicosanoid synthesis pathway inhibitors, the inhibition of the expression of ADD1 by arachidonic acid was partially recovered. These results suggest that the mechanism by which PUFA decrease ADD1 mRNA is due to the metabolic product of eicosanoids and peroxidation of these PUFA.

A procedure to assess the flavour quality of water-swellable and soluble tablets containing peppermint oil was developed. Menthol, the predominant ingredient in peppermint oil, was extracted and then analysed using gas chromatography (GC). Sample tablets containing peppermint oil were pulverised, dissolved in double distilled water and then extracted prior to GC analysis. Methyl tert-butyl ether (MTBE) was found to be the most effective amongst the four solvents evaluated for menthol extraction. With the GC column temperature initially held at 60°C for 5 min, a linear program from 60 to 200°C at 4°C/min followed by holding at 200°C for 9 min gave the highest signal-to-noise ratios (SNRs). A discrete peak of menthol was obtained at 19.92 min of retention time. An excellent representation of the total amount of peppermint oil in the tablets was achieved by using the amount of menthol detected by GC, as compared to the results from the Soxhlet method. The most dramatic loss of flavour happened during the first month, whereas only 0.01% reduction was observed afterwards. It is suggested that the proposed procedure could be used for routine quality control of peppermint flavour in water-swellable and soluble tablets.

Background Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease and there are few nationwide estimates for prevalence and incidence in Taiwan. Objectives The aim of this study was to determine trends in the incidence and prevalence of AS between 2005 and 2010 among general population of Taiwan. Methods The National Health Insurance Research Database was used to identify gout patients and to estimate the prevalence and incidence of AS for each year from 2005 to 2010. To determine the trends in prevalence, incidence and management of AS, we calculated age- and sex-standardised prevalence and incidence of gout in each calendar year from 2005 to 2010 with the population structure in year 2010 as the reference. Results A total of 54,857 cases with an AS diagnosis alive in December 2010 was identified. Men had a higher prevalence (0.28% versus 0.19%) and incidence (0.51 versus 0.33 per 1,000 person-year) of AS than women. The standardised prevalence of AS had decreased from 0.30% in 2005 to 0.24% in 2010. The incidence of AS is between 0.42 and 0.50 per 1,000 person-years during 2005 and 2010. The incidence of AS in men was low in individuals younger than 19 years of age, peaked rapidly in the ages 20 to 24 years and decreased gradually. The incidence and prevalence of regions in 2010 highest in the town of Tainan (0.6% and 1.79 per 1,000 person-years) and Ilan (1.17% and 1.52 per 1,000 person-years) than other regions. Conclusions AS is a common rheumatic disease in Taiwan with a similar prevalence to rheumatoid arthritis. Disclosure of Interest None declared

Background Concurrent use of methotrexate (MTX) and trimethoprim-sulfamethoxazole (TMP-SMX) has been linked to the development of cytopenia as a result of reduced renal clearance of MTX. However, the risk of adverse outcomes has not been estimated in a population setting. Objectives This study aimed to examine the risk for emergency department visits or hospitalisation after concurrent use of MEX and TMP-SMX in patients with rheumatoid arthritis (RA) in Taiwan using the National Health Insurance (NHI) data. Methods This was a retrospective cohort analysis of RA patients identified from the entire NHI database which contains essentially all residents in Taiwan. The case definition of RA was based on a rheumatologist diagnosis with a verification of expert panel commissioned by the Administration of National Health Insurance. Overall we identified 30,285 RA patients between 2000 and 2010. RA patients filled prescription for MTX in 453,114 person-quarters in which 9018 person-quarters they also filled a prescription for TMP-SMX. The main outcome measure was emergency department visit or hospital admission in person-quarters with concurrent fills of MTX and TMP-SMX compared with the rates in person-quarters with MTX prescription only. Multivariable logistic regression was used to adjust for age, sex, comorbidity, and socioeconomic status with a Generalised Estimating Equation (GEE) model to calculated the crude ORs (95% CIs) and adjusted ORs. Results Hospitalisations were more common in person-quarters with MTX and TMP-SMX use (688 events/8330 quarters) compared with quarters with MTX use alone (20,616 events/423,480 quarters) with a crude OR of 1.49 (95% confidence interval [CI], 1.36–1.62] and an adjusted OR of 1.45 (95% CI, 1.33–1.58). However, the risk for emergency department visits associated with MTX and TMP-SMX use (536 events/8,482 person-quarters) was not higher (21,115 events/422,981 person-quarters). The crude OR was 1.08 (95% CI, 0.97–1.19) for emergency department visits and the adjusted OR was 1.05 (95% CI 0.95–1.15]). Conclusions MTX use along with TMP-SMX is associated with an increased risk for hospitalisations which suggests a significant drug interaction between MTX and TMP-SMX in RA patients. Disclosure of Interest None declared

