K-ras mutation detected by peptide nucleic acid-clamping polymerase chain reaction, Ki-67, S100P, and SMAD4 expression can improve the diagnostic accuracy of inconclusive pancreatic EUS-FNB specimens.

OBJECTIVES: We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases. METHODS: Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed. RESULTS: K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases. CONCLUSIONS: K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.

Endoplasmic reticular stress as an emerging therapeutic target for chronic pain: a narrative review.

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

Bias reduction for semi-competing risks frailty model with rare events: application to a chronic kidney disease cohort study in South Korea.

In a semi-competing risks model in which a terminal event censors a non-terminal event but not vice versa, the conventional method can predict clinical outcomes by maximizing likelihood estimation. However, this method can produce unreliable or biased estimators when the number of events in the datasets is small. Specifically, parameter estimates may converge to infinity, or their standard errors can be very large. Moreover, terminal and non-terminal event times may be correlated, which can account for the frailty term. Here, we adapt the penalized likelihood with Firth's correction method for gamma frailty models with semi-competing risks data to reduce the bias caused by rare events. The proposed method is evaluated in terms of relative bias, mean squared error, standard error, and standard deviation compared to the conventional methods through simulation studies. The results of the proposed method are stable and robust even when data contain only a few events with the misspecification of the baseline hazard function. We also illustrate a real example with a multi-centre, patient-based cohort study to identify risk factors for chronic kidney disease progression or adverse clinical outcomes. This study will provide a better understanding of semi-competing risk data in which the number of specific diseases or events of interest is rare.

Femoral Tunnel Geometry and Graft Inclination Angles in Anterior Cruciate Ligament Reconstruction Using a Flexible Reamer System.

Background and Objectives: The aim of this study is to investigate the femoral tunnel geometry (femoral tunsnel location, femoral graft bending angle, and femoral tunnel length) on three-dimensional (3D) computed tomography (CT) and graft inclination on magnetic resonance imaging (MRI) after anatomic anterior cruciate ligament (ACL) reconstruction using a flexible reamer system. Materials and Methods: A total of 60 patients who underwent anatomical ACL reconstruction (ACLR) using a flexible reamer system were retrospectively reviewed. One day after the ACLR procedure was performed, all patients underwent three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI). The femoral tunnel location, femoral graft bending angle, femoral tunnel length, and graft inclination were assessed. Results: In the 3D-CTs, the femoral tunnel was located at 29.7 ± 4.4% in the posterior to anterior (deep to shallow) direction and at 24.1 ± 5.9% in the proximal to distal (high to low) direction. The mean femoral graft bending angle was 113.9 ± 5.7°, and the mean femoral tunnel length was 35.2 ± 3.1 mm. Posterior wall breakage was observed in five patients (8.3%). In the MRIs, the mean coronal graft inclination was 69.2 ± 4.7°, and the mean sagittal graft inclination was 52.4 ± 4.6°. The results of this study demonstrated that a comparable femoral graft bending angle and longer femoral tunnel length were observed compared with the reported outcomes from previous studies that used the rigid reamer system. Conclusions: ACLR using a flexible reamer system allowed for an anatomic femoral tunnel location and a comparable graft inclination to that of the native ACL. In addition, it achieved a tolerable femoral graft bending angle and femoral tunnel length.

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.

Overall assessment for selected markers from high-throughput data.

Reproducibility, a hallmark of science, is typically assessed in validation studies. We focus on high-throughput studies where a large number of biomarkers is measured in a training study, but only a subset of the most significant findings is selected and re-tested in a validation study. Our aim is to get the statistical measures of overall assessment for the selected markers, by integrating the information in both the training and validation studies. Naive statistical measures, such as the combined P $$ P $$ -value by conventional meta-analysis, that ignore the non-random selection are clearly biased, producing over-optimistic significance. We use the false-discovery rate (FDR) concept to develop a selection-adjusted FDR (sFDR) as an overall assessment measure. We describe the link between the overall assessment and other concepts such as replicability and meta-analysis. Some simulation studies and two real metabolomic datasets are considered to illustrate the application of sFDR in high-throughput data analyses.

Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset.

BACKGROUND: Prior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results. We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field. METHODS: ALS patients diagnosed within 12 months and their spouses as healthy controls (n = 150 couples) were screened. For eligible sALS and bALS patients (n = 36) and healthy controls (n = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences. Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels. ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R). RESULTS: sALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes-ratio (F/B-ratio). In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral F/B-ratio. For sALS patients, gut-dysbiosis (a shift in fecal F/B-ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.8006, P < 0.0001) and more severe symptoms (r = 0.9470, P < 0.0001). In contrast, for bALS patients, oral-dysbiosis (a shift in oral F/B-ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.9860, P < 0.0001) and greater disease severity (r = 0.9842, P < 0.0001). For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r = 0.7924, P < 0.0001; bALS: r = 0.7496, P = 0.0067). Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS. This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS. CONCLUSIONS: We found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients. Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease. Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.

