Analysing cerebrospinal fluid with explainable deep learning: From diagnostics to insights.

AIM: Analysis of cerebrospinal fluid (CSF) is essential for diagnostic workup of patients with neurological diseases and includes differential cell typing. The current gold standard is based on microscopic examination by specialised technicians and neuropathologists, which is time-consuming, labour-intensive and subjective. METHODS: We, therefore, developed an image analysis approach based on expert annotations of 123,181 digitised CSF objects from 78 patients corresponding to 15 clinically relevant categories and trained a multiclass convolutional neural network (CNN). RESULTS: The CNN classified the 15 categories with high accuracy (mean AUC 97.3%). By using explainable artificial intelligence (XAI), we demonstrate that the CNN identified meaningful cellular substructures in CSF cells recapitulating human pattern recognition. Based on the evaluation of 511 cells selected from 12 different CSF samples, we validated the CNN by comparing it with seven board-certified neuropathologists blinded for clinical information. Inter-rater agreement between the CNN and the ground truth was non-inferior (Krippendorff's alpha 0.79) compared with the agreement of seven human raters and the ground truth (mean Krippendorff's alpha 0.72, range 0.56-0.81). The CNN assigned the correct diagnostic label (inflammatory, haemorrhagic or neoplastic) in 10 out of 11 clinical samples, compared with 7-11 out of 11 by human raters. CONCLUSIONS: Our approach provides the basis to overcome current limitations in automated cell classification for routine diagnostics and demonstrates how a visual explanation framework can connect machine decision-making with cell properties and thus provide a novel versatile and quantitative method for investigating CSF manifestations of various neurological diseases.

Prognostic Nutritional Index and Postoperative Pulmonary Complications in Patients With Major Burns.

INTRODUCTION: Burns can cause multiple organ systemic derangements, particularly in respiratory systems. The prognostic nutritional index (PNI) can predict postoperative outcomes. We evaluated the incidence and risk factors, including PNI, for postoperative pulmonary complications (PPCs) in patients with major burns. METHODS: PNI was calculated as 10 × (serum albumin level) + 0.005 × (total lymphocyte count). Major burn patients admitted to the ICU without burn-induced lung injuries were retrospectively included. The incidence of PPCs was measured within 1 wk of burn surgery. A multivariable logistic regression analysis was performed to evaluate the risk factors for PPCs. Receiver operating characteristic curve analysis and propensity-score matched analysis were conducted to estimate the influence of PNI on PPCs. Outcomes after burn surgery were also assessed. RESULTS: Of 444 major burn patients, 138 (31.1%) showed PPCs. Risk factors for PPCs were PNI, gender, total body surface area burned, interval between burn and surgery, and red blood cell transfusion rate. The area under the curve of PNI for predicting PPCs was 0.709 (cutoff value = 31.5). The incidence of PPCs was significantly higher in the PNI ≤ 31.5 group than in the PNI > 31.5 group (55.7% versus 22.8%, P < 0.001) after propensity-score matching. The intensive care unit stay duration was longer and 90-d mortality was higher in patients who developed PPCs (19 [9-27] d versus 8 [4-17] d, P < 0.001; 11.6% versus 0.3%, P < 0.001). CONCLUSIONS: The prevalence of PPCs in patients with major burns was 31.1% and preoperative PNI was a predictor of PPCs in these patients. PNI ≤ 31.5 was significantly related to a higher incidence of PPCs.

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours.

AIMS: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours. METHODS: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis. RESULTS: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test). CONCLUSION: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma.

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity.

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas-including the prognostically relevant SDH mutations-are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.

Acute kidney injury after burn surgery: Preoperative neutrophil/lymphocyte ratio as a predictive factor.

