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Objective To compare the risk of blindness and vision-threatening ocular comorbidities in patients with Behçet’s disease (BD) vs the general population. Methods Using 2002–2017 Korea National Health Insurance Service database, we did a population-based cohort study comparing newly diagnosed BD patients and age- and sex-matched non-BD controls at a 1:5 ratio. The primary outcome was blindness, defined as a best-corrected visual acuity of ≤20/500 in the better-seeing eye. Secondary outcomes were vision-threatening ocular comorbidities (cataract, glaucoma and retinal disorders) that require surgical interventions and incident uveitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. We performed subgroup analyses by sex and BD diagnosis age. Results We included 31 228 BD patients and 156 140 controls. During a follow-up of 9.39 years, the incidence rate of blindness per 1000 person-years was 0.24 in BD and 0.02 in controls with an HR of 10.73 (95% CI 7.10, 16.22). The HR for secondary outcomes was 2.06 (95% CI 1.98, 2.15) for cataract surgery, 5.43 (4.57, 6.45) for glaucoma surgery and 2.71 (2.39, 3.07) for retinal surgery. The HR of incident uveitis was 6.19 (95% CI 5.83, 6.58). Males suffered a disproportionately higher risk of blindness than females due to greater severity rather than a lower incidence of uveitis. The risk of uveitis and blindness decreased as BD diagnosis age increased. Conclusions In this large population-based cohort study, BD patients compared with the general population have a 10.73-fold risk of blindness in 10 years and also a substantially higher risk of diverse ocular comorbidities that pose potential threats to vision.

Flaviviruses are a family of viruses that cause many diseases in humans. Their similarity in the antigenic structure causes a cross-reaction, which complicates the precise diagnostic of disease causing agents. Tick-borne encephalitis virus (TBEV), a member of the flavivirus family, is the cause of tick-borne encephalitis (TBE). Worldwide the awareness of this disease is raising, however, in many countries such as the Republic of Kazakhstan (KZ) there is a lack of serological investigation of flaviviruses in humans. In our study, we focused on two TBE endemic regions of KZ (East Kazakhstan Oblast (EKO) and Almaty (AO)) and a region where TBE cases were registered only since 2010 (Akmola Oblast (AkO)). In KZ, up to 400 cases of serous meningitis of unknown origin were registered annually in the period from 2017 to 2019. Our goals were to calculate the prevalence of antibodies against TBEV in patients with suspected meningitis. We collected 179 sera and 130 cerebrospinal fluid (CSF) samples from patients and included a questionnaire with focus on socio-demographical factors and observed tick bites. The human samples were tested with TBEV and West-Nile fever virus (WNFV) IgM and IgG ELISA, by immunofluorescence assay using a flavivirus biochip, and TBEV-specific real-time RT-PCR. We found TBEV and WNFV antibodies in 31 samples by serological and molecular techniques. Seven serum samples out of 31 showed TBEV-specific antibodies, and three serum pairs had WNFV antibodies. Correlating the serological results with the information gained from the questionnaires it becomes apparent that the number of tick bites is a significant factor for a TBEV infection. This result has an impact on diagnostic in KZ and physicians should be aware that both flaviviruses play a role for serous meningitis of unknown origin in KZ.

Undifferentiated febrile illness still represents a demanding medical problem all over the world, but primarily in low- and middle-income countries. Scientific and clinical investigations related to undifferentiated febrile illness and rickettsial diseases in Kazakhstan are lacking. This study reflects the investigation of antibodies against spotted fever group (SFG) and typhus group (TG) rickettsiae in patients with undifferentiated febrile illness in the southern region of Kazakhstan (Almaty and Kyzylorda oblasts). Paired serum samples were gathered from 13 hospitals in these two oblasts and explored for the presence of IgM and IgG antibodies against typhus group and IgG antibodies against spotted fever group rickettsiae using ELISA. Patient’s questionnaires were statistically analyzed. In total, 802 inpatients from Almaty (N = 9) and Kyzylorda (N = 4) hospitals were included in this research. Based on ELISA results, 250 patients out of 802 (31.2%) from both oblasts had IgG antibodies against SFG rickettsiae. Results from 11 (1.4%) patients indicated acute infection with tick-borne rickettsiosis. Regarding TG rickettsiae (R. typhi), a past infection was detected in 248 (30.9%) febrile patients and acute infection in 22 (2.7%) patients in the two selected oblasts. The data indicated that SFG and TG rickettsioses are present in Kazakhstan. Kazakh physicians should be aware of these emerging diseases in both investigated oblasts because the occurrence of these diseases is not suspected during day-to-day clinical practice. The identification of rickettsial pathogens and implementation of modern laboratory methods for the diagnostics of rickettsioses are in need throughout Kazakhstan.

Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotional disorders, which can pave the way for new interventions by targeting cortical asymmetry. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00802-w.

