PZLAST: an ultra-fast amino acid sequence similarity search server against public metagenomes.

SUMMARY: : Similarity searches of amino acid sequences against the public metagenomic data can provide users insights about the function of sequences based on the environmental distribution of similar sequences. However, a considerable reduction in the amount of data or the accuracy of the result was necessary to conduct sequence similarity searches against public metagenomic data, because of the vast data size more than Terabytes. Here, we present an ultra-fast service for the highly accurate amino acid sequence similarity search, called PZLAST, which can search the user's amino acid sequences to several Terabytes of public metagenomic sequences in ∼10-20 min. PZLAST accomplishes its search speed by using PEZY-SC2, which is a Multiple Instruction Multiple Data many-core processor. Results of PZLAST are summarized by the ontology-based environmental distribution of similar sequences. PZLAST can be used to predict the function of sequences and mine for homologs of functionally important gene sequences. AVAILABILITY AND IMPLEMENTATION: PZLAST is freely accessible at https://pzlast.riken.jp/meta without requiring registration. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A machine learning model that emulates experts' decision making in vancomycin initial dose planning.

Vancomycin is a glycopeptide antibiotic that is a primary treatment for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended. Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician's experience and expertise. In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. Although small training sets were used, we established a predictive model with a target attainment rate comparable to those of experts, another ML model, and commonly used vancomycin dosing software. Our strategy will help develop an expert-like predictive model that aids in decision making for initial vancomycin dosing, particularly in settings where dose planning consultations are unavailable.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Cky811 protein expressed by polydnavirus and venom gland of Cotesia kariyai regulates the host Mythimna separata larvae immune response function of C-type lectin responsible for foreign substance recognition which suppresses its melanization and encapsulation.

Cotesia kariyai (Ck) larvae implanted into the body cavity of the Mythimna separata (armyworm) larvae get melanized and encapsulated after adhesion by hemocytes called hyperspread cells (HSCs). The present study showed that HSCs could not adhere to the implanted Ck larvae in armyworm larvae after injection of Ck polydnavirus (CkPDV) + venom (V), thus melanization and encapsulation could not occur. A C-type lectin called Mys-IML of the host armyworm larvae was considered to be involved in the recognition of foreign substances which always expressed in hemocytes. The CkPDV DNA encodes a C-type lectin called Cky811 that has high amino acid homology to Mys-IML. HSCs did not adhere when CkPDV + V was mixed with the hemolymph of armyworm larvae on glass slides and incubated in vitro, but the addition of anti-Cky811 antibody enabled HSCs to adhere. The messenger RNA (mRNA) expression of Mys-IML in armyworm larvae injected with CkPDV + V became undetectable by 6 h. On the contrary, Cky811 mRNA was well expressed in the hemocytes of armyworm larvae injected with CkPDV + V from 0.5 to 6 h. Cky811 protein was also detected in the crude extracts from Ck venom gland + Ck venom reservoir, suggesting that these proteins regulate foreign substance recognition by the armyworm within 0.5 h. These results suggest that CkPDV + V suppresses mRNA expression of Mys-IML, and that Cky811 protein expressed in hemocytes regulates foreign substance recognition of Mys-IML, resulting in inhibition of the downstream reaction steps: HSCs adhesion, melanization, and encapsulation.

Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a Ryanodine Receptor Type 2 Missense Mutation.

BACKGROUND: Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the sameryanodine receptor type 2(RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC .Methods and Results:Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the sameRYR2-R169Q missense mutation and no other CPVT- or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca2+imaging and [3H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca2+release from the sarcoplasmic reticulum and increased fractional Ca2+release. CONCLUSIONS: The rare association of LVNC and CPVT phenotypes withRYR2mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.

Multivariate analysis of TU wave complex on electrocardiogram in Andersen-Tawil syndrome with KCNJ2 mutations.

