Development and validation of a machine learning model to predict time to renal replacement therapy in patients with chronic kidney disease.

BACKGROUND: Predicting time to renal replacement therapy (RRT) is important in patients at high risk for end-stage kidney disease. We developed and validated machine learning models for predicting the time to RRT and compared its accuracy with conventional prediction methods that uses the rate of estimated glomerular filtration rate (eGFR) decline. METHODS: Data of adult chronic kidney disease (CKD) patients who underwent hemodialysis at Oita University Hospital from April 2016 to March 2021 were extracted from electronic medical records (N = 135). A new machine learning predictor was compared with the established prediction method that uses the eGFR decline rate and the accuracy of the prediction models was determined using the coefficient of determination (R2). The data were preprocessed and split into training and validation datasets. We created multiple machine learning models using the training data and evaluated their accuracy using validation data. Furthermore, we predicted the time to RRT using a conventional prediction method that uses the eGFR decline rate for patients who had measured eGFR three or more times in two years and evaluated its accuracy. RESULTS: The least absolute shrinkage and selection operator regression model exhibited moderate accuracy with an R2 of 0.60. By contrast, the conventional prediction method was found to be extremely low with an R2 of -17.1. CONCLUSIONS: The significance of this study is that it shows that machine learning can predict time to RRT moderately well with continuous values from data at a single time point. This approach outperforms the conventional prediction method that uses eGFR time series data and presents new avenues for CKD treatment.

[Construction of System to Making Antibiograms Based was used by Japan Nosocomial Infections Surveillance (JANIS) Data].

Making the antibiogram necessary for infectious disease treatment is an important operation of the microbiology laboratory. Antibiogram is required to be up-to-date and to keep up with the annual updates of the Clinical & Laboratory Standards Institute (CLSI). However, these operation and managements require a lot of effort. In addition, even in the surveillance and analysis comparison of multiple facilities, the difference in CLSI base year becomes a barrier, making unified analysis difficult. On the other hand the antibiogram by Japan Nosocomial Infections Surveillance (JANIS) has restrictions on the bacterial species, antibacterial agents, and date range. Accordingly we focused on the fact that the data transmitted to JANIS is in a common format, and attempt construction a system to making the antibiogram based on this. This system uses data transmitted to JANIS, is convenient, can use not only the latest but also past base year CLSI category, has no restrictions on bacterial species, antibacterial agents, date range, works on Microsoft Windows environment, pursuit of compliance with the guidelines, and automatically making the antibiogram.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient.

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

[Statistical approach to evaluate the occurrence of out-of acceptable ranges and accuracy for antimicrobial susceptibility tests in inter-laboratory quality control program].

To evaluate the occurrence of out-of acceptable ranges and accuracy of antimicrobial susceptibility tests, we applied a new statistical tool to the Inter-Laboratory Quality Control Program established by the Kyushu Quality Control Research Group. First, we defined acceptable ranges of minimum inhibitory concentration (MIC) for broth microdilution tests and inhibitory zone diameter for disk diffusion tests on the basis of Clinical and Laboratory Standards Institute (CLSI) M100-S21. In the analysis, more than two out-of acceptable range results in the 20 tests were considered as not allowable according to the CLSI document. Of the 90 participating laboratories, 46 (51%) experienced one or more occurrences of out-of acceptable range results. Then, a binomial test was applied to each participating laboratory. The results indicated that the occurrences of out-of acceptable range results in the 11 laboratories were significantly higher when compared to the CLSI recommendation (allowable rate < or = 0.05). The standard deviation indices(SDI) were calculated by using reported results, mean and standard deviation values for the respective antimicrobial agents tested. In the evaluation of accuracy, mean value from each laboratory was statistically compared with zero using a Student's t-test. The results revealed that 5 of the 11 above laboratories reported erroneous test results that systematically drifted to the side of resistance. In conclusion, our statistical approach has enabled us to detect significantly higher occurrences and source of interpretive errors in antimicrobial susceptibility tests; therefore, this approach can provide us with additional information that can improve the accuracy of the test results in clinical microbiology laboratories.

Phytotoxic components produced by pathogenic Fusarium against morning glory.

A pathogenic isolate of Fusarium, F. oxysporum f. sp. batatas O-17 (PF), causes wilt disease in leaf etiolation in sweet potato (Ipomoea batatas) and morning glory (Ipomoea tricolor). Extracts from PF cultures were screened for phytotoxic components using a growth inhibition assay with morning glory seedlings. The extracts were fractionated using differential solvent extraction and two active compounds, ergosterol and fusalanipyrone, were isolated from the less-polar fraction. Growth inhibition of morning glory seedlings showed a sigmoidal dose-response relationship, with fusalanipyrone exhibiting a two order of magnitude higher EC50 value than ergosterol (18 nM and 1.6 microM, respectively). Both compounds showed lower growth inhibition activity towards lettuce seedlings (Lactuca sativa). This study provides information on the phytotoxic components of PF and discusses the mechanism behind PFf-induced phytotoxicity.

