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Introduction: Emerging evidence suggests that Chemotherapy (CT) treated breast cancer survivors (BCS) who have “risk variants” in genes may be more susceptible to cognitive impairment (CI) and/or poor cardiac phenotypes. The objective of this preliminary study was to examine whether there is a relationship between genetic variants and objective/subjective cognitive or cardiac phenotypes. Methods and Analysis: BCS were recruited from Moffitt Cancer Center, Morsani College of Medicine, AdventHealth Tampa and Sarasota Memorial Hospital. Genomic DNA were collected at baseline for genotyping analysis. A total of 16 single nucleotide polymorphisms (SNPs) from 14 genes involved in cognitive or cardiac function were evaluated. Three genetic models (additive, dominant, and recessive) were used to test correlation coefficients between genetic variants and objective/subjective measures of cognitive functioning and cardiac outcomes (heart rate, diastolic blood pressure, systolic blood pressure, respiration rate, and oxygen saturation). Results: BCS (207 participants) with a mean age of 56 enrolled in this study. The majority were non-Hispanic white (73.7%), married (63.1%), and received both CT and radiation treatment (77.3%). Three SNPs in genes related to cognitive functioning (rs429358 in APOE, rs1800497 in ANKK1, rs10119 in TOMM40) emerged with the most consistent significant relationship with cognitive outcomes. Among five candidate SNPs related to cardiac functioning, rs8055236 in CDH13 and rs1801133 in MTHER emerged with potential significant relationships with cardiac phenotype. Conclusions: These preliminary results provide initial targets to further examine whether BCS with specific genetic profiles may preferentially benefit from interventions designed to improve cognitive and cardiac functioning following CT.

Background: Long-term comparative outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stents and coronary artery bypass grafting (CABG) are limited in patients with multivessel coronary artery disease. Methods: This prospective, multicenter, randomized controlled trial was conducted in 27 international heart centers and was designed to randomly assign 1776 patients with angiographic multivessel coronary artery disease to receive PCI with everolimus-eluting stents or CABG. After inclusion of 880 patients (438 in the PCI group and 442 in the CABG group) between July 2008 and September 2013, the study was terminated early because of slow enrollment. The primary end point was the composite of death from any cause, myocardial infarction, or target vessel revascularization. Results: During a median follow-up of 11.8 years (interquartile range, 10.6–12.5 years; maximum, 13.7 years), the primary end point occurred in 151 patients (34.5%) in the PCI group and 134 patients (30.3%) in the CABG group (hazard ratio [HR], 1.18 [95% CI, 0.88–1.56]; P =0.26). No significant differences were seen in the occurrence of a safety composite of death, myocardial infarction, or stroke between groups (28.8% and 27.1%; HR, 1.07 [95% CI, 0.75–1.53]; P =0.70), as well as the occurrence of death from any cause (20.5% and 19.9%; HR, 1.04 [95% CI, 0.65–1.67]; P =0.86). However, spontaneous myocardial infarction (7.1% and 3.8%; HR, 1.86 [95% CI, 1.06–3.27]; P =0.031) and any repeat revascularization (22.6% and 12.7%; HR, 1.92 [95% CI, 1.58–2.32]; P Conclusions: In patients with multivessel coronary artery disease, there were no significant differences between PCI and CABG in the incidence of major adverse cardiac events, the safety composite end point, and all-cause mortality during the extended follow-up. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT05125367 and NCT00997828.

Aims This study compared patients who underwent arthroscopic repair of large to massive rotator cuff tears (LMRCTs) with isolated incomplete repair of the tear and patients with incomplete repair with biceps tendon augmentation. We aimed to evaluate the additional benefit on clinical outcomes and the capacity to lower the re-tear rate. Methods We retrospectively reviewed 1,115 patients who underwent arthroscopic rotator cuff repair for full-thickness tears between October 2011 and May 2019. From this series, we identified 77 patients (28 male, 49 female) with a mean age of 64.1 years (50 to 80). Patients were classified into groups A (n = 47 incomplete) and B (n = 30 with biceps augmentation) according to the nature of their reconstruction. Clinical scores were checked preoperatively and at six months, one year, and two years postoperatively. In preoperative MRI, we measured the tear size, the degree of fatty infiltration, and muscle volume ratio of the supraspinatus. In postoperative MRI, the integrity of the repaired rotator cuff tendon was assessed using the Sugaya classification. Tendon thickness at the footprint was evaluated on T2-weighted oblique coronal view. Results There were no significant differences in the initial preoperative demographic characteristics. In both groups, there were significant improvements in postoperative clinical scores (p < 0.001). However, most clinical outcomes, including range of motion measurements (forward elevation, external rotation, internal rotation, and abduction), showed no differences between the pre- and postoperative values. Comparing the postoperative outcomes of both groups, no further improvement from biceps augmentation was found. Group B, although not reaching statistical significance, had more re-tears than group A (30% vs 15%; p = 0.117). Conclusion In LMRCTs, biceps augmentation provided no significant improvement of an incomplete repair. Therefore, biceps augmentation is not recommended in the treatment of LMRCTs. Cite this article: Bone Joint J 2022;104-B(11):1234–1241.

To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing.Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children.Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children.A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

Cancer patients are less likely to undergo percutaneous coronary intervention (PCI) after cardiac arrest, although they demonstrate improved mortality benefit from the procedure. We produced the largest nationally representative analysis of mortality of cardiac arrest and PCI for patients with cancer versus non-cancer.Propensity score adjusted multivariable regression for mortality was performed in this case-control study of the United States' largest all-payer hospitalized dataset, the 2016 National Inpatient Sample. Regression models of mortality and PCI weighted by the complex survey design were fully adjusted for age, race, income, cancer metastases, NIS-calculated mortality risk by Diagnosis Related Group (DRG), acute coronary syndrome, and likelihood of undergoing PCI.Of the 30,195,722 hospitalized adult patients, 15.43% had cancer, and 0.79% of the whole sample presented with cardiac arrest (of whom 20.57% underwent PCI). In fully adjusted regression analysis among patients with cardiac arrest, PCI significantly reduced mortality (OR 0.15, 95 %CI 0.13-0.19; p 0.001) among patients with cancer greater than those without it (OR 0.21, 95 %CI 0.20-0.23; p 0.001).This nationally representative study suggests that post-cardiac arrest PCI is underutilized among patients with cancer despite its significant mortality reduction for such patients (independent of clinical acuity).

