Fibrotic Burden in Patients With Hepatitis B Virus-Related Cirrhosis Is Independently Associated With Poorer Kidney Outcomes.

BACKGROUND: We investigated whether higher fibrotic burden was independently associated with poorer kidney outcomes in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS: A total of 1691 patients with radiologically diagnosed HBV-related cirrhosis but without baseline chronic kidney disease (CKD) who underwent transient elastography (TE) between March 2012 and August 2018 were selected. The study outcome was the composite of development of incident CKD, defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 or proteinuria (≥1+ on dipstick test) on 2 consecutive measurements during follow-up, 50% decline in eGFR or onset of end-stage kidney disease (initiation of chronic dialysis), or all-cause mortality. RESULTS: The mean age was 53.4 years and 1030 (60.9%) patients were male. During 8379 person-years of follow-up (median 5.2 years), 60 (3.5%) patients experienced study outcomes. When stratified according to TE-defined fibrotic burden, multivariable Cox models revealed that risk of poorer kidney outcomes was 2.77-fold (95% confidence interval, 1.16-6.63; P < .001) higher in patients with liver stiffness range indicating cirrhosis (≥11.7 kPa), compared to those without significant liver fibrosis (<7.9 kPa). These associations remained significant even after adjusting for vigorous confounders. CONCLUSIONS: Higher fibrotic burden assessed using TE was independently associated with poorer kidney outcomes in patients with HBV-related cirrhosis.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

Loss of Krüppel-like factor-10 facilitates the development of chemical-induced liver cancer in mice.

BACKGROUND: Krüppel-like factor 10 (KLF10) is involved in a positive feedback loop that regulates transforming growth factor ß (TGFß) signaling, and TGFß plays an important role in the pathogenesis of liver disease. Here, we investigated whether KLF10 deletion affects the development of liver fibrosis and hepatocellular carcinoma (HCC). METHODS: We induced KLF10 deletion in C57BL/6 mice. Liver fibrosis was induced by feeding a diet high in fat and sucrose (high-fat diet [HFD]), whereas HCC was produced by intraperitoneal administration of N-diethylnitrosamine (DEN). An in vitro experiment was performed to evaluate the role of KLF10 in the cancer microenvironment using Hep3B and LX2 cells. An immunohistochemical study of KLF10 expression was performed using human HCC samples from 60 patients who had undergone liver resection. RESULTS: KLF10 deletion resulted in an increased DEN-induced HCC burden with significant upregulation of SMAD2, although loss of KLF10 did not alter HFD-induced liver fibrosis. DEN-treated mice with KLF10 deletion exhibited increased levels of mesenchymal markers (N-cadherin and SNAI2) and tumor metastasis markers (matrix metalloproteinases 2 and 9). KLF10 depletion in Hep3B and LX2 cells using siRNA was associated with increased invasiveness. Compared with co-culture of KLF10-preserved Hep3B cells and KLF10-intact LX2 cells, co-culture of KLF10-preserved Hep3B cells and KLF10-depleted LX2 cells resulted in significantly enhanced invasion. Low KLF10 expression in resected human HCC specimens was associated with poor survival. CONCLUSION: The results of this study suggest that loss of KLF10 facilitates liver cancer development with alteration in TGFß signaling.

Baseline and on-treatment HBcrAg levels as predictors of HBeAg seroconversion in chronic hepatitis B patients treated with antivirals.

HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log10 U/mL (p = .006), 4.9(4.5-5.1) vs. 4.5(4.1-5.0) log10 IU/mL (p = .044) in the no seroconversion group and seroconversion group, respectively. In the multivariate analysis, the serum HBcrAg levels at baseline and 2 years after antiviral therapy were predictive factors for HBeAg seroconversion ([HR]; 0.326; [CI], 0.111-0.958; p = .042 and HR, 0.4555; CI, 0.211-0.984; p = .045). HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy had sensitivities of 53.1% and 69.8%, specificities of 95.2% and 70.6%, positive predictive values of 82.6% and 50.0%, and negative predictive values of 82.6% and 84.5%, respectively, with AUROCs of 0.712 (95%CI, 0.596-0.830) and 0.745 (95%CI, 0.599-0.891) for predicting HBeAg seroconversion. In chronic hepatitis B patients treated with NAs, HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy were useful predictive factors of HBeAg seroconversion.