Morning glory systemically accumulates scopoletin and scopolin after interaction with Fusarium oxysporum.

An isolate of non-pathogenic Fusarium, Fusarium oxysporum 101-2 (NPF), induces resistance in the cuttings of morning glory against Fusarium wilt caused by F. oxysporum f. sp. batatas O-17 (PF). The effect of NPF on phenylpropanoid metabolism in morning glory cuttings was studied. It was found that morning glory tissues responded to treatment with NPF bud-cell suspension (108 bud-cells/ml) with the activation of phenylalanine ammonia-lyase (PAL). PAL activity was induced faster and greater in the NPF-treated cuttings compared to cuttings of a distilled water control. High performance liquid chromatography analysis of the extract from tissues of morning glory cuttings after NPF treatment showed a quicker induction of scopoletin and scopolin synthesis than that seen in the control cuttings. PF also the induced synthesis of these compounds at 10(5) bud-cells/ml, but inhibited it at 10(8) bud-cells/ml. Possibly PF produced constituent(s) that elicited the inhibitory effect on induction of the resistance reaction. These compounds could potentially be useful as markers to detect early beginning interactions between Fusarium and morning glory tissues cuttings.

[Evaluation of the new detectable method of the specimen mix-up in a microbiological examination].

To date, it has been difficult to detect a mix-up of specimens for microbiological examinations. We developed and evaluated a computer program that detects specimen mix-up during the examinations. Once some bacterial species such as Pseudomonas aeruginosa and MRSA are detected in an examination, it is not easy for these bacteria to disappear on subsequent examinations. It is possible to speculate that there has been a specimen mix-up when there are differences in the existence of bacterial species between the results of the past and current examinations. In this study, 1379 false mix-up specimens were created and evaluated for the detection of specimen mix-ups using this method and 417 of the 1379 specimens were detected as mix-ups (sensitivity; 30.2%). Furthermore, when 1486 real specimens were evaluated for the detection of mix-ups, 114 samples were judged to have been mixed-up. Three of these samples were mixed up during the examinations (specificity; 92.5%). These findings suggest that this method is useful for the detection of specimen mix-up during microbiological examinations.

Chromobacterium haemolyticum Pneumonia Possibly Due to the Aspiration of Runoff Water.

Here, we report a case of pneumonia possibly caused by the aspiration of runoff water containing Chromobacterium haemolyticum. A 69-year-old man became intoxicated with alcohol, fell into a ditch, and lost consciousness after suffering a blow to the head. The lower half of his body was completely paralyzed because of damage to his spinal cord, and he aspirated runoff water from the ditch. Chest computed tomography scans revealed consolidation in the right upper lobe and bilateral lower lobes. A sputum culture detected gram-negative bacteria that was identified as C. haemolyticum. Antibacterial chemotherapy was initiated, and the clinical course was favorable. To the best of our knowledge, this is the first report of C. haemolyticum pneumonia in the literature.

Inhibition of [3H]ponasterone A binding by ecdysone agonists in the intact Kc cell line.

Inhibition of the binding of [3H]ponasterone A ([3H]PoA) by ecdysone agonists including diacylhydrazines such as RH-5849, tebufenozide (RH-5992) and methoxyfenozide (RH-2485) was examined in intact Drosophila Kc cells. The reciprocal logarithm of the concentration at which there is 50% inhibition of [3H]PoA binding, pIC(50) (M), was determined as the binding activity for all compounds from each concentration-response curve. The order of the activity was PoA>20-hydroxyecdysone>cyasterone>inokosterone>or=makisterone A>methoxyfenozide>or=tebufenozide>ecdysone>RH-5849. The ranking of steroidal ecdysone analogs is consistent with that obtained against Spodoptera Sf-9 cells. Furthermore, in terms of pIC(50), all binding activity for ecdysone analogs, except ecdysone, estimated in the Kc cell line system was significantly higher than that for the Sf-9 cell line system. However, the activity of ecdysone was comparable between Kc and Sf-9 cells. The activity of diacylhydrazine analogs against Kc cells was significantly low compared with that against Sf-9 cells. The potency of methoxyfenozide was 1/200 that of PoA, which showed the highest activity in the Kc cell line system among all compounds tested. The activity of tebufenozide analogs having an n-pentyl or n-hexyl group instead of a 4-ethylphenyl group was similar to that of RH-5849.

Relationship between structure and permeability of tryptophan derivatives across human intestinal epithelial (Caco-2) cells.