The transcriptome landscapes of citrus leaf in different developmental stages.

KEY MESSAGE: The temporal expression profiles of citrus leaves explain the sink-source transition of immature leaves to mature leaves and provide knowledge regarding the differential responses of mature and immature leaves to biotic stress such as citrus canker and Asian citrus psyllid (Diaphorina citri). Citrus is an important fruit crop worldwide. Different developmental stages of citrus leaves are associated with distinct features, such as differences in susceptibilities to pathogens and insects, as well as photosynthetic capacity. Here, we investigated the mechanisms underlying these distinctions by comparing the gene expression profiles of mature and immature citrus leaves. Immature (stages V3 and V4), transition (stage V5), and mature (stage V6) Citrus sinensis leaves were chosen for RNA-seq analyses. Carbohydrate biosynthesis, photosynthesis, starch biosynthesis, and disaccharide metabolic processes were enriched among the upregulated differentially expressed genes (DEGs) in the V5 and V6 stages compared with that in the V3 and V4 stages. Glucose level was found to be higher in V5 and V6 than in V3 and V4. Among the four stages, the largest number of DEGs between contiguous stages were identified between V5 and V4, consistent with a change from sink to source, as well as with the sucrose and starch quantification data. The differential expression profiles related to cell wall synthesis, secondary metabolites such as flavonoids and terpenoids, amino acid biosynthesis, and immunity between immature and mature leaves may contribute to their different responses to Asian citrus psyllid infestation. The expression data suggested that both the constitutive and induced gene expression of immunity-related genes plays important roles in the greater resistance of mature leaves against Xanthomonas citri compared with immature leaves. The gene expression profiles in the different stages can help identify stage-specific promoters for the manipulation of the expression of citrus traits according to the stage. The temporal expression profiles explain the sink-source transition of immature leaves to mature leaves and provide knowledge regarding the differential responses to biotic stress.

Prospective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation.

The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000-mg dose of vancomycin, samples were collected 9 times per patient prospectively. A population PK model was developed using a nonlinear mixed-effect model. The probability of target attainment (PTA) of vancomycin was evaluated for various dosing strategies using Monte Carlo simulation. The ratio of the area under the vancomycin concentration-time curve at steady state over 24 h to the MIC (AUC/MIC ratio) was investigated by applying the vancomycin breakpoint distribution of MICs for methicillin-resistant Staphylococcus aureus A total of 22 adult patients with 194 concentration measurements were included. The population PK was best described by a three-compartment model with a proportional residual error model. Vancomycin clearance and steady-state volume of distribution were 4.01 liters/h (0.0542 liters/h/kg) and 29.6 liters (0.400 liters/kg), respectively. If the treatment target AUC/MIC value was only ≥400, a total daily dose of 3 to 4 g would be optimal (PTA of ≥90%) for patients with normal renal function (estimated glomerular filtration rate [eGFR] = 60 to 120 ml/min/1.73 m2) when the MIC was presumed to be 1 mg/liter. However, AUC/MIC values of 400 to 600 were difficult to attain with any dosing strategy regardless of MIC and eGFR. Thus, it is hard to achieve efficacy and safety targets in patients on ECMO using the population dosing approach with Monte Carlo simulations, and therapeutic drug monitoring should be implemented in these patients.

Residue Dynamics of Streptomycin in Citrus Delivered by Foliar Spray and Trunk Injection and Effect on 'Candidatus Liberibacter asiaticus' Titer.