Objectives We aimed to compare tuberculosis (TB) risk during biologics treatment between patients with RA who did (prophylaxis) and did not (non-prophylaxis) undergo chemoprophylaxis following pre-biologic latent TB screening in Korea of an intermediate TB burden. Methods Using the 2002–16 Korea National Health Insurance database, we conducted a cohort study examining TB risk, defined by International Classification of Diseases Tenth Revision codes plus anti-TB drugs, among RA patients initiating a biologic drug with and without chemoprophylaxis after screening triage for latent TB. To control baseline confounding, we used propensity score-based fine stratification (PSS) and weighting. Cox proportional hazards models estimated hazard ratios and 95% CIs comparing TB risk between the prophylaxis vs non-prophylaxis groups. Results The PSS-weighted study cohort (mean age 57.0 years; 81.3% female) included 2249 and 7225 RA patients in the prophylaxis and non-prophylaxis groups, respectively. During 2.42 years of biologics treatment, 118 patients developed TB with the incidence rate per 100 person-years of 0.33 in the prophylaxis and 0.63 in the non-prophylaxis groups. The PSS-weighted hazard ratio (95% CI) for TB associated with the prophylaxis was 0.52 (0.32, 0.86). During the follow-up time, the incidence rate of TB remained consistently low in the prophylaxis group but it was highest in the first year, then time-dependently declined in the non-prophylaxis group. Conclusion This population-based cohort study warns that the current screening-based preventive strategy generates a substantially higher TB risk after biologics initiation among screening-negative patients compared with screening-positive patients receiving chemoprophylaxis, when the background TB burden is not low.

In this population-based cohort study on comparative osteoporotic fracture risks between different biologic disease-modifying drugs among patients with rheumatoid arthritis (RA), we did not find a significant difference in the risk of osteoporotic fractures between RA patients receiving TNF inhibitors versus abatacept or tocilizumab. We aimed to investigate the comparative risk of osteoporotic fractures between rheumatoid arthritis (RA) patients who initiated TNF inhibitors (TNFis) versus abatacept or tocilizumab. Using the Korea National Health Insurance Service datasets from 2002 to 2016, RA patients who initiated TNFis, abatacept, or tocilizumab were identified. The primary outcome was a composite end point of non-vertebral fractures and hospitalized vertebral fractures; secondary outcomes were two components of the primary outcome and fractures occurring at the humerus/forearm. Propensity score (PS) matching with a variable ratio up to 10 TNFi initiators per 1 comparator drug initiator was used to adjust for > 50 baseline confounders. We estimated hazard ratios (HRs) and 95% confidence interval (CI) of fractures comparing TNFi initiators to abatacept and to tocilizumab by Cox proportional hazard models stratified by a matching ratio. After PS-matching, 2307 TNFi initiators PS-matched on 588 abatacept initiators, and 2462 TNFi initiators on 640 tocilizumab initiators were included. A total of 77 fractures occurred during a mean follow-up of 454 days among TNFi and abatacept initiators and 83 fractures during 461 days among TNFi and tocilizumab initiators. The PS-matched HR (95% CI) was 0.91 (0.48–1.71) comparing TNFi versus abatacept initiators, and 1.00 (0.55–1.83) comparing TNFi versus tocilizumab initiators. Analysis on vertebral and non-vertebral fractures showed similar results. In this nationally representative cohort, we did not find a significant difference in the risk of fractures between TNFi initiators versus abatacept or tocilizumab among RA patients.

To re-evaluate comparative cardiovascular (CV) safety of febuxostat versus allopurinol among patients with gout following recent accumulated use of febuxostat.Using 2011-2019 Korea National Health Insurance database, we conducted a cohort study comparing gout patients initiating febuxostat versus allopurinol, 1:1 matched on a propensity-score (PS) for60 covariates. The primary outcome was a composite endpoint of myocardial infarction, coronary revascularization, and stroke. Secondary outcomes were individual components of the primary outcome, hospitalized heart failure, and all-cause mortality. Subgroup analyses were done for those at high CV risk, long-term users (follow-up3 years), and those without chronic kidney disease. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).We included 160,930 PS-matched pairs of febuxostat and allopurinol users (mean age 59.3 years, 79.6% male). Incidence rates of the primary outcome were 2.06 and 2.27 per 100 person-years for febuxostat and allopurinol users, respectively, with a HR [95% CI] of 1.03 [0.95-1.12] comparing febuxostat versus allopurinol initiators. We also observed similar risks for secondary outcomes, except for reduced all-cause mortality among febuxostat users (HR [95% CI] of 0.84 [0.78-0.91]). Subgroup analyses also showed non-inferior CV safety of febuxostat.In this population-based cohort study including the largest number of febuxostat users to date, we found non-inferior CV safety of febuxostat versus allopurinol. There was a 16% reduction in all-cause mortality among febuxostat users.

To examine the association between sarcopenia and comorbidities among patients with rheumatoid arthritis (RA).We selected RA patients and age- and sex-matched non-RA controls at a 1:5 ratio from 2008-2011 Korea National Health and Nutrition Examination Survey database. Sarcopenia was defined by appendicular skeletal muscle mass. After investigating associations between sarcopenia and individual comorbidities among RA patients, we performed a stratified analysis comparing three subgroups (RA/sarcopenia, RA/non-sarcopenia, non-RA/sarcopenia) versus a non-RA/non-sarcopenia subgroup to evaluate interactive as well as independent effects of sarcopenia and RA on comorbidities. Health-related behaviors (exercise, smoking, drinking, and diet) were also examined. The weighted logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, sex, and income.We included 400 RA patients and 2,000 non-RA controls (mean age 57.4 years, 79.6% female). Sarcopenia was observed in 20.5% of RA and 19.3% of non-RA group. Among RA patients, sarcopenia was associated with obesity (OR 2.61, 95% CI 1.42-4.83), dyslipidemia (3.09, 1.37-6.99), diabetes (2.07, 0.99-4.33), chronic obstructive pulmonary disease (18.77, 2.40-146.55), and hepatitis B ever-infection (8.69, 1.15-65.58). Among three stratified subgroups, only a RA/sarcopenia subgroup was associated with such comorbidities, cardiovascular diseases, and depression compared to a non-RA/non-sarcopenia subgroup. Health-related behaviors were comparable between patients with and without sarcopenia.In this nation-wide cross-sectional study, a wide spectrum of comorbidities were preferentially found among RA patients with sarcopenia than without, suggesting that sarcopenia is significantly associated with RA-related comorbidities. Particular attention should be paid to comorbidities of sarcopenic RA patients.