Background Psoriasis is a chronic inflammatory disease that involves hyperproliferation of keratinocytes in the epidermis. Several studies have reported the relationship between psoriasis and cancer. Population-based estimates for cancer risks in patients with psoriasis is rare Objectives This study estimated the standardised incidence ratio (SIR) of cancer in patients with psoriasis in Taiwan. Methods The primary data source was the National Health Insurance database of Taiwan. We identified patients with psoriasis based on a rheumatologist or dermatologist diagnosis. Incident cases who were free or cancers in 2000 were identified. Incidence of cancer was estimated in both incident psoriasis patients and the general population in 2000. To measure the relative risk of cancer in psoriasis patients, we calculated a SIR for all types of cancers and also each cancer type. SIRs were computed as ratios of observed numbers of cancers to the expected number of cancers on the basis of age-specific incidence rates in 5-year age intervals of the entire NHI covered population in 2000. Results A total of 6,835 incident psoriasis patients (4,472 men, 2,363 women) were identified from 21,226,181 cancer-free beneficiaries of NHI in 2000. Mean age was 46.96 years in men and 41.27 years in women. After a median follow-up of 11 years, cancer was diagnosed in 527 patients with psoriasis and 860,084 in the general population. The most common cancers sites were gastrointestinal tract, oral cavity and pharynx in patients with psoriasis. The overall incidence of cancer was higher in psoriasis patients than the general population (6.92 vs. 3.34 cases per 1,000 patient-years, P Conclusions Compared with the general population, psoriasis patients have an increased risk for cancer. Disclosure of Interest None declared

Background Hydroxychloroquine is a disease-modifying anti-rheumatic drug for patients with Sjogren9s syndrome who have an increased risk of malignancies, particularly lymphoma. Inhibition of systemic inflammation and autophagy by hydroxychloroquine has been linked to antineoplastic effects but there is a lack of evidence on the effect of hydroxychloroquine on the risk of cancers in patients with Sjogren9s syndrome. Objectives This study aimed to explore the effect of hydroxychloroquine on the risk of cancers in patients with Sjogren9s syndrome. Methods We compared cancer incidence in incident patients with Sjogren9s syndrome who received hydroxychloroquine for at least 6 months within one year or three years to those did not using the Taiwan National Health Insurance Research Database. Landmark analysis was used to account for immortal time bias and propensity score matching was used to control for potential effects of known confounders. Results Of 4,262 Sjogren9s syndrome patients was identified between 2000 to 2005, we included 4,175 patients who were alive and did not have cancer at one year from initial diagnosis of Sjogren9s syndrome. The propensity score matched 1,141 patients who exposed to 6 months of hydroxychloroquine prescription on the date 1 year from the initial diagnosis and 1,141 patients who was not exposed to hydroxychloroquine. The median follow year was 6 years from one-year landmark. There were 71 hydroxychloroquine users and 56 non-hydroxychloroquine users had cancer during the follow-up. The hazard ratio for cancer was 1.31 (95% confidence interval [CI], 0.92–1.86) in the one year landmark analysis. We further conducted three-year landmark analysis and 6-month hydroxychloroquine exposure was associated with a hazard ratio of 1.33 (95% CI, 0.98–1.81) in the three-year landmark analysis between hydroxychloroquine users and non-hydroxychloroquine users, was 1.31 (0.92–1.86) in the one landmark analysis. There was no difference in overall survival based on Kaplan-Meier estimates between hydroxychloroquine user and non-users in both the one-year (log-rank test p=0.15) and three-year landmark analysis (log-rank test p=0.09). Conclusions This propensity score matched landmark analysis in a population of incident patients with Sjogren9s syndrome in Taiwan found a neutral effect of 6-month hydroxychloroquine treatment early in the clinical course on the risk of cancer, but whether a higher dose or an longer exposure to hydroxychloroquine could influence the risk of cancer remains to be determined. Disclosure of Interest None declared