Impact of boost sequence in concurrent chemo-radiotherapy on newly diagnosed IDH-wildtype glioblastoma multiforme.

BACKGROUND: The standard of care for glioblastoma multiforme (GBM) is maximal surgical resection followed by conventional fractionated concurrent chemoradiotherapy (CCRT) with a total dose of 60 Gy. However, there is currently no consensus on the optimal boost technique for CCRT in GBM. METHODS: We conducted a retrospective review of 398 patients treated with CCRT between 2016 and 2021, using data from two institutional databases. Patients were divided into two groups: those receiving sequential boost (SEB, N = 119) and those receiving simultaneous integrated boost (SIB, N = 279). The primary endpoint was overall survival (OS). To minimize differences between the SIB and SEB groups, we conducted propensity score matching (PSM) analysis. RESULTS: The median follow-up period was 18.6 months. Before PSM, SEB showed better OS compared to SIB (2-year, 55.6% vs. 44.5%, p = 0.014). However, after PSM, there was no significant difference between two groups (2-year, 55.6% vs. 51.5%, p = 0.300). The boost sequence was not associated with inferior OS before and after PSM (all p-values > 0.05). Additionally, the rates of symptomatic pseudo-progression were similar between the two groups (odds ratio: 1.75, p = 0.055). CONCLUSIONS: This study found no significant difference in OS between SEB and SIB for GBM patients treated with CCRT. Further research is needed to validate these findings and to determine the optimal boost techniques for this patient population.

The care cascade for hepatitis C virus and prognosis of chronic hepatitis C patients treated with antiviral agents in a tertiary hospital.

BACKGROUND: Some studies have analyzed the frequency of HCV RNA testing and actual treatment among anti-HCV positive patients in Korea, which has a low prevalence of HCV infection. This study aimed to analyze the diagnosis process, treatment results, and prognosis according to care cascade in patients who are anti-HCV positive. METHODS: Three thousand two hundred fifty-three anti-HCV positive patients presented to a tertiary hospital between January 2005 and December 2020. The number of patients who underwent HCV RNA testing, treatment, and proportion of sustained virologic response (SVR) according to the type of antivirals was investigated. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and liver cirrhosis. RESULTS: Of a total of 3,253 people, 1,177 (36.2%) underwent HCV RNA testing and 858 (72.9%) were positive for HCV RNA. 494 (57.6%) of HCV RNA positive patients received antiviral treatment, and 443 (89.7%) of initiated hepatitis C treatment experienced SVR. Of the 421 treated patients, 16 (14.2%) developed HCC. The cumulative incidence of HCC at 15 years was significantly different according to the presence of liver cirrhosis (10/83, 29.5% vs. 6/338, 10.8%, p < 0.001). The cumulative incidences of HCC or liver cirrhosis did not show significant differences according to the presence of SVR12 (14/388, 13.2% vs. 2/33, 52.5%, p = 0.084, 21/319, 15.0%, vs. 3/22, 28.7%, p = 0.051). CONCLUSIONS: Owing to the introduction of direct-acting antivirals, high SVR12 was achieved, but the proportion of anti-HCV positive patients who received HCV RNA testing and treatment was not high. HCC surveillance after SVR12 is recommended for chronic hepatitis C patients with cirrhosis.

Equilibria of semi-volatile isothiazolinones between air and glass surfaces measured by gas chromatography and Raman spectroscopy.