L-Trp and its derivatives were used as model compounds to clarify structural factors which influence the intestinal epithelial permeation and metabolism of amino-acid derivatives. Permeability of model compounds through Caco-2 cells was used as an in vitro absorption model for human intestinal epithelial cells. The influence of compound concentration, the effects of various transporter substrates on permeability coefficients, and pH dependency of permeability coefficients were investigated. The transcellular permeability of Trp and Trp-NH2 in the direction from the apical side to the basolateral side, in which nutrients and drugs were ordinarily absorbed, declined with increasing concentration and saturated at more than 1 and 0.4 mM, respectively. The permeability coefficients for N-terminal protected Trp derivatives and Ac-Trp-NH2 showed similar and constant values in both from the apical-to-basolateral and basolateral-to-apical directions. In addition, significant inhibition of the apical-to-basolateral permeation of Trp by Leu and Phe was observed. The permeability coefficient ratio at pH 6.3 to that at pH 7.3 was explained by the ratio of the ionic form to the neutral form of the compounds. Based upon these results and the partition coefficients in the 1-octanol/water system, possible absorption mechanism of Trp and its derivatives across Caco-2 cells was proposed.

[Quality control for antimicrobial susceptibility test using correlation between MIC results].

The method of National Committee for Clinical Laboratory Standards (NCCLS) is widely used for the daily quality control of the antimicrobial susceptibility test. This method, however, cannot detect the accidental error, although it is useful to detect the systematic error in the examination. We developed a computer program using the correlation between the various antimicrobial susceptibility test results to detect an accidental error. The combinations of the MIC results determined for two antimicrobial agents which showed a high correlation coefficient (> or = 0.7), were selected from 98 bacterial species (2122 strains) isolated from January 2000 to December 2000 at Oita Medical University Hospital. Subsequently, a total of 127 combinations of antimicrobial agents for 13 species were selected on the basis of acceptable correlation ranges. Then, the method were verified with 666 strains (5753 combinations) isolated during the period of January to June, 2001. Twenty-six strains (47 combinations) were identified as an unexpected result, and the occurrence of error were confirmed in 3 strains (12 combinations). These results suggest that this method which evaluated the correlation between MICs against different antimicrobial agents is applicable for the quality control of antimicrobial susceptibility testings.

Phytotoxic sesterterpene, 11-epiterpestacin, from Bipolaris sorokiniana NSDR-011.

The structure of siccanol, a phytotoxic sesterterpene of fungal origin, was analyzed after chemical conversion by NMR spectroscopy. Siccanol was found to be an epimer of terpestacin that has been isolated from Arthrinium sp., and was thus renamed 11-epiterpestacin. Its stereochemistry was also identical with that of fusaproliferin, a structurally related mycotoxin from Fusarium proliferatum. Therefore, this sesterterpene may also be referred to as 24-deacetyl fusaproliferin. The phytotoxicity of 11-epiterpestacin was almost equal to that of terpestacin, but significantly higher than that of fusaproliferin.

Relationship between structure and permeability of dipeptide derivatives containing tryptophan and related compounds across human intestinal epithelial (Caco-2) cells.

The permeability of dipeptide derivatives containing tryptophans and indole derivatives through Caco-2 cells was used as an in vitro intestinal absorption model in order to clarify structural factors which influence their intestinal epithelial permeation and metabolism. Most peptide derivatives were hydrolysed not only by the cytosolic enzymes in Caco-2 cells during permeation but also by enzymes released to the apical solution before cell permeation. The N-terminal blocked dipeptides were more resistant to hydrolases expressed in the Caco-2 cells and indole derivatives were not entirely degraded. Based on compound concentration dependency and comparison of permeability coefficients in apical-to-basolateral and basolateral-to-apical directions, the main absorption mechanism of compounds were determined. Compounds were then classified into three groups; (1) passively transported compounds, (2) actively transported compounds and (3) compounds excreted by P-glycoprotein.

Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability.

To evaluate absorption of compounds across the membrane via a transcellular route, the permeability of peptide derivatives and related compounds was measured by the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients by PAMPA were analyzed quantitatively using classical QSAR and Volsurf approaches with the physicochemical parameters. The results from both approaches showed that hydrogen bonding ability of molecules in addition to hydrophobicity at a particular pH were significant in determining variations in PAMPA permeability coefficients. The relationship between Caco-2 cell permeability and artificial lipid membrane permeability was then determined. The compounds were sorted according to their absorption pathway in the plot of the Caco-2 cell and PAMPA permeability coefficients.

Inhibitory activity of analogs of AM-toxin, a host-specific phytotoxin from the Alternaria alternata apple pathotype, on photosynthetic O2 evolution in apple leaves.

The effect of the host-specific phytotoxins, AM-toxins, on the photosynthetic activity of leaves from susceptible apple cultivars was investigated by using an oxygen electrode. The photosynthetic O2 evolution was inhibited by AM-toxin I in a host-specific manner. The inhibitory activity of several AM-toxin analogs against photosynthesis was also evaluated and the findings were correlated with their necrosis-inducing activity.