Background Psoriasis is a known risk factor of cardiovascular disorders in addition to traditional risk factors such as diabetes mellitus (DM). However, the association between psoriasis and DM is unclear. Objectives To quantify the risk by comparing the incidence of DM between patients with psoriasis and the general population in Taiwan. Methods The study cohort consisted of two populations. The first population is the whole patients first diagnosed with psoriasis in 2000 in Taiwan, and the second population is a nationally representative cohort of 1,000,000 individuals from the Longitudinal Health Research Database in 2000. Those who younger than age of 10 or had DM before 2000 were excluded from analysis. They were followed from 2000 until the occurrence of DM, death or 31 December 2012. Incidence rates of DM were calculated. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for DM, adjusted for age, gender and pre-existing comorbidity. Results The study cohort comprised 756,333 subjects with a mean follow-up of 11.27 years; among them 15,099 patients with incident psoriasis were identified. Patients with psoriasis had a higher comorbidity of renal disease (1.48%), congestive heart failure (0.91%), cardiac dysrhythmia (1.82%), cerebrovascular disease (2.74%) and peripheral vascular disease (0.94%) than the general population. The incidence rate for DM was 2.04 (95% CI, 2.01–2.08) per 100 person-years for psoriasis patients comparing to 1.10 (95% CI 1.03–1.16) per 100 person-year in the general population. The adjusted IRR of incident DM was 1.34 (95% CI 1.29–1.38) for patients with psoriasis. Conclusions Patients with psoriasis has an increased risk for DM. A vigilant monitoring for DM in patients with incident psoriasis is warranted to reduce long-term cardiovascular risks. Disclosure of Interest None declared

Nationwide data on the epidemiology of dermatomyositis (DM) and polymyositis (PM) were limited.This study was to estimate the incidence, occurrence of cancer and mortality of DM and PM in Taiwan.Both the register of critical illness of the Taiwan National Health Insurance Research Dataset and the National Death Registry of Taiwan were used to calculate estimates of the incidence, cancer association, and mortality of DM and PM between 2003 and 2007.A total of 803 DM and 500 PM cases were identified between 2003 and 2007. Mean age at diagnosis was 44·0 ± 18·3 years for DM and 49·2 ± 15·9 years for PM. The overall annual incidences of DM and PM were 7·1 (95% CI 6·6-7·6) and 4·4 (95% CI 4·0-4·8) cases per million population. The incidence of both DM and PM increased with age and reached a peak at age 50-59 years. One hundred and eleven (13·8%) patients with DM and 31 (6·2%) patients with PM had cancers. The diagnosis of most cancers was made after the diagnoses of DM (n = 71; 64·0%) and PM (n = 21; 67·7%). Overall, the standardized incidence ratios (SIR) for cancer were 5·36 (4·12-6·87) and 1·80 (1·10-2·79) among patients with DM and PM; however, during the first year, SIRs for cancer were 24·55 (95% CI 18·62-31·79) and 9·17 (95% CI 14·82-15·93) in patients with DM and PM, respectively. The most common types of cancer were nasopharyngeal cancer for men and breast cancer for women. Patients with DM and PM had standardized mortality ratios of 7·68 (6·41-9·01) and 5·29 (4·28-6·48).This study reports robust estimates of important aspects of the epidemiology of both DM and PM in Taiwan. This highlights the rarity of these diseases, and their associated cancer risks and increased mortality.

Steep growth in location-based services and applications, riding on the wave of the mobile market, is expected in years to come. GPS/GALILEO engines embedded in cellular phones will allow network-based positioning, such as the GSM network and WCDMA network, to be implemented. However, challenging issues have to be overcome before the integration can be done successfully. This paper will discuss about the single RF front-end GPS equipped with GALILEO capability, designed to be integrated into an embedded system, such as the cellular phone. The receiver architecture is selected to have the flexibility for integrating into a larger system.

