Association between Mycobacterium tuberculosis infection and the risk of inflammatory arthritides.

OBJECTIVES: Tuberculosis is a highly contagious disease that has a significant impact on global health. Emerging evidence suggests that tuberculosis can lead to an altered immune response. We investigated the association between tuberculosis and the onset of inflammatory arthritides (IA). METHODS: Patients with incident tuberculosis in the South Korean National Claims database from 2010 to 2021 were included, and those who had undergone appendectomy during 2010-2011 served as controls. The onset of IA (including seropositive rheumatoid arthritis [SPRA], ankylosing spondylitis [AS], and psoriatic arthritis [PsA]) after tuberculosis was compared between patients with tuberculosis and the control group. Sensitivity analysis was performed using stabilised inverse probability of treatment weighting (sIPTW). RESULTS: A total of 408,685 patients with tuberculosis and 159,675 controls were included. During the mean follow-up of 7.5 years, a total of 1,957 (0.3%) were diagnosed with IA (SPRA, 1,397; AS, 481; and PsA, 79). Multivariable Cox hazard analysis indicated that the overall risk of IA was elevated in the tuberculosis group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.51-1.93) compared with controls. This increased incidence in patients with tuberculosis was identical among IA subgroups even after adjustment (SPRA [HR, 1.72; 95% CI, 1.49-2.00], AS [HR, 1.64; 95% CI, 1.30-2.06], and PsA [HR, 2.59; 95% CI, 1.32-5.07]) and was replicated in the sIPTW. CONCLUSIONS: The increased overall risk of developing IA after tuberculosis corroborates the hypothesis that tuberculosis can trigger dysregulated immunity. This necessitates an increased awareness of autoimmunity in this patient group.

Risk of Subsequent Primary Cancers Among Adult-Onset 5-Year Cancer Survivors in South Korea: Retrospective Cohort Study.

BACKGROUND: The number of cancer survivors who develop subsequent primary cancers (SPCs) is expected to increase. OBJECTIVE: We evaluated the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types considering sex and age. METHODS: We conducted a retrospective cohort study using the Health Insurance Review and Assessment database of South Korea including 5-year cancer survivors diagnosed with an FPC in 2009 to 2010 and followed them until December 31, 2019. We measured the SPC incidence per 10,000 person-years and the standardized incidence ratio (SIR) compared with the incidence expected in the general population. RESULTS: Among 266,241 survivors (mean age at FPC: 55.7 years; 149,352/266,241, 56.1% women), 7348 SPCs occurred during 1,003,008 person-years of follow-up (median 4.3 years), representing a 26% lower risk of developing SPCs (SIR 0.74, 95% CI 0.72-0.76). Overall, men with 14 of the 20 FPC types had a significantly lower risk of developing any SPCs; women with 7 of the 21 FPC types had a significantly lower risk of developing any SPCs. The risk of developing any SPC type differed by age; the risk was 28% higher in young (<40 years) cancer survivors (SIR 1.28, 95% CI 1.16-1.42; incidence: 30 per 10,000 person-years) and 27% lower in middle-aged and older (≥40 years) cancer survivors (SIR 0.73, 95% CI 0.71-0.74; incidence: 80 per 10,000 person-years) compared with the age-corresponding general population. The most common types of FPCs were mainly observed as SPCs in cancer survivors, with lung (21.6%) and prostate (15.2%) cancers in men and breast (18.9%) and lung (12.2%) cancers in women. The risks of brain cancer in colorectal cancer survivors, lung cancer in laryngeal cancer survivors, and both kidney cancer and leukemia in thyroid cancer survivors were significantly higher for both sexes. Other high-risk SPCs varied by FPC type and sex. Strong positive associations among smoking-related cancers, such as laryngeal, head and neck, lung, and esophageal cancers, were observed. Substantial variation existed in the associations between specific types of FPC and specific types of SPC risk, which may be linked to hereditary cancer syndrome: for women, the risks of ovarian cancer for breast cancer survivors and uterus cancers for colorectal cancer survivors, and for men, the risk of pancreas cancer for kidney cancer survivors. CONCLUSIONS: The varying risk for SPCs by age, sex, and FPC types in cancer survivors implies the necessity for tailored prevention and screening programs targeting cancer survivors. Lifestyle modifications, such as smoking cessation, are essential to reduce the risk of SPCs in cancer survivors. In addition, genetic testing, along with proactive cancer screening and prevention strategies, should be implemented for young cancer survivors because of their elevated risk of developing SPCs.

Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF.

PURPOSE: Patients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF. METHODS: A patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq). RESULTS: CITE-seq analysis revealed that before treatment, the patient's PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs-e.g., STAT1, IRF1, MX1, and OAS1-were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient's autoimmune features were aggravated, which is in line with sustained epigenetic abnormality. CONCLUSIONS: In a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs.

Incidence and disease burden of autoimmune inflammatory rheumatic diseases after non-pharmaceutical interventions in the COVID-19 era: A nationwide observational study in Korea.

BACKGROUND: Infections are considered risk factors for autoimmune inflammatory rheumatic diseases (AIRDs), the incidence of which is considered to have been impacted by the COVID-19 pandemic. The impact of non-pharmaceutical interventions (NPIs) on the incidence of AIRDs and their associated health care services and medical expenses in Korea was investigated. METHODS: We included all AIRD cases reported between January 2016 and February 2021 based on the National Health Insurance Service data. We evaluated changes in incidence trends for each AIRD before and after NPI implementation (Feb 2020 to Feb 2021) using segmented regression analysis. Changes in health care utilization and medical costs for each AIRD before and after NPI implementation were also investigated. RESULTS: After NPI implementation, monthly incidence rates declined significantly by 0.205 per 1 000 000 (95% confidence interval [CI], -0.308 to -0.101, p < .001) in patients with systemic lupus erythematosus (SLE). No significant changes in the incidence of all AIRDs other than SLE were observed before and after implementation. Further, annual outpatient department visits per patient were lower during implementation for all diseases, except juvenile idiopathic arthritis (JIA). The prescription days per outpatient visit increased significantly during implementation for all diseases, except JIA and ankylosing spondylitis. During implementation, the total annual medical costs per patient tended to decrease for all diseases, except JIA and mixed connective tissue disease. CONCLUSION: Implementation of NPIs to contain the pandemic led to a reduction in the incidence of SLE and changed patterns of medical care utilization and treatment cost for most AIRDs.

A simulation-based comparison of drug-drug interaction signal detection methods.

Several statistical methods have been proposed to detect adverse drug reactions induced by taking two drugs together. These suspected adverse drug reactions can be discovered through post-market drug safety surveillance, which mainly relies on spontaneous reporting system database. Most previous studies have applied statistical models to real world data, but it is not clear which method outperforms the others. We aimed to assess the performance of various detection methods by implementing simulations under various conditions. We reviewed proposed approaches to detect signals indicating drug-drug interactions (DDIs) including the Ω shrinkage measure, the chi-square statistic, the proportional reporting ratio, the concomitant signal score, the additive model and the multiplicative model. Under various scenarios, we conducted a simulation study to examine the performances of the methods. We also applied the methods to Korea Adverse Event Reporting System (KAERS) data. Of the six methods considered in the simulation study, the Ω shrinkage measure and the chi-square statistic with threshold = 2 had higher sensitivity for detecting the true signals than the other methods in most scenarios while controlling the false positive rate below 0.05. When applied to the KAERS data, the two methods detected one known DDI for QT prolongation and one unknown (suspected) DDI for hyperkalemia. The performance of various signal detection methods for DDI may vary. It is recommended to use several methods together, rather than just one, to make a reasonable decision.

A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma.

PURPOSE: Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. PATIENTS AND METHODS: Patients with resectable HNSCC were randomized to receive a single dose of preoperative durvalumab (D) with or without tremelimumab (T) before resection, followed by postoperative (chemo)radiotherapy based on multidisciplinary discretion and 1-year D treatment. Artificial intelligence (AI)-powered spatial distribution analysis of tumor-infiltrating lymphocytes and high-dimensional profiling of circulating immune cells tracked dynamic intratumoral and systemic immune responses. RESULTS: Of the 48 patients enrolled (D, 24 patients; D+T, 24 patients), 45 underwent surgical resection per protocol (D, 21 patients; D+T, 24 patients). D±T had a favorable safety profile and did not delay surgery. Distant recurrence-free survival (DRFS) was significantly better in patients treated with D+T than in those treated with D monotherapy. AI-powered whole-slide image analysis demonstrated that D+T significantly reshaped the tumor microenvironment toward immune-inflamed phenotypes, in contrast with the D monotherapy or cytotoxic chemotherapy. High-dimensional profiling of circulating immune cells revealed a significant expansion of T-cell subsets characterized by proliferation and activation in response to D+T therapy, which was rare following D monotherapy. Importantly, expansion of specific clusters in CD8+ T cells and non-regulatory CD4+ T cells with activation and exhaustion programs was associated with prolonged DRFS in patients treated with D+T. CONCLUSIONS: Preoperative D±T is feasible and may benefit patients with resectable HNSCC. Distinct changes in the tumor microenvironment and circulating immune cells were induced by each treatment regimen, warranting further investigation.