Artificial intelligence (AI) is an emerging tool for high-resolution behavioural analysis and conduction of human-free behavioural experiments. Here, we applied an AI-based system, AVATAR, which automatically virtualises 3D motions from the detection of 9 body parts. This allows quantification, classification and detection of specific action sequences in real-time and facilitates closed-loop manipulation, triggered by the onset of specific behaviours, in freely moving mice.

Objective Orthohantaviruses are geographically widely distributed and present various clinical manifestations from mild symptoms to the severe form of haemorrhagic fever with renal syndrome (HFRS) in Eurasia. Official registration of HFRS in Kazakhstan started in the year 2000. However, the true prevalence of human infections by orthohantaviruses within Kazakhstan is unknown. The aim of this study was to investigate of the seroprevalence of orthohantavirus infections in patients with fever of unknown origin (FUO) in two regions, Almaty and Kyzylorda region. Methods Paired serum samples from 802 patients with FUO were screened for the presence of orthohantavirus IgG and IgM antibodies by ELISA. Positive samples were further tested by immunoblotting and indirect immunofluorescence tests (IIFT) to determine the respective orthohantavirus serotypes. Suspected acute serum samples were additionally checked by a RT-PCR to identify viral RNA. Results In total 178/802 (22.2%) serum samples reacted with orthohantavirus IgG antibodies and 4/802 (0.5%) with IgM antibodies. All positive samples were tested by immunoblotting which resulted in 2.9% positive samples with IgG antibodies against Puumala (PUUV), Hantaan (HTNV) and Dobrava (DOBV) virus serotypes in Almaty region and 5.4% to PUUV and DOBV serotypes in Kyzylorda region, respectively. In the IFFT, 1.9% positive samples from Almaty and 3.1% from Kyzylorda were confirmed for PUUV and DOBV serotypes. Out of four IgM ELISA positive samples only three were positive against PUUV in the immunoblot and showed weak positive reactivity for the Saaremaa (SAAV), PUUV and HTNV serotypes in the IFFT. Conclusions This study demonstrates the presence of orthohantavirus infections among patients with FUO in Kazakh regions that were so far considered as non-endemic. The healthcare system needs to be prepared accordingly in order to be capable of detecting cases and providing adequate management of patients.

Objective To compare cardiovascular (CV) risk among gout patients initiating allopurinol vs febuxostat. Methods Using 2002–2015 Korean National Health Insurance Service data for the entire Korean population, we conducted a cohort study on gout patients initiating allopurinol or febuxostat. The primary outcome was a composite CV end point of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. Secondary outcomes were individual components of the primary outcome, and all-cause mortality. We used propensity score-matching with a 4:1 ratio for allopurinol and febuxostat initiators to control for confounding. Competing risk analyses were done for non-fatal outcomes accounting for deaths. Results We included 39 640 allopurinol initiators propensity score-matched on 9910 febuxostat initiators. The mean age was 59.1 years and 78.4% were male. The incidence rate per 100 person-years for the primary outcome was 1.89 for allopurinol and 1.84 for febuxostat initiators. The corresponding hazard ratio comparing allopurinol vs febuxostat initiators was 1.09 (95% CI: 0.90, 1.32). No significant difference was found for the secondary outcomes, including all-cause mortality (hazard ratio 0.96; 95% CI: 0.79, 1.16). Subgroup analyses limited to those at high CV risk and to equipotent-dose initiators (i.e. allopurinol ⩾300 mg/day vs febuxostat ⩾40 mg/day) showed similar results. Conclusion Overall, this large Korean population-based study suggests no difference in the risk of non-fatal CV events and all-cause mortality between allopurinol and febuxostat initiators. These findings are consistent with the recent US Medicare population study, although the current study population consisted of younger Asians.

Objective To compare all-cause and cause-specific mortality between rheumatoid arthritis (RA) patients versus the general population of Korea. Methods A nationally representative RA population aged ≥ 40 years was identified from Korea National Health Insurance Service (KNHIS) database. We estimated age- and sex-adjusted all-cause and cause-specific standardized mortality ratios (SMRs) with 95% confidence intervals (CIs), comparing RA patients to the general population. Subgroup analyses were done by sex, age group, calendar year, and biologics use. Results We identified 79,352 RA patients with 6404 deaths during 2011–2016. The all-cause SMR [95% CI] of RA patients compared to the general population was 1.53 [1.49–1.56]. The top five causes of death were cancer (19.5%), respiratory disease (19.1%), cardiovascular disease (18.8%), systemic rheumatic diseases (9.5%, 9.1% due to RA), and infection (6.1%). Cause-specific SMRs [95% CI] were 0.95 [0.90–1.01] for cancer, 3.34 [3.15–3.52] for respiratory disease, 1.26 [1.18–1.33] for cardiovascular disease, 3.41 [3.08–3.75] for infection, and 4.88 [3.10–6.65] for non-RA systemic rheumatic disease. The SMR of RA population was slightly higher among men than women, and highest in their 60s and 70s. The yearly SMR increased from 1.10 [1.01–1.18] in 2011 to 1.85 [1.75–1.95] in 2016 due to population aging and comorbidity accumulation. Users of biologics showed a higher SMR than non-users (1.82 [1.69–1.96] vs. 1.50 [1.46–1.54]), due to higher RA activity, and more comorbidities despite a younger mean age. Conclusion RA patients in Korea experienced 1.5-fold increase in all-cause mortality compared to the general population. Except for cancer, the top five causes of death were associated with excess mortality among RA patients. RA-associated mortality was largely determined by age, RA activity, and comorbidity status.