A high performance RFCMOS SoC GPS navigation solution is introduced. It supports various location and navigation applications, including autonomous GPS, SBAS, DGPS (RTCM), and AGPS in L1-band at 1575.42MHz. A wide range of reference frequencies are supported to comply with other handheld specifications. The base-band architecture is optimized for the correlation efficiency and the power consumption of one single correlating operation. Hence this SoC receiver achieves the industry's highest levels of sensitivity, accuracy, and Time-to-First-Fix (TTFF) with the lowest power consumption. PMIC is also integrated in the SoC, no external LDO and power switching circuit is needed for all voltage domains, including RTC.

Low resistivity and high transparent ITO, RuO x (1lxl2) and TiW ohmic contacts to ZnO film was achieved by RF sputter system and annealing treatment. The transmittance of 450°C-annealing ITO, 650°C-annealing Ru and 200°C-annealing TiW were measured to be 94, 68 and 61%, with wavelength of 400 nm, respectively. Moreover, the specific contact resistance of 450°C-annealing ITO, 650°C-annealing Ru and 200°C-annealing TiW on ZnO films was estimated to be 2.15x10 -4 , 2.72x10 -4 and 2.56x10 -4 O-cm 2 by circular transmission line model (CTLM) method, respectively. In the study of ZnO-based photodiodes, high quality and vertical well-aligned ZnO nanowires were selectively grown on ZnO:Ga/glass templates by vapor-liquid-solid method. Ultraviolet (UV) photodetectors using these vertical ZnO nanowires were also fabricated by spin-on-glass technology. With 2 V applied bias, it was found that dark current density of the fabricated device was only 3.8x10 -9 A/cm 2 . It was also found that UV-to-visible rejection ratio and quantum efficiency of the fabricated ZnO nanowire photodetectors were more than 1000 and 12.6%, respectively.

Adipocyte determination and differentiation-dependent factor 1 (ADD1) drives the expression of several lipogenic genes in mammals. Polyunsaturated fatty acids decrease ADD1 mRNA abundance in differentiating porcine adipocytes. The current study was designed to explore the mechanisms by which PUFA inhibit the expression of ADD1 in porcine adipocytes. Porcine preadipocytes were differentiated for 24 h with 0 or 100 microM of docosahexaenoic acid (DHA) and mixtures of different concentrations of antioxidants to investigate the effect of DHA and antioxidants on the ADD1 mRNA abundance. We found the relative mRNA abundance was decreased by the addition of 100 microM DHA to the medium for porcine differentiating adipocytes, and adding an antioxidant mixture to the medium prevented part of the decrease in ADD1 mRNA abundance. These data suggest that DHA decreased the steady-state transcription factor ADD1 mRNA through a mechanism related to fatty acid peroxidation. Indeed, adding 7.5 microM vitamin E (a natural antioxidant) also restored the concentrations of ADD1 and fatty acid synthase mRNA, which were decreased by DHA treatment; however, the DHA or the antioxidant treatment did not change the expression of antioxidation genes (superoxide dismutase 1 and glutathione peroxidase 1) in porcine stromal vascular cells. When supplemented with the eicosanoid synthesis pathway inhibitors, the inhibition of the expression of ADD1 by arachidonic acid was partially recovered. These results suggest that the mechanism by which PUFA decrease ADD1 mRNA is due to the metabolic product of eicosanoids and peroxidation of these PUFA.