Incidence of systemic vasculitides after Mycobacterium tuberculosis infection: A population-based cohort study in Korea.

BACKGROUND: Tuberculosis (TB) is a highly prevalent disease associated with significant morbidity and mortality globally, and is reported to be associated with the onset of autoimmunity. This study investigated the association between TB and the incidence of systemic vasculitides (SV). METHODS: Data were obtained from the South Korean National Claims database to identify patients with TB and controls (who had undergone appendectomy). The overall occurrence of SV and disease subtypes during the observation period was compared between the two groups. Adjusted Cox proportional hazards regression and Kaplan-Meier analysis were performed to identify the relationship between TB and SV and to compare SV incidence. RESULTS: We identified 418 677 patients with TB and 160 289 controls. The overall SV incidence rate was 192/1,000 000 person-years during a mean follow-up of 7.5 years and was higher in patients with TB than controls. Cox regression revealed that the risk of SV was elevated in the TB group independently (adjusted hazard ratio [aHR]: 1.72, 95% confidence interval [CI]: 1.45-2.05). Furthermore, the risk of SV was significantly higher in extrapulmonary TB (aHR: 4.28, 95% CI: 3.52-5.21) when the TB group was categorized into pulmonary and extrapulmonary TB. The findings remained identical even after applying a stabilized inverse probability of treatment weighting analysis. CONCLUSIONS: Patients with TB have increased risk of SV, which is prominent in extrapulmonary TB. As well as confirming TB is associated with increased incidence of immune-related vasculitis, our findings highlight the need for clinical vigilance for early diagnosis and initiation of treatment.

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial.

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10-4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Changes in tuberculosis risk after transplantation in the setting of decreased community tuberculosis incidence: a national population-based study, 2008-2020.

BACKGROUND: Transplant recipients are immunocompromised and vulnerable to developing tuberculosis. However, active tuberculosis incidence is rapidly declining in South Korea, but the trend of tuberculosis infection among transplant recipients has not been elucidated. This study aimed to evaluate the risk of active tuberculosis after transplantation, including risk factors for tuberculosis and standardized incidence ratios, compared with that in the general population. METHODS: This retrospective study was conducted based on the South Korean health insurance review and assessment database among those who underwent transplantation (62,484 recipients) between 2008 and 2020. Tuberculosis incidence was compared in recipients treated during higher- (2010-2012) and lower-disease burden (2016-2018) periods. Standardized incidence ratios were analyzed using the Korean Tuberculosis Surveillance System. The primary outcome was the number of new tuberculosis cases after transplantation. RESULTS: Of 57,103 recipients analyzed, the overall cumulative incidence rate 1 year after transplantation was 0.8% (95% confidence interval [CI]: 0.7-0.8), significantly higher in the higher-burden period than in the lower-burden period (1.7% vs. 1.0% 3 years after transplantation, P < 0.001). Individuals who underwent allogeneic hematopoietic stem cell transplantation had the highest tuberculosis incidence, followed by those who underwent solid organ transplantation and autologous hematopoietic stem cell transplantation (P < 0.001). The overall standardized incidence ratio was 3.9 (95% CI 3.7-4.2) and was the highest in children aged 0-19 years, at 9.0 (95% CI 5.7-13.5). Male sex, older age, tuberculosis history, liver transplantation, and allogeneic hematopoietic stem cell transplantation were risk factors for tuberculosis. CONCLUSIONS: Transplant recipients are vulnerable to developing tuberculosis, possibly influenced by their immunocompromised status, solid organ transplant type, age, and community prevalence of tuberculosis. Tuberculosis prevalence by country, transplant type, and age should be considered to establish an appropriate tuberculosis prevention strategy for high-risk groups.

