Combined Use of Tocilizumab and Mesenchymal Stem Cells Attenuate the Development of an Anti-HLA-A2.1 Antibody in a Highly Sensitized Mouse Model.

Sensitization to HLA can result in allograft loss for kidney transplantation (KT) patients. Therefore, it is required to develop an appropriate desensitization (DSZ) technique to remove HLA-donor-specific anti-HLA antibody (DSA) before KT. The aim of this research was to investigate whether combined use of the IL-6 receptor-blocking antibody, tocilizumab (TCZ), and bone-marrow-derived mesenchymal stem cells (BM-MSCs) could attenuate humoral immune responses in an allo-sensitized mouse model developed using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and treated with TCZ, BM-MSC, or both TCZ and BM-MSC. We compared HLA.A2-specific IgG levels and subsets of T cells and B cells using flow cytometry among groups. HLA.A2-specific IgG level was decreased in all treated groups in comparison with that in the allo-sensitized control (Allo-CONT) group. Its decrease was the most significant in the TCZ + BM-MSC group. Regarding the B cell subset, combined use of TCZ and BM-MSC increased proportions of pre-pro B cells but decreased proportions of mature B cells in BM (p < 0.05 vs. control). In the spleen, an increase in transitional memory was observed with a significant decrease in marginal, follicular, and long-lived plasma B cells (p < 0.05 vs. control) in the TCZ + BM-MSC group. In T cell subsets, Th2 and Th17 cells were significantly decreased, but Treg cells were significantly increased in the TCZ+BM-MSC group compared to those in the Allo-CONT group in the spleen. Regarding RNA levels, IL-10 and Foxp3 showed increased expression, whereas IL-23 and IFN-γ showed decreased expression in the TCZ + BM-MSC group. In conclusion, combined use of TCZ and BM-MSC can inhibit B cell maturation and up-regulate Treg cells, finally resulting in the reduction of HLA.A2-specific IgG in a highly sensitized mouse model. This study suggests that the combined use of TCZ and BM-MSC can be proposed as a novel strategy in a desensitization protocol for highly sensitized patients.

Prediction of intradialytic hypotension using pre-dialysis features-a deep learning-based artificial intelligence model.

BACKGROUND: Intradialytic hypotension (IDH) is a serious complication of hemodialysis (HD) that is associated with increased risks of cardiovascular morbidity and mortality. However, its accurate prediction remains a clinical challenge. The aim of this study was to develop a deep learning-based artificial intelligence (AI) model to predict IDH using pre-dialysis features. METHODS: Data from 2007 patients with 943 220 HD sessions at seven university hospitals were used. The performance of the deep learning model was compared with three machine learning models (logistic regression, random forest and XGBoost). RESULTS: IDH occurred in 5.39% of all studied HD sessions. A lower pre-dialysis blood pressure (BP), and a higher ultrafiltration (UF) target rate and interdialytic weight gain in IDH sessions compared with non-IDH sessions, and the occurrence of IDH in previous sessions was more frequent among IDH sessions compared with non-IDH sessions. Matthews correlation coefficient and macro-averaged F1 score were used to evaluate both positive and negative prediction performances. Both values were similar in logistic regression, random forest, XGBoost and deep learning models, developed with data from a single session. When combining data from the previous three sessions, the prediction performance of the deep learning model improved and became superior to that of other models. The common top-ranked features for IDH prediction were mean systolic BP (SBP) during the previous session, UF target rate, pre-dialysis SBP, and IDH experience during the previous session. CONCLUSIONS: Our AI model predicts IDH accurately, suggesting it as a reliable tool for HD treatment.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients.

We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

The tacrolimus metabolism affect post-transplant outcome mediating acute rejection and delayed graft function: analysis from Korean Organ Transplantation Registry data.