BACKGROUND: Severe inflammation and acute kidney injury (AKI) are serious adverse events after burn injuries. The neutrophil/lymphocyte ratio (NLR) is a marker of inflammation. We evaluated the independent risk factors for postoperative AKI, including NLR, in burn-injured patients. METHODS: The preoperative, intraoperative, and postoperative variables of 473 burn-injured patients were collected. The risk factors for AKI after burn surgery were evaluated using univariate and multivariate logistic regression analyses. The receiver operating characteristic (ROC) curve analysis of preoperative NLR was performed. The 3-month mortality after surgery was also compared between AKI and non-AKI groups using Kaplan-Meier analysis with a log-rank test. RESULTS: Postoperative AKI occurred in 71 of 473 (15.0%) burn patients. The total body surface area burned (odds ratio (OR), 1.013; 95% confidence interval (CI), 1.001-1.026; P = 0.037), inhalation injury (OR, 1.821; 95% CI, 1.008-3.292; P = 0.047), and preoperative NLR (OR, 1.094; 95% CI, 1.064-1.125; P < 0.001) were risk factors for AKI after surgery. The area under the ROC curve was 0.767, with an optimal cut-off value of 11.7. Moreover, the 3-month mortality after surgery was significantly higher in the AKI group than in the non-AKI group (49.3% vs 14.9%, P < 0.001). CONCLUSION: Total body surface area burned, inhalation injury, and preoperative NLR are risk factors for AKI after burn surgery, which is associated with early postoperative mortality. Preoperative NLR can provide useful information for the early detection of postoperative AKI and subsequent mortality in burn-injured patients.

Relationship between Stroke Volume Variation and Blood Transfusion during Liver Transplantation.

BACKGROUND: Intraoperative blood transfusion increases the risk for perioperative mortality and morbidity in liver transplant recipients. A high stroke volume variation (SVV) method has been proposed to reduce blood loss during living donor hepatectomy. Herein, we investigated whether maintaining high SVV could reduce the need for blood transfusion and also evaluated the effect of the high SVV method on postoperative outcomes in liver transplant recipients. METHODS: We retrospectively analyzed 332 patients who underwent liver transplantation, divided into control (maintaining <10% of SVV during surgery) and high SVV (maintaining 10-20% of SVV during surgery) groups. We evaluated the blood transfusion requirement and hemodynamic parameters, including SVV, as well as postoperative outcomes, such as incidences of acute kidney injury, durations of postoperative intensive care unit and hospital stay, and rates of 1-year mortality. RESULTS: Mean SVV values were 7.0% ± 1.3% in the control group (n = 288) and 11.2% ± 1.8% in the high SVV group (n = 44). The median numbers of transfused packed red blood cells and fresh frozen plasmas in the high SVV group were significantly lower than those in control group (0 vs. 2 units, P = 0.003; and 0 vs. 3 units, P = 0.033, respectively). No significant between-group differences were observed for postoperative outcomes. CONCLUSIONS: Maintaining high SVV can reduce the blood transfusion requirement during liver transplantation without worsening postoperative outcomes. These findings provide insights into improving perioperative management in liver transplant recipients.

Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant.

HIV prevention with pre-exposure prophylaxis (PrEP) constitutes a major pillar in fighting the ongoing epidemic. While daily oral PrEP adherence may be challenging, long-acting (LA-)PrEP in oral or implant formulations could overcome frequent dosing with convenient administration. The novel drug islatravir (ISL) may be suitable for LA-PrEP, but dose-dependent reductions in CD 4 + $$ \mathrm{CD}{4}^{+} $$ T cell and lymphocyte counts were observed at high doses. We developed a mathematical model to predict ISL pro-drug levels in plasma and active intracellular ISL-triphosphate concentrations after oral vs. subcutaneous implant dosing. Using phase II trial data, we simulated antiviral effects and estimated HIV risk reduction for multiple dosages and dosing frequencies. We then established exposure thresholds where no adverse effects on immune cells were observed. Our findings suggest that implants with 56-62 mg ISL offer effective HIV risk reduction without reducing lymphocyte counts. Oral 0.1 mg daily, 3-5 mg weekly, and 10 mg biweekly ISL provide comparable efficacy, but weekly and biweekly doses may affect lymphocyte counts, while daily dosing regimen offered no advantage over existing oral PrEP. Oral 0.5-1 mg on demand provided > 90 % $$ >90\% $$ protection, while not being suitable for post-exposure prophylaxis. These findings suggest ISL could be considered for further development as a promising and safe agent for implantable PrEP.