Risk Factors of Postpartum Depression Among Korean Women: An Analysis Based on the Korean Pregnancy Outcome Study (KPOS).

BACKGROUND: Postpartum depression (PPD) can negatively affect infant well-being and child development. Although the frequency and risk factors of PPD symptoms might vary depending on the country and culture, there is limited research on these risk factors among Korean women. This study aimed to elucidate the potential risk factors of PPD throughout pregnancy to help improve PPD screening and prevention in Korean women. METHODS: The pregnant women at 12 gestational weeks (GW) were enrolled from two obstetric specialized hospitals from March 2013 to November 2017. A questionnaire survey was administered at 12 GW, 24 GW, 36 GW, and 4 weeks postpartum. Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale, and PPD was defined as a score of ≥ 10. RESULTS: PPD was prevalent in 16.3% (410/2,512) of the participants. Depressive feeling at 12 GW and postpartum factors of stress, relationship with children, depressive feeling, fear, sadness, and neonatal intensive care unit admission of baby were significantly associated with a higher risk of PPD. Meanwhile, high postpartum quality of life and marital satisfaction at postpartum period were significantly associated with a lower risk of PPD. We developed a model for predicting PPD using factors as mentioned above and it had an area under the curve of 0.871. CONCLUSION: Depressive feeling at 12 GW and postpartum stress, fear, sadness, relationship with children, low quality of life, and low marital satisfaction increased the risk of PPD. A risk model that comprises significant factors can effectively predict PPD and can be helpful for its prevention and appropriate treatment.

New-onset atrial fibrillation in seropositive rheumatoid arthritis: association with disease-modifying anti-rheumatic drugs treatment.

OBJECTIVE: Atrial fibrillation (AF) is a potentially lethal complication that leads to increased hospitalization, disability and mortality. Furthermore, the risk of cardiovascular disease is increased in RA. We evaluated whether DMARD treatment is associated with incident AF in patients with seropositive RA (SPRA). METHODS: The South Korean Health Insurance Review and Assessment Service database was used to identify patients newly diagnosed with SPRA between 2010 and 2020. A nested case-control analysis was performed to match AF-affected patients to unaffected controls for age, sex, follow-up duration, and index year of SPRA diagnosis at a 1:4 ratio. Adjusted conditional logistic regression was used to identify the predictive factors for AF. RESULTS: Of the 108 085 patients with SPRA, 2,629 (2.4%) developed new-onset AF, and the proportion of females was ∼67%. In the matched population, pre-existing comorbidities of hypertension, chronic kidney disease, and heart failure were associated with increased risk of AF. Meanwhile, the use of methotrexate (MTX) decreased the risk of incident AF [adjusted odds ratio (aOR), 0.89], whereas the use of leflunomide (LEF) increased AF (aOR, 1.21). In a subgroup of patients aged ≥50 years, LEF and adalimumab increased the occurrence of AF, while MTX decreased AF in males and LEF increased this risk in females. CONCLUSION: Although the number of subjects developing new-onset AF was small, MTX decreased and LEF increased incident AF in patients with RA. Especially, a distinct pattern of AF risk with DMARDs usage was observed according to age and sex.

Incidence and Features of Lymphoid Proliferation and Lymphomas after Solid Organ or Hematopoietic Stem Cell Transplantation in a National Database Cohort.

PURPOSE: Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. MATERIALS AND METHODS: We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. RESULTS: During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). CONCLUSION: We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death.

Optimizing the maximum reported cluster size for the multinomial-based spatial scan statistic.

BACKGROUND: Correctly identifying spatial disease cluster is a fundamental concern in public health and epidemiology. The spatial scan statistic is widely used for detecting spatial disease clusters in spatial epidemiology and disease surveillance. Many studies default to a maximum reported cluster size (MRCS) set at 50% of the total population when searching for spatial clusters. However, this default setting can sometimes report clusters larger than true clusters, which include less relevant regions. For the Poisson, Bernoulli, ordinal, normal, and exponential models, a Gini coefficient has been developed to optimize the MRCS. Yet, no measure is available for the multinomial model. RESULTS: We propose two versions of a spatial cluster information criterion (SCIC) for selecting the optimal MRCS value for the multinomial-based spatial scan statistic. Our simulation study suggests that SCIC improves the accuracy of reporting true clusters. Analysis of the Korea Community Health Survey (KCHS) data further demonstrates that our method identifies more meaningful small clusters compared to the default setting. CONCLUSIONS: Our method focuses on improving the performance of the spatial scan statistic by optimizing the MRCS value when using the multinomial model. In public health and disease surveillance, the proposed method can be used to provide more accurate and meaningful spatial cluster detection for multinomial data, such as disease subtypes.

