Objectives: Estimating the number of deaths caused by smoking is crucial for developing and evaluating tobacco control and smoking cessation policies. This study aimed to determine smoking-attributable mortality (SAM) in Korea in 2020. Methods: Four large-scale cohorts from Korea were analyzed. A Cox proportional-hazards model was used to determine the hazard ratios (HRs) of smoking-related death. By conducting a meta-analysis of these HRs, the pooled HRs of smoking-related death for 41 diseases were estimated. Population-attributable fractions (PAFs) were calculated based on the smoking prevalence for 1995 in conjunction with the pooled HRs. Subsequently, SAM was derived using the PAF and the number of deaths recorded for each disease in 2020. Results: The pooled HR for all-cause mortality attributable to smoking was 1.73 for current men smokers (95% confidence interval [CI], 1.53 to 1.95) and 1.63 for current women smokers (95% CI, 1.37 to 1.94). Smoking accounted for 33.2% of all-cause deaths in men and 4.6% in women. Additionally, it was a factor in 71.8% of men lung cancer deaths and 11.9% of women lung cancer deaths. In 2020, smoking was responsible for 53 930 men deaths and 6283 women deaths, totaling 60 213 deaths. Conclusions Cigarette smoking was responsible for a significant number of deaths in Korea in 2020. Monitoring the impact and societal burden of smoking is essential for effective tobacco control and harm prevention policies.

Purpose: To report a rare case of slow progression of carotid cavernous fistula (CCF) with central retinal vein occlusion (CRVO).Case summary: A 66-year-old man presented with conjunctival injection and proptosis in the right eye. Best-corrected visual acuity was 0.8 and 0.5 in the right and left eye, respectively, and conjunctival vessel enlargement and subconjunctival hemorrhage were observed in the right eye on slit lamp examination. Due to suspicion of CCF, computed tomography, computed tomography angiography, magnetic resonance imaging, and magnetic resonance angiography were performed. These analyses showed no vascular abnormalities associated with arteriovenous shunt, so the patient was followed up closely. About 1 month later, his conjunctival vessel engorgement became severe and CRVO derived from venous stasis by CCF occurred, so transfemoral cerebral angiography was performed and a diagnosis of CCF was made. Intravitreal anti-vascular endothelial growth factor injection was performed for CRVO, and best corrected visual acuity improved to 1.0 in the right eye. Conclusions Slowly progressing CCF can be accompanied with rare intraocular disease, such as CRVO, so appropriate diagnosis through detailed evaluation is important for treatment.

Purpose: Interleukin-37 (IL-37) is an anti-inflammatory cytokine that inhibits a broad spectrum of inflammatory responses in various human cells, including neutrophils, macrophages, and endothelial cells. The aim of this study was to identify the role of IL-37 in toll-like receptor 9 (TLR9) signaling in human macrophages. Materials and Methods: Human macrophage U937 cells treated with CpG-oligonucleotides (CpG-ODN), recombinant IL-37, or dexamethasone were used in an in vitro study. IL-37 small interfering RNA (siRNA) and TLR9 siRNA were used to silence endogenous IL-37 and TLR9, respectively. Expression levels of phosphorylated nuclear factor-κB (NF-κB), IκBα, IL-37, IL-1β, tumor necrosis factor-α (TNF-α), and IL-6 protein were assessed by real-time quantitative polymerase chain reaction and Western blotting. CpG-ODN-mediated IL-37 expression stimulated by dexamethasone was detected using immunofluorescent analysis. Results: U937 cells treated with CpG-ODN induced activation of the NF-κB pathway and increased the expression of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, but reduced that of IL-37. Recombinant IL-37 attenuated phosphorylation of NF-κB and IκBα and the expression of IL-1β, TNF-α, and IL-6 stimulated by CpG-ODN. Human macrophages transfected with IL-37 siRNA augmented the expression of IL-1β, TNF-α, and IL-6 mRNA and protein in cells treated with CpG-ODN. Dexamethasone markedly inhibited expression of pro-inflammatory cytokines in U937 cells, whereas IL-37 expression was increased with the addition of dexamethasone. Inflammatory responses elicited by CpG-ODN were dependent on an MyD88-TRAF6 pathway. IL-37 inhibited CpG-ODN-induced ubiquitination of TRAF6 in U937 macrophages. Conclusion IL-37 inhibits CpG-ODN-mediated inflammatory responses through regulation of a TRAF6- NF-κB pathway in human macrophages.

