The role of 2'-5'-oligoadenylate synthase-like protein (OASL1) in biliary and hepatotoxin-induced liver injury in mice.

Following an injury, the liver embarks on a process that drives the accumulation and reformation of the extracellular matrix, leading to hepatic fibrosis. Type I interferons (IFNs), including IFN-α and IFN-ß, play a crucial role in averting chronic liver injury through the activation of IFN-stimulated genes (ISGs), which are instrumental in sculpting adaptive immunity. The role of 2'-5'-oligoadenylate synthase-like protein 1 (OASL1), an antiviral ISG, in the context of liver fibrosis remains to be elucidated. To elicit liver fibrosis, a diet containing 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) were employed to induce cholestatic- and hepatotoxin-mediated liver fibrosis, respectively. Histological analyses of both models revealed that OASL1-/- mice exhibited reduced liver damage and, consequently, expressed lower levels of fibrotic mediators, notably α-smooth muscle actin. OASL1-/- mice demonstrated significantly elevated IFN-α and IFN-ß mRNA levels, regulated by the IFN regulatory factor 7 (IRF7). Additionally, OASL1-/- ameliorated chronic liver fibrosis through the modulation of nuclear factor-κB (NF-κB) signaling. The effect of OASL1 on type I IFN production in acute liver damage was further explored and OASL1-/- mice consistently showed lower alanine transaminase levels and pro-inflammatory cytokines, but IFN-α and IFN-ß mRNA levels were upregulated, leading to amelioration of acute liver injury. Additionally, the study discovered that F4/80-positive cells were observed more frequently in OASL1-/- CCl4 acutely treated mice. This implies that there is a significant synergy in the function of macrophages and OASL1 deficiency. These results demonstrate that in instances of liver injury, OASL1 inhibits the production of type I IFN by modulating the NF-κB signaling pathway, thereby worsening disease.

Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

A pilot clinical study to evaluate feasibility of using single patient classifier as a prognostic test in stage II-III gastric cancer patients.

Objective: Precision medicine approaches emphasize the importance of reliable prognostic tools for guiding individualized therapy decisions. In this study, we evaluated the clinical feasibility of the single patient classifier (SPC) test, a new clinical-grade prognostic assay, in stage II-III gastric cancer patients. Methods: A prospective multicenter study was conducted, involving 237 patients who underwent gastrectomy between September 2019 and August 2020 across nine hospitals. The SPC test was employed to stratify patients into risk groups, and its feasibility and performance were evaluated. The primary endpoint was the proportion of the cases in which the test results were timely delivered before selecting postoperative treatment. Furthermore, 3-year disease-free survivals of risk groups were analyzed. Results: The SPC test met the primary endpoint criteria. The 99.5% of SPC tests were timely delivered to hospitals before the postoperative treatment started. In a clinical setting, the median time from the specimen transfer to laboratory to the result delivery to hospital was 4 d. Furthermore, 3-year disease-free survivals were significantly different between risk groups classified with SPC tests. Conclusions: This study highlights the SPC test's feasibility in offering crucial information timely delivered for making informed decisions regarding postoperative treatment strategies. It also provides evidence to support the implementation of a future prospective clinical trial aimed at evaluating the clinical utility of the SPC test in guiding personalized treatment decisions for gastric cancer patients.

Prenatal cigarette smoke exposure sensitizes acetaminophen-induced liver injury by modulating miR-34a-5p in male offspring mice.

Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 µg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.

Hepatocyte-Specific Casein Kinase 1 Epsilon Ablation Ameliorates Metabolic Dysfunction-Associated Steatohepatitis by Up-Regulating Tumor Necrosis Factor Receptor-Associated Factor 3 in Mice.

Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, is known to phosphorylate a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1εΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1εfl/fl) and Cre-expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1εΔHEP was associated with a decreased severity of WD- or methionine- and choline-deficient diet-induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1εΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1εΔHEP WD-fed mice showed significantly down-regulated TNF receptor-associated factor 3, phosphorylated (p) transforming growth factor-ß-activated kinase 1, p-TANK-binding kinase 1, and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid-induced steatohepatitis in vitro and attenuated WD-induced metabolic profile in vivo. In conclusion, CK1ε up-regulates TNF receptor-associated factor 3, which, in turn, causes transforming growth factor-ß-activated kinase 1-dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction-associated steatotic liver disease.

Cholesin and GPR146 in Modulating Cholesterol Biosynthesis.

BACKGROUND: Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear. SUMMARY: This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis. KEY MESSAGES: The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.

Evaluation of Droplet Digital PCR for the Detection of BRAF V600E in Fine-Needle Aspiration Specimens of Thyroid Nodules.