Background/Aims: Neutrophilia is frequently observed in bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. Granulocyte colony-stimulating factor (G-CSF) is a potent neutrophil-activating glycoprotein. However, the clinical implications of G-CSF remain poorly understood.in patients with IPF. Therefore, we evaluated the relationship between the G-CSF concentration in BALF and the progression of fibrosis, including in terms of the decline in lung function and long-term survival rate.Methods: G-CSF concentrations were measured in BALF using enzyme-linked immunosorbent assay (ELISA). The survival rate was estimated using Kaplan-Meier survival analyses.Results: G-CSF protein levels were significantly higher in IPF (n = 87; 1.88 [0 to 5.68 pg/mL]), nonspecific interstitial pneumonia (n = 22; 0.58 [0 to 11.64 pg/mL]), and hypersensitivity pneumonitis (n = 19; 2.48 [0.46 to 5.71 pg/mL]) patients than in normal controls (n = 33; 0 [0 to 0.68 pg/mL]) (all p < 0.01). A receiver operating characteristic curve showed a difference in G-CSF levels between IPF and NC (area under the curve, 0.769): The G-CSF cut-off of 0.96 pg/mL indicated 84.9% specificity and 63.2% sensitivity for IPF. The survival rate was significantly lower in the group with G-CSF > 2.872 pg/mL than in the group with ≤ 2.872 pg/mL (hazard ratio, 2.69; p = 0.041). The annual decline in diffusing capacity of the lung for carbon monoxide was positively correlated with the G-CSF level (p = 0.018).Conclusions: G-CSF may participate in the development of IPF and be useful for predicting the prognosis of IPF. Therefore, G-CSF should be analyzed in BALF, in addition to differential cell counts.

Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42-6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19-1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83-2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (pThe 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

This study aimed to analyze the association between temperature and precipitation and the incidence of hepatitis A in Seoul, Korea, as meteorological factors may have different effects on specific diseases depending on the lifestyle in each region. Weekly cases of hepatitis A, weekly mean daily precipitation, and temperature data from 2016 to 2020 were analyzed. Quasi-Poisson-generalized linear models with time variable adjusted by spline function were used considering 0-6-week lags. The association of each variable and hepatitis A incidence was assessed by the single lag and the constrained distributed lag model. Multivariable distributed lag linear and non-linear models were used to develop models with significant independent variables. Weekly mean of daily mean temperature (Tmean) and maximum temperature (Tmax) were negatively associated with hepatitis A in the 6-week lag. Precipitation was negatively associated with hepatitis A in the 5- and 6-week lags. The multivariable model showed the negative association of Tmax, precipitation and hepatitis A in the 5- and 6-week lags. In the non-linear models, the incidence rate ratio (IRR) was the highest at a Tmax of 11 °C and decreased thereafter. IRR was the highest at 12 mm of precipitation and showed decrease pattern to 25 mm and then gradually increased in the 5- and 6-week lags. Identifying the impact of climate factors on hepatitis A incidence would help in the development of strategies to prevent diseases and indirectly estimate the impact of climate change on hepatitis A epidemiology.

Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed.

Significant changes in CpG methylation have been identified in nasal polyps, which are the main targets of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD); however, these polyps are composed of various cellular components. In the present study, whole-genome CpG methylation in peripheral blood lymphocytes (PBLs) was analyzed to define the epigenetic changes in lymphocytes, which are the primary immune cells involved in NERD.Genomic DNA from peripheral blood mononuclear cells from 27 NERD and 24 aspirin-tolerant asthma (ATA) was subjected to bisulfate conversion and a methylation array. Quantitative CpG methylation, the β-values as a quantitative measure of DNA methylation, in lymphocytes were calculated after adjustments for cellular composition.Fifty-six hypermethylated and three hypomethylated differentially methylated CpGs (DMCs) in PBLs in the NERD compared with ATA. The top 10 CpG loci predicted the methylation risk score, with a positive predictive value of 91.3%, a negative predictive value of 81.5% and an accuracy of 84.3%. As demonstrated in the nasal polyps, 30 DMCs were predicted to bind to the following 10 transcription factors, ranked in descending order: AP-2alphaA, TFII-1, STAT4, FOXP3, GR, c-Est-1, E2F-1, XBP1, ENKTF-1 and NF-1. Gene ontology analysis identified 13 categories such as regulation of T-helper 17 cell differentiation, including SMAD7 and NFKBIZ. PBLs in NERD contained no DMCs in genes associated with the prostaglandin and leukotriene pathways, which were found in ATA.PBLs in NERD form a unique pattern of DNA CpG methylation, and the combined analysis may provide predictive values for NERD.

With the introduction of immunotherapy, significant improvement has been made in the treatment of head and neck squamous cell carcinoma (HNSCC). However, only a small subset of patients with HNSCC benefit from immunotherapy. The current biomarker, a programmed cell death protein ligand 1 (PD-L1) expression that is widely used in treatment decision making for advanced HNSCC, has only a moderate predictive value. Additionally, PD-L1-based assay has critical inherent limitations due to its highly dynamic nature and lack of standardization. With the advance in molecular techniques and our understanding of biology, more reliable, reproducible, and practical novel biomarkers are being developed. These include but are not limited to neoantigen/mutation characteristics, immune transcriptomes, tumor-infiltrating immune cell composition, cancer epigenomic, proteomics and metabolic characteristics, and plasma-based and organoid assays.

Background Data regarding Asian patients with mycosis fungoides (MF) are limited. Objective We aimed to investigate the clinical profile and long-term outcomes of patients with MF in Korea. Methods A retrospective review of 223 patients with MF who were followed up for more than 6 months or died of MF within 6 months of diagnosis was performed. Results Approximately 96.4% and 3.6% of the patients had an early stage and advanced stage, respectively. The mean age at diagnosis was 44.8 years. The mean duration of symptoms before diagnosis was 47.0 months. Various subtypes were noted, including mycosis fungoides palmaris et plantaris (21.5%), folliculotropic (8.5%), pityriasis lichenoides-like (6.7%), ichthyosiform (4.0%), lichenoid purpura-like (2.7%), and hypopigmented (2.2%) MF. Juvenile patients accounted for 16.6%. The higher the skin T stage, the poorer the response to treatment. The 10-year overall survival was 96.8% in early-stage patients and 25.0% in advanced-stage patients. General prognosis was favorable, while recurrence and subtype switching were seen in 29.4% and 2.7% of patients, respectively. Limitations Our patients may not represent all Korean patients with MF. Conclusion MF in Korea has a high proportion of variants, a younger age at onset, and favorable prognosis. A high index of suspicion and skin biopsy are needed for early diagnosis.