Purpose: We report two cases of tacrolimus-related transplant-associated thrombotic microangiopathy (TA-TMA) retinopathy in leukemia patients who had undergone allogenic peripheral blood stem cell transplantation (PBSCT).Case summary: (Case 1) A 58-year-old woman with a history of PBSCT due to acute myelocytic leukemia and taking tacrolimus was referred to the ophthalmology clinic with visual disturbance. Her visual acuity (VA) was 0.4 in the right eye and 0.5 in the left eye. Multiple cotton wool spots and retinal hemorrhages were found in both eyes on fundus examination. Multiple capillary non-perfusions were seen on fluorescein angiography (FA). Tacrolimus-related TA-TMA retinopathy was suspected. Tacrolimus was discontinued and plasmapheresis was performed. After 3 months, neovascular glaucoma developed and her VA became “counting fingers” at 20 cm in both eyes. (Case 2) A 20-year-old man with a history of PBSCT due to acute lymphocytic leukemia and taking tacrolimus was referred to our clinic because of decreased VA in both eyes. His VA was 0.05 in the right eye and 0.025 in the left eye. Fundus and FA findings were the same as in Case 1, and the patient was suspected to have tacrolimus-related TA-TMA retinopathy. Tacrolimus was discontinued and plasmapheresis was performed. His VA was 0.2 in the right eye and 0.4 in the left eye at 1 month after treatment. Conclusions It is necessary to consider TA-TMA retinopathy in leukemia patients taking calcineurin inhibitors, such as tacrolimus, who have decreased VA. Early diagnosis and treatment are important.

Objective: To intraindividually compare hepatocellular carcinoma (HCC) washout between MRIs using hepatobiliary agent (HBA) and extracellular agent (ECA). Materials and Methods: This study included 114 prospectively enrolled patients with chronic liver disease (mean age, 55 ± 9 years; 94 men) who underwent both HBA-MRI and ECA-MRI before surgical resection for HCC between November 2016 and May 2019. For 114 HCCs, the lesion-to-liver visual signal intensity ratio (SIR) using a 5-point scale (-2 to +2) was evaluated in each phase. Washout was defined as negative visual SIR with temporal reduction of visual SIR from the arterial phase. Illusional washout (IW) was defined as a visual SIR of 0 with an enhancing capsule. The frequency of washout and MRI sensitivity for HCC using LR-5 or its modifications were compared between HBA-MRI and ECA-MRI. Subgroup analysis was performed according to lesion size (< 20 mm or ≥ 20 mm). Results: The frequency of portal venous phase (PP) washout with HBA-MRI was comparable to that of delayed phase (DP) washout with ECA-MRI (77.2% [88/114] vs. 68.4% [78/114]; p = 0.134). The frequencies were also comparable when IW was allowed (79.8% [91/114] for HBA-MRI vs. 81.6% [93/114] for ECA-MRI; p = 0.845). The sensitivities for HCC of LR-5 (using PP or DP washout) were comparable between HBA-MRI and ECA-MRI (78.1% [89/114] vs. 73.7% [84/114]; p = 0.458). In HCCs < 20 mm, the sensitivity of LR-5 was higher on HBA-MRI than on ECA-MRI (70.8% [34/48] vs. 50.0% [24/48]; p = 0.034). The sensitivity was similar to each other if IW was added to LR-5 (72.9% [35/48] for HBA-MRI vs. 70.8% [34/48] for ECA-MRI; p > 0.999). Conclusion Extracellular phase washout for HCC diagnosis was comparable between MRIs with both contrast agents, except for tumors < 20 mm. Adding IW could improve the sensitivity for HCC on ECA-MRI in tumors < 20 mm.