Aims With the high prevalence of gout and associated cardiovascular (CV) diseases, information on the comparative CV safety of individual urate-lowering drugs becomes increasingly important. However, few studies examined the CV risk of uricosuric agents. We compared CV risk among patients with gout who initiated allopurinol vs. benzbromarone.Methods and results Using the Korean National Health Insurance claims data (2002–17), we conducted a cohort study of 124 434 gout patients who initiated either allopurinol (n = 103 695) or benzbromarone (n = 20 739), matched on propensity score at a 5:1 ratio. The primary outcome was a composite CV endpoint of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. To account for competing risk of death, we used cause-specific hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes comparing allopurinol initiators with benzbromarone. Over a mean follow-up of 1.16 years, 2258 patients developed a composite CV event. The incidence rate of the composite CV event was higher in allopurinol initiators (1.81 per 100 person-years) than benzbromarone (1.61 per 100 person-years) with a HR of 1.22 (95% CI 1.05–1.41). The HR for all-cause mortality was 1.66 (95% CI 1.43–1.93) among allopurinol initiators compared with benzbromarone.Conclusion In this large population-based cohort of gout patients, allopurinol was associated with an increased risk of composite CV events and all-cause mortality compared to benzbromarone. Benzbromarone may reduce CV risk and mortality in patients with gout, although more studies are necessary to confirm our findings and to advance our understanding of the underlying mechanisms.

To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX).Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi.Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results.In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.

Objective: To identify risk factors of biological disease-modifying anti-rheumatic drugs (bDMARDs) initiation in patients with rheumatoid arthritis (RA). Methods: Using the 2002-2016 Korea National Health Insurance database, we conducted a nested case-control study on seropositive RA patients. Cases (bDMARD users) and controls (users of conventional synthetic DMARDs only) were 1:4 matched on the calendar year/month of RA diagnosis and index dates (bDMARD initiation dates). Potential risk factors from two time periods, 1-year post-RA-diagnosis and 1-year pre-index, were separately assessed on the association with bDMARD initiation by conditional logistic regression analyses. Results: The study included 6,985 cases and 27,940 controls. Older age, female gender, use of methotrexate (MTX), leflunomide, or tacrolimus as a first csDMARD, higher initial MTX dose, and initial csDMARD combination during 1-year post-diagnosis were negatively associated with later bDMARD initiation, while use of sulfasalazine as a first csDMARD, corticosteroid therapy, and higher maximal MTX dose were positively associated. Among covariates from 1-year period before bDMARD initiation, use of leflunomide, sulfasalazine, or tacrolimus, parenteral MTX, higher maximal MTX dose, corticosteroid, and csDMARD combination were positively associated with subsequent bDMARD initiation. Effects of comorbidities on bDMARD initiation were heterogenous across involved systems. Conclusion: In this population-based nationwide study, we identified period-specific risk factors of bDMARD initiation among RA patients in Korea. Overall, initial aggressive RA treatment after diagnosis was associated with less use of later bDMARD, while highly intensive therapy observed just before bDMARD initiation rather reflects refractory nature of RA during this period, and did not prevent bDMARD use.