Preventive effects of nano-graphene oxide against Parkinson's disease via reactive oxygen species scavenging and anti-inflammation.

We investigated the neuroprotective effects of deca nano-graphene oxide (daNGO) against reactive oxygen species (ROS) and inflammation in the human neuroblastoma cell line SH-SY5Y and in the 6-hydroxydopamine (6-OHDA) induced Parkinsonian rat model. An MTT assay was performed to measure cell viability in vitro in the presence of 6-OHDA and/or daNGO. The intracellular ROS level was quantified using 2',7'-dichlorofluorescein diacetate. daNGO showed neuroprotective effects against 6-OHDA-induced toxicity and also displayed ROS scavenging properties. We then tested the protective effects of daNGO against 6-OHDA induced toxicity in a rat model. Stepping tests showed that the akinesia symptoms were improved in the daNGO group compared to the control group. Moreover, in an apomorphine-induced rotation test, the number of net contralateral rotations was decreased in the daNGO group compared to the control group. By immunofluorescent staining, the animals in the daNGO group had more tyrosine hydroxylase-positive cells than the controls. By anti-Iba1 staining, 6-OHDA induced microglial activation showed a significantly decrease in the daNGO group, indicating that the neuroprotective effects of graphene resulted from anti-inflammation. In conclusion, nanographene oxide has neuroprotective effects against the neurotoxin induced by 6-OHDA on dopaminergic neurons. [BMB Reports 2023; 56(3): 202-207].

Cardioembolic stroke: dual-energy cardiac CT for differentiation of left atrial appendage thrombus and circulatory stasis.

PURPOSE: To assess the diagnostic performance of dual-energy cardiac computed tomography (CT) in the detection of left atrial appendage (LAA) thrombi and differentiation between thrombus and circulatory stasis in patients with stroke, by using transesophageal echocardiography (TEE) as the reference standard. MATERIALS AND METHODS: The institutional review board approved this study, and patients provided informed consent. Thirty-two patients with stroke who had atrial fibrillation (AF) and either thrombus or the spontaneous echo contrast (SEC) echo pattern at TEE were prospectively enrolled. For the control group, 31 patients who were planning to undergo AF ablation and who had no abnormalities at TEE were enrolled. All patients underwent dual-energy cardiac CT that was not electrocardiographically gated. For quantitative analysis, iodine concentration was measured on CT images. The statistical significance of differences in mean iodine concentration between thrombus and SEC as measured at CT was assessed by using the Student t test. RESULTS: Among the 63 patients, a total of 13 thrombi and 19 instances of SEC were detected at TEE. Using TEE as the reference standard, the overall sensitivity, specificity, positive predictive value, and negative predictive value of dual-energy cardiac CT in the detection of thrombi and SEC in the LAA were 97% (95% confidence interval [CI]: 82%, 100%), 100% (95% CI: 86%, 100%), 100%, and 97%, respectively. At CT, the mean iodine concentration was 1.23 mg/mL ± 0.34 (standard deviation) for thrombus and 3.61 mg/mL ± 1.01 for SEC (P = .001). CONCLUSION: Dual-energy cardiac CT is a highly sensitive modality for detecting LAA thrombus and for differentiating thrombus from SEC in patients with stroke.

Anomalous origin of the right coronary artery from the left coronary sinus with an interarterial course: subtypes and clinical importance.