Harmful effect of repetitive intravenous iodinated contrast media administration on the long-term renal function of patients with early gastric cancer.

This retrospective study investigated whether repetitive exposure to intravenous iodinated contrast media (ICM) affects long-term renal function in patients who undergo curative surgery for early gastric cancer (EGC) collected from the Korean Health Insurance and Review Assessment (HIRA) database. Patients diagnosed with gastric cancer between January 2010 and December 2013 underwent regular computed tomography (CT) scans to monitor for extragastric recurrence. Patients who already had chronic kidney disease (CKD) before cancer diagnosis or had undergone chemotherapy or repeated surgery were excluded. A nested case-control study design was chosen to analyze the effect of repetitive ICM exposure to long-term renal function by comparing patients who developed CKD 2 years after cancer diagnosis and patients who did not. Among 59,971 patients collected according to inclusion and exclusion criteria, 1021 were diagnosed with CKD 2 years after cancer diagnosis. Using 1:5 matching after adjusting for age, sex and date of cancer diagnosis, 5097 control patients were matched to 1021 CKD patients. Conditional logistic regression showed that the number of CTs taken using ICM slightly increased the odds of CKD (odds ratio, 1.080; 95% confidence interval (CI): 1.059, 1.100; P < 0.0001). Thus, the administration of ICM might contribute to chronic renal function impairment.

Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins.

Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. Ten-eleven translocation (TET) proteins catalyze the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized methylcytosines in DNA, thereby serving as central modulators of DNA methylation-demethylation dynamics. TET loss of function is causally related to neoplastic transformation across various cell types while its genetic or pharmacological activation exhibits anti-cancer effects, making TET proteins promising targets for epigenetic cancer therapy. Here, we developed a robust cell-based screening system to identify novel TET activators and evaluated their potential as anti-cancer agents. Using a carefully curated library of 4533 compounds provided by the National Cancer Institute, Bethesda, MD, USA, we identified mitoxantrone as a potent TET agonist. Through rigorous validation employing various assays, including immunohistochemistry and dot blot studies, we demonstrated that mitoxantrone significantly elevated 5hmC levels. Notably, this elevation manifested only in wild-type (WT) but not TET-deficient mouse embryonic fibroblasts, primary bone marrow-derived macrophages, and leukemia cell lines. Furthermore, mitoxantrone-induced cell death in leukemia cell lines occurred in a TET-dependent manner, indicating the critical role of TET proteins in mediating its anti-cancer effects. Our findings highlight mitoxantrone's potential to induce tumor cell death via a novel mechanism involving the restoration of TET activity, paving the way for targeted epigenetic therapies in cancer treatment.

Signal detection statistics of adverse drug events in hierarchical structure for matched case-control data.

The tree-based scan statistic is a data mining method used to identify signals of adverse drug reactions in a database of spontaneous reporting systems. It is particularly beneficial when dealing with hierarchical data structures. One may use a retrospective case-control study design from spontaneous reporting systems (SRS) to investigate whether a specific adverse event of interest is associated with certain drugs. However, the existing Bernoulli model of the tree-based scan statistic may not be suitable as it fails to adequately account for dependencies within matched pairs. In this article, we propose signal detection statistics for matched case-control data based on McNemar's test, Wald test for conditional logistic regression, and the likelihood ratio test for a multinomial distribution. Through simulation studies, we demonstrate that our proposed methods outperform the existing approach in terms of the type I error rate, power, sensitivity, and false detection rate. To illustrate our proposed approach, we applied the three methods and the existing method to detect drug signals for dizziness-related adverse events related to antihypertensive drugs using the database of the Korea Adverse Event Reporting System.

Impact of Non-Pharmaceutical Interventions on the Incidence and Treatment of Chronic Rhinosinusitis during the COVID-19 Pandemic: A Nationwide Retrospective Cohort Study.