Although the mean corpuscular volume (MCV) has been associated with various diseases, these associations in relation to the age-related trends in MCV remain unclear. Therefore, we used a dataset with over one million values to identify the relationship between ageing and MCV changes. All laboratory data obtained between November 1998 and November 2019 at Chungbuk National University Hospital were retrospectively collected. After excluding cases with missing values for individual complete blood count parameters, outlier MCV values, and ages less than 1 year and more than 88 years, 977,335 MCV values were obtained from 309,393 patients. Principal component analysis of blood components with ages and analysis of the median value changes for each blood component across decade-wise age groups were conducted to identify relationships between ageing and changes in blood components. The median values of MCV showed gradual increments with age. The linear relationship for patients aged 1-25 years had a larger slope than that for patients aged 26-88 years. For MCV, the equation for patients aged 1-25 years was 0.40*(age) + 81.24 in females and 0.45*(age) + 79.58 in males. The equation for patients aged 26-90 years was 0.04*(age) + 88.97 in females and 0.06*age + 88.30 in males. Among patients aged40 years, the MCV value was higher in men than in women. Analysis of a large dataset showed that the MCV gradually increased with age and the linear relationship differed between patients aged 1-25 and 26-88 years.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED.

We aimed to evaluate the impacts of disability on the diagnosis, treatment, and prognosis of bile duct cancer (BDC) according to the severity and type of disability. Patients diagnosed with BDC were selected from an age- and sex-matched population (1:3 ratio) with or without disabilities from the National Disability Database, the Korean Central Cancer Registry, and the Korean National Health Insurance claims database. The cohort included 15,065 patients with BDC, with a significantly lower rate in those with severe disabilities than in people without or with mild disabilities (110.6 vs. 136.5 vs. 147.6 per 105 persons, respectively). People with severe disabilities were diagnosed with BDC at an earlier age but were less likely to undergo surgery (adjusted odds ratio (aOR) = 0.52, 95% confidence interval (CI): 0.45–0.61) or chemotherapy (aOR = 0.76, 95% CI: 0.61–0.95) compared to those without disabilities. This trend was more evident in patients with mental disabilities. The overall and cancer-specific mortality rates were higher in patients (especially women) with disabilities than in those without. There needs systemic approach to ensure equal access to quality cancer care for people with disabilities.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, specific prognostic biomarkers have not yet been developed. In this study, we identified dysregulated microRNAs (miRNAs) in TNBC by profiling miRNA and mRNA expression. In patients with TNBC, miR-371b-5p expression was reduced, and miR-371b-5p overexpression significantly mitigated TNBC cell growth, migration, and invasion. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 expression alleviated TNBC cell growth by regulating RAC1 transcription. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 leads to weak interaction between RNAPII p-CTD and CDK7, resulting in a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data demonstrate that miR-371b-5p is a tumor-suppressive miRNA that regulates the CSDE1/Rac1 axis and could be a potential prognostic biomarker for TNBC.

Host immune responses, such as those initiated by pattern recognition receptor (PRR) activation, are important for viral clearance and pathogenesis. However, little is known about the interactions of viral proteins with surface PRRs or, more importantly, the association of innate immune activation with viral pathogenesis. In this study, we showed that internal influenza virus proteins were released from infected cells. Among these proteins, nucleoprotein (NP) played a critical role in viral pathogenesis by stimulating neighboring cells through toll-like receptor (TLR)2, TLR4, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Through the activation of these PRRs, NP induced the production of interleukin (IL)-1β and IL-6, which subsequently led to the induction of trypsin. Trypsin induced by NP increased the infectivity of influenza virus, leading to increases in viral replication and pathology upon subsequent viral infection. These results reveal the role of released NP in influenza pathogenesis and highlight the importance of the interactions of internal viral proteins with PRRs in the extracellular compartment during viral pathogenesis.

We investigated sex-related differences in the in-hospital management of patients with out-of-hospital cardiac arrest (OHCA).We retrospectively analyzed prospectively collected data from the Korean Cardiac Arrest Resuscitation Consortium (KoCARC) registry, a prospective, multicenter OHCA registry. We enrolled adult patients with OHCA between October 2015 and June 2020. The primary outcomes were coronary angiography (CAG), percutaneous coronary intervention (PCI), targeted temperature management (TTM), and extracorporeal membrane oxygenation (ECMO) performed in the hospital. Propensity score matching (PSM) was performed to minimize differences in baseline demographics and characteristics.Among 12,321 patients in the KoCARC registry, we analyzed 8,177 with OHCA. PSM yielded 5,564 matched patients (2,782 women and men, respectively). In the unmatched cohort, women were less likely to undergo CAG, PCI, TTM, and ECMO. In the PSM cohort, women were less likely to undergo CAG and PCI (6.4% vs. 9.1%, p 0.001 and 1.9% vs. 3.7%, p 0.001). The duration of cardiopulmonary resuscitation was shorter in women (19 vs. 20 min, p 0.001). TTM, ECMO use, and survival outcomes did not differ significantly between sexes. The subgroup analysis according to age showed that among patients aged 65 years, women were less likely than men to undergo CAG and PCI (12.7% vs. 19.2%, p 0.001 and 2.3% vs. 8.1%, p 0.001).In the PSM cohort, women with OHCA underwent CAG and PCI less frequently than men, regardless of the initial rhythm. However, these sex-related differences narrowed with increasing age. Further studies are needed to confirm the sex-related disparities in the in-hospital management of patients with OHCA.

Some patients show severe humeral bone stress shielding even one year after press-fit humeral stem, which can be a risk factor for implant durability. This study compared humeral stress shielding and clinical outcomes between high and low filling ratio (HFR and LFR) stems in primary reverse shoulder arthroplasty (RSA).From 2015 to 2020, 104 patients who underwent RSA with a non-cemented standard-length humeral stem were examined. The humeral stems included large press-fit stems (HFR group, 53 patients) or small non-press-fit stems with autogenous cancellous bone grafting (LFR group, 51 patients). The radiologic and clinical outcomes were compared between the groups one year post-operatively.One patient in the LFR group with early infectious dislocation was excluded from the 1-one year evaluation. No stress shielding was observed in 27/50 (54.0%) and 5/53 (9.4%) of patients in the LFR and HFR groups, while 3/50 (6%) and 19/53 (35.8%) patients showed high-stress shielding, respectively. However, the stem alignment change, subsidence, complications and evidence of loosening did not differ between the groups. The final range-of-motion and functional scores were significantly poorer in the LFR group than those in the HFR group, although the difference was minimal.Even at one year follow-up, patients receiving LFR stems with autogenous bone grafting had significantly less humeral stress shielding compared to patients with HFR stem with press-fit in primary RSA, without compromising stem stability.