PURPOSE: To classify anomalous origins of the right coronary artery (RCA) from the left coronary sinus (AORL) with an interarterial course into two subtypes and to evaluate the clinical importance of each. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study, and informed consent was waived. Through a retrospective review of 22,925 consecutive cardiac computed tomographic (CT) scans, 124 cases of AORL with an interarterial course were identified. These anomalies were classified into two subtypes according to the location of the anomalous RCA ostium: high interarterial course (between the aorta and the pulmonary artery) and low interarterial course (between the aorta and the right ventricular outflow tract). The clinical records were evaluated, and differences in prevalence of typical angina and major adverse cardiac events (MACEs) between the subtypes were analyzed through the χ(2) contingency tables or Fisher exact test. RESULTS: After excluding patients with combined cardiac disease, 87 patients (51 [59%] men, 36 [41%] women; mean age, 56.0 years) were enrolled. Of the 87 patients, 53 had a high interarterial course and 34 had a low interarterial course. A significant difference in the prevalence of typical angina (high [43%] vs low [6%], P = .001) and MACE (high [28%] vs low [6%], P = .012) was observed between the two subtypes. For patients with a high interarterial course, the odds ratio for typical angina was 12.3 (95% confidence interval: 2.7, 56.6), and the odds ratio for MACE was 6.3 (95% confidence interval: 1.3, 29.7). CONCLUSION: The prevalence of typical angina and that of MACE were significantly higher in patients with a high interarterial course than in those with a low interarterial course.

Additional diagnostic value of tumor markers in cytological fluid for diagnosis of non-small-cell lung cancer.

BACKGROUND: Cytological fluid from a needle aspiration biopsy (NAB) is obtained directly from tumor tissue, therefore many biomarker candidates will be present in high concentrations. The aim of this study was to prospectively assess and validate the tumor markers CYFRA 21-1, CEA, and SCC in cytological fluid obtained from NAB samples to determine if they improved the performance of NAB for diagnosing non-small cell lung cancer (NSCLC). METHODS: A total of 194 patients (M:F = 128:66, mean age 63.7 years) with suspected malignant pulmonary lesions were prospectively enrolled and underwent percutaneous NAB. Levels of CYFRA 21-1, CEA, and SCC were measured by immunoassay in serum and cytological fluid obtained during aspiration biopsy. Cut-off values to determined malignancy were 3.3 ng/mL in serum and 15.7 ng/mL in cytological fluid for CYFRA 21-1, 5 ng/mL and 0.6 ng/mL for CEA, and 2 ng/mL and 0.86 ng/mL for SCC. RESULTS: Of 194 patients, 139 patients (71.6%) had NSCLC and 55 (28.4%) had benign lesions. Sensitivity increased significantly for NAB combined with cytological tumor markers compared with NAB alone (CYFRA 21-1: 95% versus 83.5%, p < 0.001, CEA: 92.1% versus 83.5%, p = 0.002, SCC: 91.4% versus 83.5%, p = 0.003). Accuracy improved significantly for NAB combined with cytological CYFRA 21-1 compared with NAB alone (95.9% versus 88.1%, p < 0.001). The area under curve (AUC) of NAB with cytological CYFRA 21-1 was significantly larger than for NAB alone (0.966 versus 0.917, p = 0.009). CONCLUSION: Of the tested tumor markers, cytological fluid measurements of CYFRA 21-1 improved the diagnostic performance of NAB for NSCLC.

CsPOM1, a DYRK Family Kinase, Plays Diverse Roles in Fungal Development, Virulence, and Stress Tolerance in the Anthracnose Pathogen Colletotrichum scovillei.