Tacrolimus is a key drug in kidney transplantation (KT) with a narrow therapeutic index. The association between the tacrolimus metabolism rate and KT outcomes have not been investigated in large-scale multi-center studies. The Korean Organ Transplantation Registry (KOTRY) datasets were used. A total of 3456 KT recipients were analyzed. The tacrolimus metabolism rate was defined as blood trough concentration of tacrolimus (C0 ) divided by the daily dose (D). The patients were grouped into fast, intermediate, or slow metabolizers by the C0 /D measured 6 months after transplantation. The slow metabolism group was associated with a 2.7 ml/min/1.73 m2 higher adjusted estimated glomerular filtration rate (eGFR) at 6 months [95% confidence interval (C.I.) 1.2-4.3, P = 0.001], less acute rejection (AR) within 6 months [Odds ratio (OR) 0.744, 95% C.I. 0.585-0.947, P = 0.016], and less interstitial fibrosis and tubular atrophy [OR 0.606, 95% C.I. 0.390-0.940, P = 0.025]. Fast tacrolimus metabolism affected the 6-month post-KT eGFR through mediation of AR [natural indirect effect (NIE) -0.434, 95% C.I. -0.856 to -0.012, P = 0.044) and delayed graft function (DGF; NIE -0.119, 95% C.I. -0.231 to -0.007, P = 0.038). Slow tacrolimus metabolism was associated with better post-KT eGFR. AR and DGF were found to be significant mediators.

Clinical significance of heart rate variability for the monitoring of cardiac autonomic neuropathy in end-stage renal disease patients.

BACKGROUND AND AIMS: The aim of this study is to determine whether the measurement of continuous heart rate variability (HRV) is useful in the evaluation of cardiac autonomic neuropathy (CAN) in end-stage renal disease (ESRD) patients. METHODS AND RESULTS: This cross-sectional study was performed at Seoul St. Mary's hospital between June 2017 and February 2018. Seventy-seven ESRD patients, and 29 healthy controls (HCs) were asked to wear a continuous ambulatory HRV monitor for 24 h. General cardiac function was evaluated using transthoracic echocardiogram (TTE), pulse wave velocity (PWV), coronary calcium scoring (CCS), and 24-h ambulatory blood pressure monitoring (ABPM). HRV parameters of ESRD patients and HCs, and the correlation of HRV parameters with cardiovascular screening methods were observed. All HRV parameters were significantly decreased in ESRD patients compared to HCs (P < 0.001). In the correlation analysis between TTE results and HRV parameters, 24-h standard deviation of all N-N intervals (24SDNN), 24-h standard deviation of sequential 5-min N-N interval means (24DANN) and Low Frequency Power/High Frequency Power (LF/HF) ratio showed negative correlations with E/e', LAVI and TR velocity which are representative indices for the diastolic function of the heart (P < 0.05). HRV parameters showed negative correlations with baPWV, CCS, and 24-h ABPM results as well (P < 0.05). Hemoglobin and serum albumin showed positive correlations with HRV parameters, and glucose, BUN, creatinine, and iPTH levels showed negative correlations (P < 0.05). CONCLUSION: Continuous HRV monitoring may be a useful tool for the evaluation of CAN in ESRD.

BAFF Inhibition Effectively Suppresses the Development of Anti-HLA.A2 Antibody in the Highly Sensitized Mouse Model.

B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (Δ-13.62 vs. Δ27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (≤2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.

The Natural Course of Biopsy-Proven Isolated Microscopic Hematuria: a Single Center Experience of 350 Patients.

The increasing interest in healthcare and health screening events is revealing additional cases of asymptomatic isolated microscopic hematuria (IMH). However, a consensus of the evaluation and explanation of the IMH prognosis is controversial among physicians. Here, we present the natural course of IMH together with the pathological diagnosis and features to provide supportive data when approaching patients with IMH. We retrospectively evaluated 350 patients with IMH who underwent a renal biopsy between 2002 and 2011, and the pathological diagnosis and chronic histopathological features (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) were reviewed. Deterioration of renal function was examined during follow up. The patients with IMH were evaluated for a mean of 86 months. IgA nephropathy was the most common diagnosis in 164 patients (46.9%). Chronic histopathological changes were observed in 166 (47.4%) but was not correlated with proteinuria or a decline in renal function. Ten patients developed proteinuria, and all of them had IgA nephropathy. Three patients progressed to chronic kidney disease with an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) but none progressed to end stage renal disease. In conclusion, IMH had a generally benign course during 7-years of observation, although IgA nephropathy should be monitored if it progresses to proteinuria. Future prospective randomized studies may help conclude the long-term prognosis and lead to a consensus for managing IMH.