Trace amounts of semi-volatile organic compounds (SVOCs) of the two isothiazolinones of 2-methylisothiazol-3(2H)-one (MIT) and 2-octyl-4-isothiazolin-3-one (OIT) were detected both in the air and on glass surfaces. Equilibria of SVOCs between air and glass were examined by solid phase microextraction-gas chromatography/mass spectrometry (SPME-GC/MS). Surface to air distribution ratios of Ksa for MIT and OIT were determined to be 5.10 m and 281.74 m, respectively, suggesting more abundant MIT in the gas phase by a factor of ∼55. In addition, a facile method of silver nanocube (AgNC)-assisted surface-enhanced Raman scattering (SERS) has been developed for the rapid and sensitive detection of MIT and OIT on glass surfaces. According to MIT and OIT concentration-correlated SERS intensities of Raman peaks at ∼1585 cm-1 and ∼1125 cm-1, respectively. Their calibration curves have been obtained in the concentration ranges between 10-3 to 10-10 M and 10-3 to 10-11 M with their linearity of 0.9986 and 0.9989 for MIT and OIT, respectively. The limits of detection (LODs) of the two isothiazolinones were estimated at 10-10 M, and 10-11 M for MIT and OIT, respectively. Our results indicate that AgNC-assisted SERS spectra are a rapid and high-ultrasensitive method for the quantification of MIT and OIT in practical applications. The development of analytical methods and determination of the Ksa value obtained in this study can be applied to the prediction of the exposure to MIT and OIT from various chemical products and dynamic behaviors to assess human health risks in indoor environments.

Surgical Outcomes of Percutaneous Pinning and Open Locking Plating in Patients With Intra-articular Fractures of the Base of the Fifth Metacarpal.

PURPOSE: The purpose of the study was to demonstrate the results of surgical treatment, including percutaneous K-wire fixation after closed reduction (CRKF) or locking plate fixation after open reduction (ORPF), in patients with intra-articular fractures of the base of the fifth metacarpal. METHODS: We retrospectively reviewed data of 29 patients who received surgical treatment for closed, intra-articular fractures of the base of the fifth metacarpal and were followed up for at least 1 year after surgery. Sixteen of the 29 patients underwent CRKF, whereas 13 patients underwent ORPF. Attempts were made to address intra-articular step-off with closed reduction in all the patients; however, if inadequate, ORPF was performed. Clinical outcomes were evaluated using Disabilities of the Arm, Shoulder, and Hand scores, visual analog scale pain scores, the total active motion (TAM) of the little finger, and grip strength. Osseous union and posttraumatic arthritis of the fifth carpometacarpal joint were also evaluated. RESULTS: K-wire fixation after closed reduction was performed for 13 simple fractures and 3 comminuted fractures; ORPF was performed for 6 simple fractures and 7 comminuted fractures. All the patients had satisfactory subjective outcomes with over 90% grip strength compared with that on the contralateral side and nearly full TAM. All the patients in both the groups achieved osseous union. There were five cases of grade 1 posttraumatic arthritis after CRKF and seven cases of grade 1 posttraumatic arthritis after ORPF. CONCLUSIONS: Surgical treatment provided satisfactory results in patients with intra-articular fractures of the base of the fifth metacarpal treated with either CRKF or ORPF. Our data showed that the patients who underwent CPKF had good results, and those who underwent ORPF after attempt failure of close reduction also had good results. Our experience suggests that ORPF can be a backup plan when CRKF cannot be accomplished in a satisfactory way. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Similar risk of kidney function decline between tenofovir alafenamide and besifovir dipivoxil maleate in chronic hepatitis B.

BACKGROUND AND AIMS: Although tenofovir alafenamide (TAF) and besifovir dipivoxil maleate (BSV) are potent antiviral agents in the treatment of chronic hepatitis B (CHB) infection, their renal safety profiles have not been previously compared. This study compared the risk of kidney function decline among patients with treatment-naïve CHB treated with TAF or BSV. METHODS: This multicenter, retrospective, longitudinal cohort study included 556 patients with treatment-naïve CHB treated with TAF (n = 366) or BSV (n = 190) between November 2017 and August 2021. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. RESULTS: 1:1 Propensity score matching yielded 154 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.4 vs. 100.3 ml/min/1.73 m2 in the TAF and BSV groups respectively. A total of 25 patients developed a progression in CKD stage ≥1, of which 13 and 12 patients were from the TAF and BSV treated groups respectively (3.1 vs. 3.3 per 1000 person-years; p = .751). The unadjusted hazard ratio for risk of progression in CKD stage ≥1 of the BSV group (vs. the TAF group) was 1.13 (95% confidence interval, 0.50-2.58; p = .758). This association persisted even after adjusting for potential confounders. Virological, serological and biochemical responses were also similar between the two treatment groups (all p > .05). CONCLUSIONS: TAF and BSV showed a similar risk of kidney function decline in patients with treatment-naïve CHB. Further prospective randomized studies are warranted for validation.

