Soonchunhyang University Hospital Seoul

Lists of authors and their affiliations appear in the online version of the paper Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry 1 . We identified 65 new loci that are associated with overall breast cancer risk at P < 5 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genomewide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Autophagy is an intracellular degradative process that occurs under several stressful conditions, including organelle damage, the presence of abnormal proteins, and nutrient deprivation. The mechanism of autophagy initiates the formation of autophagosomes that capture degraded components and then fuse with lysosomes to recycle these components. The modulation of autophagy plays dual roles in tumor suppression and promotion in many cancers. In addition, autophagy regulates the properties of cancer stem-cells by contributing to the maintenance of stemness, the induction of recurrence, and the development of resistance to anticancer reagents. Although some autophagy modulators, such as rapamycin and chloroquine, are used to regulate autophagy in anticancer therapy, since this process also plays roles in both tumor suppression and promotion, the precise mechanism of autophagy in cancer requires further study. In this review, we will summarize the mechanism of autophagy under stressful conditions and its roles in tumor suppression and promotion in cancer and in cancer stem-cells. Furthermore, we discuss how autophagy is a promising potential therapeutic target in cancer treatment.

Obesity is a prevalent and complex disease. The prevalence of obesity in Korea increased from 29.7% in 2010 to 35.7% in 2018, with the prevalence of abdominal obesity being 23.8% in 2018. Obesity contributes to medical costs and socioeconomic burden due to associated comorbidities. The treatment and management of obesity is changing based on new clinical evidence. The 2020 Korean Society for the Study of Obesity Guideline for the Management of Obesity in Korea summarizes evidence-based recommendations and treatment guidelines.

This review aimed to arrange the concepts of a network meta-analysis (NMA) and to demonstrate the analytical process of NMA using Stata software under frequentist framework. The NMA tries to synthesize evidences for a decision making by evaluating the comparative effectiveness of more than two alternative interventions for the same condition. Before conducting a NMA, 3 major assumptions-similarity, transitivity, and consistency-should be checked. The statistical analysis consists of 5 steps. The first step is to draw a network geometry to provide an overview of the network relationship. The second step checks the assumption of consistency. The third step is to make the network forest plot or interval plot in order to illustrate the summary size of comparative effectiveness among various interventions. The fourth step calculates cumulative rankings for identifying superiority among interventions. The last step evaluates publication bias or effect modifiers for a valid inference from results. The synthesized evidences through five steps would be very useful to evidence-based decision-making in healthcare. Thus, NMA should be activated in order to guarantee the quality of healthcare system.

Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.

Thermal ablation using radiofrequency is a new, minimally invasive modality employed as an alternative to surgery in patients with benign thyroid nodules and recurrent thyroid cancers. The Task Force Committee of the Korean Society of Thyroid Radiology (KSThR) developed recommendations for the optimal use of radiofrequency ablation for thyroid tumors in 2012. As new meaningful evidences have accumulated, KSThR decided to revise the guidelines. The revised guideline is based on a comprehensive analysis of the current literature and expert consensus.