Durable response after just one cycle of belotecan-based chemotherapy in a patient with relapsed primary peritoneal serous carcinoma.

The efficacy of second-line chemotherapy for relapsed primary peritoneal serous carcinoma has been numerously reported, but reports on durable response after second-line therapy have been rare. We report the case of a 66-year-old woman with relapsed primary peritoneal serous carcinoma who showed durable response after just one cycle of second-line belotecan-based therapy. The response might be a complete pathologic remission. Considering the fact that our patient suffered from neutropenic sepsis during her treatment, we concluded that belotecan-based chemotherapy could be a good option for second-line chemotherapy in some selected patients, so patient selection should be carefully performed due to the toxicity of belotecan.

Single-cell RNA sequencing revealed the role of the Th17 pathway in the development of anti- human leukocyte antigen antibodies in a highly sensitized mouse model.

Background: The aim of this study is to investigate the specific pathway involved in human leukocyte antigen (HLA) sensitization using single-cell RNA-sequencing analysis and an allo-sensitized mouse model developed with an HLA.A2 transgenic mouse. Methods: For sensitization, wild-type C57BL/6 mouse received two skin grafts from C57BL/6-Tg(HLA-A2.1)1Enge/J mouse (allogeneic mouse, ALLO). For syngeneic control (SYN), skin grafts were transferred from C57BL/6 to C57BL/6. We performed single-cell RNA-sequencing analysis on splenocytes isolated from ALLO and SYN and compared the gene expression between them. Results: We generated 9,190 and 8,890 single-cell transcriptomes from ALLO and SYN, respectively. Five major cell types (B cells, T cells, natural killer cells, macrophages, and neutrophils) and their transcriptome data were annotated according to the representative differentially expressed genes of each cell cluster. The percentage of B cells was higher in ALLO than it was in SYN. Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the highly expressed genes in the B cells from ALLO were mainly associated with antigen processing and presentation pathways, allograft rejection, and the Th17 cell differentiation pathway. Upregulated genes in the T cells of ALLO were involved in the interleukin (IL)-17 signaling pathway. The ratio of Th17 cluster and Treg cluster was increased in the ALLO. On flow cytometry, the percentage of Th17 (IL-17+/CD4+ T) cells was higher and regulatory T cells (FOXP3+/CD4+ T) was lower in the ALLO compared to those in the SYN. Conclusion: Our results indicate that not only the B cell lineage but also the Th17 cells and their cytokine (IL-17) are involved in the sensitization to HLA.

Validation of prediction model for successful discontinuation of continuous renal replacement therapy: a multicenter cohort study.

BACKGROUND: Continuous renal replacement therapy (CRRT) has become the standard modality of renal replacement therapy (RRT) in critically ill patients. However, consensus is lacking regarding the criteria for discontinuing CRRT. Here we validated the usefulness of the prediction model for successful discontinuation of CRRT in a multicenter retrospective cohort. METHODS: One temporal cohort and four external cohorts included 1,517 patients with acute kidney injury who underwent CRRT for >2 days from 2018 to 2020. The model was composed of four variables: urine output, blood urea nitrogen, serum potassium, and mean arterial pressure. Successful discontinuation of CRRT was defined as the absence of an RRT requirement for 7 days thereafter. RESULTS: The area under the receiver operating characteristic curve (AUROC) was 0.74 (95% confidence interval, 0.71-0.76). The probabilities of successful discontinuation were approximately 17%, 35%, and 70% in the low-score, intermediate-score, and highscore groups, respectively. The model performance was good in four cohorts (AUROC, 0.73-0.75) but poor in one cohort (AUROC, 0.56). In one cohort with poor performance, attending physicians primarily controlled CRRT prescription and discontinuation, while in the other four cohorts, nephrologists determined all important steps in CRRT operation, including screening for CRRT discontinuation. CONCLUSION: The overall performance of our prediction model using four simple variables for successful discontinuation of CRRT was good, except for one cohort where nephrologists did not actively engage in CRRT operation. These results suggest the need for active engagement of nephrologists and protocolized management for CRRT discontinuation.