Bevacizumab plus irinotecan with or without gamma knife radiosurgery after failure of concurrent chemo-radiotherapy for high-grade glioma.

INTRODUCTION: Concurrent chemo-radiotherapy (CCRT) with temozolomide (TMZ) is a standard first-line treatment for high-grade glioma. However, if CCRT with TMZ treatment fails, second-line treatment options have limited value. Bevacizumab plus irinotecan is the only available treatment option for such patients. The role of gamma knife radiosurgery (GKS) in patients with high-grade gliomas is not well-established. In this study, we evaluated the efficacy and safety of bevacizumab plus irinotecan with or without GKS in the treatment of high-grade glioma patients who progressed after initially being treated with CCRT with TMZ. METHODS: We collected clinical data of patients with biopsy-proven high-grade glioma (glioblastoma multiforme (GBM) or anaplastic astrocytoma) who were treated at Samsung Medical Center from January 2015 to December 2020, retrospectively. We evaluated the overall survival (OS), progression-free survival (PFS), and safety of bevacizumab plus irinotecan with or without GKS. RESULTS: In total, 203 patients were diagnosed with high-grade glioma, including GBM and anaplastic astrocytoma. The median OS was 8.73 months (95% confidence interval [CI]: 7.27-10.18), and the median PFS was 4.36 months (95% CI: 3.75-4.97). Sixty-eight (33.4%) patients underwent GKS prior to bevacizumab plus irinotecan treatment, which led to a significantly prolonged OS (10.13 months, 95% CI: 8.65-11.60 vs. 8.26 months, 95% CI: 7.01-9.51, p = 0.012). The most common adverse events of any grade were neutropenia (36.9%) and thrombocytopenia (22.6%). However, the incidence of adverse events in patients who underwent GKS prior to bevacizumab plus irinotecan was not different compared with those in patients who did not undergo GKS. CONCLUSIONS: Bevacizumab plus irinotecan was well-tolerated and moderately effective in patients with high-grade gliomas. The addition of GKS prior to bevacizumab plus irinotecan led to a significant OS benefit with a manageable safety profile. GKS prior to bevacizumab plus irinotecan can therefore be considered a potential treatment option for these patients.

Analysis of semi-volatile organic compounds in indoor dust and organic thin films by house type in South Korea.

In this study, semi-volatile organic compounds (SVOCs) in samples of indoor dust and organic thin films obtained from 100 residential houses in South Korea, were examined, based on both target analysis using gas chromatography-mass spectrometry (GC-MS) and non-target analysis by gas chromatography-quadrupole time-of flight mass spectrometry (GC-QTOF-MS) screening. In the targeted approach, phthalates and polycyclic aromatic hydrocarbons (PAHs) were analyzed in dust and organic film samples, to find that both these classes of SVOCs were detected in dust and organic film samples, with the median concentrations of eight phthalates (Σ8 phthalate) and 16 PAHs (Σ16 PAH) being 1015.93 µg/g and 1824.97 ng/g in the dust samples, and 75.79 µg/m2 and 2252.78 ng/m2 in the organic film samples, respectively. Among the phthalates, in all house types. bis(2-ethylhexyl) phthalate (DEHP) was detected at the highest concentration, followed by dibutyl phthalate (DBP) and diisobuthyl phthalate (DiBP), with DEHP levels found to be highest in dwelling houses. DEHP levels were found to be significantly associated with building age and renovation status. Lower levels of DEHP were detected in houses less than 10 years old or that had undergone renovation in the previous 10 years. Among the assessed PAHs, a significant correlation was detected between benzo(a)pyrene in dust and building age (p < 0.05). These findings imply that the inhabitants of older houses are at a greater risk of exposure to SVOCs originating from indoor dust and organic films. Non-target screening of selected dust and organic film samples using GC-QTOF-MS data revealed the presence of numerous SVOC compounds, including triphenylphosphine oxide, (Z)-9-octadecenamide, and cyclosiloxanes, along with certain organophosphate flame retardants including tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloroisopropyl) phosphate (TDCPP), and plasticizers. These compounds identified in the non-target screening are of emerging concern, and their presence in dust and organic films needs to be estimated.