Streptomycin (STR) has been used to control citrus huanglongbing (HLB) caused by 'Candidatus Liberibacter asiaticus' (CLas) via foliar spray. Here, we studied the residue dynamics of STR and its effect on CLas titers in planta applied by foliar spray and trunk injection of 3-year-old citrus trees that were naturally infected by CLas in the field. After foliar spray, STR levels in leaves peaked at 2 to 7 days postapplication (dpa) and gradually declined thereafter. The STR spray did not significantly affect CLas titers in leaves of treated plants as determined by quantitative PCR. After trunk injection, peak levels of STR were observed 7 to 14 dpa in the leaf and root tissues, and near-peak levels were sustained for another 14 days before significantly declining. At 12 months after injection, moderate to low or undetectable levels of STR were observed in the leaf, root, and fruit, depending on the doses of STR injected, with a residue level of 0.28 µg/g in harvested fruit at the highest injection concentration of 2.0 µg/tree. CLas titers in leaves were significantly reduced by trunk injection of STR at 1.0 or 2.0 g/tree, starting from 7 dpa and throughout the experimental period. The reduction of CLas titers was positively correlated with STR residue levels in leaves. The in planta minimum effective concentration of STR needed to suppress the CLas titer to an undetectable level (cycle threshold ≥36.0) was 1.92 µg/g fresh weight. Determination of the in planta minimum effective concentration of STR against CLas and its spatiotemporal residue levels in planta provides the guidance to use STR for HLB management.

In silico prediction of the full United Nations Globally Harmonized System eye irritation categories of liquid chemicals by IATA-like bottom-up approach of random forest method.

As an alternative to in vivo Draize rabbit eye irritation test, this study aimed to construct an in silico model to predict the complete United Nations (UN) Globally Harmonized System (GHS) for classification and labeling of chemicals for eye irritation category [eye damage (Category 1), irritating to eye (Category 2) and nonirritating (No category)] of liquid chemicals with Integrated approaches to testing and assessment (IATA)-like two-stage random forest approach. Liquid chemicals (n = 219) with 34 physicochemical descriptors and quality in vivo data were collected with no missing values. Seven machine learning algorithms (Naive Bayes, Logistic Regression, First Large Margin, Neural Net, Random Forest (RF), Gradient Boosted Tree, and Support Vector Machine) were examined for the ternary categorization of eye irritation potential at a single run through 10-fold cross-validation. RF, which performed best, was further improved by applying the 'Bottom-up approach' concept of IATA, namely, separating No category first, and discriminating Category 1 from 2, thereafter. The best performing training dataset achieved an overall accuracy of 73% and the correct prediction for Category 1, 2, and No category was 80%, 50%, and 77%, respectively for the test dataset. This prediction model was further validated with an external dataset of 28 chemicals, for which an overall accuracy of 71% was achieved.

Incidence, cost and gender differences of oropharyngeal and noncervical anogenital cancers in South Korea.

BACKGROUND: Human papillomavirus (HPV) is associated with a significant public health burden, yet few studies have been conducted in Asia, especially on noncervical cancers. We estimated the incidence and cost of oropharyngeal and noncervical anogenital (anal, vulvar, vaginal, penile) cancer in Korea. METHODS: We conducted a retrospective cohort study using Korea's National Health Insurance (NHI) claim database from 2013 to 2016. The main outcome measures were the number of respective cancer incidences during the study period and the annual costs per patient in the first year after diagnosis, which was adjusted by relevant variables based on the regression analysis. RESULTS: During the study period, 8022 patients with these cancers were identified, and oropharyngeal cancer comprised 46% of them. The crude incidence rate for male oropharyngeal cancer was significantly higher than that of females (3.1 vs. 0.7 per 100,000 as of 2016, respectively). Additionally, the crude incidence of male oropharyngeal cancer increased from 2.7 in 2013 to 3.1 in 2016, whereas that of female and other cancers was stable during the study period. The mean annual incidence-based cost per patient in 2016 was highest for oropharyngeal cancers (21,870 USD), and it was significantly higher in males than in females based on then regression analysis (p < .001). CONCLUSIONS: Oropharyngeal cancer comprises the highest number of HPV-associated noncervical cancer incidences in Korea, and the incidence and cost of oropharyngeal cancer was significantly higher among males than females. More aggressive public health policy toward males may decrease gender gap of oropharyngeal cancer.

Comparison of Depth Camera and Terrestrial Laser Scanner in Monitoring Structural Deflections.

Modeling a structure in the virtual world using three-dimensional (3D) information enhances our understanding, while also aiding in the visualization, of how a structure reacts to any disturbance. Generally, 3D point clouds are used for determining structural behavioral changes. Light detection and ranging (LiDAR) is one of the crucial ways by which a 3D point cloud dataset can be generated. Additionally, 3D cameras are commonly used to develop a point cloud containing many points on the external surface of an object around it. The main objective of this study was to compare the performance of optical sensors, namely a depth camera (DC) and terrestrial laser scanner (TLS) in estimating structural deflection. We also utilized bilateral filtering techniques, which are commonly used in image processing, on the point cloud data for enhancing their accuracy and increasing the application prospects of these sensors in structure health monitoring. The results from these sensors were validated by comparing them with the outputs from a linear variable differential transformer sensor, which was mounted on the beam during an indoor experiment. The results showed that the datasets obtained from both the sensors were acceptable for nominal deflections of 3 mm and above because the error range was less than ±10%. However, the result obtained from the TLS were better than those obtained from the DC.