Background: Droplet digital (dd)PCR is a new-generation PCR technique with high precision and sensitivity; however, the positive and negative droplets are not always effectively separated because of the "rain" phenomenon. We aimed to develop a practical optimization and evaluation process for the ddPCR assay and to apply it to the detection of BRAF V600E in fine-needle aspiration (FNA) specimens of thyroid nodules, as an example. Methods: We optimized seven ddPCR parameters that can affect "rain." Analytical and clinical performance were analyzed based on histological diagnosis after thyroidectomy using a consecutive prospective series of 242 FNA specimens. Results: The annealing time and temperature, number of PCR cycles, and primer and probe concentrations were found to be more important considerations for assay optimization than the denaturation time and ramp rate. The limit of blank and 95% limit of detection were 0% and 0.027%, respectively. The sensitivity of ddPCR for histological papillary thyroid carcinoma (PTC) was 82.4% (95% confidence interval [CI], 73.6%-89.2%). The pooled sensitivity of BRAF V600E in FNA specimens for histological PTC was 78.6% (95% CI, 75.9%-81.2%, I2=60.6%). Conclusions: We present a practical approach for optimizing ddPCR parameters that affect the separation of positive and negative droplets to reduce rain. Our approach to optimizing ddPCR parameters can be expanded to general ddPCR assays for specific mutations in clinical laboratories. The highly sensitive ddPCR can compensate for uncertainty in cytological diagnosis by detecting low levels of BRAF V600E.

An atypical case involving real, ghost, and pseudo-ghost images on a panoramic radiograph.

Purpose: This report presents a unique case featuring real, ghost, and pseudo-ghost images on the panoramic radiograph of a patient wearing earrings. It also explains the formation of these images in an easy-to-understand manner. Material and Methods: One real image and two ghost images appeared on each side of a panoramic radiograph of a patient wearing earrings on both sides. Of the two ghost images on each side, one was considered a typical ghost image and the other was considered a ghost-like real image (pseudo-ghost image). The formation zones of the real, double, and ghost images were examined based on the path and angles of the X-ray beam from the Planmeca ProMax. To simulate the pseudo-ghost and typical ghost images on panoramic radiography, a radiopaque marker was affixed to the right mandibular condyle of a dry mandible, and the position of the mandible was adjusted accordingly. Results: The center of rotation of the Planmeca ProMax extended beyond the jaw area, and the area of double image formation also reached beyond the jaw. The radiopaque-marked mandibular condyle, situated in the outwardly extending area of double image formation, exhibited triple images consisting of real, double (pseudo-ghost), and ghost images. These findings helped to explain the image formation associated with the patient's earrings observed in the panoramic radiograph. Conclusion: Dentists must understand the characteristics and principles of the panoramic equipment they use and apply this understanding to taking and interpreting panoramic radiographs.

Impact of insertion into the left internal jugular vein in chemoport-associated infections: a retrospective single-center study of 1690 cases.

We analyzed chemoport insertion procedures to evaluate infectious morbidity and factors causing infection. This single-center retrospective study included 1690 cases of chemoport implantation between January 2017 and December 2020. Overall, chemoports were inserted in 1582 patients. The average duration of chemoport use was 481 days (range 1-1794, median 309). Infections occurred in 80 cases (4.7%), with 0.098 per 1000 catheter-days. Among the 80 cases in which chemoports were removed because of suspected infection, bacteria were identified in 48 (60%). Significantly more cases of left internal jugular vein punctures were noted in the infected group (15 [18.8%] vs. 147 [9.1%]; p = 0.004). Pulmonary embolism was significantly different between the infection groups (3 [3.8%] vs. 19 (1.2%), p = 0.048). The hazard ratio was 2.259 (95% confidence interval [CI] 1.288-3.962) for the left internal jugular vein, 3.393 (95% CI 1.069-10.765) for pulmonary embolism, and 0.488 (95% CI 0.244-0.977) for chronic obstructive pulmonary disease. Using the right internal jugular vein rather than the left internal jugular vein when performing chemoport insertion might reduce subsequent infections.

Long-term oncologic outcomes of unselected triple-negative breast cancer patients according to BRCA1/2 mutations.

Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10-20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3-152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers (P = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P < 0.0001). Interestingly, among 29 patients with CBC recurrence, 24 patients (82.8%) had recurring TNBC subtype and among the CBC recurrence patients, 19 patients (65.5%) resumed chemotherapy. In the TNBC subtype, appropriate genetic testing and counseling are pivotal for surgical decisions like risk-reducing mastectomy (RRM). Furthermore, long-term surveillance is warranted, especially in BRCA1/2 carriers who did not receive RRM.

Sulfation of chondroitin and bile acids converges to antagonize Wnt/ß-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis.

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/ß-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/ß-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

Comparison of the problem-solving performance of ChatGPT-3.5, ChatGPT-4, Bing Chat, and Bard for the Korean emergency medicine board examination question bank.