IMPORTANCE: There is limited information about the clinical course and viral load in asymptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OBJECTIVE: To quantitatively describe SARS-CoV-2 molecular viral shedding in asymptomatic and symptomatic patients. DESIGN, SETTING, AND PARTICIPANTS: A retrospective evaluation was conducted for a cohort of 303 symptomatic and asymptomatic patients with SARS-CoV-2 infection between March 6 and March 26, 2020. Participants were isolated in a community treatment center in Cheonan, Republic of Korea. MAIN OUTCOMES AND MEASURES: Epidemiologic, demographic, and laboratory data were collected and analyzed. Attending health care personnel carefully identified patients' symptoms during isolation. The decision to release an individual from isolation was based on the results of reverse transcription-polymerase chain reaction (RT-PCR) assay from upper respiratory tract specimens (nasopharynx and oropharynx swab) and lower respiratory tract specimens (sputum) for SARS-CoV-2. This testing was performed on days 8, 9, 15, and 16 of isolation. On days 10, 17, 18, and 19, RT-PCR assays from the upper or lower respiratory tract were performed at physician discretion. Cycle threshold (Ct) values in RT-PCR for SARS-CoV-2 detection were determined in both asymptomatic and symptomatic patients. RESULTS: Of the 303 patients with SARS-CoV-2 infection, the median (interquartile range) age was 25 (22-36) years, and 201 (66.3%) were women. Only 12 (3.9%) patients had comorbidities (10 had hypertension, 1 had cancer, and 1 had asthma). Among the 303 patients with SARS-CoV-2 infection, 193 (63.7%) were symptomatic at the time of isolation. Of the 110 (36.3%) asymptomatic patients, 21 (19.1%) developed symptoms during isolation. The median (interquartile range) interval of time from detection of SARS-CoV-2 to symptom onset in presymptomatic patients was 15 (13-20) days. The proportions of participants with a negative conversion at day 14 and day 21 from diagnosis were 33.7% and 75.2%, respectively, in asymptomatic patients and 29.6% and 69.9%, respectively, in symptomatic patients (including presymptomatic patients). The median (SE) time from diagnosis to the first negative conversion was 17 (1.07) days for asymptomatic patients and 19.5 (0.63) days for symptomatic (including presymptomatic) patients (P = .07). The Ct values for the envelope (env) gene from lower respiratory tract specimens showed that viral loads in asymptomatic patients from diagnosis to discharge tended to decrease more slowly in the time interaction trend than those in symptomatic (including presymptomatic) patients (β = -0.065 [SE, 0.023]; P = .005). CONCLUSIONS AND RELEVANCE: In this cohort study of symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center in Cheonan, Republic of Korea, the Ct values in asymptomatic patients were similar to those in symptomatic patients. Isolation of asymptomatic patients may be necessary to control the spread of SARS-CoV-2.

BACKGROUND: Mammography is the current standard for breast cancer screening. This study aimed to develop an artificial intelligence (AI) algorithm for diagnosis of breast cancer in mammography, and explore whether it could benefit radiologists by improving accuracy of diagnosis. METHODS: In this retrospective study, an AI algorithm was developed and validated with 170 230 mammography examinations collected from five institutions in South Korea, the USA, and the UK, including 36 468 cancer positive confirmed by biopsy, 59 544 benign confirmed by biopsy (8827 mammograms) or follow-up imaging (50 717 mammograms), and 74 218 normal. For the multicentre, observer-blinded, reader study, 320 mammograms (160 cancer positive, 64 benign, 96 normal) were independently obtained from two institutions. 14 radiologists participated as readers and assessed each mammogram in terms of likelihood of malignancy (LOM), location of malignancy, and necessity to recall the patient, first without and then with assistance of the AI algorithm. The performance of AI and radiologists was evaluated in terms of LOM-based area under the receiver operating characteristic curve (AUROC) and recall-based sensitivity and specificity. FINDINGS: The AI standalone performance was AUROC 0·959 (95% CI 0·952-0·966) overall, and 0·970 (0·963-0·978) in the South Korea dataset, 0·953 (0·938-0·968) in the USA dataset, and 0·938 (0·918-0·958) in the UK dataset. In the reader study, the performance level of AI was 0·940 (0·915-0·965), significantly higher than that of the radiologists without AI assistance (0·810, 95% CI 0·770-0·850; p<0·0001). With the assistance of AI, radiologists' performance was improved to 0·881 (0·850-0·911; p<0·0001). AI was more sensitive to detect cancers with mass (53 [90%] vs 46 [78%] of 59 cancers detected; p=0·044) or distortion or asymmetry (18 [90%] vs ten [50%] of 20 cancers detected; p=0·023) than radiologists. AI was better in detection of T1 cancers (73 [91%] vs 59 [74%] of 80; p=0·0039) or node-negative cancers (104 [87%] vs 88 [74%] of 119; p=0·0025) than radiologists. INTERPRETATION: The AI algorithm developed with large-scale mammography data showed better diagnostic performance in breast cancer detection compared with radiologists. The significant improvement in radiologists' performance when aided by AI supports application of AI to mammograms as a diagnostic support tool. FUNDING: Lunit.

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

The objective of this study is to describe the general approaches to network meta-analysis that are available for quantitative data synthesis using R software. We conducted a network meta-analysis using two approaches: Bayesian and frequentist methods. The corresponding R packages were "gemtc" for the Bayesian approach and "netmeta" for the frequentist approach. In estimating a network meta-analysis model using a Bayesian framework, the "rjags" package is a common tool. "rjags" implements Markov chain Monte Carlo simulation with a graphical output. The estimated overall effect sizes, test for heterogeneity, moderator effects, and publication bias were reported using R software. The authors focus on two flexible models, Bayesian and frequentist, to determine overall effect sizes in network meta-analysis. This study focused on the practical methods of network meta-analysis rather than theoretical concepts, making the material easy to understand for Korean researchers who did not major in statistics. The authors hope that this study will help many Korean researchers to perform network meta-analyses and conduct related research more easily with R software.

This study aimed to explore the effects of age, education and gender on the performance of eight tests in the Korean version of the CERAD neuropsychological assessment battery and to provide normative information on the tests in the Korean elderly. The battery was administered to 618 healthy volunteers aged from 60 to 90. People with serious neurological, medical and psychiatric disorders, including dementia, were excluded. Multiple linear regression analyses were performed to assess the relative contribution of the demographic factors on the score of each cognitive test. Age, education, and gender were found to have significant effects on the performance of many tests in the battery. Based on these results, 4 overlapping age normative tables (60 to 74, 65 to 79, 70 to 84, and 75 to 90 years of age) with 3 educational strata (0 to 3 years, 4 to 6 years, and 7 years and more) for both genders are presented. The normative information will be useful for a clinical interpretation of the CERAD neuropsychological battery in Korean elderly as well as for comparing the performance of the battery across countries.

BACKGROUND: It is expected that artificial intelligence (AI) will be used extensively in the medical field in the future. OBJECTIVE: The purpose of this study is to investigate the awareness of AI among Korean doctors and to assess physicians' attitudes toward the medical application of AI. METHODS: We conducted an online survey composed of 11 closed-ended questions using Google Forms. The survey consisted of questions regarding the recognition of and attitudes toward AI, the development direction of AI in medicine, and the possible risks of using AI in the medical field. RESULTS: A total of 669 participants completed the survey. Only 40 (5.9%) answered that they had good familiarity with AI. However, most participants considered AI useful in the medical field (558/669, 83.4% agreement). The advantage of using AI was seen as the ability to analyze vast amounts of high-quality, clinically relevant data in real time. Respondents agreed that the area of medicine in which AI would be most useful is disease diagnosis (558/669, 83.4% agreement). One possible problem cited by the participants was that AI would not be able to assist in unexpected situations owing to inadequate information (196/669, 29.3%). Less than half of the participants(294/669, 43.9%) agreed that AI is diagnostically superior to human doctors. Only 237 (35.4%) answered that they agreed that AI could replace them in their jobs. CONCLUSIONS: This study suggests that Korean doctors and medical students have favorable attitudes toward AI in the medical field. The majority of physicians surveyed believed that AI will not replace their roles in the future.

PURPOSE Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748 ) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m 2 , oxaliplatin 100 mg/m 2 intravenously day 1, S-1 40 mg/m 2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

BACKGROUND: This study aimed to investigate the recent prevalence, management, and comorbidities of diabetes among Korean adults aged ≥30 years by analyzing nationally representative data. METHODS: This study used data from the Korea National Health and Nutrition Examination Survey from 2016 to 2018, and the percentage and total number of people ≥30 years of age with diabetes and impaired fasting glucose (IFG) were estimated. RESULTS: In 2018, 13.8% of Korean adults aged ≥30 years had diabetes, and adults aged ≥65 years showed a prevalence rate of 28%. The prevalence of IFG was 26.9% in adults aged ≥30 years. From 2016 to 2018, 35% of the subjects with diabetes were not aware of their condition. Regarding comorbidities, 53.2% and 61.3% were obese and hypertensive, respectively, and 72% had hypercholesterolemia as defined by low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dL in people with diabetes. Of the subjects with diabetes, 43.7% had both hypertension and hypercholesterolemia. With regard to glycemic control, only 28.3% reached the target level of <6.5%. Moreover, only 11.5% of subjects with diabetes met all three targets of glycosylated hemoglobin, blood pressure, and LDL-C. The percentage of energy intake from carbohydrates was higher in diabetes patients than in those without diabetes, while that from protein and fat was lower in subjects with diabetes. CONCLUSION: The high prevalence and low control rate of diabetes and its comorbidities in Korean adults were confirmed. More stringent efforts are needed to improve the comprehensive management of diabetes to reduce diabetes-related morbidity and mortality.

OBJECTIVE: We prospectively evaluated transabdominal and transvaginal sonographic findings of patients with pelvic congestion syndrome and compared them with those of healthy volunteers. SUBJECTS AND METHODS. We examined 32 patients with pelvic congestion syndrome and 35 control subjects. Using transabdominal sonography, we evaluated the ovarian veins for diameter and flow direction, presence of pelvic varicocele, diameter of the pelvic veins, change of the duplex waveform during the Valsalva's maneuver, volume of the uterus, and presence of polycystic changes in the ovaries. We compared and statistically analyzed each parameter in the pelvic congestion syndrome group and in the control group. RESULTS: The mean (+/- SD) diameter of the left ovarian vein was 0.79 +/- 0.23 cm in the pelvic congestion syndrome group and 0.49 +/- 0.15 cm in the control group (p = 0.000). Reversed caudal flow in the left ovarian vein was present in 22 of 22 patients and in four of 16 control subjects. Pelvic varicoceles were present in all patients with pelvic congestion syndrome and in six control subjects. The mean diameter of the left pelvic vein was 0.68 +/- 0.21 cm in the pelvic congestion syndrome group and 0.42 +/- 0.19 cm in the control group; the mean diameter of the right pelvic vein was 0.64 +/- 0.24 cm in the pelvic congestion syndrome group and 0.35 +/- 0.14 cm in the control group (p = 0.000). Polycystic changes of the ovary were present in 13 patients with pelvic congestion syndrome (40.6%) and four control subjects (11.4%). CONCLUSION: Sonographic findings of pelvic congestion syndrome were dilated left ovarian vein with reversed caudal flow, presence of varicocele, dilated arcuate veins crossing the uterine myometrium, polycystic changes of the ovary, and variable duplex waveform during the Valsalva's maneuver. Combined transabdominal and transvaginal sonography are potentially useful as a noninvasive screening tool for determining which patients with chronic pelvic pain may benefit from selective ovarian venography and transcatheter embolization.

Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

BACKGROUND: The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. METHODS AND RESULTS: Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46-1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44-1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). CONCLUSIONS: Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259.

Incidental thyroid nodules are commonly detected on ultrasonography (US). This has contributed to the rapidly rising incidence of low-risk papillary thyroid carcinoma over the last 20 years. The appropriate diagnosis and management of these patients is based on the risk factors related to the patients as well as the thyroid nodules. The Korean Society of Thyroid Radiology (KSThR) published consensus recommendations for US-based management of thyroid nodules in 2011 and revised them in 2016. These guidelines have been used as the standard guidelines in Korea. However, recent advances in the diagnosis and management of thyroid nodules have necessitated the revision of the original recommendations. The task force of the KSThR has revised the Korean Thyroid Imaging Reporting and Data System and recommendations for US lexicon, biopsy criteria, US criteria of extrathyroidal extension, optimal thyroid computed tomography protocol, and US follow-up of thyroid nodules before and after biopsy. The biopsy criteria were revised to reduce unnecessary biopsies for benign nodules while maintaining an appropriate sensitivity for the detection of malignant tumors in small (1-2 cm) thyroid nodules. The goal of these recommendations is to provide the optimal scientific evidence and expert opinion consensus regarding US-based diagnosis and management of thyroid nodules.

This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).