Beam Deflection Monitoring Based on a Genetic Algorithm Using Lidar Data.

The Light Detection And Ranging (LiDAR) system has become a prominent tool in structural health monitoring. Among such systems, Terrestrial Laser Scanning (TLS) is a potential technology for the acquisition of three-dimensional (3D) information to assess structural health conditions. This paper enhances the application of TLS to damage detection and shape change analysis for structural element specimens. Specifically, estimating the deflection of a structural element with the aid of a Lidar system is introduced in this study. The proposed approach was validated by an indoor experiment by inducing artificial deflection on a simply supported beam. A robust genetic algorithm method is utilized to enhance the accuracy level of measuring deflection using lidar data. The proposed research primarily covers robust optimization of a genetic algorithm control parameter using the Taguchi experiment design. Once the acquired data is defined in terms of plane, which has minimum error, using a genetic algorithm and the deflection of the specimen can be extracted from the shape change analysis.

Clinical Case of a Transfusion-Associated Canine Mycoplasma haemocanis Infection in the Republic of Korea: A Case Report.

This report describes the first clinical case of a transfusion-associated Mycoplasma haemocanis infection in a dog in Korea. A 6-year-old male Maltese underwent a red blood cell transfusion for idiopathic immune-mediated hemolytic anemia. Eighteen days after the blood transfusion, the recipient's packed cell volume decreased and basophilic organisms were found on erythrocytes. A polymerase chain reaction and sequential analysis showed that both the donor dog and recipient dog had M. haemocanis. Six weeks after doxycycline administration, no organisms were detected and the recipient's anemia had improved.

DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. CONCLUSION: The dysregulation of SIRT1-DEPTOR-mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1-S6K1 signaling may have therapeutic potential for treating ALD in humans. (Hepatology 2018).

Nephrotoxicity of amikacin in noncritically ill patients
.

AIMS: Several studies have reported that critically ill patients who require amikacin for the treatment of severe infection require therapeutic drug monitoring (TDM) to prevent acute kidney injury. Moreover, studies so far have mainly focused on patients with critical illnesses; therefore, the probability of occurrence of nephrotoxicity in noncritically ill patients is less known and tends to be overestimated. Recently, with the emergence of multidrug resistant bacteria, the need for aminoglycosides has resurfaced. Therefore, the aim of this study was to investigate the nephrotoxicity and tolerability of amikacin in noncritically ill patients. MATERIALS AND METHODS: This was a retrospective study that included 224 patients who were administered amikacin. Relevant data on patients' clinical course of disease, comorbidities, and clinical laboratory measurements were statistically analyzed. Nephrotoxicity was defined as a serum creatinine level increase by ≥ 0.3 mg/dL or ≥ 50% after therapy initiation. RESULTS: The mean (SD) daily amikacin dose was 13.04 (4.21) mg/kg. The mean (SD) duration of treatment was 12.09 (12.89) days. The incidence rate (95% CI) of amikacin-induced nephrotoxicity was 1.076/person-year (0.46 - 2.12) for the total person-time (3.44 years). In the risk analysis, no risk factor associated with nephrotoxicity could be found. However, an increasing trend of AKI risk was observed in patients with low baseline estimated glomerular filtration rate. CONCLUSION: In noncritically ill patients, the incidence of amikacin-induced nephrotoxicity was lower than that reported in previous studies. The initial monitoring for kidney function in clinical laboratories may be useful, and therapeutic drug monitoring (TDM) may not be necessary in patients with normal kidney function.

The in Planta Effective Concentration of Oxytetracycline Against 'Candidatus Liberibacter asiaticus' for Suppression of Citrus Huanglongbing.

Huanglongbing (HLB) or greening currently is the most devastating citrus disease worldwide. The fastidious phloem-colonizing bacterium 'Candidatus Liberibacter asiaticus' (CLas) is the causal agent of citrus HLB in Florida. Bactericides containing the active ingredient oxytetracycline (OTC) have been used in foliar spray to control citrus HLB in Florida since 2016. However, the minimum concentration of OTC required to suppress CLas in planta remains unknown. We developed a new method for evaluating the effects of OTC treatment on CLas titers in infected plants and determined the relationship between OTC residue levels and control levels achieved for CLas using mathematical modeling in greenhouse and field experiments. In both greenhouse and field, OTC spray did not reduce the titers of CLas, and it produced undetectable or mild levels of OTC residue in leaves within 7 days post-application (DPA). In greenhouse, OTC injection at 0.05 g per tree decreased CLas titers to an undetectable level (cycle threshold value ≥ 36.0) from 7 to 30 DPA and produced a residue level of OTC at 0.68 to 0.73 µg/g of fresh tissue over this period. In the field, OTC injection at 0.50 g per tree resulted in the decline of CLas titers by 1.52 log reduction from 14 to 60 DPA, with residue levels of OTC at 0.27 to 0.33 µg/g of fresh tissue. In both trials, a first-order compart model of OTC residue dynamics in leaves of trunk-injected trees was specified for estimating the retention of effective concentrations. Furthermore, nonlinear modeling revealed significant positive correlations between OTC residue levels in leaves and the control levels for CLas achieved. The results suggested that the minimum concentrations of OTC required to suppress CLas populations in planta to below the detection limit are 0.68 and 0.86 µg/g and that the minimum concentrations of OTC required for initial inhibition of CLas growth in planta are ∼0.17 and ∼0.215 µg/g in leaf tissues under greenhouse and field conditions, respectively. This finding highlights that a minimum concentration of OTC should be guaranteed to be delivered to target CLas in infected plants for effective control of citrus HLB.

Effect of pharmacokinetic model misspecification on antibiotic probability of target attainment predicted by Monte Carlo simulation
.

OBJECTIVE: The first aim of this study was to compare the predictability of efficacy by Monte Carlo simulation between a true one-compartment model and a true two-compartment model for doripenem. The second aim was to explore how we can identify the usefulness of a one-compartment model when the pharmacokinetic/pharmacodynamic (PK/PD) indices between three misspecified one-compartment models and a true two-compartment model are compared. MATERIALS AND METHODS: The reported two-compartment model parameters of two doripenem studies and a vancomycin study were used to generate 200 virtual concentration-time profiles for each study. Sparse and dense sampling designs were selected to build the one- and two-compartment models, respectively. The probability of target attainment (PTA) for the PK/PD indices were compared between the one- and two-compartment models of the same drug, applying the clinical breakpoint distribution of minimum inhibitory concentrations (MICs). RESULTS: The simulated concentration-time profiles reproduced the original data well. In addition, PTAs were similar between the one- and two-compartment models when infusion time and MIC were the same in the doripenem studies. For vancomycin simulations, the maximum difference was 65.9% between a misspecified one-compartment model and the true two-compartment model. CONCLUSION: When a misspecified one-compartment model was established with sparse sampling data, the PTA was significantly different from that of the two-compartment model. Thus, a useful PK model must be verified through diagnostic plots and visual predictive checks and the range of sampling time should be sufficient to explain the PK of a drug.

Statistical analysis of the reproducibility and predictive capacity of MCTT HCE™ eye irritation test, a me-too test method for OECD TG 492.

We aimed to conduct additional statistical analysis of the reproducibility and predictive capacity of MCTT HCE™ eye irritation test (EIT), a me-too test method for OECD TG 492 with the data generated during the validation study in which 30 reference chemicals were tested in three repeated runs by three independent laboratories. We evaluated the within-laboratory reproducibility (WLR) and the between-laboratory reproducibility (BLR) through tabulation and graphs and presented the concordance of eye irritancy prediction with 95% Wilson's confidence intervals (CIs). Also, the analyses of the Intra-Class Correlation Coefficient (ICC) and Bland-Altman plot were applied to confirm the reproducibility and the comparability, referring to the validated methods of OECD TG 492. Kappa analysis was also performed to check the degree of agreement of the within- and between-laboratory reproducibility and agreement between MCTT HCE™ EIT and the reference methods. We calculated the predictive capacity via misprediction over total prediction method. The predictive capacity (sensitivity, specificity, and accuracy) was presented with 95% of Wilson's CIs. Also, bootstrap resampling was performed to express the 95% CI by the simple percentile methods for 30 chemicals and 141 reference chemicals additionally tested. Collectively, WLR (92.2%) and BLR (93.3%) met the criteria of the performance standards (WLR ≥ 90% and BLR ≥ 85%), and the results of ICC analysis and the Bland-Altman plot suggested an acceptable WLR and BLR and comparability to other validated methods of OECD TG 492. Also, the predictive capacity results for the 30 reference chemicals confirmed the good performance of the MCTT HCE™ EIT by satisfying the criteria of sensitivity, specificity, and the accuracy stated in the PS. The bootstrap resampling method showed a predictive capacity, sufficiently satisfying the criteria stated in the Performance Standards.