Pirfenidone Alleviates Inflammation and Fibrosis of Acute Respiratory Distress Syndrome by Modulating the Transforming Growth Factor-ß/Smad Signaling Pathway.

Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-ß1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-ß1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.

Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.

Comparisons of Audiologic Characteristics in Patients with Continuous and Intermittent Tinnitus.

BACKGROUND: No studies to date have compared audiologic characteristics in patients with continuous and intermittent tinnitus. The present study classified tinnitus patients into continuous and intermittent groups based on tinnitus duration and compared their audiologic characteristics. METHODS: This study enrolled 604 patients with tinnitus from January 2019 to December 2022. Clinical manifestations, PTA results, the frequency and loudness of tinnitus, ABR, DPOAE, and TEOAE tests were compared in patients with continuous and intermittent tinnitus. RESULTS: Of the 604 patients, 231 (38.2%) had continuous and 373 (61.8%) had intermittent tinnitus. There were no significant between-group differences in otologic symptoms, tinnitus onomatopoeia. PTA showed that hearing thresholds, except at 125 Hz, were significantly higher in patients with continuous rather than intermittent tinnitus. The loudness of tinnitus was significantly greater in patients with continuous rather than intermittent tinnitus. ABR tests showed that the absolute latency of wave V was significantly longer in continuous than in intermittent tinnitus. Signal-to-noise ratios on TEOAE tests were significantly lower in patients with continuous rather than intermittent tinnitus at all frequencies tested (1, 1.5, 2, 3, and 4 kHz). Response rates to sound stimuli at all frequencies, except for 1 kHz, were significantly lower on DPOAE tests in patients with continuous rather than intermittent tinnitus. CONCLUSIONS: Continuous tinnitus is more common in males, more persistent over time, and is associated with a higher rate of hearing loss. In contrast, intermittent tinnitus is more common in women, appears acutely, and is associated with a relatively lower rate of hearing loss. Based on the findings of the current paper, it seems that audiologic characteristics may differ between patients with continuous and intermittent tinnitus.

Genotyping-by-Sequencing Analysis Reveals Associations between Agronomic and Oil Traits in Gamma Ray-Derived Mutant Rapeseed (Brassica napus L.).

Rapeseed (Brassica napus L.) holds significant commercial value as one of the leading oil crops, with its agronomic features and oil quality being crucial determinants. In this investigation, 73,226 single nucleotide polymorphisms (SNPs) across 95 rapeseed mutant lines induced by gamma rays, alongside the original cultivar ('Tamra'), using genotyping-by-sequencing (GBS) analysis were examined. This study encompassed gene ontology (GO) analysis and a genomewide association study (GWAS), thereby concentrating on agronomic traits (e.g., plant height, ear length, thousand-seed weight, and seed yield) and oil traits (including fatty acid composition and crude fat content). The GO analysis unveiled a multitude of genes with SNP variations associated with cellular processes, intracellular anatomical structures, and organic cyclic compound binding. Through GWAS, we detected 320 significant SNPs linked to both agronomic (104 SNPs) and oil traits (216 SNPs). Notably, two novel candidate genes, Bna.A05p02350D (SFGH) and Bna.C02p22490D (MDN1), are implicated in thousand-seed weight regulation. Additionally, Bna.C03p14350D (EXO70) and Bna.A09p05630D (PI4Kα1) emerged as novel candidate genes associated with erucic acid and crude fat content, respectively. These findings carry implications for identifying superior genotypes for the development of new cultivars. Association studies offer a cost-effective means of screening mutants and selecting elite rapeseed breeding lines, thereby enhancing the commercial viability of this pivotal oil crop.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex.

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUSpMHC and VACINUSTCR: VACINUSpMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUSTCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUSpMHC and VACINUSTCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUSpMHC, 48 peptides were ultimately selected using VACINUSTCR. In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUSTCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex.

Real-World Effectiveness of Biologics in Patients With Severe Asthma: Analysis of the KoSAR.

