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Background: Organ crosstalk between the kidney and the heart has been suggested. Acute kidney injury (AKI) and acute heart failure (AHF) are well-known independent risk factors for mortality in hospitalized patients. This study aimed to investigate if these conditions have an additive effect on mortality in hospitalized patients, as this has not been explored in previous studies.Methods: We retrospectively reviewed the records of 101,804 hospitalized patients who visited two tertiary hospitals in the Republic of Korea over a period of 5 years. AKI was diagnosed using serum creatinine-based criteria, and AHF was classified using International Classification of Diseases codes within 2 weeks after admission. Patients were divided into four groups according to the two conditions. The primary outcome was all-cause mortality.Results: AKI occurred in 6.8% of all patients (n = 6,920) and AHF in 1.2% (n = 1,244). Three hundred thirty-one patients (0.3%) developed both conditions while AKI alone was present in 6,589 patients (6.5%) and AHF alone in 913 patients (0.9%). Among the 5,181 patients (5.1%) who died, 20.8% died within 1 month. The hazard ratio for 1-month mortality was 29.23 in patients with both conditions, 15.00 for AKI only, and 3.39 for AHF only. The relative excess risk of interaction was 11.85 (95% confidence interval, 2.43‒21.27), and was more prominent in patients aged

Background Guidelines recommending additional imaging for adrenal nodules lack relevant epidemiologic evidence. Purpose To measure the prevalence of adrenal nodules detected at staging CT in patients with potentially resectable gastric cancer and the proportion of patients with malignant nodules among them. Materials and Methods This retrospective study included 10 250 consecutive patients (median age, 63 years; interquartile range, 53-71 years; 6884 men) who underwent staging CT and had potentially resectable gastric cancer in a tertiary center (May 2003 to December 2018). All 10 250 CT studies were retrospectively reviewed, and patients with adrenal nodules (or thickening ≥10 mm) were identified to measure the prevalence of adrenal nodules. Among patients with adrenal nodules, the per-patient proportions of malignant nodules, adrenal metastasis from gastric cancer, and additional adrenal examinations were measured. A secondary analysis was performed by using data from the original CT reports. The same metrics that were used in the retrospective review were assessed. Results The prevalence of adrenal nodules was 4.5% (95% CI: 4.1, 4.9; 462 of 10 250). The proportions of malignant nodules and adrenal metastasis from gastric cancer were 0.4% ( 95% CI: 0.1, 1.6; two of 462) and 0% (95% CI: 0.0, 0.8; 0 of 462), respectively. A total of 27% of the patients (95% CI: 23, 31; 123 of 462) underwent additional adrenal examination. According to original CT reports, the prevalence of adrenal nodules and the proportions of malignant nodules, adrenal metastases from gastric cancer, and additional adrenal examination were 2.7% (95% CI: 2.4, 3.0; 272 of 10 250), 0.7% (95% CI: 0.1, 2.6; two of 272), 0% (95% CI: 0.0, 1.4; 0 of 272), and 42.6% (95% CI: 36.7, 48.8; 116 of 272), respectively. Conclusion Although adrenal nodules were detected frequently on staging CT images of patients with otherwise resectable gastric cancer, these nodules were rarely malignant. ©RSNA, 2021

Although angiomyolipoma (AML) is commonly found in the kidney, its appearance in the liver is rare. The first hepatic AML was reported by Ishak in 1976. Since then, there have been various reports of AML. An AML is a tumour affecting adipocytes, muscle tissues, and blood vessels. Hepatic AML has been associated with tuberous sclerosis. Its spontaneous occurrence has also been noticed. It can have a varied presentation with some being asymptomatic, others presenting with a dull aching pain, while some with disastrous consequences due to rupture and torrential bleeding intra-abdominally. Herein, we present a case of a 47-year-old female with a large hepatic AML having an internal hemorrhage that caused changes in hepatic arteries. In our case, magnetic resonance imaging was unable to establish a diagnosis. Intraoperatively, AML caused dilatation and engorgement of vessels around the porta. Immediately post resection, vessel dilatation and engorgement were reduced on table. Another notable feature was that these changes caused no intra-operative or post-operative hemodynamic changes. We report a case of a huge hepatic AML with internal hemorrhage associated with perihepatic vascular changes having a successful surgical treatment.

The authors report a rare case of sequentially developed bilateral internal carotid artery (ICA) fusiform giant aneurysms in a patient with pathologically confirmed intimal fibroplasia. Both ICA fusiform aneurysms were treated with multiple flow diverter insertion and were well-managed over the past 5.5 years of follow-up. The development of aneurysms in this rare disease entity appears to be a lifelong process based on the authors’ observations in serial angiographic follow-up studies. Reconstruction therapy using flow-diverting stents in this unique condition may be a safe and effective treatment modality.

Background A laparoscopic approach is widely used in abdominal surgery. Although several studies have compared surgical and oncological outcomes between laparoscopic surgery (LS) and open surgery (OS) in rectal cancer patients, there have been few studies on postoperative renal outcomes. Methods We conducted a retrospective cohort study involving 1,633 patients who underwent rectal cancer surgery between 2003 and 2017. Postoperative acute kidney injury (AKI) was diagnosed according to the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes classification. Results Among the 1,633 patients, 1,072 (65.6%) underwent LS. After matching propensity scores, 395 patients were included in each group. The incidence of postoperative AKI in the LS group was significantly lower than in the OS group (9.9% vs. 15.9%; p = 0.01). Operation time, estimated blood loss, and incidence of transfusion in the LS group were significantly lower than those in the OS group. Cox proportional hazard models revealed that LS was associated with decreased risk of postoperative AKI (hazard ratio [HR], 0.599; 95% confidence interval [CI], 0.402-0.893; p = 0.01) and postoperative transfusion was associated with increased risk of AKI (HR, 2.495; 95% CI, 1.529-4.072; p < 0.001). In the subgroup analysis, the incidence of postoperative AKI in patients with middle or high rectal cancer who underwent LS was much lower than in those who underwent OS (HR, 0.373; 95% CI, 0.197-0.705; p = 0.002). Conclusion This study showed that LS may have a favorable effect on the development of postoperative AKI in patients with rectal cancer.