Purpose: Interleukin-37 (IL-37) is an anti-inflammatory cytokine that inhibits a broad spectrum of inflammatory responses in various human cells, including neutrophils, macrophages, and endothelial cells. The aim of this study was to identify the role of IL-37 in toll-like receptor 9 (TLR9) signaling in human macrophages. Materials and Methods: Human macrophage U937 cells treated with CpG-oligonucleotides (CpG-ODN), recombinant IL-37, or dexamethasone were used in an in vitro study. IL-37 small interfering RNA (siRNA) and TLR9 siRNA were used to silence endogenous IL-37 and TLR9, respectively. Expression levels of phosphorylated nuclear factor-κB (NF-κB), IκBα, IL-37, IL-1β, tumor necrosis factor-α (TNF-α), and IL-6 protein were assessed by real-time quantitative polymerase chain reaction and Western blotting. CpG-ODN-mediated IL-37 expression stimulated by dexamethasone was detected using immunofluorescent analysis. Results: U937 cells treated with CpG-ODN induced activation of the NF-κB pathway and increased the expression of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, but reduced that of IL-37. Recombinant IL-37 attenuated phosphorylation of NF-κB and IκBα and the expression of IL-1β, TNF-α, and IL-6 stimulated by CpG-ODN. Human macrophages transfected with IL-37 siRNA augmented the expression of IL-1β, TNF-α, and IL-6 mRNA and protein in cells treated with CpG-ODN. Dexamethasone markedly inhibited expression of pro-inflammatory cytokines in U937 cells, whereas IL-37 expression was increased with the addition of dexamethasone. Inflammatory responses elicited by CpG-ODN were dependent on an MyD88-TRAF6 pathway. IL-37 inhibited CpG-ODN-induced ubiquitination of TRAF6 in U937 macrophages. Conclusion IL-37 inhibits CpG-ODN-mediated inflammatory responses through regulation of a TRAF6- NF-κB pathway in human macrophages.

Background: Coronavirus disease 2019 (COVID-19) outbreaks occur in hospitals in many parts of the world. In hospital settings, the possibility of airborne transmission needs to be investigated thoroughly. Materials and Methods: There was a nosocomial outbreak of COVID-19 in a hematologic ward in a tertiary hospital, Seoul, Korea. We found 11 patients and guardians with COVID-19 through vigorous contact tracing and closed-circuit television monitoring. We found one patient who probably had acquired COVID-19 through airborne-transmission. We performed airflow investigation with simulation software, whole-genome sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Of the nine individuals with COVID-19 who had been in the hematologic ward, six stayed in one multi-patient room (Room 36), and other three stayed in different rooms (Room 1, 34, 35). Guardian in room 35 was close contact to cases in room 36, and patient in room 34 used the shared bathroom for teeth brushing 40 minutes after index used.Airflow simulation revealed that air was spread from the bathroom to the adjacent room 1 while patient in room 1 did not used the shared bathroom. Airflow was associated with poor ventilation in shared bathroom due to dysfunctioning air-exhaust, grill on the door of shared bathroom and the unintended negative pressure of adjacent room. Conclusion Transmission of SARS-CoV-2 in the hematologic ward occurred rapidly in the multi-patient room and shared bathroom settings. In addition, there was a case of possible airborne transmission due to unexpected airflow.

Background: Coronavirus disease 2019 (COVID-19) outbreaks occur in hospitals in many parts of the world. In hospital settings, the possibility of airborne transmission needs to be investigated thoroughly. Materials and Methods: There was a nosocomial outbreak of COVID-19 in a hematologic ward in a tertiary hospital, Seoul, Korea. We found 11 patients and guardians with COVID-19 through vigorous contact tracing and closed-circuit television monitoring. We found one patient who probably had acquired COVID-19 through airborne-transmission. We performed airflow investigation with simulation software, whole-genome sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Of the nine individuals with COVID-19 who had been in the hematologic ward, six stayed in one multi-patient room (Room 36), and other three stayed in different rooms (Room 1, 34, 35). Guardian in room 35 was close contact to cases in room 36, and patient in room 34 used the shared bathroom for teeth brushing 40 minutes after index used.Airflow simulation revealed that air was spread from the bathroom to the adjacent room 1 while patient in room 1 did not used the shared bathroom. Airflow was associated with poor ventilation in shared bathroom due to dysfunctioning air-exhaust, grill on the door of shared bathroom and the unintended negative pressure of adjacent room. Conclusion Transmission of SARS-CoV-2 in the hematologic ward occurred rapidly in the multi-patient room and shared bathroom settings. In addition, there was a case of possible airborne transmission due to unexpected airflow.