Many countries have implemented non-pharmaceutical interventions (NPIs) to prevent the spread of COVID-19. However, the impacts of NPIs on the epidemiology and treatment of chronic rhinosinusitis (CRS) remain unclear. We analyzed 671,216 patients to investigate changes in the incidence rate and treatment frequency of CRS using Korean nationwide health insurance data between 2017 and 2021. The incidence rate (p < 0.001) and the number of outpatients (p < 0.001), patients hospitalized (p < 0.001), and patients prescribed antibiotics (p < 0.001) or steroids (p = 0.024) were significantly lower in the pandemic period than in the pre-pandemic period; however, the number of patients who underwent surgery was not different (p = 0.205). Additionally, the frequency of surgeries per patient was significantly lower in patients during the pandemic period (p < 0.001). In the interrupted time series analysis, the trends in the number of outpatients (p < 0.001), patients hospitalized (p < 0.001), patients who underwent surgery (p < 0.001), and patients prescribed antibiotics (p < 0.001) or steroids (p < 0.001) significantly changed after the onset of the COVID-19 pandemic. In summary, NPI implementation during the COVID-19 pandemic was associated with a reduction in the incidence and treatment of CRS.

Impact of thyroid hormone replacement on the risk of second cancer after thyroidectomy: a Korean National Cohort Study.

We aimed to investigate the effect of thyroid hormone administration on the risk of second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer. Data were extracted from the medical billing data of the Health Insurance Review and Assessment Service in South Korea. Patients between 19 and 80 years old who underwent thyroid surgery at least once between January 2009 and June 2020 were included. Data of patients with second primary cancer and control patients with matched age, sex, operation date, and follow-up duration were extracted at a ratio of 1:4. A nested case-control analysis was performed to exclude length bias to confirm the correlation between the duration of thyroid hormone administration, dose, and incidence of second primary cancer. Of the 261,598 patients who underwent surgery for thyroid cancer included in the study, 11,790 with second primary cancer and 47,160 without second primary cancer were matched. The average dose of thyroid hormone increased the adjusted odds ratio (OR) for both low (≤ 50 µg, OR 1.29, confidence interval (CI) 1.12-1.48) and high (< 100 µg, OR 1.24, CI 1.12-1.37) doses. Analyzing over time, the adjusted OR of second primary cancer increased, especially in short (≤ 1 year) (OR 1.19; CI 1.06-1.34) and long (> 5 years) duration (OR 1.25; CI 1.10-1.41). In conclusion, insufficient and excessive thyroid hormone replacement might be linked to increased second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer.

Risk of depression and anxiety disorders according to long-term glycemic variability.

BACKGROUND: Poor glycemic control has been linked to psychiatric symptoms. However, studies investigating the relationship between glycemic variability (GV) and depression and anxiety disorders are limited. We investigated the association of GV with depression and anxiety disorders. In addition, the relationship between trends in fasting plasma glucose (FPG) levels and these disorders were explored. METHODS: We analyzed the National Health Insurance Service-National Sample Cohort database (2002-2013) with 151,814 participants who had at least three health screenings between 2002 and 2010. Visit-to-visit FPG variability was measured as variability independent of the mean (VIM). Depression and anxiety disorders were diagnosed using ICD-10 codes (F41 for anxiety and F32 or F33 for depression) after index date. We analyzed the association between GV and incidences of these disorders using Kaplan-Meier and Cox proportional hazards methods. Trajectory analysis was conducted to explore the relationship between FPG trends and these disorders. RESULTS: During follow-up, 7166 and 14,149 patients were newly diagnosed with depression and anxiety disorders, respectively. The highest quartile group of FPG-VIM had a greater incidence of depression and anxiety than the lowest quartile group, with adjusted hazard ratios of 1.09 (95 % confidence interval [CI]: 1.02-1.17) and 1.08 (95 % CI: 1.03-1.14). Group with persistent hyperglycemia, identified through trajectory clustering of FPG levels, had a 1.43-fold increased risk of depression compared to those with consistently low FPG levels. LIMITATIONS: Potential selection bias by including participants with at least three health screenings. CONCLUSIONS: High GV and persistent hyperglycemia are associated with increased incidence of depression and anxiety disorders.