MAFLD Predicts the Risk of Cardiovascular Disease Better than NAFLD in Asymptomatic Subjects with Health Check-Ups.

BACKGROUND AND AIM: Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We investigated the superiority of MAFLD versus NAFLD in predicting the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: A total of 2,144 subjects without a history of ASCVD, who underwent a comprehensive medical health check-up, were selected for the study. The associations between fatty liver status and coronary risk surrogates, such as coronary artery calcium score (CACS), coronary artery disease, quantitative stenosis grade, and 10-year ASCVD risk, were analyzed. RESULTS: MAFLD and NAFLD were identified in 995 (46.4%) and 891 (41.6%) subjects, respectively. Subjects with MAFLD or NAFLD were more likely to be male and had a significantly higher prevalence of central obesity, obesity, hypertension, diabetes, and dyslipidemia (all, p < 0.05) than their counterparts. In terms of coronary risk surrogates, the MAFLD or NAFLD population had a significantly higher proportion of subjects with CACS > 100, coronary artery disease, higher grade of coronary artery stenosis, and higher 10-year ASCVD risk (all, p < 0.05) than their counterparts. Multivariable logistic regression models showed an independent association between MAFLD/NAFLD and coronary risk surrogates (all, p < 0.05). However, NAFLD only, defined as 'NAFLD, but not MAFLD,' was not associated with an increased coronary risk, compared to MAFLD. CONCLUSIONS: Although both MAFLD and NAFLD discriminated different ASCVD risks, MAFLD predicted the risk of ASCVD better than NAFLD in asymptomatic subjects who underwent medical health check-ups.

Anti-HBc IgG Levels: A Predictor of HBsAg Seroclearance in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue-Induced HBeAg Seroclearance.

BACKGROUND/AIMS: We investigated the efficiency of the indirect ratio of anti-HBc IgG at predicting HBsAg seroclearance in patients with nucleos(t)ide analogue (NA)-induced HBeAg seroclearance. METHODS: We performed a retrospective study that included 366 chronic hepatitis B patients (March 2007 to December 2016) at a single tertiary hospital. These patients were HBsAg seropositive, and experienced NA-induced HBeAg seroclearance. The indirect ratio of light absorbance of anti-HBc IgG levels were measured with chemiluminescent microparticle immunoassay using the Architect Anti-HBc assay (Abbott Laboratories, IL, USA) as a qualitative method prior to antiviral therapy. We calculated the cumulative incidences of HBsAg seroclearance based on the anti-HBc IgG levels. RESULTS: After a 10-year follow-up, 48 patients experienced HBsAg seroclearance (13.1%). Thirty-three of 179 patients who had an indirect ratio of light absorbance of anti-HBc IgG < 11 RLU (relative light unit) showed HBsAg seroclearance (18.4%); 15 of 187 patients who had an indirect ratio of light absorbance of anti-HBc IgG ≥ 11 RLU showed HBsAg seroclerance (8.0%) (p = 0.003). In multivariate analysis, age, and ALT at the time of HBeAg seroclearance were predictors of HBsAg seroclearance. Especially, the relative risk of HBsAg seroclearance in patients with baseline anti-HBc IgG levels < 11 RLU was 2.213 (95% CI, 1.220-4.014), compared to that in patients with higher levels of anti-HBc IgG at baseline (p = 0.009). CONCLUSION: Using an indirect method for anti-HBc IgG levels, baseline anti-HBc IgG levels (< 11RLU), age (≥ 50 years), and ALT (≥ 40 IU/L) might be associated with HBsAg seroclearance in patients with NA-induced HBeAg seroclearance.

Combined endoscopic endonasal and transorbital multiportal approach for complex skull base lesions involving multiple compartments.