PURPOSE: Severe asthma is associated with high morbidity and healthcare utilization; however, treatment options for these patients are limited. This study aimed to determine the therapeutic effects of biologics in clinical practice. METHODS: This multicenter, retrospective cohort study included 136 patients who received biologics for at least 4 months between September 2017 and July 2022 at 25 medical centers affiliated with the Korean Severe Asthma Registry (KoSAR). The study evaluated the treatment effects, including acute exacerbation rates, maintenance of oral corticosteroid dosages, lung function, quality of life, blood eosinophil count, and fractional exhaled nitric oxide (FeNO) levels, by comparing measurements before and after 4 months of biologic treatment. Responses for each medication was evaluated based on the Global Evaluation of Treatment Effectiveness score, and any adverse reactions were summarized. RESULTS: With the administration of biologics over the course of 4 months, there was a reduction in asthma acute exacerbations, a significant improvement in lung function, and a significant decrease in daily maintenance dose of oral steroid. Blood eosinophil counts decreased in the mepolizumab and reslizumab groups, while FeNO levels decreased only in the dupilumab group. The Asthma Control Test, Quality of Life Questionnaire for Adult Korean Asthmatics, and the EuroQol-visual analogue scale scores showed a significant improvement. Most patients (80.15%) responded to the biologic treatment. Meanwhile, non-responders often had chronic rhinosinusitis as a comorbidity, exhibited lower lung function, and required higher doses of oral steroids. No severe adverse events were reported. CONCLUSIONS: Biologics are highly effective in Korean patients with Type 2 severe asthma, significantly reducing acute exacerbation rates and doses of oral corticosteroids, while also improving lung function. Therefore, it seems beneficial to administer biologics without any restrictions to patients exhibiting Type 2 severe asthma.

Pirfenidone improves voiding function by suppressing bladder fibrosis in underactive bladder rats.

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.

Simultaneous Treatment of 5-Aminosalicylic Acid and Treadmill Exercise More Effectively Improves Ulcerative Colitis in Mice.

Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in the body. In the current study, the effects of simultaneous treatment of treadmill exercise and 5-ASA were compared with monotherapy with physical exercise or 5-ASA in UC mice. To induce the UC animal model, the mice consumed 2% dextran sulfate sodium dissolved in drinking water for 7 days. The mice in the exercise groups exercised on a treadmill for 1 h once a day for 14 days after UC induction. The 5-ASA-treated groups received 5-ASA by enema injection using a 200 µL polyethylene catheter once a day for 14 days. Simultaneous treatment improved histological damage and increased body weight, colon weight, and colon length, whereas the disease activity index score and collagen deposition were decreased. Simultaneous treatment with treadmill exercise and 5-ASA suppressed pro-inflammatory cytokines and apoptosis following UC. The benefits of this simultaneous treatment may be due to inhibition on nuclear factor-κB/mitogen-activated protein kinase signaling activation. Based on this study, simultaneous treatment of treadmill exercise and 5-ASA can be considered as a new therapy of UC.

Cough Response to High-Dose Inhaled Corticosteroids in Patients with Chronic Cough and Fractional Exhaled Nitric Oxide Levels ≥ 25 ppb: A Prospective Study.

This study aimed to investigate the effects of high-dose inhaled corticosteroids (ICS) on chronic cough patients with elevated fractional exhaled nitric oxide (FeNO) levels. In a prospective study, adults with chronic cough and FeNO ≥ 25 ppb, without any other apparent etiology, received fluticasone furoate (200 mcg) for three weeks. Outcomes were evaluated using FeNO levels, cough severity, and Leicester Cough Questionnaire (LCQ) before and after treatment. Of the fifty participants (average age: 58.4 years; 58% female), the treatment responder rate (≥ 1.3-point increase in LCQ) was 68%, with a significant improvement in cough and LCQ scores and FeNO levels post-treatment. However, improvements in cough did not significantly correlate with changes in FeNO levels. These findings support the guideline recommendations for a short-term ICS trial in adults with chronic cough and elevated FeNO levels, but the lack of correlations between FeNO levels and cough raises questions about their direct mechanistic link.

Efficacy and safety of three-dimensional magnetically assisted capsule endoscopy for upper gastrointestinal and small bowel examination.

