Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review

Purpose Hereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea. Materials and Methods We defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: (“hereditary hemorrhagic telangiectasia” AND “Korea”) OR (“Osler-Weber-Rendu” AND “Korea”). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea. Results We extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4–82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations. Conclusion The prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented

What we need to know when performing and interpreting US elastography

According to the increasing need for accurate staging of hepatic fibrosis, the ultrasound (US) elastography techniques have evolved significantly over the past two decades. Currently, US elastography is increasingly used in clinical practice. Previously published studies have demonstrated the excellent diagnostic performance of US elastography for the detection and staging of liver fibrosis. Although US elastography may seem easy to perform and interpret, there are many technical and clinical factors which can affect the results of US elastography. Therefore, clinicians who are involved with US elastography should be aware of these factors. The purpose of this article is to present a brief overview of US techniques with the relevant technology, the clinical indications, diagnostic performance, and technical and biological factors which should be considered in order to avoid misinterpretation of US elastography results

Development and validation of a deep learning-based automatic segmentation model for assessing intracranial volume: comparison with NeuroQuant, FreeSurfer, and SynthSeg

Background and purposeTo develop and validate a deep learning-based automatic segmentation model for assessing intracranial volume (ICV) and to compare the accuracy determined by NeuroQuant (NQ), FreeSurfer (FS), and SynthSeg.Materials and methodsThis retrospective study included 60 subjects [30 Alzheimer’s disease (AD), 21 mild cognitive impairment (MCI), 9 cognitively normal (CN)] from a single tertiary hospital for the training and validation group (50:10). The test group included 40 subjects (20 AD, 10 MCI, 10 CN) from the ADNI dataset. We propose a robust ICV segmentation model based on the foundational 2D UNet architecture trained with four types of input images (both single and multimodality using scaled or unscaled T1-weighted and T2-FLAIR MR images). To compare with our model, NQ, FS, and SynthSeg were also utilized in the test group. We evaluated the model performance by measuring the Dice similarity coefficient (DSC) and average volume difference.ResultsThe single-modality model trained with scaled T1-weighted images showed excellent performance with a DSC of 0.989 ± 0.002 and an average volume difference of 0.46% ± 0.38%. Our multimodality model trained with both unscaled T1-weighted and T2-FLAIR images showed similar performance with a DSC of 0.988 ± 0.002 and an average volume difference of 0.47% ± 0.35%. The overall average volume difference with our model showed relatively higher accuracy than NQ (2.15% ± 1.72%), FS (3.69% ± 2.93%), and SynthSeg (1.88% ± 1.18%). Furthermore, our model outperformed the three others in each subgroup of patients with AD, MCI, and CN subjects.ConclusionOur deep learning-based automatic ICV segmentation model showed excellent performance for the automatic evaluation of ICV

Amyloid Precursor Protein Binding Protein-1 Modulates Cell Cycle Progression in Fetal Neural Stem Cells

Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of the amyloid precursor protein (APP) and serves as the bipartite activation enzyme for the ubiquitin-like protein, NEDD8. In the present study, we explored the physiological role of APP-BP1 in the cell cycle progression of fetal neural stem cells. Our results show that cell cycle progression of the cells is arrested at the G1 phase by depletion of APP-BP1, which results in a marked decrease in the proliferation of the cells. This action of APP-BP1 is antagonistically regulated by the interaction with APP. Consistent with the evidence that APP-BP1 function is critical for cell cycle progression, the amount of APP-BP1 varies depending upon cell cycle phase, with culminating expression at S-phase. Furthermore, our FRET experiment revealed that phosphorylation of APP at threonine 668, known to occur during the G2/M phase, is required for the interaction between APP and APP-BP1. We also found a moderate ubiquitous level of APP-BP1 mRNA in developing embryonic and early postnatal brains; however, APP-BP1 expression is reduced by P12, and only low levels of APP-BP1 were found in the adult brain. In the cerebral cortex of E16 rats, substantial expression of both APP-BP1 and APP mRNAs was observed in the ventricular zone. Collectively, these results indicate that APP-BP1 plays an important role in the cell cycle progression of fetal neural stem cells, through the interaction with APP, which is fostered by phopshorylation of threonine 668

Candida haemulonii and Closely Related Species at 5 University Hospitals in Korea: Identification, Antifungal Susceptibility, and Clinical Features

Background. Candida haemulonii, a yeast species that often exhibits antifungal resistance, rarely causes human infection. During 2004-2006, unusual yeast isolates with phenotypic similarity to C. haemulonii were recovered from 23 patients (8 patients with fungemia and 15 patients with chronic otitis media) in 5 hospitals in Korea. Methods. Isolates were characterized using D1/D2 domain and ITS gene sequencing, and the susceptibility of the isolates to 6 antifungal agents was tested in vitro. Results. Gene sequencing of the blood isolates confirmed C. haemulonii group I (in 1 patient) and Candida pseudohaemulonii (in 7 patients), whereas all isolates recovered from the ear were a novel species of which C. haemulonii is its closest relative. The minimum inhibitory concentration (MIC) ranges of amphotericin B, fluconazole, itraconazole, and voriconazole for all isolates were 0.5-32 mu g/mL (MIC(50), 1 mu g/mL), 2-128 mu g/mL (MIC(50), 4 mu g/mL), 0.125-4 mu g/mL (MIC(50), 0.25 mu g/mL), and 0.03-2 mu g/mL (MIC(50), 0.06 mu g/mL), respectively. All isolates were susceptible to caspofungin (MIC, 0.125-0.25 mu g/mL) and micafungin (MIC, 0.03-0.06 mu g/mL). All cases of fungemia occurred in patients with severe underlying diseases who had central venous catheters. Three patients developed breakthrough fungemia while receiving antifungal therapy, and amphotericin B therapeutic failure, which was associated with a high MIC of amphotericin B (32 mu g/mL), was observed in 2 patients. Conclusions. Candida species that are closely related to C. haemulonii are emerging sources of infection in Korea. These species show variable patterns of susceptibility to amphotericin B and azole antifungal agents.Shin JH, 2007, J CLIN MICROBIOL, V45, P2385, DOI 10.1128/JCM.00381-07Khan ZU, 2007, J CLIN MICROBIOL, V45, P2025, DOI 10.1128/JCM.00222-07Lee JS, 2007, J CLIN MICROBIOL, V45, P1005, DOI 10.1128/JCM.02264-06Pfaller MA, 2006, J CLIN MICROBIOL, V44, P819, DOI 10.1128/JCM.44.3.819-826.2006Sugita T, 2006, MICROBIOL IMMUNOL, V50, P469Clancy CJ, 2005, ANTIMICROB AGENTS CH, V49, P3171, DOI 10.1128/AAC.49.8.3171-3177.2005Odds FC, 2004, J CLIN MICROBIOL, V42, P3475, DOI 10.1128/JCM.42.8.3475-3482.2004Rodero L, 2002, J CLIN MICROBIOL, V40, P2266, DOI 10.1128/JCM.40.6.2266-2269.2002*CLSI, 2002, M27A2 CLSISugita T, 1999, J CLIN MICROBIOL, V37, P1985Pfaller MA, 1998, DIAGN MICR INFEC DIS, V32, P223Nguyen MH, 1998, J INFECT DIS, V177, P425Kurtzman CP, 1997, J CLIN MICROBIOL, V35, P1216LEHMANN PF, 1993, J CLIN MICROBIOL, V31, P1683GARGEYA IB, 1991, J MED VET MYCOL, V29, P335

Prevalence of Neuropathic Pain and Patient-Reported Outcomes in Korean Adults with Chronic Low Back Pain Resulting from Neuropathic Low Back Pain

Study DesignA noninterventional, multicenter, cross-sectional study.PurposeWe investigated the prevalence of neuropathic pain (NP) and patient-reported outcomes (PROs) of the quality of life (QoL) and functional disability in Korean adults with chronic low back pain (CLBP).Overview of LiteratureAmong patients with CLBP, 20%–55% had NP.MethodsPatients older than 20 years with CLBP lasting for longer than three months, with a visual analog scale (VAS) pain score higher than four, and with pain medications being used for at least four weeks before enrollment were recruited from 27 general hospitals between December 2014 and May 2015. Medical chart reviews were performed to collect demographic/clinical features and diagnosis of NP (douleur neuropathique 4, DN4). The QoL (EuroQoL 5-dimension, EQ-5D; EQ-VAS) and functional disability (Quebec Back Pain Disability Scale, QBPDS) were determined through patient surveys. Multiple linear regression analyses were performed to compare PROs between the NP (DN4≥4) and non-NP (DN4<4) groups.ResultsA total of 1,200 patients (females: 65.7%; mean age: 63.4±13.0 years) were enrolled. The mean scores of EQ-5D, EQ-VAS, and QBPDS were 0.5±0.3, 55.7±19.4, and 40.4±21.1, respectively. Among all patients, 492 (41.0%; 95% confidence interval, 38.2%–43.8%) suffered from NP. The prevalence of NP was higher in male patients (46.8%; p<0.01), in patients who had pain based on radiological and neurological findings (59.0%; p<0.01), and in patients who had severe pain (49.0%; p<0.01). There were significant mean differences in EQ-5D (NP group vs. non-NP group: 0.4±0.3 vs. 0.5±0.3; p<0.01) and QBPDS (NP group vs. non-NP group: 45.8±21.2 vs. 36.3±20.2; p<0.01) scores. In the multiple linear regression, patients with NP showed lower EQ-5D (β=−0.1; p<0.01) and higher QBPDS (β=7.0; p<0.01) scores than those without NP.ConclusionsNP was highly prevalent in Korean patients with CLBP. Patients with CLBP having NP had a lower QoL and more severe dysfunction than those without NP. To enhance the QoL and functional status of patients with CLBP, this study highlights the importance of appropriately diagnosing and treating NP

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field