Large language models (LLMs) have been deployed in diverse fields, and the potential for their application in medicine has been explored through numerous studies. This study aimed to evaluate and compare the performance of ChatGPT-3.5, ChatGPT-4, Bing Chat, and Bard for the Emergency Medicine Board Examination question bank in the Korean language. Of the 2353 questions in the question bank, 150 questions were randomly selected, and 27 containing figures were excluded. Questions that required abilities such as analysis, creative thinking, evaluation, and synthesis were classified as higher-order questions, and those that required only recall, memory, and factual information in response were classified as lower-order questions. The answers and explanations obtained by inputting the 123 questions into the LLMs were analyzed and compared. ChatGPT-4 (75.6%) and Bing Chat (70.7%) showed higher correct response rates than ChatGPT-3.5 (56.9%) and Bard (51.2%). ChatGPT-4 showed the highest correct response rate for the higher-order questions at 76.5%, and Bard and Bing Chat showed the highest rate for the lower-order questions at 71.4%. The appropriateness of the explanation for the answer was significantly higher for ChatGPT-4 and Bing Chat than for ChatGPT-3.5 and Bard (75.6%, 68.3%, 52.8%, and 50.4%, respectively). ChatGPT-4 and Bing Chat outperformed ChatGPT-3.5 and Bard in answering a random selection of Emergency Medicine Board Examination questions in the Korean language.

Report for the Eighth Asian National Control Laboratory Network meeting in 2023: Self-sufficiency strategy of plasma-derived medicinal products and regulatory harmonisation.

The Eighth Asian National Control Laboratory (NCL) Network meeting, entitled "Biological Products Quality Control and Self-Sufficiency Strategy focusing on plasma-derived medicinal products (PDMPs)" was held in Seoul on 31 August 2023. The participants were NCL experts from Indonesia, Japan, Malaysia, the Philippines, Vietnam, and the Republic of Korea. Special lectures included the PDMPs self-sufficiency strategies of the World Health Organization (WHO) and Indonesian Food and Drug Authority, and a case study on Global Benchmarking Tool (GBT) assessment for vaccines by the Korea Ministry of Food and Drug Safety. The NCL delegates shared their current experiences with national lot releases and biological standardisation. The meeting contributed to a mutual understanding of the progress of the PDMPs self-sufficiency among Asian countries, the WHO's support strategies, and the NCL's plan for the preparation of the WHO GBT assessment. In the panel discussion, all participants agreed that building capacity in blood safety in the Asian region and harmonisation of relevant international regulatory requirements will support appropriate emergency preparedness, particularly source materials in the region, and will build the foundation for resolving the PDMPs supply insecurity that has worsened after the COVID-19 pandemic in some countries.

The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review.

Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.

Enhancing the Reliability of PMP22 Copy Number Variation Detection with an Inherited Peripheral Neuropathy Panel.

The utility of the next-generation sequencing (NGS) panel could be increased in hereditary peripheral neuropathies, given that the duplication of PMP22 is a major abnormality. In the present study, the analytical performance of an algorithm for detecting PMP22 copy number variation (CNV) from the NGS panel data was evaluated. The NGS panel covers 141 genes, including PMP22 and five genes within 1.5-megabase duplicated region at 17p11.2. CNV calling was performed using a laboratory-developed algorithm. Among the 92 cases subjected to targeted NGS panel from March 2018 to January 2021, 26 were suggestive of PMP22 CNV. Multiplex ligation-dependent probe amplification analysis was performed in 58 cases, and the results were 100% concordant with the NGS data (23 duplications, 2 deletions, and 33 negatives). Analytical performance of the pipeline was further validated by another blind data set, including 14 positive and 20 negative samples. Reliable detection of PMP22 CNV was possible by analyzing not only PMP22 but also the adjacent genes within the 1.5-megabase region of 17p11.2. On the basis of the high accuracy of CNV calling for PMP22, the testing strategy for diagnosis of peripheral polyneuropathies could be simplified by reducing the need for multiplex ligation-dependent probe amplification.

Electroencephalographic slowing during REM sleep in older adults with subjective cognitive impairment and mild cognitive impairment.