Mortality of elderly patients with acute kidney injury undergoing continuous renal replacement therapy: is age a risk factor?

BACKGROUND: Whether advanced age is associated with poor outcomes of elderly patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is controversial. This study aimed to evaluate age effect and predictors for mortality in elderly AKI patients undergoing CRRT. METHODS: Data of 480 elderly AKI patients who underwent CRRT were retrospectively analyzed. Subjects were stratified into two groups according to age: younger-old (age, 65-74 years; n = 205) and older-old (age, ≥75 years; n = 275). Predictors for 28-day and 90-day mortality and age effects were analyzed using multivariable Cox regression analysis and propensity score matching. RESULTS: Urine output at the start of CRRT (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.99-1.00; p = 0.04), operation (aHR, 0.53; 95% CI, 0.30-0.93; p = 0.03), and use of an intra-aortic balloon pump (aHR, 3.60; 95% CI, 1.18-10.96; p = 0.02) were predictors for 28-day mortality. Ischemic heart disease (aHR, 1.74; 95% CI, 1.02-2.98; p = 0.04) and use of a ventilator (aHR, 0.56; 95% CI, 0.36-0.89; p = 0.01) were predictors for 90-day mortality. The older-old group did not exhibit a higher risk for 28- day or 90-day mortality than the younger-old group in multivariable or propensity score-matched models. CONCLUSION: Advanced age was not a risk factor for mortality among elderly AKI patients undergoing CRRT, suggesting that advanced age should not be considered for therapeutic decisions in critically ill elderly patients with AKI requiring CRRT.

Impact of Low-Level Donor-Specific Anti-HLA Antibody on Posttransplant Clinical Outcomes in Kidney Transplant Recipients.

Background: The clinical significance of low-level donor-specific anti-HLA antibody (low-DSA) remains controversial. We investigated the impact of low-DSA on posttransplant clinical outcomes in kidney transplant (KT) recipients. Methods: We retrospectively reviewed 1,027 KT recipients, namely, 629 living donor KT (LDKT) recipients and 398 deceased donor KT (DDKT) recipients, in Seoul St. Mary's Hospital (Seoul, Korea) between 2010 and 2018. Low-DSA was defined as a positive anti-HLA-DSA result in the Luminex single antigen assay (LABScreen single antigen HLA class I - combi and class II - group 1 kits; One Lambda, Canoga Park, CA, USA) but a negative result in a crossmatch test. We compared the incidence of biopsy-proven allograft rejection (BPAR), changes in allograft function, allograft survival, patient survival, and posttransplant infections between subgroups according to pretransplant low-DSA. Results: The incidence of overall BPAR and T cell-mediated rejection did not differ between the subgroups. However, antibody-mediated rejection (ABMR) developed more frequently in patients with low-DSA than in those without low-DSA in the total cohort and the LDKT and DDKT subgroups. In multivariate analysis, low-DSA was identified as a risk factor for ABMR development. Its impact was more pronounced in DDKT (odds ratio [OR]: 9.60, 95% confidence interval [CI]: 1.79-51.56) than in LDKT (OR: 3.76, 95% CI: 0.99-14.26) recipients. There were no significant differences in other outcomes according to pretransplant low-DSA. Conclusions: Pretransplant low-DSA has a significant impact on the development of ABMR, and more so in DDKT recipients than in LDKT recipients, but not on long-term outcomes.

Severity of COVID-19 Pneumonia in Kidney Transplant Recipients According to SARS-CoV-2 Vaccination.

We reviewed 24 kidney transplantat recipients (KTRs) who had radiologically confirmed coronavirus disease 2019 (COVID-19) pneumonia. Enrolled KTRs were divided into a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-vaccination (+) group (n = 18) and a vaccination (-) group (n = 6). Clinical outcomes of the two groups including death, pulmonary outcome, and renal outcome were compared. COVID-19 pneumonia was worse in vaccination (-) KTRs. Two out of six vaccination (-) KTRs needed continuous renal replacement therapy (CRRT) and mechanical ventilator (MV) and expired. In contrast, only one KTR expired and required CRRT and MV out of 18 vaccination (+) KTRs. Our results suggest that SARS-CoV-2 vaccination attenuates severity of COVID-19 pneumonia in KTRs.