Colletotrichum scovillei is the major anthracnose fungus of sweet pepper and chili pepper (Capsicum annuum L.), causing significant losses in the yield and quality of the pepper fruits. Molecular mechanisms governing development and pathogenicity have been widely studied in many foliar fungal pathogens, but the information on fruit diseases is still limited. In this study, we determined the functional roles of the dual-specificity tyrosine phosphorylation-regulated kinase CsPOM1 in C. scovillei. Knockout mutant for CsPOM1 gene was obtained via homology-dependent gene replacement. The ΔCspom1 mutant exhibited a reduction in vegetative growth on osmotic stress, surface hydrophobicity, and conidiation compared with wild-type. Conidia of the ΔCspom1 mutant were already two-celled before inoculation on an induction surface, indicating that CsPOM1 negatively regulates conidial cell division. The ΔCspom1 mutant, similar to wild-type, formed appressoria on the plant surface, but was significantly reduced on hydrophobic coverslips, probably due to a defect in the recognition of surface hydrophobicity. Treatment of conidia with cutin monomers restored appressorium formation on hydrophobic coverslips in the ΔCspom1 mutant. On pepper fruits, the ΔCspom1 mutant exhibited delayed penetration and invasive growth, leading to significantly reduced virulence. Collectively, the results showed that CsPOM1 is important for stress tolerance, conidiation, surface hydrophobicity, appressorium formation, and virulence in C. scovillei.

Prognostic Nutritional Index and Major Adverse Cardiac Events After Burn Surgery: A Propensity Score Matching Analysis.

Burn injuries can cause significant malnutrition, leading to cardiovascular impairments. The prognostic nutritional index (PNI) predicts postoperative complications. We evaluated the impact of preoperative PNI on major adverse cardiac events (MACE) after burn surgery. PNI was calculated using the equation, 10×(serum albumin level)+0.005×(total lymphocyte count). Multivariable logistic regression analysis was conducted to evaluate the predictors for MACE at 6 months after burn surgery. Receiver operating characteristic curve and propensity score matching analyses were conducted. Additionally, Kaplan-Meier analysis was conducted to compare postoperative 1-year mortality between MACE and non-MACE groups. MACE after burn surgery occurred in 184 (17.5%) of 1049 patients. PNI, age, American Society of Anesthesiologists physical status, and TBSA burned were significantly related to MACE. The area under the receiver operating characteristic curve of PNI was 0.729 (optimal cutoff value = 35). After propensity score matching, the incidence of MACE in the PNI <35 group was higher than that in the PNI ≥35 group (20.1% vs 9.6%, P < .001). PNI <35 was related to an increased incidence of MACE (odds ratio = 2.373, 95% confidence interval = 1.499-3.757, P < .001). The postoperative 1-year mortality was higher in the MACE group than in the non-MACE group (54.9% vs 9.1%, P < .001). Preoperative PNI was a predictor for MACE after burn surgery. PNI <35 was significantly related to an increased incidence of MACE. Moreover, MACE was related to higher postoperative 1-year mortality.

Zika virus infection accelerates Alzheimer's disease phenotypes in brain organoids.

Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases characterized by ß-amyloid (Aß) production and Phosphorylated-Tau (p-Tau) protein in the cerebral cortex. The precise mechanisms of the cause, responsible for disease pathology and progression, are not well understood because there are multiple risk factors associated with the disease. Viral infection is one of the risk factors for AD, and we demonstrated that Zika virus (ZIKV) infection in brain organoids could trigger AD pathological features, including Aß and p-Tau expression. AD-related phenotypes in brain organoids were upregulated via endoplasmic reticulum (ER) stress and unfolded protein response (UPR) after ZIKV infection in brain organoids. Under persistent ER stress, activated-double stranded RNA-dependent protein kinase-like ER-resident (PERK) triggered the phosphorylation of Eukaryotic initiation factor 2 (eIF2α) and then BACE, and GSK3α/ß related to AD. Furthermore, we demonstrated that pharmacological inhibitors of PERK attenuated Aß and p-Tau in brain organoids after ZIKV infection.

Red cell distribution width/albumin ratio and 90-day mortality after burn surgery.