STUDY OBJECTIVES: In older adults with Alzheimer's disease, slowing of electroencephalographic (EEG) activity during REM sleep has been observed. Few studies have examined EEG slowing during REM in those with mild cognitive impairment (MCI) and none have examined its relationship with cognition in this at-risk population. METHODS: Two hundred and ten older adults (mean age = 67.0, SD = 8.2 years) underwent comprehensive neuropsychological, medical, and psychiatric assessment and overnight polysomnography. Participants were classified as subjective cognitive impairment (SCI; n = 75), non-amnestic MCI (naMCI, n = 85), and amnestic MCI (aMCI, n = 50). REM EEG slowing was defined as (δ + θ)/(α + σ + ß) power and calculated for frontal, central, parietal, and occipital regions. Analysis of variance compared REM EEG slowing between groups. Correlations between REM EEG slowing and cognition, including learning and memory, visuospatial and executive functions, were examined within each subgroup. RESULTS: The aMCI group had significantly greater REM EEG slowing in the parietal and occipital regions compared to the naMCI and SCI groups (partial η2 = 0.06, p < 0.05 and 0.06, p < 0.05, respectively), and greater EEG slowing in the central region compared to SCI group (partial η2 = 0.03, p < 0.05). Greater REM EEG slowing in parietal (r = -0.49) and occipital regions (r = -0.38 [O1/M2] and -0.33 [O2/M1]) were associated with poorer visuospatial performance in naMCI. CONCLUSIONS: REM EEG slowing may differentiate older adults with memory impairment from those without. Longitudinal studies are now warranted to examine the prognostic utility of REM EEG slowing for cognitive and dementia trajectories.

Benefit in physical function and quality of life to nonsurgical treatment of varicose veins: Pilot study.

BACKGROUND: Studies on varicose veins have focused its effects on physical function; however, whether nonsurgical treatments alter muscle oxygenation or physical function remains unclear. Moreover, the differences in such functions between individuals with varicose veins and healthy individuals remain unclear. AIM: To investigate changes in physical function and the quality of life (QOL) following nonsurgical treatment of patients with varicose veins and determine the changes in their muscle oxygenation during activity. METHODS: We enrolled 37 participants (those with varicose veins, n = 17; healthy individuals, n = 20). We performed the following measurements pre- and post-nonsurgical treatment in the varicose vein patients and healthy individuals: Calf muscle oxygenation during the two-minute step test, open eyes one-leg stance, 30 s sit-to-stand test, visual analog scale (VAS) for pain, Pittsburgh sleep quality index, physical activity assessment, and QOL assessment. RESULTS: Varicose veins patients and healthy individuals differ in most variables (physical function, sleep quality, and QOL). Varicose veins patients showed significant differences between pre- and post-nonsurgical treatment- results in the 30 sit-to-stand test [14.41 (2.45) to 16.35 (4.11), P = 0.018), two-minute step test [162.29 (25.98) to 170.65 (23.80), P = 0.037], VAS for pain [5.35 (1.90) to 3.88 (1.73), P = 0.004], and QOL [39.34 (19.98) to 26.69 (17.02), P = 0.005]; however, no significant difference was observed for muscle oxygenation. CONCLUSION: Nonsurgical treatment improved lower extremity function and QOL in varicose veins patients, bringing their condition close to that of healthy individuals. Future studies should include patients with severe varicose veins requiring surgery to confirm our findings.

Overcoming challenges associated with identifying FBN1 deep intronic variants through whole-genome sequencing.

BACKGROUND: Marfan syndrome (MFS), caused by pathogenic variants of FBN1 (fibrillin-1), is a systemic connective tissue disorder with variable phenotypes and treatment responsiveness depending on the variant. However, a significant number of individuals with MFS remain genetically unexplained. In this study, we report novel pathogenic intronic variants in FBN1 in two unrelated families with MFS. METHODS: We evaluated subjects with suspected MFS from two unrelated families using Sanger sequencing or multiplex ligation-dependent probe amplification of FBN1 and/or panel-based next-generation sequencing. As no pathogenic variants were identified, whole-genome sequencing was performed. Identified variants were analyzed by reverse transcription-PCR and targeted sequencing of FBN1 mRNA harvested from peripheral blood or skin fibroblasts obtained from affected probands. RESULTS: We found causative deep intronic variants, c.6163+1484A>T and c.5788+36C>A, in FBN1. The splicing analysis revealed an insertion of in-frame or out-of-frame intronic sequences of the FBN1 transcript predicted to alter function of calcium-binding epidermal growth factor protein domain. Family members carrying c.6163+1484A>T had high systemic scores including prominent skeletal features and aortic dissection with lesser aortic dilatation. Family members carrying c.5788+36C>A had more severe aortic root dilatation without aortic dissection. Both families had ectopia lentis. CONCLUSION: Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies. This study expands the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in MFS diagnosis.

CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy.

Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype. Dilated cardiomyopathy (DCM) is a disorder with a highly heterogeneous genetic etiology involving more than 60 causative genes, hindering genetic diagnosis. In this study, we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant in NM_001289808.2:c.527A>G of CRYAB in one patient. The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues, p.(Ter176TrpextTer19), which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin. The proband, diagnosed with DCM at age 32, had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms. He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant. This study expands the mutational spectrum of CRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies.