Predicting long-term mortality of patients with postoperative acute kidney injury following noncardiac general anesthesia surgery using machine learning.

Background: This study addresses the gap in knowledge regarding the long-term mortality implications of postoperative acute kidney injury (PO-AKI) utilizing advanced machine learning techniques to predict outcomes more accurately than traditional statistical models. Methods: A retrospective cohort study was conducted using data from seven institutions between March 2009 and December 2019. Machine learning models were developed to predict all-cause mortality of PO-AKI patients using 23 preoperative variables and one postoperative variable. Model performance was compared to a traditional statistical approach with Cox regression analysis. The concordance index was used as a predictive performance metric to compare prediction capabilities among different models. Results: Among 199,403 patients, 2,105 developed PO-AKI. During a median follow-up of 144 months (interquartile range, 99.61-170.71 months), 472 in-hospital deaths occurred. Subjects with PO-AKI had a significantly lower survival rate than those without PO-AKI (p < 0.001). For predicting mortality, the XGBoost with an accelerated failure time model had the highest concordance index (0.7521), followed by random survival forest (0.7371), multivariable Cox regression model (0.7318), survival support vector machine (0.7304), and gradient boosting (0.7277). Conclusion: XGBoost with an accelerated failure time model was developed in this study to predict long-term mortality associated with PO-AKI. Its performance was superior to conventional models. The application of machine learning techniques may offer a promising approach to predict mortality following PO-AKI more accurately, providing a basis for developing targeted interventions and clinical guidelines to improve patient outcomes.

A Rare Case of Stroke in a 76-Year-Old Woman: Left Atrial Papillary Fibroelastoma as the Culprit.

BACKGROUND Papillary fibroelastoma is the most common type of benign primary cardiac tumor and is usually asymptomatic. However, tumor fragments or surface thrombus can embolize and cause transient ischemic attacks, strokes, or myocardial infarction. This report describes a 76-year-old woman who presented with dysarthria and right-sided weakness due to a stroke associated with a left atrial papillary fibroelastoma. CASE REPORT A 76-year-old woman visited the Emergency Department because she had right-sided weakness and dysarthria from 12 h ago. Brain magnetic resonance image was done at the Emergency Department, showing multiple small embolic, acute infarction in left basal ganglia and fronto-temporo-parietal lobes. Transthoracic and transesophageal echocardiogram showed a hypermobile echogenic mass (0.8×1.5 cm) with villous surface on the orifice of left atrial appendage. Twenty-four-hour Holter monitoring was performed to evaluate the cause of cerebral infarction, and there was no paroxysmal atrial fibrillation. Thoracic computed tomography angiography also showed a sea anemone-shaped mass around the left atrial appendage. Cardiac tumor excision was done via a lower partial sternotomy. Histopathologic analysis showed multiple delicate fronds, and the avascular fibroelastic cores were lined by a single layer of CD31-positive endothelial cells. Histopathologic findings were consistent with papillary fibroelastoma. The patient was discharged without any other complications on day 30 of hospitalization. CONCLUSIONS This case highlights the importance of cardiac imaging in patients with acute stroke, including transthoracic and transesophageal echocardiography, which can show the typical imaging features of papillary fibroelastoma and other intracardiac sources of embolus.

Topographic Consideration on the Occurrence of Ipsilesional Facial Paresis in Lateral Medullary Infarction.

INTRODUCTION: The purpose of this study was to identify course of the corticobulbar tract and factors associated with the occurrence of facial paresis (FP) in lateral medullary infarction (LMI). METHODS: Patients diagnosed with LMI who were admitted to tertiary hospital were retrospectively investigated and divided into two groups based on the presence of FP. FP was defined as grade 2 or more by the House-Brackmann scale. Differences between the two groups were analyzed with respect to anatomical location of the lesions, demographic data (age, sex), risk factors (diabetes, hypertension, smoking, prior stroke, atrial fibrillation, and other cardiac risk factors for stroke), large vessel involvement on magnetic resonance angiography, other symptoms and signs (sensory symptoms, gait ataxia, limb ataxia, dizziness, Horner syndrome, hoarseness, dysphagia, dysarthria, nystagmus, nausea/vomiting, headache, neck pain, diplopia, and hiccup). RESULTS: Among 44 LMI patients, 15 patients (34%) had FP, and all of them had ipsilesional central-type FP. The FP group tended to involve upper (p < 0.0001) and relative ventral (p = 0.019) part of the lateral medulla. Horizontally large lesion was also related to the presence of FP (p = 0.044). Dysphagia (p = 0.001), dysarthria (p = 0.003), and hiccups (p = 0.034) were more likely to be accompanied by FP. Otherwise, there were no significant differences. CONCLUSION: The results of present study indicate that the corticobulbar fibers innervating the lower face decussate at the upper level of the medulla and ascend through the dorsolateral medulla, where the concentration of the fibers is densest near the nucleus ambiguus.

3D Cell Printing of Advanced Vascularized Proximal Tubule-on-a-Chip for Drug Induced Nephrotoxicity Advancement.

Renal dysfunction due to drug-induced nephrotoxicity (DIN) affects >20% of the adult population worldwide. The vascularized proximal tubule is a complex structure that is often the primary site of drug-induced kidney injury. Herein, a vascularized proximal tubule-on-a-chip (Vas-POAC) was fabricated, demonstrating improved physiological emulation over earlier single-cell proximal tubule models. A perfusable model of vascularized proximal tubules permits the growth and proliferation of renal proximal tubule cells and adjacent endothelial cells under various conditions. An in vitro Vas-POAC showed mature expressions of the tubule and endothelial cell markers in the mature epithelium and endothelium lumens after 7 days of culture. Expression in the mature proximal tubule epithelium resembled the polarized expression of sodium-glucose cotransporter-2 and the de novo synthesis of ECM proteins. These perfusable Vas-POACs display significantly improved functional properties relative to the proximal tubules-on-a-chip (POAC), which lacks vascular components. Furthermore, the developed Vas-POAC model evaluated the cisplatin-induced nephrotoxicity and revealed enhanced drug receptivity compared to POAC. We further evaluated the capability of the developed proximal tubule model to act as a functional platform that targets screening drug doses that can cause renal proximal tubule injury in adults. Thus, our cell-printed models may prove valuable for screening, thoughtful mechanistic investigations of DIN, and discovery of drugs that interfere with tubule formation.

Electrochemical Detection of Dopamine Release from Living Neurons Using Graphene Oxide-Incorporated Polypyrrole/Gold Nanocluster Hybrid Nanopattern Arrays.

Stem-cell-based therapeutics have shown immense potential in treating various diseases that are currently incurable. In particular, partial recovery of Parkinson's disease, which occurs due to massive loss or abnormal functionality of dopaminergic (DAnergic) neurons, through the engraftment of stem-cell-derived neurons ex vivo is reported. However, precise assessment of the functionality and maturity of DAnergic neurons is still challenging for their enhanced clinical efficacy. Here, a novel conductive cell cultivation platform, a graphene oxide (GO)-incorporated metallic polymer nanopillar array (GOMPON), that can electrochemically detect dopamine (DA) exocytosis from living DAnergic neurons, is reported. In the cell-free configuration, the linear range is 0.5-100 µm, with a limit of detection of 33.4 nm. Owing to its excellent biocompatibility, a model DAnergic neuron (SH-SY5Y cell) can be cultivated and differentiated on the platform while their DA release can be quantitatively measured in a real-time and nondestructive manner. Finally, it is showed that the functionality of the DAnergic neurons derived from stem cells can be precisely assessed via electrochemical detection of their DA exocytosis. The developed GOMPON is highly promising for a wide range of applications, including real-time monitoring of stem cell differentiation into neuronal lineages, evaluating differentiation protocols, and finding practical stem cell therapies.

Role of increased neutrophil extracellular trap formation on acute kidney injury in COVID-19 patients.