BACKGROUND: Magnetically assisted capsule endoscopy (MACE) showed the feasibility for upper gastrointestinal examination. To further enhance the performance of conventional MACE, it is necessary to provide quality-improved and three-dimensional images. The aim of this clinical study was to determine the efficacy and safety of novel three-dimensional MACE (3D MACE) for upper gastrointestinal and small bowel examination at once. METHODS: This was a prospective, single-center, non-randomized, and sequential examination study (KCT0007114) at Dongguk University Ilsan Hospital. Adult patients who visited for upper endoscopy were included. The study protocol was conducted in two stages. First, upper gastrointestinal examination was performed using 3D MACE, and a continuous small bowel examination was performed by conventional method of capsule endoscopy. Two hours later, an upper endoscopy was performed for comparison with 3D MACE examination. The primary outcome was confirmation of major gastric structures (esophagogastric junction, cardia/fundus, body, angle, antrum, and pylorus). Secondary outcomes were confirmation of esophagus and duodenal bulb, accuracy for gastric lesions, completion of small bowel examination, 3D image reconstruction of gastric lesion, and safety. RESULTS: Fifty-five patients were finally enrolled. The examination time of 3D MACE was 14.84 ± 3.02 minutes and upper endoscopy was 5.22 ± 2.39 minutes. The confirmation rate of the six major gastric structures was 98.6% in 3D MACE and 100% in upper endoscopy. Gastric lesions were identified in 43 patients during 3D MACE, and 40 patients during upper endoscopy (Sensitivity 0.97). 3D reconstructed images were acquired for all lesions inspected by 3D MACE. The continuous small bowel examination by 3D MACE was completed in 94.5%. 3D MACE showed better overall satisfaction (3D MACE 9.55 ± 0.79 and upper endoscopy 7.75 ± 2.34, p<0.0001). There were no aspiration or significant adverse event or capsule retention in the 3D MACE examination. CONCLUSIONS: Novel 3D MACE system is more advanced diagnostic modality than the conventional MACE. And it is possible to perform serial upper gastrointestinal and small bowel examination as a non-invasive and one-step test. It would be also served as a bridge to pan-endoscopy.

The preventive effect of Gastrodia elata Blume extract on vancomycin-induced acute kidney injury in rats.

BACKGROUND: Gastrodia elata Blume (GEB), a traditional medicinal herb, has been reported to have pharmacological effect including protection against liver, neuron and kidney toxicity. However, explanation of its underlying mechanisms remains a great challenge. This study investigated the protective effects of GEB extract on vancomycin (VAN)-induced nephrotoxicity in rats and underlying mechanisms with emphasis on the anti-oxidative stress, anti-inflammation and anti-apoptosis. The male Sprague-Dawley rats were randomly divided three groups: control (CON) group, VAN group and GEB group with duration of 14 days. RESULTS: The kidney weight and the serum levels of blood urea nitrogen and creatinine in the GEB group were lower than the VAN group. Histological analysis using hematoxylin & eosin and periodic acid Schiff staining revealed pathological changes of the VAN group. Immunohistochemical analysis revealed that the expression levels of N-acetyl-D-glucosaminidase, myeloperoxidase and tumor necrosis factor-alpha in the GEB group were decreased when compared with the VAN group. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, phosphohistone and malondialdehyde levels were lower in the GEB group than VAN group. The levels of total glutathione in the GEB group were higher than the VAN group. CONCLUSIONS: The findings of this study suggested that GEB extract prevents VAN-induced renal tissue damage through anti-oxidation, anti-inflammation and anti-apoptosis.

Deciphering perivascular macrophages and microglia in the retinal ganglion cell layers.

Introduction: The classically defined two retinal microglia layers are distributed in inner and outer plexiform layers. Although there are some reports that retinal microglia are also superficially located around the ganglion cell layer (GCL) in contact with the vitreous, there has been a lack of detailed descriptions and not fully understood yet. Methods: We visualized the microglial layers by using CX3CR1-GFP (C57BL6) transgenic mice with both healthy and disease conditions including NaIO3-induced retinal degeneration models and IRBP-induced auto-immune uveitis models. Result: We found the GCL microglia has two subsets; peripheral (pph) microglia located on the retinal parenchyma and BAM (CNS Border Associated Macrophage) which have a special stretched phenotype only located on the surface of large retinal veins. First, in the pph microglia subset, but not in BAM, Galectin-3 and LYVE1 are focally expressed. However, LYVE1 is specifically expressed in the amoeboid or transition forms, except the typical dendritic morphology in the pph microglia. Second, BAM is tightly attached to the surface of the retinal veins and has similar morphology patterns in both the healthy and disease conditions. CD86+ BAM has a longer process which vertically passes the proximal retinal veins. Our data helps decipher the basic anatomy and pathophysiology of the retinal microglia in the GCL. Discussion: Our data helps decipher the basic anatomy and pathophysiology of the retinal microglia in the GCL.