Purpose: Radiation-induced lymphopenia is associated with worse outcomes in solid tumors. We assessed the impact of interleukin-7 (IL-7), a key cytokine in lymphocyte homeostasis, on radiation-induced lymphopenia. Materials and Methods: A post-hoc analysis was performed in a prospective cohort of 98 patients with hepatocellular carcinoma who were treated with radiotherapy in 2016-2018. Blood IL-7 levels were assayed before and at the end of radiotherapy. Acute severe lymphopenia (ASL) was defined as a total lymphocyte count of < 200/μL during radiotherapy. Cox and logistic regression analyses were performed to identify predictors of survival and ASL development, respectively. Results: Patients with ASL (n=41) had significantly poorer overall survival than those without (12.0 months vs. 25.3 months, p=0.001). Patients with lymphocyte recovery showed significantly longer overall survival than those without (21.8 months vs. 10.3 months, p=0.042). ASL was an independent predictor of poor survival (hazard ratio, 2.07; p=0.015). Patients with ASL had significantly lower pre-radiotherapy IL-7 levels (2.07 pg/mL vs. 3.01 pg/mL, p=0.010). A high pre-radiotherapy IL-7 level was an independent predictor of a reduced risk of ASL development (hazard ratio, 0.40; p=0.004). IL-7 levels reflected a feedback response to ASL, with a higher ΔIL-7 in patients with ASL and a lower ΔIL-7 in those without ASL (0.48 pg/mL vs. –0.66 pg/mL, p < 0.001). Post-radiotherapy IL-7 levels were significantly positively correlated with the total lymphocyte counts at 2 months. Conclusion IL-7 is associated with the development of and recovery from ASL, which may impact survival. To overcome radiation-induced lymphopenia, a novel strategy using IL-7 may be considered.

Background: Post-transplant immunosuppression with calcineurin inhibitors (CNIs) is associated with kidney function impairment while mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, can be used for its renal-sparing effects. In this study, we compared the efficacy and safety of everolimus with low dose tacrolimus (EVR+Low TAC) and conventional dose tacrolimus (TAC) in liver transplantation recipients. Methods: Medical records of recipients who received liver transplantation at Seoul National University Bundang Hospital from January 1st 2009 to December 31st 2018 were retrospectively reviewed. Cohort entry date was defined as the day everolimus was initiated and tacrolimus dosage was reduced. All patients were followed up for 1 year. Indicator of efficacy was the incidence of rejection and safety was evaluated by incidence of drug adverse events including renal function. Results: Among 118 patients, there were 40 patients (33.9%) in EVR+Low TAC group. Incidence of rejection, including both biopsy proven acute rejection and clinical rejection, was similar in two groups [7.5% (n=3) vs. 6.4% (n=5), p=1.000]. Renal dysfunction was less frequent in EVR+Low TAC [17.5% (n=7) vs. 35.9% (n=28), p=0.038]. However, incidence rates of dyslipidemia, oral ulcer were more frequent in EVR+Low TAC [45.0% (n=18) vs. 21.8% (n=17), p=0.009; 15.0% (n=6) vs. 1.3% (n=1), p=0.006]. Conclusions In terms of prevention of rejection, EVR+Low TAC was as effective as TAC and had renal-sparing effect but was associated with increased risk of dyslipidemia and oral ulcer. This study demonstrates that EVR+Low TAC could be an alternative to liver transplant recipients with nephrotoxicity after administration of conventional dose tacrolimus.