PURPOSE: This study defines the specific areas that connect the surgical corridors of the endoscopic endonasal (EEA) and transorbital approach (TOA) to identify adequate clinical applications and perspectives of this combined multiportal approach. METHODS: Consecutive patients who underwent combined EEA and TOA procedures for various pathologies involving multiple compartments of the skull base were enrolled. RESULTS: A total of eight patients (2 chondrosarcomas, 2 meningiomas, 2 schwannomas, 1 glioma, and 1 traumatic optic neuropathy) were included between August 2016 and April 2021. The cavernous sinus (CS) was targeted as the connection area of the combined approach in four patients with tumors infiltrating the middle cranial fossa (MCF) and central skull base through the CS. For two patients with MCF tumors extending into the infratemporal fossa (ITF), the horizontal portion of the greater sphenoid wing and the foramen ovale were utilized as the connection area. In the remaining 2 patients, connection was achieved through the optic canal (OC). Gross total and near total resection was achieved in 5 patients with tumors, and circumferential removal of bone composing the OC was performed in one patient with traumatic compressive optic neuropathy. Postoperative complications included one cardiac arrest due to underlying cardiovascular disease and one case of oculomotor nerve palsy. CONCLUSIONS: The combined EEA and TOA procedure is a useful strategy for complex lesions involving multiple compartments of the skull base. Herein, we identified the specific areas connecting the two surgical approaches, allowing a common path for EEA and TOA procedures.

IntraBrain Injector (IBI): A Stereotactic-Guided Device for Repeated Delivery of Therapeutic Agents Into the Brain Parenchyma.

BACKGROUND: To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. METHODS: We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. RESULTS: We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. CONCLUSION: Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.

Epidemiology, injury characteristics and clinical outcomes of bicycle and motorcycle accidents in the under 20 population: South Korea.

BACKGROUND: Bicycles and motorcycles are a main means of transportation and leisure for individuals aged under 20 years in South Korea. We aimed to identify the epidemiology of injuries and describe and compare patterns of injury and clinical outcomes of two-wheel vehicle-related accidents in these individuals. METHODS: We analysed data obtained from the National Emergency Department Information System for 401 emergency departments (EDs) from January 2016 to December 2018. We included patients aged < 20 years who experienced injuries while driving or a passenger on two-wheeled vehicles. We analysed patients with a bicycle-related injury and those with a motorcycle-related injury, and then compared two groups and performed a regression analysis for factors predicting severe trauma. RESULTS: This study enrolled 54,342 two-wheel vehicle injury patients (37,410 bicycle and 16,932 motorcycle-related), of which, 86.8% (bicycle) and 94.9% (motorcycle) were males. External injuries were the most common. ED mortality was 9 (0.0%) for bicycles and 53 (0.3%) for motorcycles. Overall, 3,346 (8.9%) patients were hospitalised with bicycle injuries and 4,096 (24.2%) with motorcycle injuries. Among admitted patients with bicycle-related injuries, 48.7% had upper extremity injuries and among those admitted patients with motorcycle-related injuries, 76.0% had lower extremity injuries. Among hospitalised patients, the mean injury severity score (ISS) was 12.0 ± 12.6 in bicycle-related injury and 17.6 ± 15.4 in motorcycle-related injury. The number of patients with ISS ≥ 16 was 27.6% for bicycle related injuries and 45.2% for motorcycle-related injuries. The mean length of hospital stay was 191.5.8 ± 224.2 h for bicycle injury, and 359.6 ± 416.7 h for motorcycles. Hospital mortality cases were 0.2% with bicycle injury and 1.2% with motorcycle injury. Motorcycle-related injuries had more severe injury (ISS ≥ 16), with an adjusted odds ratio of 2.825 (95% confidence interval 2.610-3.059) compared to bicycle-related injuries. CONCLUSIONS: In the population aged under 20 years, two-wheel vehicle-related occurred predominantly in males. When using two-wheeled vehicles, motorcycle injuries were higher in patients aged over 14 years and were associated with higher ISS (≥ 16). Political efforts should be made to educate under 20 years of age for safe driving and to wear protective gear, including helmets to prevent severe injury.

Effects of Statin Use on the Development and Progression of Nonalcoholic Fatty Liver Disease: A Nationwide Nested Case-Control Study.