The aim of this prospective randomized multicenter study was to find out if there is one or several promising regimens containing lansoprazole with various combinations of antibiotics which have a high eradication rate of Helicobacter pylori, few side-effects, good patient compliance, and relative low cost if possible. Two hundred and ninety-seven patients with H. pylori positive duodenal ulcer were enrolled and randomly allocated into one of the five treatment groups: 1) group A: received lansoprazole 30 mg once daily for 2 weeks plus amoxicillin (AM) 500 mg and metronidazole (MZ) 500 mg twice daily for one week in the first week; 2) group B: the AM in group A was replaced by clarithromycin (CM) 250 mg; 3) group C: the MZ in group A was replaced by CM 250 mg; 4) group D: the AM and CM in group C was used for 2 wk; 5) group E: the CM in group D was doubled to 500 mg twice daily. All patients received endoscopies pre- and 4-6 weeks post termination of treatment. H. pylori was detected by culture, histology and rapid urease test (CLO test). 13C-urea breath test was performed if the patients refused the second endoscopy. The E-test was adopted to evaluate the MZ and CM resistance of H. pylori. Totally, 253 patients completed the study. The eradication rate of groups A, B, C, D and E were 75%, 80%, 78%, 92%, and 96%, respectively. The eradication rate of group E was significantly higher than that of groups A, B, or C. There were no significant differences of eradication rates between the groups D and E. Sixty-seven cases (28.8%) were MZ-resistant. The difference of eradication rates between MZ-S and MZ-R patients was significant in group A (85.3% vs. 42.9%) and in the combination of groups A and B (83.8% vs. 59.4%). Good compliance (defined as taking90% of medications) was seen in more than 90% of cases in each group. Triple therapy containing lansoprazole 30 mg once daily, AM 500 mg and CM 250 mg twice daily for two weeks is a promising regimen which reaches a high eradication rate, avoids MZ resistance, and has very good patient compliance at an acceptable cost.

Dengue virus infection causes a wide range of diseases from dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). The mechanisms involved in DHF/DSS pathogenesis remain unclear. Patient sera collected from an outbreak in southern Taiwan from November 1998 to January 1999 were studied. The presence of antibodies which cross-reacted with platelets could be detected in patient sera, and the isotype of these autoantibodies was IgM. The anti-platelet IgM levels were higher in DHF/DSS than in dengue fever patient sera in disease acute phase. These autoantibodies were still detectable in convalescent stage (1-3 weeks after acute phase) and even eight to nine months after illness. The platelet binding activity was not observed in other virus-infected patient sera tested. Further investigation showed that dengue patient sera caused platelet lysis in the presence of complement. The platelet cytotoxicity induced by DHF/DSS patient sera was higher than that by dengue fever sera. Dengue patient sera also inhibited platelet aggregation which, however, appeared to be not related to DHF/DSS development.

Inflammatory fibroid polyp of jejunum is a very rare nonneoplastic lesion of gastrointestinal tract. We reported a 66-year-old male who presented with abdominal fullness, colicky pain, and vomiting for 4 days. Plain abdomen showed intestinal obstruction with dilated small bowel loops. The exploratory laparotomy was performed under the clinical impression of intussusception caused by small bowel tumor. The diagnosis of an inflammatory fibroid polyp causing jejunojejunal intussusception was confirmed after surgery.

Arsenic, a human carcinogen, possesses a serious environmental threat but the mechanism of its toxicity remains unclear. Knowledge of how arsenic induces cell death and how cells escape the death path may help to understand arsenic carcinogenesis. We have investigated the nature of sodium arsenite-induced cell death in Chinese hamster ovary K1 cells. Following phosphate-citric acid buffer extraction, apoptotic cells with lower DNA content than the G1 cells were detected by flow cytometry. Immediately after 4 h of 40 microM arsenite treatment, no appreciable fraction of cells with sub-G1 DNA content was detected; however, the sub-G1 cell fraction increased with postarsenite incubation time, and detectable increase started at 8 h of incubation, whereas the intracellular peroxide level as measured by the fluorescent intensity of 2',7'-dichlorofluorescein increased immediately following a 4-h arsenite treatment. Simultaneous treatment with arsenite plus antioxidant (N-acetyl-cysteine, Trolox, and Tempo); copper ion chelator (neocuproine); protein kinase inhibitor (H-7) or protein synthesis inhibitor (cycloheximide) reduced the fraction of sub-G1 cell and internucleosomal DNA degradation. Trolox, neocuproine, or cycloheximide given after arsenite treatment also effectively reduced apoptosis. These results lead to a working hypothesis that arsenite-induced apoptosis in CHO-K1 cells is triggered by the generation of hydrogen peroxide, followed by a copper-mediated Fenton reaction that catalyzes the production of hydroxyl radicals, which selectively activates protein kinase through de novo synthesis of macromolecules.