Background: A strong association between elevated neutrophil extracellular trap (NET) levels and poor clinical outcomes in patients with coronavirus infection 2019 (COVID-19) has been reported. However, while acute kidney injury (AKI) is a common complication of COVID-19, the role of NETs in COVID-19-associated AKI is unclear. We investigated the association between elevated NETs and AKI and the prognostic role of NETs in COVID-19 patients. Methods: Two representative markers of NETs, circulating nucleosomes and myeloperoxidase-DNA, were measured in 115 hospitalized patients. Serum levels of interleukin [IL]-6, monocyte chemotactic protein-1 [MCP-1], plasma von Willebrand factor (vWF) and urinary biomarkers of renal tubular damage (ß2-microglobulin [ß2M] and kidney injury molecule 1 [KIM-1]) were measured. Results: AKI was found in 43 patients (37.4%), and pre-existing chronic kidney disease (CKD) was a strong risk factor for AKI. Higher circulating NET levels were a significant predictor of increased risk of initial ICU admission, in-hospital mortality (adjusted HR 3.21, 95% CI 1.08-9.19) and AKI (OR 3.67, 95% CI 1.30-10.41), independent of age, diabetes, pre-existing CKD and IL-6 levels. There were strong correlations between circulating nucleosome levels and urinary KIM-1/creatinine (r=0.368, p=0.001) and ß2M (r=0.218, p=0.049) levels. NETs were also strongly closely associated with serum vWF (r = 0.356, p<0.001), but not with IL-6 or MCP-1 levels. Conclusions: Elevated NETs were closely associated with AKI, which was a strong predictor of mortality. The close association between NETs and vWF may suggest a role for NETs in COVID-19-associated vasculopathy leading to AKI.

Kidney Decellularized Extracellular Matrix Enhanced the Vascularization and Maturation of Human Kidney Organoids.

Kidney organoids derived from human pluripotent stem cells (hPSCs) have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of kidney organoids have been still remained to overcome. Extracellular matrix (ECM) can provide mechanical support and a biochemical microenvironment for cell growth and differentiation. Here in vitro methods using a kidney decellularized extracellular matrix (dECM) hydrogel to culture hPSC-derived kidney organoids, which have extensive vascular network and their own endothelial cells, are reported. Single-cell transcriptomics reveal that the vascularized kidney organoids cultured using the kidney dECM have more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of α-galactosidase A (GLA)-knock-out hPSCs generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulate Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerates the recruitment of endothelial cells from the host mouse kidney and maintains vascular integrity with the more organized slit diaphragm-like structures than those without kidney dECM. The kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.

Population pharmacokinetics of piperacillin/tazobactam in critically ill Korean patients and the effects of extracorporeal membrane oxygenation.

OBJECTIVES: To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients. METHODS: Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24 h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation. RESULTS: A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16 g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170 mL/min/1.73 m2. CONCLUSIONS: ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8 mg/L or when patients have an eGFR of 130-170 mL/min/1.73 m2.

Feasibility of isodose-shaped scintillation detectors for the measurement of gamma knife output factors.

PURPOSE: Scintillation detectors were 3D printed based on a gamma knife (GK) dose distribution to calculate the volume averaging effect. The collimator output factors were measured using isodose-shaped scintillators (ISSs) and compared with those of a micro-diamond detector and previous reports. METHODS: An absorbed dose distribution in a spherical dosimetry phantom with a radius of 8 cm was obtained from GK treatment planning software (Leksell GammaPlan [LGP], Elekta AB, Stockholm, Sweden). Two types of ISSs were fabricated to fit the 97.2% (ISS-1) and 95.6% (ISS-2) isodose surfaces. The volume averaging correction factors were obtained by dividing the absorbed dose to water in the central voxel (CV) by that in the ISS. The correction effect due to the difference between the ISS and water was calculated by Monte Carlo simulations. Ten ISS detectors, five of each type, were used to measure the output factors of the 4- and 8-mm collimators of a GK Icon to assess system consistency. The output factors of seven GKs were measured using two ISS detectors, one of each type, and a PTW T60019 (PTW, Freiburg, Germany) micro-diamond detector. RESULTS: The detector output ratios (DORs) measured using the five ISSs of each type were consistent, with standard uncertainties less than 0.2%. In the 4-mm field, the volume averaging correction factor ratios were 1.018 and 1.026, and the output factors after all corrections were 0.827 (0.006) and 0.825 (0.006) for ISS-1 and ISS-2, respectively. In the 8-mm field, the volume averaging correction factor ratios were 1.000 for both ISS types, and the output factors were 0.898 (0.003) and 0.900 (0.003) for ISS-1 and ISS-2, respectively. The ISS detectors could measure the output factors of a GK with uncertainties comparable to that of the PTW 60019 detector. The output factors of all detectors decreased with the dose rate. CONCLUSION: The volume averaging effect of an ISS developed in-house could be calculated using known dose distributions. The collimator output factors of the GK Perfexion/Icon models measured using ISS detectors were consistent with those of a commercial synthetic micro-diamond detector and recent studies.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50-130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Human kidney organoids reveal the role of glutathione in Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by a mutation in the galactosidase alpha (GLA) gene. Despite advances in therapeutic technologies, the lack of humanized experimental models of Fabry disease has limited the development of new therapies to cure the disease. Herein, we modeled Fabry disease using human inducible pluripotent stem cell (iPSC)-derived kidney organoids and the CRISPR-Cas9 genome-editing system. GLA-mutant human kidney organoids revealed deformed podocytes and tubular cells with accumulation of globotriaosylceramide (Gb3). Ultrastructural analysis showed abundant electron-dense granular deposits and electron-dense lamellate lipid-like deposits that formed concentric bodies (zebra bodies) in the cytoplasm of podocytes and tubules. The oxidative stress level was increased in GLA-mutant kidney organoids, and the increase was accompanied by apoptosis. Enzyme replacement treatment (ERT) with recombinant human α-Gal A decreased the Gb3 accumulation and oxidative stress, which resulted in amelioration of the deformed cellular structure of the GLA-mutant kidney organoids. Transcription profile analyses showed decreased glutathione (GSH) metabolism in GLA-mutant kidney organoids. GSH replacement treatment decreased oxidative stress and attenuated the structural deformity of the GLA-mutant kidney organoids. GSH treatment also increased the expression of podocyte and tubular markers and decreased apoptosis. In conclusion, GLA-mutant kidney organoids derived from human iPSCs are valuable tools for studying the mechanisms and developing novel therapeutic alternatives for Fabry disease.