Some young individuals present with shoulder pain without a definite history or complaint of instability. However, careful history taking, physical examination, and high-quality magnetic resonance imaging may reveal evidence of instability of which the patient is unaware. Therefore, a clearer definition of these ambiguous patients is needed. This study aimed to report the characteristics and surgical outcomes of patients with microinstability compared to those of patients with classic recurrent anterior shoulder instability.From 2005 to 2018, 35 patients with microinstability (group M) underwent arthroscopic anterior labral repair (AALR) and were compared to 35 sex- and age-matched patients with classic recurrent anterior shoulder instability (group C) who also underwent AALR. Baseline characteristics, preoperative apprehension test findings, preoperative imaging for the presence of anterior labral and Hill-Sachs lesions, preoperative and postoperative (over 2 years) range of motion (ROM) and functional scores, final complications, and patient satisfaction were analysed.The most common chief complaints in groups M and C were pain (29/35) and both pain and instability (27/35), respectively. Only pain during the apprehension test was predominant in group M (M vs. C, 27 vs. 1, p 0.001). High incidence of chronic repetitive injuries (26/35) and acute trauma (28/35) were observed in groups M and C, respectively. Over half of the patients in group M showed anterior labral lesions on magnetic resonance arthrography (MRA, 18/35), and 21 patients had Hill-Sachs lesions on MRA/three-dimensional computed tomography. Finally, 29 patients showed either anterior labral or Hill-Sachs lesions on preoperative imaging. The lesion severity was higher in group C than that in group M. All patients underwent AALR with/without the remplissage procedure, with no significant differences in final clinical outcomes, complications, and patient satisfaction between the groups.Microinstability is diagnostically challenging and can be diagnosed in young patients with ambiguous shoulder pain during motion, without instability. Pain on anterior apprehension test and subtle labral and/or Hill-Sachs lesion on imaging study could be diagnostic clues. This condition can be managed with arthroscopic anterior labral repair with or without the remplissage procedure. The possibility of microinstability in young patients with shoulder pain should always be considered, and small anterior labral or Hill-Sachs lesions should be closely monitored.III.

To evaluate the efficacy and safety of tamsulosin and Hachimijiogan or Ryutanshakanto in patients with lower urinary tract symptoms due to benign prostatic hyperplasia.A prospective, randomized, double-blind method was used to determine the efficacy and safety of the combination or placebo at baseline and 4, 8, and 12 weeks of study. The International Prostate Symptom Score, quality of life index, complete voiding diary, and National Institutes of Health-Chronic Prostatitis Symptom Index were studied. Uroflowmetery and postvoid residual urine volume were measured and compared. Laboratory tests including prostate-specific antigen were performed.In all groups, International Prostate Symptom Score and quality of life showed improvement, but no significant differences were shown among the groups. Prostate volume increased after treatment, and uroflowmetric parameters showed improvements after treatment without significance among the three groups. The total score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant improvement in all groups, without significant differences among the groups. Only the pain sub-score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant decrease in the tamsulosin with Ryutanshakanto group compared to the control group. A total of 11 adverse reactions occurred, but they were mild and not related to the study drugs.Ryutanshakanto can provide pain relief in patients with chronic prostatitis and chronic pelvic pain syndrome. If more research is conducted, Hachimijiogan and Ryutanshakanto may be applied as add-on treatments in patients with storage symptoms with alpha-blocker monotherapy.

While performing musculoskeletal long bone fracture reduction surgery, assistant surgeons can often suffer from physical fatigue as they provide resistance against the tension from surrounding muscles pulling on the patient’s broken bones. These days, robotic systems are being actively developed to mitigate this physical workload by realigning and holding these fractured bones for surgeons. This has led to one consortium proposing the development of a robot-assisted fracture reduction system consisting of a 6-DOF positioning robot along with a 1-DOF traction device. With the introduction of the 1-DOF traction device, the positioning robot does not have to fight these contraction forces so can be compact improving its maneuverability and overall convenience; however, considering surgeon-robot interactions, this approach adds the requirement of controlling two different types of robots simultaneously. As such, an advanced cooperative control methodology is required to control the proposed bone fracture reduction robot system. In this paper, a human-robot-robot cooperative control (HRRCC) scheme is proposed for collaboration between the surgeon, the positioning robot, and the traction device. First, the mathematical background of this HRRCC scheme is provided. Next, we describe a series of experiments that show how the proposed scheme facilitates a reduction in the load placed on the positioning robot from strong muscular contraction forces making it possible to conduct fracture reduction procedures more safely despite the muscular forces.

Background/Aims: While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown.Methods: Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared.Results: Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD.Conclusions: In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.

Objective Premature ovarian insufficiency (POI) is a clinical disease that is diagnosed by the loss of ovarian function before the age of 40. Despite recent progress in molecular diagnosis, the genetic etiology of POI is not well established. The aim of this study is to reveal pathogenic genetic variants involved in POI. Study design and main outcome measures To reveal pathogenic genetic variants involved in POI, whole exome sequencing was performed in nonconsanguineous family members with POI. Constitutional variants were filtered against population databases and a missense mutation of natriuretic peptide C (NPPC) (c.131A>G, p.Q44R) was selected as a convincing candidate mutation among 14 heterozygous mutant alleles in 13 genes. Results The wild-type NPPC and mutant NPPC (NPPC131A>G) were expressed in HeLa cells, and cells expressing NPPC131A>G secreted unique peptides. The ProP 1.0 Server, a neural network prediction tool, predicted the presence of a cleavage site at the substituted arginine residue (p.Q44R) of NPPC. The molecular weight of predicted cleaved peptides processed from mutant NPPC precursor corresponded to that of the actual mutant peptide. The cGMP synthetic activity of NPR2-expressing cells was significantly decreased by interaction with the mutant NPPC peptide compared with wild-type NPPC. Conclusions The peptide generated by a rare mutation of NPPC might influence paracrine C-type natriuretic peptide (CNP)-mediated preantral follicle development and/or sustain meiotic arrest in oocytes. We therefore suggest that a mutation of the NPPC gene is involved in the pathogenesis of POI.