BACKGROUND: Red cell distribution width (RDW) and serum albumin concentration are associated with postoperative outcomes. However, the usefulness of the RDW/albumin ratio in burn surgery remains unclear. Therefore, we evaluated the association between RDW/albumin ratio and 90-day mortality after burn surgery. METHODS: Between 2013 and 2020, a retrospective review of patients in a burn intensive care unit (ICU) was performed. Receiver operating characteristic curve, multivariate Cox logistic regression, multivariate logistic regression and Kaplan-Meier analyses were conducted to evaluate the association between RDW/albumin ratio and 90-day mortality after burn surgery. Additionally, prolonged ICU stay rate (>60 days) and ICU stay were assessed. RESULTS: Ninety-day mortality was 22.5% (210/934) in burn patients. Risk factors for 90-day mortality were RDW/albumin ratio at postoperative day 1, age, American Society of Anesthesiologists physical status, diabetes mellitus, inhalation injury, total body surface area burned, hypotensive event and red blood cell transfusion volume. The area under the curve of the RDW/albumin ratio at postoperative day 1 to predict 90-day mortality, after adjusting for age and total body surface area burned, was 0.875 (cut-off value, 6.8). The 90-day mortality was significantly higher in patients with RDW/albumin ratio >6.8 than in those with RDW/albumin ratio ≤6.8 (49.2% vs 12.3%, p < 0.001). Prolonged ICU stay rate and ICU stay were significantly higher and longer in patients with RDW/albumin ratio >6.8 than in those with RDW/albumin ratio ≤6.8 (34.5% vs 26.5%; 21 [11-38] vs 18 [7-32] days). CONCLUSION: RDW/albumin ratio >6.8 on postoperative day 1 was associated with higher 90-day mortality, higher prolonged ICU stay rate and longer ICU stay after burn surgery.

Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.

Mitochondrial dysfunction is associated with familial Alzheimer's disease (fAD), and the accumulation of damaged mitochondria has been reported as an initial symptom that further contributes to disease progression. In the amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by ß-secretase to generate a C-terminal fragment, which is then cleaved by γ-secretase to produce amyloid-beta (Aß). The accumulation of Aß and its detrimental effect on mitochondrial function are well known, yet the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) contributing to this pathology have rarely been reported. We demonstrated the effects of APP-CTFs-related pathology using induced neural stem cells (iNSCs) from AD patient-derived fibroblasts. APP-CTFs accumulation was demonstrated to mainly occur within mitochondrial domains and to be both a cause and a consequence of mitochondrial dysfunction. APP-CTFs accumulation also resulted in mitophagy failure, as validated by increased LC3-II and p62 and inconsistent PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) recruitment to mitochondria and failed fusion of mitochondria and lysosomes. The accumulation of APP-CTFs and the causality of impaired mitophagy function were also verified in AD patient-iNSCs. Furthermore, we confirmed this pathological loop in presenilin knockout iNSCs (PSEN KO-iNSCs) because APP-CTFs accumulation is due to γ-secretase blockage and similarly occurs in presenilin-deficient cells. In the present work, we report that the contribution of APP-CTFs accumulation is associated with mitochondrial dysfunction and mitophagy failure in AD patient-iNSCs as well as PSEN KO-iNSCs.

Dual-enhanced cardiac CT for detection of left atrial appendage thrombus in patients with stroke: a prospective comparison study with transesophageal echocardiography.

BACKGROUND AND PURPOSE: A noninvasive method with high reliability and accuracy comparable to transesophageal echocardiography for identification of left atrial appendage thrombus would be of significant clinical value. The aim of this study was to assess the diagnostic performance of a dual-enhanced cardiac CT protocol for detection of left atrial appendage thrombi and for differentiation between thrombus and circulatory stasis in patients with stroke. METHODS: We studied 83 consecutive patients with stroke (56 men and 27 women; mean age, 62.6 years) who had high risk factors for thrombus formation and had undergone both dual-source CT and transesophageal echocardiography within a 3-day period. CT was performed with prospective electrocardiographic gating, and scanning began 180 seconds after the test bolus. RESULTS: Among the 83 patients, a total of 13 thrombi combined with spontaneous echo contrast and 14 spontaneous echo contrasts were detected by transesophageal echocardiography. All 13 thrombi combined with spontaneous echo contrast were correctly diagnosed on CT. Using transesophageal echocardiography as the reference standard, the overall sensitivity and specificity of CT for the detection of thrombi and circulatory stasis in the left atrial appendage were 96% (95% CI, 78% to 99%), and 100% (95% CI, 92% to 100%), respectively. On CT, the mean left atrial appendage/ascending aorta Hounsfield unit ratios were significantly different between thrombus and circulatory stasis (0.15 Hounsfield unit versus 0.27 Hounsfield unit, P=0.001). The mean effective radiation dose was 3.11 mSv. CONCLUSIONS: Dual-enhanced cardiac CT with prospective electrocardiographic gating is a noninvasive and sensitive modality for detecting left atrial appendage thrombus with an acceptable radiation dose.