Hypertriglyceridemia Is Associated with More Severe Histological Glomerulosclerosis in IgA Nephropathy.

IgA nephropathy (IgAN) is a globally well-known primary glomerular nephropathy. Hypertriglyceridemia (HTG) is one factor contributing to atherosclerosis and is a common complication of renal failure. HTG is a significant risk factor for decreased renal function in patients with IgAN. We evaluated the association of HTG with the histopathological features of IgAN patients. A total of 480 patients diagnosed with IgAN via kidney biopsy from eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea were included in the final cohort. Pathological features were evaluated by eight expert pathologists with hospital consensus. HTG was defined as a serum triglyceride (TG) level of ≥150 mg/dL. In the study population analysis, the HTG group was older, with more males; higher body mass index (BMI), low-density lipoprotein cholesterol (LDL-C) and spot urine protein ratio; and lower estimated glomerular filtration rate (eGFR). In the lipid profile analysis, eGFR was negatively correlated with TGs/ high-density lipoprotein cholesterol (HDL) and triglyceride-glucose index (TyG). Proteinuria positively correlated with TGs/HDL, non-HDL/HDL, LDL/HDL, TyG, TGs and LDL. The percentages of global sclerosis (GS), segmental sclerosis (SS) and capsular adhesion (CA), and the scores for mesangial matrix expansion (MME) and mesangial cell proliferation (MCP), were more elevated in the HTG group compared to the normal TG group. Multivariable linear regression analysis showed that the percentages of global sclerosis, segmental sclerosis and capsular adhesion, as well as the scores for mesangial matrix expansion and mesangial cell proliferation, were positively associated with TG level. In binary logistic regression, the HTG group showed a higher risk for global sclerosis and segmental sclerosis. In conclusion, HTG is a significant risk factor for glomerulosclerosis in IgAN.

The Serum Uric Acid Level Is Related to the More Severe Renal Histopathology of Female IgA Nephropathy Patients.

Hyperuricemia is a significant risk factor for cardiovascular morbidity and chronic kidney disease progression. IgA nephropathy (IgAN) is a well-known primary glomerular nephropathy. Hyperuricemia is associated with a poor prognosis in IgAN patients. We evaluated the association of hyperuricemia with the histopathological severity of IgAN in male and female patients; 658 patients diagnosed with IgAN via kidney biopsy were initially included. Baseline patient data were collected by eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea. Pathological features were independently evaluated by eight expert pathologists working in the hospitals, and the consensus was reached. Of the initial 658 patients, 517 were finally included (253 males and 264 females). Hyperuricemia was defined as a serum uric acid (UA) level >7.0 mg/dL for males and >5.6 mg/dL for females; 108 (42.7%) males and 95 (35.9%) females exhibited hyperuricemia. Compared to the patients with normal UA levels, the global glomerulosclerosis, segmental sclerosis, mesangial matrix expansion (MME), endocapillary proliferation (ECP), interstitial fibrosis (IF), and tubular atrophy (TA) scores were higher in hyperuricemic males and females. In multivariable linear regression, the serum UA level correlated significantly with the MME, ECP, IF, and TA scores of female IgAN patients only.

Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy.

BACKGROUND/AIMS: Tacrolimus has been used as an immunosuppressive agent in organ transplantation. Despite the therapeutic benefits, tacrolimus's use is limited due to its nephrotoxicity. To reduce tacrolimus nephrotoxicity, effective humanized experimental models may be helpful. Here, we modeled tacrolimus nephrotoxicity using kidney organoids derived from human inducible pluripotent stem cells (iPSCs) in vitro. METHODS: Kidney organoids were differentiated from the CMC11 iPSC cell line, re-seeded in 96-well plates, and treated with tacrolimus at doses of 0, 30, or 60 µM for 24 hours. This in vitro model was compared to a mouse model of tacrolimus nephrotoxicity and the associated mechanisms were investigated. RESULTS: The size of the kidney organoids and cell viability decreased in dose-dependent manners after treatment with tacrolimus. The number of tubular cells decreased with a loss of polarity, similar to the effects seen in mouse tacrolimus nephrotoxicity. Ultrastructural analysis showed numerous vacuoles in the proximal tubular cells of the kidney organoids treated with tacrolimus. Tacrolimus treatment induced oxidative stress and mitochondrial dysfunction, and autophagic activity was enhanced in the kidney organoids. Rapamycin, an autophagy inducer, accelerated cell death in the kidney organoid model of tacrolimus nephrotoxicity, which was attenuated by treatment with 3-methyladenine, an autophagy inhibitor. These findings indicate that the augmentation of autophagy by rapamycin treatment accelerated tacrolimus nephrotoxicity. CONCLUSION: Our data suggest that human kidney organoids are an effective in vitro model of tacrolimus nephrotoxicity and that autophagy plays a critical role in tacrolimus nephrotoxicity.

TAZ/Wnt-ß-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated ß-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing ß-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with ß-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-ß-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.

The Impact of Obesity on the Severity of Clinicopathologic Parameters in Patients with IgA Nephropathy.

Several studies reported the effect of obesity on the progression of IgA nephropathy (IgAN). However, the impact of obesity on the clinicopathologic presentation of IgAN remains uncertain. This is a retrospective cross-sectional study from eight university hospitals in South Korea. Patients were categorized into three groups using the Asia-Pacific obesity classification based on body mass index (BMI). Clinical and histopathologic data at the time of renal biopsy were analyzed. Among 537 patients with IgAN, the obese group was more hypertensive and had lower estimated glomerular filtration rate and more proteinuria than other groups. The histologic scores for mesangial matrix expansion (MME), interstitial fibrosis, tubular atrophy, and mesangial C3 deposition differed significantly between the three groups. Among these histopathologic parameters, BMI was independently positively associated with MME score on multivariable linear regression analysis (p = 0.028). Using multivariable logistic regression analysis, the obese group was independently associated with higher MME scores compared to the normal weight/overweight group (p = 0.020). However, BMI was not independently associated with estimated glomerular filtration rate or proteinuria on multivariable analysis. Obesity was independently associated with severe MME in patients with IgAN. Obesity may play an important pathogenetic role in mesangial lesions seen in IgAN.

Graft immaturity and safety concerns in transplanted human kidney organoids.

For chronic kidney disease, regeneration of lost nephrons with human kidney organoids derived from induced pluripotent stem (iPS) cells is proposed to be an attractive potential therapeutic option. It remains unclear, however, whether organoids transplanted into kidneys in vivo would be safe or functional. Here, we purified kidney organoids and transplanted them beneath the kidney capsules of immunodeficient mice to test their safety and maturity. Kidney organoid grafts survived for months after transplantation and became vascularized from host mouse endothelial cells. Nephron-like structures in grafts appeared more mature than kidney organoids in vitro, but remained immature compared with the neighboring mouse kidney tissue. Ultrastructural analysis revealed filtration barrier-like structures, capillary lumens, and tubules with brush border in the transplanted kidney organoids, which were more mature than those of the kidney organoids in vitro but not as organized as adult mammalian kidneys. Immaturity was a common feature of three separate differentiation protocols by immunofluorescence analysis and single cell RNA sequencing. Stroma of transplanted kidney organoid grafts were filled with vimentin-positive mesenchymal cells, and chondrogenesis, cystogenesis, and stromal expansion were observed in the long term. Transcription profiles showed that long-term maintenance after kidney organoid transplantation induced transcriptomic reprogramming with prominent suppression of cell-cycle-related genes and upregulation of extracellular matrix organization. Our data suggest that kidney organoids derived from iPS cells may be transplantable but strategies to improve nephron differentiation and purity are required before they can be applied in humans as a therapeutic option.