Background:Based on the benefit of chemoprophylaxis among patients receiving biologics [1], Health Insurance Review and Assessment (HIRA) service of Korea requires patients to undergo latent tuberculosis (LT) screening before initiation of any biologics and to receive chemoprophylaxis for positive LT.Objectives:To assess the effect of chemoprophylaxis on tuberculosis infection (TI) risk among patients with rheumatoid arthritis (RA) receiving biologics in KoreaMethods:Using 2002-2016 Korea National Health Insurance database, we conducted a cohort study on RA patients initiating biologic drugs (TNF inhibitors, abatacept, tocilizumab) to compare TI risk between those who started isoniazid and/or rifampin within 1 year before biologics initiation (prophylaxis group) versus those who did not (non-prophylaxis group). TI was defined by ICD10 codes plus anti-tuberculosis medications as previously described [2]. Patients were followed-up from biologics initiation to censoring events (TI occurrence, death, biologics discontinuation, initiation of anti-tuberculosis drug due to non-TI cause, and end of database). To control >50 baseline confounders, we used propensity score (PS)-based fine stratification and weighting. A weighted Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs).Results:Before PS stratification (PSS) and weighting, we identified 2,250 and 7,259 RA patients for prophylaxis and non-prophylaxis group, respectively. Mean age was 57.6 years and 81.3% female. Three-fourths of patients in the prophylaxis group completed >70% of recommended treatment periods [3]. The incidence rate of TI per 100 person-years was 0.33 for prophylaxis group versus 0.57 for non-prophylaxis group. 28% of all TI cases (n=34) were extra-pulmonary with gastrointestinal (n=11) and miliary TI (n=9) being most common. The PSS-weighted HR (95% CI) of TI comparing prophylaxis versus non-prophylaxis group was 0.52 (0.32-0.86) (Table 1, Figure 1). Sensitivity analyses showed that the chemoprophylaxis was particularly effective for those with younger age (Table 1.Comparative risk of tuberculosis infection between prophylaxis versus non-prophylaxis groupCrudePSS-weightedNEventsPYIR per100 person-yearsHR (95% CI)Primary as-treated analysis1TotalP2,250185,5320.330.52 (0.32-0.86)NP7,25910017,5030.64ITT analyses11 year ITTP2,250102,1150.470.33 (0.17-0.64)NP7,259976,8331.422 year ITTP2,250213,9070.540.49 (0.31-0.78)NP7,25914012,6981.104 year ITTP2,250316,3050.490.56 (0.38-0.82)NP7,25918121,2780.88Sensitivity AnalysesAge P1,75194,5880.200.39 (0.19-0.78)NP5,3457213,6340.52MaleP54621,3190.150.12 (0.03-0.50)NP1,235282,6241.33Comorbidity score ≥3P82461,9080.310.34 (0.15-0.79)NP2,668526,1290.941As-treated analysis censored patients when they discontinued biologics use, while ITT analysis did not.IR=incidence rate; ITT=intention-to-treat; HR=hazard ratio; PSS=propensity-score stratification; CI=confidence interval; PY=person-years; P=prophylaxis group; NP=non-prophylaxis groupConclusion:We found 48% risk reduction of TI by chemo-prophylaxis among RA patients receiving biologics. Due to HIRA requirements, a majority of non-prophylaxis group were considered negative for LT by screening at biologics initiation [4]. These findings indicate that the risk of TI during bDMARD treatment is still high among RA patients who were negative for LT at baseline but did not undergo chemoprophylaxis, which is double the risk among RA patients who had LT and underwent chemoprophylaxis.References:[1]Carmona L et al. Arthritis Rheum. 2005;52:1766-72.[2]Lee J et al. Ann Am Thorac Soc. 2017;14:690-697.[3]https://www.cdc.gov/tb/topic/treatment/ltbi.htm[4]Kim ES et al. World J Gastroenterol. 2015;21:3308-16.Disclosure of Interests:None declared

Electronic Health (eHealth) is the use of information and communication technologies for health and plays a significant role in improving public health. The rapid expansion and development of eHealth initiatives allow researchers and healthcare providers to connect more effectively with patients. The aim of the CIHLMU Symposium 2020 was to discuss the current challenges facing the field, opportunities in eHealth implementation, to share the experiences from different healthcare systems, and to discuss future trends addressing the use of digital platforms in health. The symposium on eHealth explored how the health and technology sector must increase efforts to reduce the obstacles facing public and private investment, the efficacy in preventing diseases and improving patient quality of life, and the ethical and legal frameworks that influence the proper development of the different platforms and initiatives related to the field. This symposium furthered the sharing of knowledge, networking, and patient/user and practitioner experiences in low- and middle-income countries (LMIC) in both public and private sectors.

Background: Rheumatoid arthritis (RA) is associated with an increased risk of osteoporosis and osteoporotic fracture, but little is known about comparative risk of osteoporotic fractures between biologic agents. Objectives: To investigate the comparative risk of osteoporotic fractures among RA patients who initiated TNF inhibitors, abatacept, and tocilizumab. Methods: We identified patients aged ≥ 40 years with at least two ICD-10 diagnosis codes for RA who initiated TNF inhibitor, abatacept, or tocilizumab from the 2005-2015 Korean National Health Insurance Service datasets. The primary outcome was a composite osteoporotic fracture endpoint of spine, hip, forearm or humerus fractures requiring hospitalization. Secondary outcomes were spinal and non-spinal fractures. Follow-up period started from the day after the first dispensing date of the study drug to the earliest date among the following events: discontinuation of the study drugs, outcome occurrence, disenrollment, end of study dataset, or death. Propensity score (PS) matching with a variable ratio of 10:1 was conducted for TNF inhibitor versus abatacept initiators and for TNF inhibitor versus tocilizumab initiators to adjust for baseline confounding. We estimated hazard ratio (HR) and 95% confidence interval (CI) of osteoporotic fracture risks comparing TNF inhibitors to abatacept or tocilizumab by Cox proportional hazard models stratified by a matching ratio. Results: We included 2,339 TNF inhibitor initiators and 594 abatacept initiators, and 2,486 TNF inhibitor initiators and 647 tocilizumab initiators in each PS-matched cohort. The incidence rates per 100 person-years for the primary outcome were 1.57 and 1.65 for TNF inhibitor and abatacept initiators, and 1.69 and 2.05 for TNF inhibitor and tocilizumab initiators, respectively. The HR (95% CI) for the primary outcome was 1.10 (1.54-2.23) comparing TNF inhibitors versus abatacept and it was 1.00 (0.53-1.92) comparing TNF inhibitor versus tocilizumab initiators. We also did not find any significant difference for secondary outcomes (Table1). Conclusion: We did not find a significant difference in the risk of osteoporotic fractures between TNF inhibitor and abatacept initiators, or between TNF inhibitor and tocilizumab initiators in this Korean population-based cohort study. Disclosure of Interests: None declared