Effects of oleanolic acid and ursolic acid on depression-like behaviors induced by maternal separation in mice.

Oleanolic acid (OA) and ursolic acid (UA) are structural isomeric triterpenoids. Both triterpenoids have been reported to be able to improve depression. However, no studies have compared their effects in the same system. Whether OA or UA could ameliorate depression-like behaviors in maternal separation (MS)-induced depression-like model was investigated. MS model is a well-accepted mouse model that can reflect the phenotype and pathogenesis of depression. Depression is a mental illness caused by neuroinflammation or changes in neuroplasticity in certain brain regions, such as the prefrontal cortex and hippocampus. Depression-like behaviors were measured using splash test or forced swimming test. In addition, anxiety-like behaviors were also measured using the open field test or elevated plus-maze test. MS-treated female mice showed greater depression-like behaviors than male mice, and that OA improved several depression-like behaviors, whereas UA only relieved anxiety-like behavior of MS-treated mice. Microglial activation, expression levels of TNF-α, and mRNA levels of IDO1 were increased in the hippocampi of MS-treated female mice. However, OA and UA treatments attenuated such increases. In addition, expression levels of synaptophysin and PSD-95 were decreased in the hippocampi of MS-treated female mice. These decreased expression levels of synaptophysin were reversed by both OA and UA treatments, although decreased PSD-95 expression levels were only reversed by OA treatment. Our findings suggest that MS cause depression-like behaviors through female-specific neuroinflammation, changes of tryptophan metabolism, and alterations of synaptic plasticity. Our findings also suggest that OA could reverse MS-induced depression-like behaviors more effectively than UA.

Effects of Artemisia annua L. on postmenopausal syndrome in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. AIM OF THE STUDY: We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. MATERIALS AND METHODS: OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17ß-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK-3ß), ß-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. RESULTS: EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3ß, and ß-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. CONCLUSION: These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3ß/ß-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.

Oleanolic acid alleviates the extrapyramidal symptoms and cognitive impairment induced by haloperidol through the striatal PKA signaling pathway in mice.

Haloperidol, one of the representative typical antipsychotics, is on the market for schizophrenia but shows severe adverse effects such as extrapyramidal symptoms (EPS) or cognitive impairments. Oleanolic acid (OA) is known to be effective for tardive dyskinesia which is induced by long-term treatment with L-DOPA. This study aimed to investigate whether OA could ameliorate EPS or cognitive impairment induced by haloperidol. The balance beam, catalepsy response, rotarod and vacuous chewing movement (VCM) tests were performed to measure EPS and the novel object recognition test was used to estimate haloperidol-induced cognitive impairment. Levels of dopamine and acetylcholine, the phosphorylation levels of c-AMP-dependent protein kinase A (PKA) and its downstream signaling molecules were measured in the striatum. OA significantly attenuated EPS and cognitive impairment induced by haloperidol without affecting its antipsychotic properties. Valbenazine only ameliorated VCM. Also, OA normalised the levels of dopamine and acetylcholine in the striatum which were increased by haloperidol. Furthermore, the increased phosphorylated PKA, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) levels and c-FOS expression level induced by haloperidol were significantly decreased by OA in the striatum. In addition, cataleptic behaviour of haloperidol was reversed by sub-effective dose of H-89 with OA. These results suggest that OA can alleviate EPS and cognitive impairment induced by antipsychotics without interfering with antipsychotic properties via regulating neurotransmitter levels and the PKA signaling pathway in the striatum. Therefore, OA is a potential candidate for treating EPS and cognitive impairment induced by antipsychotics.

Immune checkpoint inhibitors in patients with chronic kidney disease: Assessing their ability to cause acute kidney injury and informing their proper use.