Antagonistic and Plant Growth-Promoting Effects of Bacillus velezensis BS1 Isolated from Rhizosphere Soil in a Pepper Field.

Pepper (Capsicum annuum L.) is an important agricultural crop worldwide. Recently, Colletotrichum scovillei, a member of the C. acutatum species complex, was reported to be the dominant pathogen causing pepper anthracnose disease in South Korea. In the present study, we isolated bacterial strains from rhizosphere soil in a pepper field in Gangwon Province, Korea, and assessed their antifungal ability against C. scovillei strain KC05. Among these strains, a strain named BS1 significantly inhibited mycelial growth, appressorium formation, and disease development of C. scovillei. By combined sequence analysis using 16S rRNA and partial gyrA sequences, strain BS1 was identified as Bacillus velezensis, a member of the B. subtilis species complex. BS1 produced hydrolytic enzymes (cellulase and protease) and iron-chelating siderophores. It also promoted chili pepper (cv. Nockwang) seedling growth compared with untreated plants. The study concluded that B. velezensis BS1 has good potential as a biocontrol agent of anthracnose disease in chili pepper caused by C. scovillei.

De Ritis ratio as a predictor of 1-year mortality after burn surgery.

BACKGROUND: Burn is an overwhelming injury. The De Ritis ratio, defined as aspartate aminotransferase to alanine aminotransferase ratio, can be used to predict poor outcomes. We evaluated the risk factors, including the De Ritis ratio, associated with 1-year mortality after burn surgery. METHODS: Patients who underwent burn surgery from 2009 to 2019 were retrospectively evaluated. Multivariate Cox regression analysis was conducted to evaluate the risk factors for 1-year mortality after burn surgery. Receiver operating characteristic (ROC) curve analysis of the De Ritis ratio was performed to predict postoperative 1-year mortality. Kaplan-Meier survival analysis was also conducted. Other postoperative outcomes, such as durations of hospital and intensive care unit stays, acute kidney injury, and major adverse cardiac events, were evaluated. RESULTS: One-year mortality after burn surgery occurred in 247 (19.9%) of 1244 patients. The risk factors for 1-year mortality after burn surgery were the De Ritis ratio, age, American Society of Anesthesiologists physical status, diabetes mellitus, total body surface area burned, inhalation injury, serum creatinine level, and serum albumin level. The area under the ROC curve for the De Ritis ratio was 0.716 (optimal cutoff=1.9). The 1-year mortality rate after burn surgery was significantly higher in patients with a De Ritis ratio >1.9 than in those with a De Ritis ratio ≤1.9 (35.8% vs. 11.8%, P<0.001). The survival rate was significantly higher in patients with a De Ritis ratio ≤1.9 than in those with a De Ritis ratio >1.9 (log-rank test, P<0.001). Intensive care unit stay, acute kidney injury, and major adverse cardiac events were significantly higher in patients with a De Ritis ratio >1.9 than in those with a De Ritis ratio ≤1.9 (P=0.006, P<0.001, and P<0.001, respectively). CONCLUSIONS: The preoperative De Ritis ratio was a risk factor for 1-year mortality after burn surgery. The De Ritis ratio >1.9 was significantly associated with an increased 1-year mortality after burn surgery. These findings emphasized the importance of identifying burn patients with an increased De Ritis ratio to reduce the mortality after burn surgery.