In this study, we aimed for the first time to evaluate the effectiveness of atomoxetine (Strattera) in the treatment of cognitive impairment and aphasia after stroke in a large sample.We reviewed the data of 106 patients with poststroke aphasia and cognitive impairment (atomoxetine treatment group = 55 patients vs control group = 51 patients), including scores of the Korean version of the Mini-Mental State Examination (K-MMSE) and the Korean version of the Western Aphasia Battery. Wilcoxon signed-rank tests were used to compare the initial and follow-up K-MMSE and Korean version of the Western Aphasia Battery scores. Mann-Whitney U tests were used to compare the degree of improvement in K-MMSE and Aphasia Quotient (AQ) scores between the atomoxetine and control groups.Baseline characteristics including age, years of education, and scores of the initial Functional Independence Measure, Korean version of the Modified Barthel Index, Hamilton Depression Rating Scale, K-MMSE, and AQ did not differ significantly between the 2 groups. Follow-up K-MMSE and AQ scores were significantly better than the initial scores in both the treatment and control groups. However, improvements in K-MMSE scores were significantly greater in the treatment group than in the control group. In addition, the atomoxetine group had significantly higher AQ scores than the control group, especially for auditory verbal comprehension and naming.Atomoxetine has been shown to significantly improve cognitive function and language in patients with poststroke aphasia. It is also the first study to report improvement in auditory comprehension and naming by administration of atomoxetine.

This study investigated whether prehospital advanced airway management (AAM) is associated with improved survival of out-of-hospital cardiac arrest (OHCA) compared with conventional bag-valve-mask (BVM) ventilation.We investigated the neurologically favorable survival of adult patients with OHCA who underwent BVM or AAM using the Korean Cardiac Arrest Research Consortium (KoCARC), a multicenter OHCA registry of Korea. The differences in clinical characteristics were adjusted by matching or weighting the clinical propensity for use of AAM or by least absolute shrinkage and selection operator (LASSO). The primary outcome was 30-day survival with neurologically favorable status defined by cerebral performance category 1 or 2.Of the 9,616 patients enrolled (median age = 71 years; 65% male), there were 6,243 AAM and 3,354 BVM patients. In unadjusted analysis, the 30-day neurologically favorable survival was lower in the AAM group compared with the BVM group (5.5% vs. 10.0%; hazard ratio [HR] = 1.21, 95% confidence interval [CI] = 1.16 to 1.27; all p 0.001). In propensity score matching-adjusted analysis, these differences were not found (9.6% vs. 10.0%; HR = 0.98, 95% CI = 0.93 to 1.03, p 0.05). Inverse probability of treatment weighting- and LASSO-adjusted analyses replicated these results.In this nationwide real-world data analysis of OHCA, the 30-day neurologically favorable survival did not differ between prehospital AAM and BVM after adjustment for clinical characteristics.

Background Acute fibrinous and organizing pneumonia (AFOP) is a rare interstitial pneumonia characterized by intra-alveolar fibrin deposition and organizing pneumonia. The clinical manifestations and long-term prognosis of AFOP are unclear. Our objective was to investigate the clinical features and prognosis of AFOP. Methods We identified patients diagnosed with AFOP by surgical lung biopsy between January 2011 and May 2018 at Seoul National University Bundang Hospital. We retrospectively reviewed clinical and radiologic findings, treatment, and outcomes of AFOP. Results Fifteen patients with histologically confirmed lung biopsies were included. The median follow-up duration was 2.4 (range, 0.1–82) months. The median age was 55 (range, 33–75) years, and four patients were immunocompromised. Fever was the most common clinical presentation (86.7%). Patchy ground-glass opacities and/or consolidations were the most predominant findings on chest computed tomography images. Nine patients (60%) received mechanical ventilator care, and eight patients (53.3%) died. The non-survivors tended to have slightly higher body mass index (BMI) and a long interval between symptom onset and diagnosis than the survivors, but these findings were not statistically significant. Among seven survivors, five patients were discharged without dyspnea and oxygen supplement. Conclusions The clinical course of AFOP was variable. Although AFOP was fatal, most of the patients who recovered from AFOP maintained normal life without supplemental oxygen therapy and respiratory symptoms.

Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple-negative breast cancers require distinct therapeutic approaches because of their different amounts of autophagy flux. We identified that autophagy flux was inhibited in triple-negative breast cancer (TNBC) CSCs. Moreover, miRNA-181a (miR-181a) expression is upregulated in both TNBC CSCs and patient tissues. Autophagy-related 5 (ATG5) and autophagy-related 2B (ATG2B) participate in the early formation of autophagosomes and were revealed as targets of miR-181a. Inhibition of miR-181a expression led to attenuation of TNBC stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR-181a-regulated mechanism in TNBC. Promoting tumor-suppressive autophagy using curcumin may be a potential method for the treatment of TNBC.

To assess the utility of machine learning (ML) algorithms in predicting clinically relevant atrial high-rate episodes (AHREs), which can be recorded by a pacemaker. We aimed to develop ML-based models to predict clinically relevant AHREs based on the clinical parameters of patients with implanted pacemakers in comparison to logistic regression (LR). We included 721 patients without known atrial fibrillation or atrial flutter from a prospective multicenter (11 tertiary hospitals) registry comprising all geographical regions of Korea from September 2017 to July 2020. Predictive models of clinically relevant AHREs were developed using the random forest (RF) algorithm, support vector machine (SVM) algorithm, and extreme gradient boosting (XGB) algorithm. Model prediction training was conducted by seven hospitals, and model performance was evaluated using data from four hospitals. During a median follow-up of 18 months, clinically relevant AHREs were noted in 104 patients (14.4%). The three ML-based models improved the discrimination of the AHREs (area under the receiver operating characteristic curve: RF: 0.742, SVM: 0.675, and XGB: 0.745 vs. LR: 0.669). The XGB model had a greater resolution in the Brier score (RF: 0.008, SVM: 0.008, and XGB: 0.021 vs. LR: 0.013) than the other models. The use of the ML-based models in patient classification was associated with improved prediction of clinically relevant AHREs after pacemaker implantation.

This study sought to compare postoperative outcomes after scaphocapitate arthrodesis (SCA) for the treatment of late-stage Kienböck disease according to the amount of ulnar translation of the carpus and to identify surgical factors associated with carpal-ulnar translation.Thirty-nine patients diagnosed with Kienböck disease (Lichtman stages III-IV) and treated with SCA were retrospectively reviewed. They were divided into the translated group (n=28) and untranslated group (n=11) according to the presence of carpal-ulnar translation. The following surgical factors in the patients were assessed: excision of the lunate, postoperative carpal height ratio, and radioscaphoid angle (RSA). Pain Visual Analog scale (VAS) score, wrist range of motion, grip strength, modified Mayo wrist score (MMWS), the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and progression of radioscaphoid osteoarthritis were also assessed.All patients showed functional improvement after a mean postoperative follow-up period of 40 months (VAS: 4.1 vs. 1.1, p0.001; grip strength, 42.3 vs. 51.2 lb., p = 0.002; MMWS, 52.6 vs. 69.5, p0.001; QuickDASH, 33.7 vs. 21.5, p0.001). No statistically significant differences were found between the two groups in terms of outcome measures. Among the assessed surgical factors, the mean postoperative RSA was significantly smaller in the translated group than in the untranslated group (34.8° vs. 46.8°, p = 0.008). The proportion of patients with postoperative RSA30° was significantly higher in the translated group than in the untranslated group (54.5% vs. 0%, p0.001).These results suggest that sufficient pain relief and functional improvement can be achieved after SCA for the treatment of late-stage Kienböck disease disregarding the occurrence of carpal-ulnar translation. In this study, overcorrection to RSA30° induced more frequent carpal-ulnar translation after SCA.

Background : The number of digital game users is increasing, and so is attention to digital gaming's effects on mental health. We aimed to reveal if risky (game addiction) and usual game use (non-risky) are associated with mental health in early adulthood. Methods : Using data from the nationwide cross-sectional Korean Epidemic Catchment Area study for psychiatric disorders, 415 participants aged 18–30 years were divided into “non-game,” “usual game,” and “risky game” user groups based on the previous month's game use and cut-off value of game overuse screening questionnaire. Multiple linear and logistic regressions revealed the association between game use groups, perceived mental health, and lifetime prevalence of clinical mental disorders including suicidal ideation. Results : Among the 415 participants, 167 were non-game users, 175, usual game users, and 73, risky game users. Risky game users self-reported decreased satisfaction and happiness, and a significantly higher lifetime prevalence of major depressive disorder, alcohol dependence, and suicidal ideation. Usual game users were significantly associated with higher lifetime prevalence of alcohol dependence and suicidal ideation. Self-reported happiness partially mediated between game use and lifetime suicidal ideation in risky, but not usual game users. Limitations : This study is a cross-sectional observational study which was not possible to define the temporal relationship. Conclusions : Both risky and usual game use are associated with mental health problems in early adulthood, indicating the need for careful mental health screening on not only risky game users but also usual game users.

Stomach cancer is a global health concern as millions of cases are reported each year. In the present study, we developed a pH-responsive microrobot with good biocompatibility, magnetic-field controlled movements, and the ability to be visualized

Introduction: Allergic rhinitis and asthma share a common inflammatory mechanism and are closely related, recognized as “one airway disease.” Thus, the guidelines recommend allergic rhinitis and asthma be treated together, and leukotriene antagonists and antihistamines have been administered simultaneously; however, there are few reports of the use of combination drugs so far. Methods: The aim of the study was to evaluate the treatment effects and adverse events of Monterizine® (a combination of montelukast and levocetirizine); a total of 2,254 patients with perennial allergic rhinitis and asthma were prospectively enrolled from 60 hospitals nationwide in Korea. They were followed up for 3 (Period 1) or 6 months (Period 2). Total nasal symptom score (TNSS), satisfaction, and safety data were collected and compared to baseline. Results: TNSS scores were analyzed for 2,254 subjects. At Period 1 (n = 2,024) and 2 (n = 1,861), the scores decreased significantly from baseline (−1.20 ± 2.49 and −1.63 ± 2.78, p < 0.001). The mean quality of life (QoL) was significantly improved at Period 1 and 2 relative to baseline (−3.75 ± 6.58, −4.83 ± 7.11, both p < 0.0001). There were no serious adverse drug reactions, but there were some minor reactions including nasopharyngitis (2.92%), rhinitis (0.37%), and somnolence (0.34%). Conclusions: TNSS score and QoL were significantly improved by 3–6 months’ treatment with Monterizine without significant adverse reactions. These results indicate that Monterizine, as a combination drug, is effective and safe for improving nasal symptoms and quality of life in patients with allergic rhinitis who also have asthma.

This multicenter study reviewed the clinical features and prognosis according to the primary site of involvement and the treatment modality in patients with B-cell primary intestinal lymphoma (PIL).Among 125 consecutive patients diagnosed with PIL, 100 patients were analyzed.The median age was 59 years, and the male to female ratio was 1.86:1. Diffuse large B-cell lymphoma (66/100, 66.0%) was the most common histological subtype. The estimated 5-year survival rate (5-YSR) was 48.5%. The 5-YSR was similar regardless of the type of primary treatment (chemotherapy alone vs. surgery/chemotherapy, 50.7 vs. 45.3%, p=0.582). A comparison of the survival according to the primary site of involvement revealed a 5-YSR of 32.5% (p=0.027), 64.3% (reference), 46.5% (p=0.113), and 49.8% (p=0.024) for the small intestine, ileocecal region, large intestine, and multiple sites, respectively. Multivariate analysis, however, revealed a low hemoglobin level, advanced Ann Arbor stage, and aggressive histological type to be independent prognostic factors for shorter survival but not ileocecal region involvement.The Ann Arbor stage, hemoglobin level, and histological type were independent prognostic factors for survival, while the primary site of involvement and treatment modality did not affect the prognosis in patients with B-cell PIL.

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively. Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6

Although previous studies identified numerous single nucleotide polymorphisms (SNPs) and their target genes predisposed to prostate cancer (PrCa) risks, SNP-related splicing associations are rarely reported. In this study, we applied distance-based sQTL analysis (sQTLseekeR) using RNA-seq and SNP genotype data from benign prostate tissue (n = 467) and identified significant associations in 3344 SNP-transcript pairs (P ≤ 0.05) at PrCa risk loci. We characterized a common SNP (rs7247241) and its target gene (PPP1R14A) located in chr19q13, an sQTL with risk allele T associated with upregulation of long isoform (P = 9.99E−7). We confirmed the associations in both TCGA (P = 2.42E−24) and GTEX prostate cohorts (P = 9.08E−78). To functionally characterize this SNP, we performed chromatin immunoprecipitation qPCR and confirmed stronger CTCF and PLAGL2 binding in rs7247241 C than T allele. We found that CTCF binding enrichment was negatively associated with methylation level at the SNP site in human cell lines (r = −0.58). Bisulfite sequencing showed consistent association of rs7247241-T allele with nearby sequence CpG hypermethylation in prostate cell lines and tissues. Moreover, the methylation level at CpG sites nearest to the CTCF binding and first exon splice-in (ψ) of PPP1R14A was significantly associated with aggressive phenotype in the TCGA PrCa cohort. Meanwhile, the long isoform of the gene also promoted cell proliferation. Taken together, with the most updated gene annotations, we reported a set of sQTL associated with multiple traits related to human prostate diseases and revealed a unique role of PrCa risk SNP rs7247241 on PPP1R14A isoform transition.

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF‐related protein 3 (HRP‐3) as a potential biomarker for lung cancer. The expression of endogenous HRP‐3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP‐3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP‐3 depletion in A549 cells impedes the binding of HRP‐3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP‐3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1‐responsive gene, thus inducing S‐phase accumulation. Therefore, our study provides evidence for the utility of HRP‐3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP‐3 to regulate the E2F1 transcription level via histone deacetylation., HRP‐3 depletion–mediated S‐phase accumulation augments E2F1 transcription. HRP‐3 depletion induces H3/H4 acetylation and obstructs HRP‐3 binding to the E2F1 promoter. The reduction of HDAC 1/2 recruitment in the E2F1 promoter by HRP‐3 depletion increases H3/H4 acetylation in the E2F1 promoter.

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing

The liver-specific microRNA, miR-122, plays an essential role in the propagation of hepatitis C virus (HCV) by binding directly to the 5′-end of its genomic RNA. Despite its significance for HCV proliferation, the host factors responsible for regulating miR-122 remain largely unknown. In this study, we identified the cellular RNA-binding protein, ELAVL1/HuR (embryonic lethal-abnormal vision-like 1/human antigen R), as critically contributing to miR-122 biogenesis by strong binding to the 3′-end of miR-122. The availability of ELAVL1/HuR was highly correlated with HCV proliferation in replicon, infectious, and chronically infected patient conditions. Furthermore, by screening a kinase inhibitor library, we identified rigosertib, an anticancer agent under clinical trials, as having both miR-122-modulating and anti-HCV activities that were mediated by its ability to target polo-like kinase 1 (PLK1) and subsequently modulate ELAVL1/HuR-miR-122 signaling. The expression of PLK1 was also highly correlated with HCV proliferation and the HCV positivity of HCC patients. ELAVL1/HuR-miR-122 signaling and its mediation of PLK1-dependent HCV proliferation were demonstrated by performing various rescue experiments and utilizing an HCV mutant with low dependency on miR-122. In addition, the HCV-inhibitory effectiveness of rigosertib was validated in various HCV-relevant conditions, including replicons, infected cells, and replicon-harboring mice. Rigosertib was highly effective in inhibiting the proliferation of not only wild-type HCVs, but also sofosbuvir resistance-associated substitution-bearing HCVs. Our study identifies PLK1-ELAVL1/HuR-miR-122 signaling as a regulatory axis that is critical for HCV proliferation, and suggests that a therapeutic approach targeting this host cell signaling pathway could be useful for treating HCV and HCV-associated diseases.

Microrobots that can be precisely guided to target lesions have been studied for in vivo medical applications. However, existing microrobots have challenges in vivo such as biocompatibility, biodegradability, actuation module, and intra- and postoperative imaging. This study reports microrobots visualized with real-time x-ray and magnetic resonance imaging (MRI) that can be magnetically guided to tumor feeding vessels for transcatheter liver chemoembolization in vivo. The microrobots, composed of a hydrogel-enveloped porous structure and magnetic nanoparticles, enable targeted delivery of therapeutic and imaging agents via magnetic guidance from the actuation module under real-time x-ray imaging. In addition, the microrobots can be tracked using MRI as postoperative imaging and then slowly degrade over time. The in vivo validation of microrobot system–mediated chemoembolization was demonstrated in a rat liver with a tumor model. The proposed microrobot provides an advanced medical robotic platform that can overcome the limitations of existing microrobots and current liver chemoembolization.

Background Extended dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is frequently used for high-risk patients in real-world practice. However, there are limited data about the long-term efficacy of extended DAPT after percutaneous coronary intervention (PCI).Methods and Results:This study investigated 1,470 patients who underwent PCI. The study population was divided into 2 groups based on DAPT duration: guideline-based DAPT (G-DAPT; DAPT ≤12 months after PCI; n=747) and extended DAPT (E-DAPT; DAPT >12 months after PCI; n=723). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as cardiac death, myocardial infarction (MI), repeat target vessel revascularization, or stroke. The median follow-up duration was 80.8 months (interquartile range 60.6-97.1 months). The incidence of MACCE was similar in the G-DAPT and E-DAPT groups (21.0% vs. 18.3%, respectively; P=0.111). However, the E-DAPT group had a lower incidence of non-fatal MI (hazard ratio [HR] 0.535; 95% confidence interval [CI] 0.329-0.869; P=0.011), and target lesion revascularization (HR 0.490; 95% CI 0.304-0.792; P=0.004), and stent thrombosis (HR 0.291; 95% CI 0.123-0.688; P=0.005). The incidence of bleeding complications, including major bleeding, was similar between the 2 groups (5.2% vs. 6.3%, respectively; P=0.471). Conclusions Although E-DAPT after DES implantation was not associated with a reduced rate of MACCE, it was associated with a significantly lower incidence of non-fatal MI, TLR, and stent thrombosis.

ObjectiveAppendicitis is usually diagnosed based on a reliable set of signs and symptoms, and can be effectively treated with surgery, with low morbidity and mortality rates. However, appendicitis is often overlooked in vulnerable populations, including people with disabilities. This study compared 10-year trends of complicated appendicitis between South Koreans with a disability, according to disability severity and type, and those without disabilitiesMethodsTo identify cases of appendicitis, we used the DRG codes in the National Health Information Database of South Korea. Patients with appendicitis were classified in terms of severity based on the DRG codes. Age-standardized incidence rates were calculated for each year during 2008–2017 according to the presence, type, and severity of the disability. Factors associated with complicated appendicitis were examined by multivariate logistic regression using the most recent data (i.e., 2016–2017).ResultsThe incidence of complicated appendicitis was higher in people with disabilities, especially those with severe disabilities (26.9 vs. 11.6%). This difference was particularly marked when considering those with a severe disability (aOR = 1.868, 95% CI:1.511–2.309), internal organ problems (aOR = 10.000, 95% CI:5.365–18.638) or a mental disability (aOR = 2.779, 95% CI:1.563–4.939).ConclusionsThe incidence of complicated appendicitis was higher in people with disability than in those without disability in all years. There was a substantial difference in the incidence of complicated appendicitis between the severe disability and non-disabled groups. Among the various disability types, the incidence of complicated appendicitis was highest for major internal organ problems, followed by intellectual or psychological disabilities. Our findings may be explained by barriers to healthcare access among people with disabilities, particularly those with a severe disability, internal organ problem, or mental disability.