Conditions promoting oxidative stress, which is implicated in many diseases, activate phospholipases A2, a family of enzymes central to phospholipid metabolism and signal transduction. Little is known about isozyme specificity with respect to this activation process. Accordingly, a dietary deficiency model known to induce oxidative stress was used to investigate phospholipase A2 isozyme activity in rat tissues. Long-Evans hooded rats were fed purified diets for 6 wk with or without the addition of vitamin E and selenium in a 2 x 2 factorial design. Phospholipase A2 activity was assessed in lung, liver, kidney and heart cytosol and microsomes in the presence (5 mmol/L CaCl2) or absence (5 mmol/L EGTA) of calcium with dipalmitoylphosphatidylcholine at pH 6.5. Lung phospholipase A2 activity was also assessed with 1-stearoyl-2-arachidonoylphosphatidylcholine as substrate at pH 8.5. Organ samples from rats deficient in both nutrients showed two- to tenfold higher calcium-independent phospholipase A2 activity in lung cytosol and microsomes, and in liver cytosol compared with samples from control and single nutrient-deficient rats. In contrast, the calcium-dependent activity was affected only slightly. The malondialdehyde concentration of the organs was measured and the pattern obtained mirrored that of enhanced phospholipase A2 activity for lung but not for liver. The enhanced phospholipase A2 activity in the lung cytosol and microsomes from rats deficient in both nutrients was partially blocked by p-bromophenacylbromide, further enhanced by dithiothreitol and unaffected by treatment with diisopropylfluorophosphate. These results suggest that deficiency of both vitamin E and selenium activates and/or induces unique calcium-independent forms of phospholipase A2 markedly in rat lung, and to a lesser extent in liver.

Gallium nitride (GaN) ultraviolet metal-semiconductor-metal photodetectors (PDs) grown on Si substrates were demonstrated. The dark current of PDs fabricated on Si substrates was substantially smaller in magnitude compared to identical devices prepared on sapphire substrates. With an incident wavelength of 359nm, the maximum responsivities of the n−‐GaN MSM photodetectors with TiW and Ni∕Au contact electrodes were 0.187 and 0.0792A∕W, corresponding to quantum efficiencies of 64.7% and 27.4%, respectively. For a given bandwidth of 1kHz and a given bias of 5V, the corresponding noise equivalent powers of our n−‐GaN MSM photodetectors with TiW and Ni∕Au electrodes were 1.525×10−12 and 5.119×10−12W, respectively. Consequently, the values of detectivity (D*) determined for devices with TiW and Ni∕Au electrodes were then calculated to be 1.313×1012 and 3.914×1011cmHz0.5W−1, respectively.

We report the fabrication of epitaxial ZnO photoconductive sensors on sapphire substrates. With an incident light wavelength of 370 nm and a 5 V applied bias, we achieved a sensor responsivity of 20.5 mA/W. It was also found that low-frequency and high-frequency noises in the fabricated sensors were dominated by I/f type and shot noises, respectively. With a 5 V applied bias, it was found that noise equivalent power and normalized detectivity of the fabricated sensors were 1.83 X 10 -6 W and 6.91 X 10 5 cm Hz 0.5 W -1 , respectively.

Vertically well-aligned ZnO nanowire ultraviolet (UV) photodetectors were fabricated by spin-on-glass technology on ZnO:Ga/glass templates. With 2V applied bias, it was found that dark current density of the fabricated device was only 2.0×10−7A∕cm2. It was also found that UV-to-visible rejection ratio and quantum efficiency of the fabricated ZnO nanowire photodetectors were more than 1000 and 12.6%, respectively.

To identify the kinds of cells in the brain that express the yes proto-oncogene, we examined chicken brains by using immunofluorescent staining and in situ hybridization. Both approaches showed that the highest level of the yes gene product was in cerebellar Purkinje cells. In addition, we analyzed Purkinje cell degeneration (pcd) mutant mice. The level of yes mRNA in cerebella of pcd mutants was four times lower than that found in cerebella of normal littermates. Our studies point to Purkinje cells as an attractive model for functional studies of the yes protein.