The Impact of the COVID-19 Pandemic on Bell's Palsy and Ramsay-Hunt Syndrome: A Multicenter Retrospective Study.

BACKGROUND: This article presents a comprehensive review of data on the impact of facial palsy during the coronavirus disease 2019 (COVID-19) pandemic. The possible causes and pathophysiological mechanisms of changes in the epidemiology of facial palsy during the COVID-19 pandemic are also discussed. METHODS: This multicenter retrospective cohort study included 943 patients diagnosed with Bell's palsy or Ramsay Hunt syndrome. This study compared patient demographics, comorbidities, symptoms, and treatments before the COVID-19 pandemic (from 2017 to 2019) and during the COVID-19 pandemic, from 2020 to 2022). RESULTS: Following the COVID-19 outbreak, there has been a significant increase in the number of cases of Bell's palsy, particularly among elderly individuals with diabetes. Bell's palsy increased after the COVID-19 outbreak, rising from 75.3% in the pre-COVID-19 era to 83.6% after the COVID-19 outbreak. The complete recovery rate decreased from 88.2% to 73.9%, and the rate of recurrence increased from 2.9% to 7.5% in patients with Bell's palsy. Ramsay Hunt syndrome showed fewer changes in clinical outcomes. CONCLUSION: This study highlights the impact of the COVID-19 pandemic on the presentation and management of facial palsy, and suggests potential associations with COVID-19. Notably, the observed increase in Bell's palsy cases among elderly individuals with diabetes emphasizes the impact of the pandemic. Identifying the epidemiological changes in facial palsy during the COVID-19 pandemic has important implications for assessing its etiology and pathological mechanisms of facial palsy disease.

Exercise before pregnancy exerts protective effect on prenatal stress-induced impairment of memory, neurogenesis, and mitochondrial function in offspring.

Stress during pregnancy has a negative effect on the fetus. However, maternal exercise has a positive effect on the cognitive function of the fetus and alleviates the negative effects of stress. This study aimed to demonstrate whether exercise before pregnancy has a protective effect on prenatal stress-induced impairment of memory, neurogenesis and mitochondrial function in mice offspring. In this experiment, immunohistochemistry, Western blot, measurement of mitochondria oxygen respiration, and behavior tests were performed. Spatial memory and short-term memory of the offspring from the prenatal stress with exercise were increased compared to the offspring from the prenatal stress. The numbers of doublecortin-positive and 5-bromo-2'-deoxyuridine-positive cells in the hippocampal dentate gyrus of the offspring from the prenatal stress with exercise were higher compared to the offspring from the prenatal stress. The expressions of brain-derived neurotrophic factor, postsynaptic density 95 kDa, and synaptophysin in the hippocampus of the offspring from the prenatal stress with exercise were enhanced compared to the offspring from the prenatal stress. Oxygen consumption of the offspring from the prenatal stress with exercise were higher compared to the offspring from the prenatal stress. Exercise before pregnancy alleviated prenatal stress-induced impairment of memory, neurogenesis, and mitochondrial function. Therefore, exercise before pregnancy may have a protective effect against prenatal stress of the offspring.

Osteoporosis Is Associated with an Increased Risk of Colorectal Neoplasms Regardless of Sex: Nationwide Population-Based Cohort Study.

Vitamin D may have anticancer effects against colorectal cancer (CRC). Bone mineral density (BMD) reflects the long-term vitamin D status. This study investigated the association between osteoporosis and colorectal neoplasms (CRN). The data were obtained from the National Health Insurance Service sample cohort, which included 60,386 osteoporosis patients and 8224 controls who underwent BMD in 2002-2019. The logistic regression models included age, sex, income level, and comorbidity. Sensitivity tests were performed using the data from the National Health Screening Program. In total, 7706 (11.2%) patients were diagnosed with CRN, and the proportion was significantly higher in osteoporosis patients than in controls (11.7% vs. 8.1%). In the multivariate analysis, osteoporosis was associated with an increased risk of CRN (odds ratio (OR) = 1.91, 95% confidence interval = 1.75-2.09, p < 0.0001), which was significant for both colorectal adenomas and CRC (OR = 1.88 and 1.83, respectively). A subgroup analysis by sex revealed a significant association between osteoporosis and CRN in both women and men (OR = 2.06 and 1.66, respectively). The sensitivity tests revealed results similar to those of the original dataset. In conclusion, osteoporosis is significantly associated with CRN risk in both sexes. In high-risk patients with low BMD, appropriate screening for CRN and vitamin D supplementation are required, regardless of sex.