Background Limited data are available on whether patients with rheumatoid arthritis (RA) are treated with conventional disease-modifying anti-rheumatic drugs (cDMARDs) according to the current recommendations before they initiate biologic DMARDs (bDMARDs) or JAK inhibitors (JAKis). Objectives We examined the treatment patterns among Korean RA patients who received bDMARDs or JAKis in a real world setting, using the 2002-2016 Korean National Health Insurance Service database that covers the entire Korean population. Methods We identified RA patients who initiated bDMARDs (TNF inhibitor, abatacept, rituximab and tocilizumab) or JAKis (tofacitinib). Their treatment patterns during 1 year after RA diagnosis (defined as free of any RA diagnosis or any DMARD use for one year before the diagnosis) and prior to the initiation of index drugs (bDMARDs or JAKis) were examined regarding: initial cDMARD used, dose and parenteral use of methotrexate (MTX), use and time to combination therapy of cDMARDs, and steroid use. Results 10,145 RA patients were identified who used index drugs from the database (mean age 57 years, 82% female). Among them, 6,986 patients had identifiable dates for RA diagnosis (mean age 57 years, 79% female). The mean (SD) duration from RA diagnosis to index drug initiation was 1,425 (1,162) days with 1,509 (22%) patients having a duration ≤1 year. At diagnosis, the most common 1st cDMARD used was hydroxychloroquine (63%), followed by MTX (55%) and sulfasalazine (29%) with steroids used in 75%. During the 1 year from the diagnosis, 85% of patients eventually used MTX, 42% ever used MTX ≥ 15mg/week, only 3% used parenteral MTX, and 85% patients used combined cDMARDs with a mean 188 days from the RA diagnosis to combination therapy. Patients whose maximal MTX dose reached 20mg/week were rare (9%) and 62% were still on steroid after 1 year. During the 1 year prior to the index drug use (n = 10,145), the most common cDMARD was MTX used in 89% patients with 46% who ever used ≥ 15mg/week and 4% of parenteral users, followed by hydroxychloroquine (55%), leflunomide (52%), sulfasalazine (38%), and tacrolimus (20%). All patients used combination therapy and 98% steroids. Conclusion These data indicate that a substantial proportion of RA patient did not try maximal dose or parenteral use of MTX during the 1 year post-diagnosis as recommended by the current treatment guideline. Instead, they often used cDMARDs combination therapy. During the 1 year before initiating bDMARDs or JAKis, they were treated with intensive cDMARD combination therapy rather than escalating their MTX dose. Reference [1] Smolen, Josef S., et al. “EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.” Annals of the rheumatic diseases 76.6 (2017): 960-977. Disclosure of Interests None declared

Animals use visual information to recognize the value of objects and respond with different behaviours, such as evasion or approach. While rodents show defensive behaviour toward an artificial looming stimulus that mimics an approaching avian predator, the visual feature that attracts them to targets with positive value, such as prey, remains unclear. Here, we reveal that rats show curiosity-related behaviours towards a virtual object on screen when it moves interactively with their movements, whereas they show less response to a static object, a regularly moving object, or interactive dislocation of the background. To mimic evading prey, we programmed the object to shrink when touched. Rats preferentially responded to interactive shrinking over interactive enlargement. These results suggest that rats exhibit a selective response to interactive objects. This would seem to be an efficient strategy for finding optimal prey using the evolutionarily conserved prey-predator relationship.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with excess mortality.Objectives:To compare all-cause and cause-specific mortality between RA patients versus general population, using a nationally representative cohort from Korea National Health Insurance Service database (KNHIS).Methods:Patients with RA aged ≥ 40 years were identified from 2010-2016 KNHIS database and their annual cohorts were constructed per each calendar year. RA patients of each cohort were required to have prevalent RA on January 1stof the given calendar year. The KNHIS were linked with Korea national mortality data to obtain cause of death information and to estimate expected deaths of RA patients in reference to mortality data of the general population in Korea. Standardized mortality ratio (SMR) with a 95% confidence interval (CI) was calculated to compare mortality of RA patients and general population.Results:A total of 6,404 deaths occurred among 79,440 RA patients during 2011-2016 period, showing all-cause SMR (95% CI) of 1.45 (1.42-1.49) compared to general population. The SMR was 1.72 (1.59-1.85) for biologics users and 1.43 (1.39-1.46) for non-users, versus general population. The annual SMR of RA patients showed a growing trend of mortality over time particularly among biologics users (Table 1). The SMRs for common causes of death among RA patients showed approximately tripled risk of dying due to pulmonary and infectious causes compared to general population (Table 2). There was approximately 20% increased risk of cardiovascular deaths but 8% decreased risk of cancer-related deaths among RA patients compared to general population (Table 2).Table 1.Annual all-cause SMR of RA patients compared to 2010 general populationCalendar year1RA patientsBiologics usersBiologics non-users20111.00 (0.92−1.07)1.13 (0.87−1.39)0.98 (0.90−1.06)20121.13 (1.06−1.21)0.98 (0.75−1.22)1.15 (1.07−1.23)20131.22 (1.14−1.30)1.29 (1.04−1.54)1.21 (1.13−1.29)20141.30 (1.23−1.38)1.53 (1.26−1.79)1.28 (1.20−1.36)20151.45 (1.38−1.53)1.81 (1.53−2.09)1.41 (1.33−1.50)20161.45 (1.37−1.52)1.94 (1.66−2.22)1.39 (1.31−1.47)CI, confidence interval; RA, rheumatoid arthritis; SMR, standardized mortality ratio12010 data were used to identify RA diagnosis dates but were not included for SMR estimation since diagnosis dates of RA were unclear for those who had RA in 2010.Table 2.Cause-specific SMR comparing RA patients versus general populationCause of deathRA patientsBiologics usersBiologics non-usersInfection3.12 (2.93−3.13)4.12 (3.36−4.88)3.03 (2.83−3.23)Cancer0.92 (0.87−0.97)0.98 (0.81−1.14)0.91 (0.85−0.96)Respiratory13.14 (2.97−3.32)4.64 (3.89−5.38)3.01 (2.83−3.19)Cardiovascular21.18 (1.12−1.25)1.26 (1.03−1.50)1.18 (1.11−1.25)CI, confidence interval; RA, rheumatoid arthritis; SMR, standardized mortality ratio1Includes pulmonary infections and chronic lung diseases (J00-J98, U04);2Includes atherosclerotic and non-atherosclerotic deaths (I00-I99).Conclusion:The all-cause mortality of RA patients during 2011-2016 was overall 45% greater than that of general Korean population, which increased annually over the study period. The increased mortality was more prominent among biologics users than non-users. The risk of infectious and respiratory deaths were tripled among RA patients compared to general population.References:[1]Sokka T, et al. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol. 2008;26(5 Suppl 51):S35-61.Acknowledgments:NoneDisclosure of Interests:None declared

Background:Biological disease-modifying anti-rheumatic drugs (bDMARDs) have significantly improved clinical prospects for patients with rheumatoid arthritis (RA).Objectives:To identify predictors of bDMARDs initiation in RA patients.Methods:Using 2002-2016 Korea National Health Insurance Service database, we conducted a nested case-control study on RA patients. Four conventional DMARD (cDMARD) users were selected by risk set sampling per each bDMARD user, matched on the calendar year/month of RA diagnosis. Potential predictors were separately assessed for two periods, 1 year after RA diagnosis and 1 year prior to bDMARD initiation, by logistic regression analyses estimating odds ratio (OR) and 95% confidence interval (CI).Results:The study included 27,940 cDMARD users and 6,985 bDMARD users. Younger age, initial use of a less potent cDMARD (sulfasalazine), corticosteroid use, and higher maximal methotrexate (MTX) dose during 1 year post-diagnosis were positive predictors for later bDMARD initiation, while male gender, initial use of a potent cDMARD (MTX, leflunomide, or tacrolimus), initial MTX dose of ≥10mg/wk, and initial cDMARD combination were negative predictors (Table 1). Use of non-MTX DMARDs (leflunomide, sulfasalazine, or tacrolimus), higher # of cDMARD used, subcutaneous administration of MTX, corticosteroid therapy, and higher maximal MTX dose were positive predictors of subsequent bDMARD. Although higher comorbidity score during 1 year before bDMARD initiation was a positive predictor, the effect was heterogenous by involved systems (Table 2).Table 1.Predictors of bDMARD initiation among RA patients during 1-year post-diagnosisPredictorsOR(95% CI)P-valueAge (/1 year)0.977(0.974-0.980)Sex (male vs. female)0.850(0.787-0.918)1st cDMARD at RA diagnosis (yes vs. no) Methotrexate0.540(0.476-0.614) Leflunomide0.463(0.388-0.552) Sulfasalazine1.305(1.197-1.424) Tacrolimus0.181(0.083-0.395)Initial MTX dose (≥10mg/week vs. 0.539(0.506-0.575)Initial cDMARD combination (yes vs. no)0.621(0.530-0.727)Subcutaneous MTX use (yes vs. no)1.456(1.156-1.834)0.001Maximal MTX dose (/1mg)1.012(1.008-1.016)Corticosteroids use (yes vs. no)2.805(2.345-3.355)Table 2.Predictors of bDMARD initiation among RA patients during 1-year prior to bDMARD initiationPredictorsOR(95% CI)P-valueAge (/1 year)0.970(0.967-0.974)Non-MTX cDMARD use (yes vs. no)1 Leflunomide1.765(1.573-1.980) Sulfasalazine1.465(1.297-1.654) Tacrolimus2.070(1.796-2.387) Subcutaneous MTX use (yes vs. no)1.731(1.577-1.900)Maximal MTX dose (/1mg)2.568(1.921-3.433)Glucocorticoid use (yes vs. no)1.015(1.010-1.021)Comorbidity index (/1 point)1.124(1.076-1.175)Individual comorbidities (yes vs. no) Stroke/ transient ischemic attack0.764(0.626-0.932)0.008 Atrial fibrillation0.666(0.455-0.973)0.036 Diabetes mellitus1.208(1.076-1.356)0.001 Joint replacement therapy1.788(1.341-2.384) Hepatitis B infection1.559(1.238-1.964) Hepatitis C infection2.117(1.532-2.925) Chronic obstructive pulmonary disease1.118(1.012-1.234)0.0281MTX was excluded since all bDMARD initiators were required to use MTX before bDMARD initiation.Conclusion:In this population-based nationwide study, we identified period-specific predictors of bDMARD initiation among RA patients in Korea. Overall, initial aggressive RA treatment after RA diagnosis were associated with less use of later bDMARD, while highly intensive therapy observed just before bDMARD initiation reflects refractory nature of RA during this period.Disclosure of Interests:None declared

Neural interfaces facilitating communication between the brain and machines must be compatible with the soft, curvilinear, and elastic tissues of the brain and yet yield enough power to read and write information across a wide range of brain areas through high-throughput recordings or optogenetics. Biocompatible-material engineering has facilitated the development of brain-compatible neural interfaces to support built-in modulation of neural circuits and neurological disorders. Recent developments in brain-compatible neural interfaces that use soft nanomaterials more suitable for complex neural circuit analysis and modulation are reviewed. Preclinical tests of the compatibility and specificity of these interfaces in animal models are also discussed.