Long-term clinical outcomes of low-density lipoprotein cholesterol (LDL-C) target attainment according to coronary lesion complexity are limited. We investigated the clinical outcomes of LDL-C target attainment after percutaneous coronary intervention (PCI) according to coronary lesion complexity.A total of 1285 patients who underwent PCI was categorized by LDL-C target attainment at 1 year and lesion complexity: LDL-C levels less than or equal to 70 mg/dl ( n = 179) and greater than 70 mg/dl ( n = 308) in complex PCI; LDL-C levels less than or equal to 70 mg/dl ( n = 315) and greater than 70 mg/dl ( n = 483) in noncomplex PCI. The primary endpoint was major adverse cardiovascular events (MACEs) and defined as cardiac death, nonfatal myocardial infarction, and target vessel revascularization.At 8-year follow-up, comparison of patients with 1-year LDL-C levels less than or equal to 70 mg/dl and 1-year LDL-C levels greater than 70 mg/dl showed similar MACE incidence in the noncomplex PCI group (8.3% vs. 11.6%; P = 0.074) and significantly lower MACE incidence in the complex PCI group (11.7% vs. 19.2%; P = 0.023). After IPTW adjustment, 1-year LDL-C levels less than or equal to 70 mg/dl was associated with reduced MACE rate in both complex PCI and noncomplex PCI groups.Although the attainment of LDL-C levels less than or equal to 70 mg/dl was associated with reduced MACE rate in both complex PCI and noncomplex PCI groups, long-term clinical benefits were prominent in the complex PCI group.

Previous studies have shown a relationship between the occurrence and recurrence of prostate cancer; however, this relationship remains controversial. We investigated the relationship between obesity and biochemical recurrence in patients with prostate cancer. Clinicopathological factors were analyzed after dividing the patient population according to the Asian population-specific body mass index (BMI) criteria for “normal” (

Background It has not been determined which specific 2-stenting strategy is the best for bifurcation lesions. Our aim was to investigate the clinical outcomes of various 2-stenting strategies in the era of 2nd-generation drug-eluting stents (2G-DES).Methods and Results:We analyzed 454 patients who finally underwent 2-stenting for a bifurcation lesion, from among 2,648 patients enrolled in the COBIS III registry. The primary outcome was target lesion failure (TLF). Patients were analyzed according to stenting sequence (provisional [main vessel stenting first] vs. systemic [side branch stenting first]) and stenting technique (crush vs. T vs. culotte vs. kissing/V stenting). Overall, 4.4 years' TLF after 2-stenting treatment for bifurcation lesion was excellent: TLF 11.2% and stent thrombosis 1.3%. There was no difference in TLF according to 2-stenting strategy (11.1% vs. 10.5%, P=0.990 for provisional and systemic sequence; 8.6% vs. 14.4% vs. 12.9% vs. 12.2%, P=0.326 for crush, T, culotte, kissing/V technique, respectively). Only left main (LM) disease and a shorter duration of dual antiplatelet therapy (DAPT) were associated with TLF. The distribution of DAPT duration differed between patients with and without TLF, and the time-point of intersection was 2.5 years. Also, the side branch was the most common site of restenosis. Conclusions The stenting sequence or technique did not affect clinical outcomes, but LM disease and shorter DAPT were associated with TLF, in patients with bifurcation lesions undergoing 2-stenting with 2G-DES.

The plasma atherogenic index (AIP) has been suggested as a useful independent predictor of cardiovascular diseases (CVDs) in high CV risk patients. We investigated the association between AIP and arterial stiffness measured by brachial–ankle pulse wave velocity (baPWV) in healthy adults. A total of 3468 healthy subjects without any metabolic or CV diseases were enrolled. Anthropometric and CV risk factors were measured. The AIP was defined as the base 10 logarithm of the ratio of the concentration of triglycerides to high-density lipoprotein-cholesterol. Subjects were classified into AIP quartiles. There were gradual deteriorations in metabolic parameters and increase in baPWV across the increasing AIP quartiles. In a fully adjusted analysis, compared with Q1 (lowest quartile) group, the odds ratio (95% confidence interval) for increased baPWV was higher in Q2 1.51, Q3 1.64, and Q4 (highest quartile) 2.77 among men, and Q2 1.09, Q3 1.55, and Q4 1.83 among women (all P trend

Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model.

OBJECTIVE We investigated (1) the associations of pre-stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional outcome, and (2) whether stroke subtypes modify these associations in first-ever ischemic stroke. METHODS This multicenter magnetic resonance imaging (MRI)-based study included 5,700 consecutive patients with acute first-ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score-based augmented inverse probability weighting was performed to estimate adjusted effects of pre-stroke aspirin use. RESULTS The mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre-stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre-stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = -5.4%, 95% confidence interval [CI] = -8.9 to -1.9). Thus, pre-stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3-month modified Rankin Scale score

Summary Background In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction. Methods In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055. Findings From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority Interpretation In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events. Funding ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

Background and ObjectivesWe evaluated the association between admission glycated hemoglobin (HbA1c) and subsequent risk of composite vascular events, including stroke, myocardial infarction (MI), and vascular death, in patients with acute ischemic stroke and diabetes.MethodsPatients who had a TIA or an acute ischemic stroke within 7 days of symptom onset and diabetes were included in a retrospective cohort design using the stroke registry of the Clinical Research Center for Stroke in Korea. The association between admission HbA1c and composite vascular events, including stroke, MI, and vascular death, during 1-year follow-up was estimated using the Fine-Gray model. The risk of composite vascular events according to the ischemic stroke subtype was explored using fractional polynomial and linear-quadratic models.ResultsOf the 18,567 patients, 1,437 developed composite vascular events during follow-up. In multivariable analysis using HbA1c as a categorical variable, the risk significantly increased at a threshold of 6.8%–7.0%. The influence of admission HbA1c level on the risk of composite vascular events was pronounced particularly among those in whom fasting glucose at admission was ≤130 mg/dL. The optimal ranges of HbA1c associated with minimal risks for composite vascular events were lowest for the small vessel occlusion subtype (6.6 [95% confidence internal [CI], 6.3–6.9]) compared to the large artery atherosclerosis (7.3 [95% CI, 6.8–7.9]) or the cardioembolic subtype (7.4 [95% CI, 6.3–8.5]).DicussionIn patients with ischemic stroke and diabetes, the risks of composite vascular events were significantly associated with admission HbA1c. The optimal range of admission HbA1c was below 6.8%–7.0% and differed according to the ischemic stroke subtype.