Brain-wide neuronal circuit connectome of human glioblastoma.

Glioblastoma (GBM), a universally fatal brain cancer, infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression 1-6 . Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic 7-9 . The extent of integration of GBM cells into brain-wide neuronal circuitry is not well understood. Here we applied a rabies virus-mediated retrograde monosynaptic tracing approach 10-12 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrated into brain-wide neuronal circuits and exhibited diverse local and long-range connectivity. Beyond glutamatergic inputs, we identified a variety of neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. Acute acetylcholine stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via the metabotropic CHRM3 receptor. CHRM3 downregulation suppressed GBM cell invasion, proliferation, and survival in vitro and in vivo. Together, these results reveal the capacity of human GBM cells to rapidly and robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain and support a model wherein rapid synapse formation onto GBM cells and transient activation of upstream neurons may lead to a long-lasting increase in fitness to promote tumor infiltration and progression.

Sex differences in the impact of body mass index on outcomes of coronary artery disease in Koreans.

BACKGROUND: Obesity is often considered a risk factor for cardiovascular disease, but recent studies have shown conflicting results regarding the effect of BMI on the prognosis of coronary artery disease (CAD). This study aimed to evaluate the relationship between BMI and clinical outcomes of CAD according to sex in a Korean population. METHODS: A total of 3476 patients with a significant CAD who underwent percutaneous coronary intervention (PCI) were enrolled. Patients were classified as follows according to BMI using the Asia-Pacific cutoff points: underweight (<18.5 kg/m 2 ), normal weight (18.5-22.9 kg/m 2 ), overweight (23.0-24.9 kg/m 2 ) and obese (≥25 kg/m 2 ) patients. Underweight and normal weight patients were further categorized into the lower BMI group, whereas overweight and obese patients were categorized into the higher BMI group. The primary endpoint was all-cause mortality. RESULTS: Among women, the higher BMI group showed poor clinical features in the prevalence of hypertension and chest pain presentation, and among men, the higher BMI group had a significantly lower rate of chronic renal failure. At the end of the follow-up period (median 53.5 months), the all-cause mortality rate was lower in the higher BMI group in men, and cardiovascular death and stroke rates were significantly lower in the higher BMI group in women. CONCLUSION: In Korean CAD patients treated with PCI, inverse correlations were observed between the clinical outcomes and BMI, but there were differences between men and women.

Safety assessment of five candidate probiotic lactobacilli using comparative genome analysis.

Micro-organisms belonging to the Lactobacillus genus complex are often used for oral consumption and are generally considered safe but can exhibit pathogenicity in rare and specific cases. Therefore, screening and understanding genetic factors that may contribute to pathogenicity can yield valuable insights regarding probiotic safety. Limosilactobacillus mucosae LM1, Lactiplantibacillus plantarum SK151, Lactiplantibacillus plantarum BS25, Limosilactobacillus fermentum SK152 and Lactobacillus johnsonii PF01 are current probiotics of interest; however, their safety profiles have not been explored. The genome sequences of LM1, SK151, SK152 and PF01 were downloaded from the NCBI GenBank, while that of L. plantarum BS25 was newly sequenced. These genomes were then annotated using the Rapid Annotation using Subsystem Technology tool kit pipeline. Subsequently, a command line blast was performed against the Virulence Factor Database (VFDB) and the Comprehensive Antibiotic Resistance Database (CARD) to identify potential virulence factors and antibiotic resistance (AR) genes. Furthermore, ResFinder was used to detect acquired AR genes. The query against the VFDB identified genes that have a role in bacterial survivability, platelet aggregation, surface adhesion, biofilm formation and immunoregulation; and no acquired AR genes were detected using CARD and ResFinder. The study shows that the query strains exhibit genes identical to those present in pathogenic bacteria with the genes matched primarily having roles related to survival and surface adherence. Our results contribute to the overall strategies that can be employed in pre-clinical safety assessments of potential probiotics. Gene mining using whole-genome data, coupled with experimental validation, can be implemented in future probiotic safety assessment strategies.