A malignancy is a fatal condition that could occur through various mechanisms. Forensic pathologists sometimes find unexpected findings during autopsy and post-mortem (PM) tests. Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The deceased was a 64-year-old man with a medical history of right hemicolectomy due to colon cancer approximately two years earlier. He was found dead at his home. He was admitted to the hospital due to subdural hemorrhage (SDH) two days prior to his demise and was discharged without the permission of the doctor after one day of hospitalization. An autopsy was performed within two days of his death. After gross dissection, the cause and manner of death were assumed to be SDH and unnatural death, respectively. Microscopic examination revealed fresh SDH and dural metastasis of signet-ring cell carcinoma. Furthermore, metastasis was identified in the heart, stomach, and peritoneum. Immunohistochemical examination revealed cancer cells to originate from the colon. After meticulous PM examination, including gross dissection, microscopic examination, PM computed tomography, and PM laboratory tests, the cause and manner of death were determined as SDH and natural death, respectively. This case report highlights the importance of comprehensive PM evaluation for investigating death.

Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

The use of sodium nitrite in suicide has become more common among young adults in the Republic of Korea. This report details the case of a 28-year-old man; the man had posted on a social network service detailing his attempt at suicide at 13:45. In the posted article, he stated that he had ingested 84 g of sodium nitrite. A post-mortem (PM) inspection was performed at 21:00, and peripheral blood (PB) was collected. An autopsy was performed approximately 44 h after death. The victim's face was dark brown in color, but the color of his oral mucosa was bright red. Toxicological analyses revealed 33% and 26% methemoglobinemia in the PB collected during PM inspection and autopsy, respectively. The concentration of nitrate in the PB collected during PM inspection, and PB and cardiac blood collected during the autopsy were 220.6 mg/L, 220.0 mg/L, and 218.5 mg/L, respectively. Nitrate was also detected in the pericardial fluid and cerebrospinal fluid at levels of 91.7 mg/L and 50.5 mg/L, respectively. The cause of death was determined to be methemoglobinemia-induced hypoxia due to sodium nitrite ingestion. This intoxication case informs some novel points about nitrite intoxication; the concentration of methemoglobin decreased during the PM period, while the concentration of nitrate was stable. There was no difference in the concentration of nitrate between cardiac and peripheral blood. Nitrate could be detected in the pericardial fluid and cerebrospinal fluid. This new information is helpful for better identifying future cases of nitrite intoxication.

Fecal microbiota transplantation (FMT) is considered as an effective treatment for Clostridioides difficile infection. However, the precise mechanism of FMT is yet to be determined. Human stool consists of the gut microbiota, bacterial debris, and metabolic products. Of these, the intestinal microbiota is the most important factor that exerts therapeutic efficacy in FMT. Fresh donor stool, blended with normal saline, has been employed for traditional FMT. Nevertheless, stool processing is a major impediment in FMT. Frozen stool and capsule formulations have similar efficacy to that of fresh stool. In addition, several novel stool products have been identified. A stool bank that provides stool products with pre-screened donor stool has been established to help physicians and thereby facilitate FMT. Recent next-generation sequencing techniques have been key in facilitating the detailed analysis of the microbiota and gut environment of individual donors and recipients.

Purpose To examine the relationships of body dysmorphic disorder (BDD) with psychiatric symptoms and quality of life in dermatological patients. Patients and Methods A total of 154 female patients with dermatological disease underwent a comprehensive clinical assessment that included the Body Dysmorphic Disorder Examination-Self Report (BDDE-SR), Symptom Checklist 90-Revised (SCL-90-R), and Skindex-29. Dermatological disease was categorized as follows: inflammatory dermatoses (reference category), isolated lesions, and unclassified dermatoses. The BDDE-SR and SCL-90-R scores were used to evaluate BDD and psychiatric symptoms, respectively. Dermatological quality of life was measured with the Skindex-29. Results The BDDE-SR score was significantly associated with the SCL-90-R and Skindex-29 total and subscores, even after controlling for age, body mass index, and dermatological diagnosis. The variables that contributed most to the BDDE-SR score were the SCL-90-R depression score and Skindex-29 emotion scores. Additional analyses revealed that the BDDE-SR score was higher in participants with unclassified dermatoses, but neither the SCL-90-R score nor Skindex-29 score was related to any dermatological diagnosis. Conclusion The BDD symptoms were especially prominent in the unclassified dermatoses group and were highly related to psychiatric symptoms and a poor quality of life in our dermatological patients. Further research including studies involving psychiatric interviews to confirm the BDD diagnosis and symptoms will improve our understanding of BDD in dermatological patients.

BACKGROUND Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC. METHODS Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated. RESULTS Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p

Purpose We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients.Materials and Methods The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists.Results The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability.Conclusion Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

Coronavirus disease-19 (COVID-19) is a respiratory syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emerged in Wuhan, China, in late 2019 It resulted in a worldwide pandemic, and spread through community transmission in the Republic of Korea (ROK) In the ROK, SARS-CoV-2 is categorized as a first-degree infectious disease of the legal communicable disease present The Korean Society for Legal Medicine (KSLM) is the sole official academic association of forensic professionals in the ROK As such, this society has played an important role in forensic medicine and science in the ROK Therefore, KSLM suggests a standard operating procedure for the postmortem inspection in a focus on COVID-19 This article includes the background of this suggested standard operation procedure, basic principles for postmortem inspections of individuals suggested of having an infectious disease, and specific procedures according to the probability level of SARSCoV- 2 infection

Optimal bowel preparation is essential for a more accurate, comfortable, and safe colonoscopy. The majority of postcolonoscopy colorectal cancers can be explained by procedural factors, mainly missed polyps or inadequate examination. Therefore the most important goal of optimal bowel preparation is to reduce the incidence of colorectal cancer. Although adequate preparation should be achieved in 85-90% or more of all colonoscopy as a quality indicator, unfortunately 20-30% shows inadequate preparation. Laxatives for oral colonoscopy bowel preparation can be classified into polyethylene glycol (PEG)-electrolyte lavage solution, osmotic laxatives, stimulant laxatives, and divided into high-volume solution (≥3 L) and low-volume solution (

Background/Aims Emerging evidence shows that the mechanism of irritable bowel syndrome (IBS) is associated with neurotrophic factors and tight junction proteins (TJPs). It is known that there are sex differences in the pathophysiology of IBS. The aim of the present study is to determine expression levels of neurotrophic factors, TJPs, and cytokines according to IBS subtype and sex. Methods From 59 IBS (33 IBS-constipation, 21 IBS-diarrhea, and 5 IBS-mixed) and 36 control patients, colonic mucosa mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1), nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and various TJPs were assessed by real-time polymerase chain reaction. Western blot was performed to determine levels of zonular occludens-1 (ZO-1). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay. Results TRPV1, GDNF, and NGF mRNA levels were significantly increased in those with IBS-constipation compared to those in controls (all P < 0.05). However, they showed no significant difference between those with IBS-diarrhea and controls. Expression level of TRPV1 correlated with that of GDNF (r = 0.741, P < 0.001) and NGF (r = 0.935, P < 0.001). ZO-1 RNA expression levels were lower (P = 0.021) in female IBS-diarrhea than those in controls, although they showed no significant differences between male IBS-diarrhea and controls. Serum IL-1β levels in female IBS were significantly higher than those of male IBS, especially in IBS-constipation (P < 0.001). Conclusion Our results suggest that neurotrophic factors and IL-1β are closely related to IBS-constipation and that decrease of ZO-1 is an important factor in female with IBS-diarrhea.

Background Allergic asthma was typically considered as an inflammatory disease mediated by type 2 immunity. However, recent studies revealed that asthma is a complex disease displaying a variety of phenotypes and endotypes. Objective We examined cellular phenotypes in the mouse model of allergic asthma sensitized with different adjuvants. The aim of our study was to determine immunologic cellular characteristics in mouse asthma models induced by ovalbumin (OVA) and a variety of adjuvants. Methods Mice were sensitized intraperitoneally with the admixture of OVA and various adjuvants such as Alhydrogel (alum), papain, lipopolysaccharide (LPS), or CpG, and subsequently challenged with OVA intranasally. The cells in bronchoalveolar lavage (BAL) fluid, lung, and mediastinal lymph node (mLN) were examined by flow cytometric analyses. Results In the lung and BAL fluid, the highest eosinophil levels were observed in the alum group while the highest neutrophil levels were detected in the LPS group. Meanwhile, the LPS group exhibited the most elevated levels of both RORγt+ innate lymphoid cells (ILCs) and IL-17A+ Th cells in the lung and mediastinal lymph node. In the lung, the number of T-bet+ ILCs was highest in the papain group whereas the number of IFN-γ+ Th cells was highest in the CpG group. Conclusions Notable variances are found in the composition of immune cells and expression of cytokines at the site of pathogenesis among the different mouse models of allergic asthma created by the sensitization with different adjuvants.

Background Interpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions. Methods Search for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above. Results Most clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL. Conclusions P63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.

Background In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC). Methods Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases. Results The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAFV600E mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27). Conclusions The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.

Capsule endoscopy (CE) has proven to be a valuable diagnostic modality for small bowel diseases over the past 20 years, particularly Crohn’s disease (CD), which can affect the entire gastrointestinal tract from the mouth to the anus. CE is not only used for the diagnosis of patients with suspected small bowel CD, but can also be used to assess disease activity, treat-to-target, and postoperative recurrence in patients with established small bowel CD. As CE can detect even mildly non-specific small bowel lesions, a high diagnostic yield is not necessarily indicative of high diagnostic accuracy. Moreover, the cost effectiveness of CE as a third diagnostic test employed usually after ileocolonoscopy and MR or CT enterography is an important consideration. Recently, new developments in colon capsule endoscopy (CCE) have increased the utility of CE in patients with ulcerative colitis (UC) and pan-enteric CD. Although deflation of the colon during the examination and the inability to evaluate dysplasia-associated lesion or mass results in an inherent risk of overestimation or underestimation, the convenience of CCE examination and the risk of flare-up after colonoscopy suggest that CCE could be used more actively in patients with UC.

OBJECTIVE Primary aldosteronism (PA) shows histological heterogeneity and clinical variability, including the coexistence of hypercortisolemia. Immunohistochemical analyses of steroidogenic enzymes in adrenal tissues have provided new insights into the pathogenesis of PA. However, a comprehensive analysis of the association between enzyme expression and clinical characteristics of PA has rarely been conducted. We aimed to investigate the correlation between clinical characteristics and steroidogenic enzyme expression in PA. DESIGN A retrospective case-control study. PATIENTS Consecutive patients who underwent unilateral adrenalectomy for PA (n = 180). Patients with adrenal Cushing's syndrome (CS) (n = 29) and nonfunctioning adenoma (n = 6) as comparator groups. MEASUREMENTS A tissue microarray of adrenal adenomas was constructed and immunostained for CYP11B1, CYP11B2 and CYP17A1. The expression of the three enzymes was compared between PA and other adrenal diseases and between PA with and without mild autonomous cortisol excess (MACE). RESULTS Adrenal adenomas in PA showed lower CYP11B1, higher CYP11B2 and lower CYP17A1 expression than those in adrenal CS (p

Renal fibrosis is a progressive chronic kidney disease that ultimately leads to end-stage renal failure. Despite several approaches to combat renal fibrosis, an experimental model to evaluate currently available drugs is not ideal. We developed fibrosis-mimicking models using three-dimensional (3D) co-culture devices designed with three separate layers of tubule interstitium, namely, epithelial, fibroblastic, and endothelial layers. We introduced human renal proximal tubular epithelial cells (HK-2), human umbilical-vein endothelial cells, and patient-derived renal fibroblasts, and evaluated the effects of transforming growth factor-β (TGF-β) and TGF-β inhibitor treatment on this renal fibrosis model. The expression of the fibrosis marker alpha smooth muscle actin upon TGF-β1 treatment was augmented in monolayer-cultured HK-2 cells in a 3D disease model. In the vascular compartment of renal fibrosis models, the density of vessels was increased and decreased in the TGF-β-treated group and TGF-β-inhibitor treatment group, respectively. Multiplex ELISA using supernatants in the TGF-β-stimulating 3D models showed that pro-inflammatory cytokine and growth factor levels including interleukin-1 beta, tumor necrosis factor alpha, basic fibroblast growth factor, and TGF-β1, TGF-β2, and TGF-β3 were increased, which mimicked the fibrotic microenvironments of human kidneys. This study may enable the construction of a human renal fibrosis-mimicking device model beyond traditional culture experiments.

Background Only 10 cases of cecal epidermoid cyst (CEC) have been reported in the literature. Furthermore, its pathogenesis remains unclear. We report a rare case of congenital CEC in neonate, and discuss its clinicopathological findings. Case presentation A cystic lesion was incidentally identified in the retroperitoneal area of the abdominal right lower quadrant during a routine prenatal ultrasonography (US), prompting an ileocolectomy 3 days after birth. This congenital cyst was composed of mucosal lining cells and submucosal connective tissues, and the inner lining mucosa was composed of stratified squamous epithelium and focally mucin-producing ciliated epithelium. Based on the macroscopic and microscopic findings, the cystic lesion was diagnosed as a congenital cecal epidermoid cyst. Conclusions The management of a fetal abdominal mass should be tailored individually, considering that epidermoid cysts can occur in the cecum during the perinatal period. We report the clinicopathological findings in this case, including its possible pathogenesis.

As the incidence of inflammatory bowel disease (IBD) are increasing with an ageing population, the incidence and prevalence of IBD in the elderly continue to increase. Older IBD patients can be classified into two groups; elderly-onset IBD patients and elderly IBD patients who were diagnosed at a young age and transitioning into advanced age. Clinicians must consider elderly-onset specific phenotypes or prognosis and age-related concerns in the treatment of elderly IBD patients. There is a paucity of evidence whether there is a different disease process when IBD occurs in older age yet. Clinicians may expect similar therapeutic effects in older and younger patients in drug selection, but since older patients are often excluded from clinical trials, evidence to support this assumption is currently lacking. Also, the risk of side effects may be higher in elderly patients. Therefore, when making management decisions in the elderly, clinicians should assess an individual's frailty rather than only considering an individual's chronological and biological age. Knowing specific requirements for managing older IBD patients may help to make an appropriate therapeutic strategy for this patient group.

Background and Aims Patients undergoing hemodialysis showed higher prevalence of sarcopenia than that of the healthy. As an intracellular water reservoir, skeletal muscle mass would be important to predict intradialytic hypotension. This study was designed to reveal the effect of skeletal muscle mass to intradialytic hypotension, which is also an indicator of volume status in patients under hemodialysis. Method 150 patients from three hemodialysis centers in 2016 and 38 patients from one center under maintenance hemodialysis in 2020 were enrolled in this study, and total 177 patients were finally analyzed. We measured skeletal muscle mass, intracellular water, extracellular water, total body water and phase angle in 50 kHz by bio-impedance analysis just after a hemodialysis session. Information including laboratory tests, chest x-ray, handgrip strength, mid-arm circumference and questionnaire to ask the patients’ general condition was collected. Intradialytic hypotension over three months was observed. We analyzed several factors including skeletal muscle mass which would have association with intradialytic hypotension over three months by multivariate logistic regression model. Results Tertile subgroups divided by the ratio of skeletal muscle to body weight defined as skeletal muscle index were compared. Patients in low skeletal muscle index had a higher rate of intradialytic hypotension (41%) while that of intermediate group was 20% and high group was 5%. Patients in low skeletal muscle mass index group was female-dominant, more obese, more diabetic and had lower handgrip strength than higher skeletal muscle index group. In patients who had higher skeletal muscle mass to body weight, the risk of Intradialytic hypotension was decreased (HR: 0.80 [95% CI 0.75-0.88], adjusted HR: 0.73 [95% CI 0.64–0.84]). Comparing tertile groups by skeletal muscle index, patients in the group of higher skeletal muscle mass index showed lower rate of intradialytic hypotension during hemodialysis, which was similar in inverse probability of treatment weighted analysis. Confounders were age, gender, diabetes mellitus, heart failure, ischemic heart disease, the ratio of ultrafiltration amount to body weight and skeletal muscle index. Model including skeletal muscle index and clinical parameters showed highest AUC area (0.877 [95% 0.823-0.930]) when the model including clinical parameters only (AUC area: 0.807 [95% CI 0.735-0.879]) or with each bioimpedance index (skeletal muscle mass to squared height, AUC area: 0.843 [95% CI 0.823-0.931]; the ratio of extracellular water to total water, AUC area: 0.809 [95% CI 0.736-0.883]; the ratio of intracellular water to total water, AUC area: 0.811 [95% CI 0.738-0.885] and phase angle, AUC area: 0.812 [95% CI 0.738-0.886]). Conclusion This study showed correlation between skeletal muscle mass by body weight and intradialytic hypotension. It especially suggested that skeletal muscle mass to weight would be a good predictor of intradialytic hypotension and would be helpful to decide appropriate dry body weight in hemodialysis.

This study was designed to evaluate the preoperative diagnostic categories of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) using thyroid core needle biopsy (CNB) and to analyze its impact on the risk of malignancy (ROM). A total of 2687 consecutive thyroid CNBs were reviewed retrospectively and classified into six diagnostic categories using a standardized reporting system similar to the Bethesda System for Reporting Thyroid Cytopathology. Diagnostic categories of CNBs were compared with the final surgical diagnoses, and the ROM in each category was calculated both before and after excluding NIFTP from malignancy. Of 946 surgically resected cases, 683 were diagnosed as papillary thyroid carcinoma (PTC), and 32 (4.7% of PTC) were reclassified as NIFTP. The CNB diagnostic categories of NIFTP were as follows: follicular neoplasm in 20 (62.5%; 14, with nuclear atypia), indeterminate lesion in 11 (34.4%), and suspicious for malignancy in one (3.1%). When combined, NIFTP and encapsulated follicular variant of PTC (EFVPTC) were more often categorized as follicular neoplasm compared with other PTC variants including infiltrative FVPTC. Exclusion of NIFTP from malignant diagnosis led to a significant decrease in the ROM in follicular neoplasm with nuclear atypia category. Thus, thyroid CNB enables to differentiate NIFTP/EFVPTC from other PTCs, providing a useful guide for optimal treatment in patients with these tumors.

Background: Health problems for expatriates are common due to their vulnerability to local infectious diseases, psychosocial problems, and chronic diseases, but many problems go largely unmet in this unique population. Introduction: Telehealth counseling was developed and tested for Korean expatriates. We explored the current status of using telehealth counseling systems and showed its feasibility and acceptability in three countries. Materials and Methods: This retrospective study was based on the “Development and demonstration of telehealth counseling program for overseas Koreans” project funded by the Korea Health Industry Development Institute. In this project, we established five Digital Healthcare Centers (DHCs): 3 in Vietnam and 1 each in Uzbekistan and Cambodia. We used data from October 2016 to September 2017; descriptive analysis and one-way ANOVA were used to present detailed information. Results: A total of 442 patients made an appointment for telehealth counseling services. Overall user satisfaction rates were 96.1%. Over two thirds of patients (302/442, 68.3%) completed one-time telehealth counseling. About 13% were referred to primary care, and 17 (3.8%) were referred to specialists or tertiary hospital. The most common diagnostic category was endocrine, nutritional, and metabolic diseases (14%), followed by diseases of the circulatory system (12.3%) for one-time visit patients. Discussion: Our telehealth counseling program for expatriates was feasible and acceptable in three countries. It also has the potential to minimize language barriers and the cost of healthcare usage. Conclusion: Further research for sustainable effective telehealth systems for expatriates will be needed.

Background/Aims: Patients with chronic kidney disease (CKD) have been found to show markedly increased rates of end-stage renal disease, major adverse car diovascular and cerebrovascular events (MACCEs), and mortality. Therefore, new biomarkers are required for the early detection of such clinical outcomes in pa tients with CKD. We aimed to determine whether the level of circulating renalase was associated with CKD progression, MACCEs, and all-cause mortality, using data from a prospective randomized controlled study, Kremezin STudy Against Renal disease progression in Korea (K-STAR; NCT 00860431). Methods: A retrospective analysis of the K-STAR data was performed including 383 patients with CKD (mean age, 56.4 years; male/female, 252/131). We measured circulating renalase levels and examined the effects of these levels on clinical outcomes. Results: The mean level of serum renalase was 75.8 ± 34.8 μg/mL. In the multi variable analysis, lower hemoglobin levels, higher serum creatinine levels, and diabetes mellitus were significantly associated with a higher renalase levels. Over the course of a mean follow-up period of 56 months, 25 deaths and 61 MACCEs occurred. Among 322 patients in whom these outcomes were assessed, 137 adverse renal outcomes occurred after a mean follow-up period of 27.8 months. Each 10- μg/mL increase in serum renalase was associated with significantly greater haz ards of all-cause mortality and adverse renal outcomes (hazard ratio [HR] = 1.112, p = 0.049; HR = 1.052, p = 0.045). However, serum renalase level was not associated with the rate of MACCEs in patients with CKD. Conclusions: Our results indicated that circulating renalase might be a predictor of mortality and adverse renal outcomes in patients with CKD.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting multiple organs, including the brain, skin, lung, and kidney. Among the multiple comorbidities in TSC, bone mineral disturbances remain relatively unrecognized, and only a few studies have reported alteration in calcium homeostasis. Hypocalcemia is a serious medical condition in patients with TSC who are at high risk for seizures. Therefore, hypocalcemia should be thoroughly evaluated by obtaining a history of associated medication use and measuring vitamin D levels. Here, we report the case of a patient with TSC who presented with severe hypocalcemia which may have been related to a history of anticonvulsant use and a recent decline in kidney function, and was successfully treated with calcium and vitamin D replacement.

AIM Hyperuricemia is a risk factor for high morbidity and mortality in several diseases. However, the relationship between uric acid (UA) and the risk of acute kidney injury (AKI) and mortality remain unresolved in hospitalized patients. METHODS Data from 18 444 hospitalized patients were retrospectively reviewed. The odds ratio (OR) for AKI and the hazard ratio (HR) for all-cause mortality were calculated based on the UA quartiles after adjustment for multiple variables. All analyses were performed after stratification by sex. RESULTS The fourth quartile group (male, UA > 6.7 mg/dL; female, UA > 5.4 mg/dL) showed a higher risk of AKI compared with the first quartile group (male, UA

Purpose This study demonstrates that estradiol downregulates inflammation and inhibits colorectal cancer (CRC) development in azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. Materials and Methods AOM/DSS-treated male and female mice were sacrificed at weeks 2, 10, and 16, to assess estrogen effects on colitis and carcinogenesis. Macroscopic and histologic severity of colitis and Western blot and quantitative real-time polymerase chain reaction were evaluated, to measure inflammatory mediators and cytokines. Results Compared with AOM/DSS-treated male mice (M-AOM/DSS group), AOM/DSS-treated male mice with estradiol administration (M-AOM/DSS+estr group) displayed at week 2 significantly decreased severity of colitis. At weeks 10 and 16, AOM/DSS-treated female mice (F-AOM/DSS group) and the M-AOM/DSS+estr group showed significantly lower tumor multiplicity compared with the M-AOM/DSS group. At week 2, F-AOM/DSS group had a lower level of nuclear factor-κB (NF-κB) expression and higher level of nuclear factor erythroid 2-related factor 2 (Nrf2) expression, compared to the M-AOM/DSS group. At week 2, expression levels of NF-κB and its related mediators decreased in the M-AOM/DSS+estr group, while levels of Nrf2 and Nrf2-related anti-oxidant enzymes increased. In addition, estradiol significantly increased Nod-like receptor protein 3 (NLRP3) inflammasome expressions in AOM/DSS-treated male mice. In contrast, at weeks 10 and 16, Nrf2 and its-related anti-oxidant enzymes and NLRP3 inflammasome were highly expressed in M-AOM/DSS group and in F-AOM/DSS group, who developed cancer. Conclusion The data suggest that estradiol inhibits the initiation of CRC by regulating Nrf2-related pathways. Moreover, these imply the dual role of Nrf2 and NLRP3 inflammasome, including promotion of tumor progression upon tumor initiation.

Background : Unlike patterns observed in the general population, obesity is associated with better survival among hemodialysis patients, which could be explained by reverse causation or illness-related weight loss. However, the time-varying effect of body mass index (BMI) on hemodialysis survival has not been investigated. Therefore, this study investigated the time-varying effect of BMI on mortality after starting hemodialysis. Methods : In the present study, we examined Korean Society of Nephrology data from 16,069 adult patients who started hemodialysis during or after the year 2000. Complete survival data were obtained from Statistics Korea. Survival analysis was performed using Cox regression and a non-proportional hazard fractional polynomial model. Results : During the median follow-up of 8.6 years, 9,272 patients (57.7%) died. Compared to individuals with normal BMI (18.5-24.9 kg/m2), the underweight group (< 18.5 kg/m2) had a higer mortality hazard ratio (HR, 1.292; 95% confidence interval [CI], 1.203-1.387; P < 0.001) and the overweight group (25.0-29.9 kg/m2) had a lower mortality HR (0.904; 95% CI, 0.829-0.985; P = 0.022). The underweight group had increasing HRs during the first 3 to 7 years after starting hemodialysis, which varied according to age group. The young obese group (< 40 years old) had a U-shaped temporal trend in their mortality HRs, which reflected increased mortality after 7 years. Conclusion : The obese hemodialysis group had better survival during the early post-dialysis period, although the beneficial effect of obesity disappeared 7 years after starting hemodialysis. The young obese group also had an increased mortality HR after 7 years.

To evaluate the efficacy and safety of CKD-11101 (biosimilar darbepoetin-alfa, Chong Kun Dang Pharm.) compared with NESP® in treatment of anaemia in patients with chronic kidney disease not on dialysis.NCT03431623.In this multi-centre, randomized, double-blind study, patients were treated with CKD-11101 and NESP. The efficacy evaluation period (EEP) was 24 weeks, during which patients were treated every 2 weeks. All patients who completed the EEP were treated with CKD-11101 every 2 weeks for the first 4 weeks and every 4 weeks for the safety evaluation period (SEP), which was from 24 weeks to 52 weeks. The primary efficacy endpoint was the change in mean haemoglobin (Hb) level from baseline to end of EEP and mean dose needed to achieve the target Hb.The mean Hb level was increased in both groups during the EEP (both p 0.001). The difference in mean Hb level change between the two groups was 0.01 g/dL (95% CI = -0.213-0.242), indicating that CKD-11101 was equivalent to NESP. The difference in mean administration dose between groups was -1.40 mcg (95% CI = -6.859-4.059) included in the equivalent range. The incidence of AEs and ADRs was not different between the two groups, and the frequency of ADRs was favourable in both groups (1.2% in CKD-11101 vs 7.7% in the NESP to CKD-11101 conversion group).CKD-11101 has an equivalent therapeutic effect as NESP in chronic kidney disease patients with renal anaemia. CKD-11101 can be safely used for long-term treatment and in patients converted from NESP.

BACKGROUND The up-regulation of the lipogenic pathway has been reported in many types of malignant tumors. However, its pathogenic role or clinical significance is not fully understood. The objective of this study was to examine the expression levels of adipophilin and related hypoxic signaling proteins and to determine their prognostic impacts and associations with the pathologic characteristics of lung adenocarcinoma. METHODS Expression levels of adipophilin, heat shock protein 27 (HSP27), carbonic anhydrase IX, and hypoxia-inducible factor 1α were examined by immunohistochemical staining using tissue microarray blocks. Correlations between protein expression levels and various clinicopathologic features were analyzed. RESULTS A total of 230 cases of primary adenocarcinoma of the lung were enrolled in this study. Adipophilin expression was more frequent in males and with the solid histologic type. It was correlated with HSP27 expression. Patients with adipophilin-positive adenocarcinoma showed a shorter progression-free survival (PFS) (median PFS, 17.2 months vs 18.4 months) in a univariable survival analysis, whereas HSP27 positivity correlated with favorable overall survival (OS) and PFS. In a multivariable analysis, adipophilin and HSP27 were independent prognostic markers of both OS and PFS. CONCLUSIONS Activated lipid metabolism and the hypoxic signaling pathway might play a major role in the progression of lung adenocarcinoma, especially in the solid histologic type.

The incidence of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) is steadily increasing. However, little is known about the characteristics of these patients or the factors affecting their prognosis. Our aim was to evaluate the pathological prognostic factors associated with survival in NAFLD patients.This was a retrospective cohort study of 575 patients who underwent resection of HCC between January 2004 and December 2018. HCC was associated purely with NAFLD or hepatitis B virus (HBV) based on the pathology and viral markers. The pathological markers of HCC were compared between patients with pure NAFLD and patients with pure HBV.The pathological factors were similar between the two groups. There were no differences in overall survival (OS; P=0.283) or recurrence-free survival (RFS; P=0.990) between the pure NAFLD and pure HBV groups. The NAFLD group had a similar local RFS (P=0.785) but a better systemic RFS compared with the HBV group, (P=0.089). In multivariable analysis using bootstrapping with resampling and replacement of data, no single factor was significantly associated with RFS. However, the Ki-67 labeling index [P=0.022; bootstrap 95% confidence interval (CI): 0.000-0.919] was the only independent factor associated with systemic recurrence in the NAFLD group.In patients with HCC associated with NAFLD, the Ki-67 labeling index determined by immunohistochemistry may predict the risk of systemic recurrence following resection, allowing for stricter monitoring protocols for such patients.

Radiologically identified para-aortic lymph node (PALN) metastasis is contraindicated for pancreatic cancer (PC) surgery. There is no clinical consensus for unexpected intraoperative PALN enlargement. To analyze the prognostic role of unexpected PALN enlargement in resectable PC, we retrospectively reviewed data of 1953 PC patients in a single tertiary center. Patients with unexpected intraoperative PALN enlargement (group A1, negative pathology, n = 59, group A2, positive pathology, n = 13) showed median overall survival (OS) of 24.6 (95% CI: 15.2–33.2) and 13.0 (95% CI: 4.9–19.7) months, respectively. Patients with radiological PALN metastasis without other metastases (group B, n = 91) showed median OS of 8.6 months (95% CI: 7.4–11.6). Compared with group A1, groups A2 and B had hazard ratios (HRs) of 2.79 (95% CI, 1.4–5.7) and 2.67 (95% CI: 1.8–4.0), respectively. Compared with group A2, group B had HR of 0.96 (95% CI: 0.5–1.9). Multivariable analysis also showed positive PALN as a negative prognostic factor (HR 2.57, 95% CI: 1.2–5.3), whereas positive regional lymph node did not (HR 1.32 95% CI: 0.8–2.3). Thus, unexpected malignant PALN has a negative prognostic impact comparable to radiological PALN metastasis. This results suggests prompt pathologic evaluation for unexpected PALN enlargements is needed and on-site modification of surgical strategy would be considered.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a dual role in carcinogenesis. We previously reported that Nrf2 deficiency enhances the anti-tumorigenic effect of 17β-estradiol (E2) in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated cancer (CAC). Herein, we aimed to determine a possible explanation for our recent work and investigated the immune microenvironment represented by programmed death-ligand 1 (PD-L1) expression. One week after the AOM injection, mice were administered with DSS in drinking water for seven days; daily E2 injections were intraperitoneally administered during this period. The mice were sacrificed 16 weeks after AOM injection and analyzed for PD-L1 expression in the distal colon tissues using Western blotting and immunohistochemistry (IHC). Based on Western blotting results, PD-L1 expression was reduced in Nrf2 knockout (KO) female and E2-treated male mice when compared with their wild-type counterparts, following AOM/DSS treatment; this supports the association of PD-L1 expression with tumor progression. Additionally, this finding was in good agreement with the IHC results for PD-L1. Furthermore, we observed that PD-L1 is predominantly expressed in stromal cells rather than on epithelial cells in the colon. Western blotting revealed that PD-L1 expression in the colon positively correlates with expressions of inducible nitric oxide synthase (iNOS) (male, P = 0.002; female, P <0.001) and cyclooxygenase-2 (COX-2) (male, P <0.001; female, P <0.001). Collectively, our findings indicate that estrogen ameliorates the immune microenvironment represented by PD-L1 expression and enhances its effect in the absence of Nrf2.

Following acute myocardial infarction (AMI), early use of beta-blockers (BBs) reduced the incidences of ventricular arrhythmia (VA) and death in the pre reperfusion era. However, some studies have reported a worsening of clinical outcomes and therefore, this study used a porcine model of AMI to evaluate the efficacy of bisoprolol on VAs and mortality. Twenty pigs were divided into two groups with one group using oral bisoprolol which was given for 3 hours before the experiment and then maintained for 7 days. A loop recorder was implanted, AMI was induced by balloon occlusion for 60 min, and then, reperfusion. One week later, the echocardiography and loop recorder data were analyzed in the surviving animals. Bisoprolol did not increase the heart rate (62.9±14.5 vs 79.0±20.3; p=0.048), lower the rate of premature ventricular contractions (PVC) (0.8±0.8 vs 11.0±12.8; p=0.021) or tend to lower recurrent VA (0.6±0.5 vs 1.1±1.1; p=0.131) during coronary artery occlusion. After reperfusion, bisoprolol did reduce VA in the early AMI period (0.1±0.3 vs 4.2±4.6; p=0.001) and it was not associated with the extent of myocardial recovery. In this porcine model, early oral bisoprolol might help reduce the incidences of PVC and recurrent VA and determine whether effects are more pronounced during the early AMI period. Our results suggest that bisoprolol might help reduce lethal VA and cardiac death following AMI in this reperfusion era.

Background Hyperchloremia is associated with the risks of several morbidities and mortality. However, its relationship with acute kidney injury (AKI) and end-stage renal disease (ESRD) in patients undergoing coronary artery bypass grafting (CABG) remains unresolved. Methods A total of 2977 patients undergoing CABG between 2003 and 2015 were retrospectively reviewed from two tertiary hospitals. Patients were categorized by serum chloride levels into normochloremia (95–105 mmol/L), mild hyperchloremia (106–110 mmol/L), and severe hyperchloremia (> 110 mmol/L). The odds ratios (ORs) for AKI and hazard ratios (HRs) for ESRD were calculated after adjustment for multiple covariates. The death-adjusted risk of ESRD was additionally evaluated. Results Postoperative AKI occurred in 798 patients (26.5%). The hyperchloremia group had a higher risk of AKI than the normochloremia group, wherein the risk was incremental depending on the severity of hyperchloremia, as follows: ORs were 1.26 (1.06–1.51) and 1.95 (1.52–2.51) in the mild and severe hyperchloremia groups, respectively. During a median period of 7 years (maximum 15 years), 70 patients (2.3%) had ESRD. The severe hyperchloremia group was at an elevated risk of ESRD compared with the normochloremia group, with an HR of 2.43 (1.28–4.63). Even after adjusting for the competing risk of death, hyperchloremia was associated with the risk of ESRD. Conclusions Preoperative hyperchloremia is associated with poor renal outcomes such as AKI and ESRD after CABG. Accordingly, serum chloride should be monitored in patients undergoing CABG.

There is a great interest in developing antigen-specific therapeutic approaches for the treatment of autoimmune diseases without compromising normal immune function. The key challenges are to control all antigen-specific lymphocyte populations that contribute to pathogenic inflammatory processes and to provide long-term protection from disease relapses. Here, we show that myelin oligodendrocyte glycoprotein (MOG)-specific tolerance can be established by ectopic expression of MOG in the immune organs. Using transgenic mice expressing MOG-specific CD4, CD8, and B cell receptors, we show that MOG expression in the bone marrow cells results in impaired development of MOG-specific lymphocytes. Ectopic MOG expression has also resulted in long-lasting protection from MOG-induced autoimmunity. This finding raises hope that transplantation of autoantigen-expressing bone marrow cells as a therapeutic strategy for specific autoantigen-driven autoimmune diseases.

Familial adenomatous polyposis (FAP) is a hereditary disease characterized by the development of numerous colorectal adenomas in young adults. Metformin, an oral diabetic drug, has been shown to have antineoplastic effects and a favorable safety profile. We performed a randomized, double-blind, controlled trial to evaluate the efficacy of metformin on the regression of colorectal and duodenal adenoma in patients with FAP. Thirty-four FAP patients were randomly assigned in a 1:2:2 ratio to receive placebo, 500 mg metformin, or 1,500 mg metformin per day orally for 7 months. The number and size of polyps and the global polyp burden were evaluated before and after the intervention. This study was terminated early based on the results of the interim analysis. No significant differences were determined in the percentage change of colorectal and duodenal polyp number over the course of treatment among the three treatment arms (P = 0.627 and P = 1.000, respectively). We found no significant differences in the percentage change of colorectal or duodenal polyp size among the three groups (P = 0.214 and P = 0.803, respectively). The overall polyp burdens of the colorectum and duodenum were not significantly changed by metformin treatment at either dosage. Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm. In conclusion, 7 months of treatment with 500 mg or 1,500 mg metformin did not reduce the mean number or size of polyps in the colorectum or duodenum in FAP patients (ClinicalTrials.gov ID: NCT01725490). Prevention Relevance: A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo. These results do not support the use of metformin to promote regression of intestinal adenomas in FAP patients.

Although American Thyroid Association guidelines offer a risk stratification scheme for thyroid cancer patients, there is a continuous need for more sophisticated biomarkers that can predict disease progression. In this study, we aim to evaluate the prognostic value of class III beta-tubulin (TUBB3) and uncover the relationship between TUBB3 and invasive potential in thyroid carcinoma. Immunohistochemistry (IHC) for TUBB3 and E-cadherin was performed on a total of 254 cases of thyroid cancer specimens. Tumor budding at the invasive margin was evaluated. In vitro functional studies were also performed, the protein and mRNA levels of TUBB3 were compared among the five cell types at baseline, with transwell invasion and after blocking of TUBB3 by shRNA. IHC revealed that the levels of TUBB3 were higher in conventional papillary carcinomas (cPTCs) and anaplastic thyroid carcinomas (ATCs). In univariate analysis, high tumor budding and TUBB3 expression were associated with inferior progression-free survival in cPTC. The results of a Western blot and RT-PCR agreed with the IHC finding. The results were further validated through data from The Cancer Genome Atlas database. Our results suggest that high expression of TUBB3 in thyroid carcinoma could predict invasive potential and possibly be linked with epithelial&ndash, mesenchymal transition.

Background Acute kidney injury (AKI) is commonly encountered in clinical practice and is associated with poor patient outcomes and increased health care costs. Despite it posing significant challenges for clinicians, effective measures for AKI prediction and prevention are lacking. Previously published AKI prediction models mostly have a simple design without external validation. Furthermore, little is known about the process of linking model output and clinical decisions due to the black-box nature of neural network models. Objective We aimed to present an externally validated recurrent neural network (RNN)–based continuous prediction model for in-hospital AKI and show applicable model interpretations in relation to clinical decision support. Methods Study populations were all patients aged 18 years or older who were hospitalized for more than 48 hours between 2013 and 2017 in 2 tertiary hospitals in Korea (Seoul National University Bundang Hospital and Seoul National University Hospital). All demographic data, laboratory values, vital signs, and clinical conditions of patients were obtained from electronic health records of each hospital. We developed 2-stage hierarchical prediction models (model 1 and model 2) using RNN algorithms. The outcome variable for model 1 was the occurrence of AKI within 7 days from the present. Model 2 predicted the future trajectory of creatinine values up to 72 hours. The performance of each developed model was evaluated using the internal and external validation data sets. For the explainability of our models, different model-agnostic interpretation methods were used, including Shapley Additive Explanations, partial dependence plots, individual conditional expectation, and accumulated local effects plots. Results We included 69,081 patients in the training, 7675 in the internal validation, and 72,352 in the external validation cohorts for model development after excluding cases with missing data and those with an estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or end-stage kidney disease. Model 1 predicted any AKI development with an area under the receiver operating characteristic curve (AUC) of 0.88 (internal validation) and 0.84 (external validation), and stage 2 or higher AKI development with an AUC of 0.93 (internal validation) and 0.90 (external validation). Model 2 predicted the future creatinine values within 3 days with mean-squared errors of 0.04-0.09 for patients with higher risks of AKI and 0.03-0.08 for those with lower risks. Based on the developed models, we showed AKI probability according to feature values in total patients and each individual with partial dependence, accumulated local effects, and individual conditional expectation plots. We also estimated the effects of feature modifications such as nephrotoxic drug discontinuation on future creatinine levels. Conclusions We developed and externally validated a continuous AKI prediction model using RNN algorithms. Our model could provide real-time assessment of future AKI occurrences and individualized risk factors for AKI in general inpatient cohorts; thus, we suggest approaches to support clinical decisions based on prediction models for in-hospital AKI.