Immune check point inhibitors (ICI) have secured regulatory approvals across the world for the treatment of various types of cancers. Though not as frequent as immune-related adverse events (AEs) involving other organs, a considerable number of ICI-related renal AE have also been reported and predicting such events has become important. We provide an updated review on possible mechanisms of ICI-related acute kidney injury (AKI), related risk factors, and the use of ICIs in patients with chronic kidney diseases (CKD). A systematic search for related articles was conducted. Acute tubulointerstitial nephritis (ATIN) is known to be the main cause of ICI-related AKI, with glomerulonephritis also a significant cause. Factors including use of concurrent medications, extra-renal immune related AEs, and combination of two or more immunotherapy drugs are possible risk factors. Use of ICI in patients with CKD may be related to increased occurrence of overall immune related AEs. If the diagnosis of ICI related renal AEs is confirmed, prompt use of steroids is recommended, and in severe cases of AKI, discontinuation of ICI should be considered.

Long-term prediction models for vision-threatening diabetic retinopathy using medical features from data warehouse.

We sought to evaluate the performance of machine learning prediction models for identifying vision-threatening diabetic retinopathy (VTDR) in patients with type 2 diabetes mellitus using only medical data from data warehouse. This is a multicenter electronic medical records review study. Patients with type 2 diabetes screened for diabetic retinopathy and followed-up for 10 years were included from six referral hospitals sharing same electronic medical record system (n = 9,102). Patient demographics, laboratory results, visual acuities (VAs), and occurrence of VTDR were collected. Prediction models for VTDR were developed using machine learning models. F1 score, accuracy, specificity, and area under the receiver operating characteristic curve (AUC) were analyzed. Machine learning models revealed F1 score, accuracy, specificity, and AUC values of up 0.89, 0.89.0.95, and 0.96 during training. The trained models predicted the occurrence of VTDR at 10-year with F1 score, accuracy, and specificity up to 0.81, 0.70, and 0.66, respectively, on test set. Important predictors included baseline VA, duration of diabetes treatment, serum level of glycated hemoglobin and creatinine, estimated glomerular filtration rate and blood pressure. The models could predict the long-term occurrence of VTDR with fair performance. Although there might be limitation due to lack of funduscopic findings, prediction models trained using medical data can facilitate proper referral of subjects at high risk for VTDR to an ophthalmologist from primary care.

Prediction of Visual Outcomes After Diabetic Vitrectomy Using Clinical Factors From Common Data Warehouse.

Purpose: We sought to analyze the visual outcome and systemic prognostic factors for diabetic vitrectomy and predicted outcomes using these factors. Methods: This was a multicenter electronic medical records (EMRs) review study of 1504 eyes with type 2 diabetes that underwent vitrectomy for proliferative diabetic retinopathy at 6 university hospitals. Demographics, laboratory results, intra-operative findings, and visual acuity (VA) values were analyzed and correlated with visual outcomes at 1 year after the vitrectomy. Prediction models for visual outcomes were obtained using machine learning. Results: At 1 year, VA was 1.0 logarithm of minimal angle resolution (logMAR) or greater (poor visual outcome group) in 456 eyes (30%). Baseline visual acuity, duration of diabetes treatment, tractional membrane, silicone oil tamponade, smoking, and vitreous hemorrhage correlated with logMAR VA at 1 year (r = 0.450, -0.159, 0.221, 0.280, 0.067, and -0.105; all P ≤ 0.036). An ensemble decision tree model trained using all variables generated accuracy, specificity, F1 score (the harmonic means of which precision and sensitivity), and receiver-operating characteristic curve area under curve values of 0.77, 0.66, 0.85, and 0.84 for the prediction of poor visual outcomes at 1 year after vitrectomy. Conclusions: Visual outcome after diabetic vitrectomy is associated with pre- and intra-operative findings and systemic factors. Poor visual outcome after diabetic vitrectomy was predictable using clinical factors. Intensive care in patients who are predicted to result in poor vision may limit vision loss resulting from type 2 diabetes. Translational Relevance: This study demonstrates that a real world EMR big data could predict outcome after diabetic vitrectomy using clinical factors.