INTRODUCTION: The use of statins in nonalcoholic fatty liver disease (NAFLD) may reduce cardiovascular morbidity, although their effect on NAFLD itself is not well known. We aimed to investigate the role of statins on the development of de novo NAFLD and progression of significant liver fibrosis. METHODS: This study included 11,593,409 subjects from the National Health Information Database of the Republic of Korea entered in 2010 and followed up until 2016. NAFLD was diagnosed by calculating fatty liver index (FLI), and significant liver fibrosis was evaluated using the BARD score. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection. RESULTS: Among 5,339,901 subjects that had a FLI < 30 and included in the non-NAFLD cohort, 164,856 subjects eventually had NAFLD developed. The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65-0.67) and was independent of associated diabetes mellitus (DM) (with DM: AOR 0.44; 95% CI 0.41-0.46, without DM: AOR 0.71; 95% CI 0.69-0.72). From 712,262 subjects with a FLI > 60 and selected in the NAFLD cohort, 111,257 subjects showed a BARD score ≥ 2 and were defined as liver fibrosis cases. The use of statins reduced the risk of significant liver fibrosis (AOR 0.43; 95% CI 0.42-0.44), independent of DM (with DM: AOR 0.31; 95% CI 0.31-0.32, without DM: AOR 0.52; 95% CI 0.51-0.52). DISCUSSION: In this large population-based study, statin use decreased the risk of NAFLD occurrence and the risk of liver fibrosis once NAFLD developed.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Obligatory role of Schwann cell-specific erythropoietin receptors in erythropoietin-induced functional recovery and neurogenic muscle atrophy after nerve injury.

BACKGROUND: Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals. METHODS: Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoRflox/flox , Mpz-EpoR-KO). Mpz-EpoR-KO and control mice were assigned to sciatic nerve crush injury followed by EPO treatment. RESULTS: EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice. CONCLUSIONS: These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.

Early hormonal recovery following endoscopic transsphenoidal surgery for silent non-functioning pituitary adenomas with hormone dysfunction.

PURPOSE: The role of transsphenoidal surgery in the recovery of preexisting hormone dysfunction from pituitary tumors remains controversial. This study aimed to investigate the incidence of hormone dysfunction among asymptomatic non-functioning pituitary adenomas and their recovery following endoscopic transsphenoidal surgery. METHODS: Eligibility criteria included age under 80 years, presence of a non-functioning pituitary adenoma compressing the normal gland resulting in deviation of the stalk, absence of visual symptoms, and availability for regular follow-up using MRI and pre- and post-operative endocrinological assessments. 182 patients with silent non-functioning pituitary adenomas were included in this study between March 2014 and December 2018. All patients underwent endoscopic transsphenoidal surgery and complete hormonal evaluation, with basal hormone assays and a combined pituitary function test before and after surgery until the end of last follow-up. RESULTS: Preoperative assessment of hormonal function revealed that 124 of 182 patients (68.1%) had at least a single hormone dysfunction preoperatively. Among these, 61 of 124 (49.2%) had a dysfunction in a single axis, and 63 (50.8%) had a hormone dysfunction in two or more axes. Overall, the median endocrinological follow-up duration was 15.0 months (6-57 months). At 1 month following surgery, 91 patients (73.4%) with hormone dysfunction experienced improvement in at least a single hormone axis. Prolactin was the most common hormone among those that recovered at the last follow up (92.8% improvement) followed by growth hormone (GH, 50.0%), thyroid stimulating hormone (TSH, 50.0%), gonadotropin (Gn, 46.9%), and adrenocorticotropic hormone (ACTH, 45.0%). Time to recovery varied from 1.1 months (for prolactin) to 2.2 months (for gonadotropin, and ACTH). In patients with preoperative deficiency in GH, and ACTH, postoperative transient diabetes insipidus was associated with poor recovery (GH: HR = 0.50, p = 0.048; ACTH: HR = 0.39, p = 0.023). CONCLUSIONS: Non-functioning pituitary adenomas with silent hormone dysfunction are often overlooked by clinicians and patients. We suggest that even silent hormone dysfunction in patients with non-functioning pituitary adenomas can be improved with effective surgical decompression and these tumors may be potential indications of endoscopic transsphenoidal surgery.