Objectives We examined the association between socioeconomic status (SES) and comorbidity distribution among patients with RA. Methods Information on comprehensive health status of 1088 RA patients (weighted n = 612 303) was obtained from the 2007–2015 Korea National Health and Nutrition Examination Survey database. SES components were household equivalence income, education and area of residence. To minimize confounding by age, patients were stratified by median age (63 years). Age-adjusted odds ratio (OR) with 95% confidence interval (95% CI) was estimated, comparing weighted prevalence of individual comorbidities between low and high SES groups in each age stratum. Results Among RA patients aged Conclusion Among Korean RA patients aged

Background Gout is associated with an increased risk of cardiovascular (CV) disease. Objectives We aimed to investigate comparative CV risk among gout patients who initiated allopurinol versus febuxostat. Methods Using the 2002–2015 Korean National Health Insurance Service (KNHIS) data for the whole Korean population, we conducted a cohort study on patients aged ≥40 years who had ICD-10 diagnosis code for gout and initiated allopurinol or febuxostat without prior history of urate lowering therapy, excluding those with chronic kidney disease, cancer, or dialysis treatment. The primary outcome was a composite CV endpoint of hospitalisation for myocardial infarction, stroke/transient ischaemic attack, or coronary revascularisation. Secondary outcomes were individual components of the primary outcome, and hospitalisation for heart failure (HF). Follow-up time started from the day after the first date the study drug was initiated and continued through to the earliest date among the following censoring events: discontinuation of the study drugs, outcome occurrence, disenrollment, end of study dataset, or death. After propensity score (PS)-matching with a 4:1 ratio for allopurinol and febuxostat initiators to adjust for baseline confounding, we estimated hazard ratio (HR) and 95% confidence interval (CI) of CV risks in allopurinol initiators versus febuxostat. Results We included 39 636 allopurinol initiators PS-matched on 9909 febuxostat initiators with a mean age of 59 years and 78% male. Before PS matching, baseline CV risk factors including hypertension, dyslipidemia, diabetes, and previous ischaemic heart disease were more prevalent in febuxostat initiators. The incidence rate per 100 person-years for primary composite endpoint was 2.33 in allopurinol and 2.12 in febuxostat initiators in the primary as-treated analysis. The HR (95% CI) for the primary outcome associated with allopurinol was 1.18 (0.98–1.42) versus febuxostat. Secondary outcome analyses showed similar results (table 1). Propensity-score matching was used to adjust more than 50 covariates including demographic characteristics, medical comorbidities such as CV risk factors, use of gout specific and non-specific medications, and health care utilisation pattern. CI=confidence interval; CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction; TIA=transient ischaemic attack Conclusions In this large Korean population-based cohort study, CV risks appear to be numerically, but not statistically significantly, elevated among allopurinol initiators compared to febuxostat initiators. Disclosure of Interest None declared

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.

Calcium (Ca(2+)) signals that are precisely modulated in space and time mediate a myriad of cellular processes, including contraction, excitation, growth, differentiation and apoptosis. However, study of Ca(2+) responses has been hampered by technological limitations of existing Ca(2+)-modulating tools. Here we present OptoSTIM1, an optogenetic tool for manipulating intracellular Ca(2+) levels through activation of Ca(2+)-selective endogenous Ca(2+) release-activated Ca(2+) (CRAC) channels. Using OptoSTIM1, which combines a plant photoreceptor and the CRAC channel regulator STIM1 (ref. 4), we quantitatively and qualitatively controlled intracellular Ca(2+) levels in various biological systems, including zebrafish embryos and human embryonic stem cells. We demonstrate that activating OptoSTIM1 in the CA1 hippocampal region of mice selectively reinforced contextual memory formation. The broad utility of OptoSTIM1 will expand our mechanistic understanding of numerous Ca(2+)-associated processes and facilitate screening for drug candidates that antagonize Ca(2+) signals.

SUMMARYCorticotropin-releasing factor (CRF), which is released from the paraventricular nucleus (PVN) of the hypothalamus, is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their rapid neuronal dynamics on the timescale of behavior remain unknown. Here, our optical recordings of PVN CRF neuronal activity in freely behaving mice revealed that PVN CRF neurons are activated immediately by a range of stress-inducing aversive stimuli, including predator odor. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli, such as food. These findings suggest that PVN CRF neurons receive real-time information about aversive and appetitive stimuli. Their role in mediating the sensory detection and regulating the neuroendocrine axis resembles those of AgRP/NPY neurons and SFO neurons that regulate neurophysiology responses and mediate sensory detection of food and water.

As animals forage, they must obtain useful targets by orchestrating appropriate actions that range from searching to chasing, biting and carrying. Here, we reveal that neurons positive for the α subunit of Ca2+/calmodulin-dependent kinase II (CaMKIIα) in the medial preoptic area (MPA) that send projections to the ventral periaqueductal gray (vPAG) mediate these target-directed actions in mice. During photostimulation of the MPA-vPAG circuit, mice vigorously engaged with 3D objects and chased moving objects. When exposed to a cricket, they hunted down the prey and bit it to kill. By applying a head-mounted object control with timely photostimulation of the MPA-vPAG circuit, we found that MPA-vPAG circuit-induced actions occurred only when the target was detected within the binocular visual field. Using this device, we successfully guided mice to navigate specified routes. Our study explains how the brain yields a strong motivation to acquire a target object along the continuum of hunting behavior.