Development of an IAEA phase-space dataset for the Leksell Gamma Knife® Perfexion™ using multi-threaded Geant4 simulations.

This study was conducted to develop a phase-space dataset in the International Atomic Energy Agency (IAEA) format for Monte Carlo (MC) simulations of the Leksell Gamma Knife® (LGK, Elekta Instrument AB, Stockholm, Sweden) Perfexion™ (PFX). An open-source MC code, namely, the Geant4 toolkit with a recently updated multi-threaded mode, was used to maximize the efficiency of the developed IAEA phase-space dataset. The absorbed dose profiles for single shots of the LGK PFX were calculated using the developed dataset and compared with those from radiochromic film measurements and Leksell GammaPlan® version 11.0.3 (LGP, Elekta Instruments) for verification. The mean relative absorbed dose differences in all single shots were less than 3.6% compared with the films and less than 4.0% compared with LGP. The collimator output factors were also calculated for all single shots and compared with the LGP results. The simulated collimator output factor was 0.816 ±â€¯0.003 for a 4-mm shot and 0.903 ±â€¯0.001 for an 8-mm shot in a spherical water phantom. The efficiency of the developed dataset was evaluated by comparing the times required for various simulations. Simulations with the phase-space dataset ran 25, 8.2 and 3.2 times faster than simulations without the phase-space dataset for 4-, 8-, and 16-mm shots, respectively. Using the dataset developed in this study, MC simulations of the LGK PFX can be performed more efficiently for various purposes, such as treatment plan verification and beam quality factor calculations.

Etiology, characteristics, and outcomes of community-onset necrotizing fasciitis in Korea: A multicenter study.

BACKGROUND: Necrotizing fasciitis (NF) is a serious skin and soft tissue infection causing high mortality. Investigating region specific epidemiologic factors associated with NF is important for establishing appropriate treatment strategies. This multicenter study was done to provide an update of the microbial etiology, clinical characteristics, and outcomes of NF in Korea. MATERIALS AND METHODS: A retrospective cohort of adult patients with NF was established using patient data from 13 general hospitals between January 2012 and December 2015 in Korea. We evaluated microbial etiology and clinical characteristics to identify risk factors associated with in-hospital mortality; analyses were performed using binary logistic regression models. RESULTS: A total of 161 patients with NF were included. The most common underlying disease was diabetes mellitus (66 cases, 41.0%). A total of 148 organisms were isolated from 119 (73.9%) patients. Enteric Gram-negative organisms (36 patients) were the most common pathogen, followed by Staphylococcus aureus (30 patients) and streptococci (28 patients). Methicillin-resistant Staphylococcus aureus (MRSA) was identified in 6.2% (10/161) of patients. Of 37 enteric Gram-negative isolates tested, 26 (70.3%) isolates were susceptible to ceftriaxone. The in-hospital mortality rate was 22.4%. Intensive care unit admission, septic shock, and Gram-negative organism infections were significantly associated with in-hospital mortality, and surgery was not a favorable prognostic factor. CONCLUSIONS: As initial empirical antibiotics, glycopeptides against MRSA and broad-spectrum antibiotics against third-generation cephalosporin-resistant organisms should be considered for patients with community-onset NF in Korea.

Rapidly Fatal Emphysematous Osteomyelitis with Multiple Septic Emboli and Liver Abscess Caused by Klebsiella pneumoniae.

Emphysematous osteomyelitis, characterized by intraosseous gas, is a rare but potentially fatal condition that requires prompt diagnosis and aggressive therapy. Causative organisms are members of the bacterial family Enterobacteriaceae or anaerobes in most cases and significant comorbidities such as diabetes mellitus and malignancy, may predispose an individual to the development of emphysematous osteomyelitis. We report a case of extensive emphysematous osteomyelitis via hematogenous spread from Klebsiella pneumoniae liver abscess, complicated by gas-containing abscesses in adjacent soft tissues and epidural space, and multiple systemic septic emboli in a diabetic patient.