BACKGROUND: The exact differences between the TU wave complex of ATS1 and that of healthy individuals remain to be investigated. We sought to characterize the TU wave complex of Andersen-Tawil syndrome type 1 (ATS1) using high frequency electrocardiogram (ECG) data. METHODS: Electrocardiograms were recorded as time series data with a 2 kHz frequency ECG amplifier in 13 patients with ATS1 (positive for KCNJ2 mutation, ATS1 group) and age-matched healthy individuals (control group). Conventional ECG parameters were measured, and principal component analysis (PCA) and independent component analysis (ICA) were applied to the TU wave complex. RESULTS: Time from T peak (Tp) to U peak (Up), time from bottom (B) to Up, and time from B to U end (BUe, U duration) (0.232 ± 0.018 vs. 0.165 ± 0.017, p < .0001), where B is the lowest point between T and U waves, were all longer in the ATS1 group than the control group. Multivariate logistic regression analysis revealed that BUe could completely differentiate the two groups. PCA ratios in the ATS1 group were significantly larger than the control group (26.5 ± 12.3 vs. 10.4 ± 6.2, p = .0005). ICA revealed 1 or 2 U-wave-specific independent components (ICs) that exclusively comprise the U wave in ATS1, whereas U waves in the control group were composed of some ICs that also comprised T waves. CONCLUSIONS: U-wave-related temporal parameters, particularly BUe, and the existence of U-wave-specific ICs, extracted in the ICA, are useful for differentiation of U waves in ATS1 from those in healthy individuals.

Establishment of immunity against Epstein-Barr virus infection in a patient with CHARGE/complete DiGeorge syndrome after peripheral blood lymphocyte transfusion.

CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T-cell count of <50/mm3 due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA-identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T-cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/µgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV-specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV-specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.

Active surveillance in response to the identification of a single carbapenemase-producing Escherichia coli at a Japanese university hospital.

This report described the experience of active surveillance culture implemented in response to the identification of a single carbapenemase-producing Escherichia coli in a Japanese university hospital. It revealed a horizontal transmission event and an additional asymptomatic carrier of carbapenemase-producing Escherichia coli with unique drug susceptibility and resistance gene profiles. Early implementation of active surveillance culture as a part of multifaceted infection control measures appeared to be useful to control further transmission of carbapenemase-producing Escherichia coli even in the low endemic facility. Further investigations on the timing and usefulness of active surveillance culture in the control of carbapenemase-producing Enterobacteriaceae would be warranted.

Ultrasonographic diagnosis of diaphragm paralysis in a neonate during mechanical ventilation after cardiac surgery.

Diaphragm excursion method is unsuitable for diagnosis of diaphragm paralysis during positive pressure ventilation. We diagnosed diaphragm paralysis in a neonate, without interrupting positive pressure respiratory support after cardiac surgery, using the diaphragm thickness fraction, which could be evaluated during mechanical ventilation and was unaffected by bowel gases. The diaphragm thickness fraction method can help diagnose diaphragm dysfunction using only echography.

Endothelial Dysfunction of Conduit Arteries in Patients with Repaired Coarctation of the Aorta.

Adult patients with repaired coarctation of the aorta (r-CoA) show high prevalence of late hypertension, but the exact mechanisms of this phenomenon are unknown. Endothelial dysfunction has been implicated in this paradoxical hypertension. We evaluated the endothelial function of both conduit and resistance arteries by using flow-mediated dilation (FMD) and digital peripheral artery tonometry (PAT).Seventeen patients with r-CoA and one patient with repaired interrupted aortic arch (r-CoA group) aged 22.0 ± 6.9 years (5 females) underwent FMD of the right brachial artery, PAT of the right finger, blood marker tests, ambulatory blood pressure monitoring, echocardiography, carotid ultrasonography, and brachio-ankle pulse wave velocity measurement. The median age at aortic arch reconstruction was 2.0 months (interquartile range: 15 days to 7.0 years). Results were compared with 17 age-matched healthy subjects (control group).Eight (44%) patients of the r-CoA group were hypertensive (5 received antihypertensive drugs). Patients in the r-CoA group showed significantly lower FMD (3.8 ± 1.5 versus 6.6 ± 2.5%, P < 0.001), larger intima-media thickness (0.63 ± 0.17 versus 0.47 ± 0.09 mm, P = 0.001), and higher left ventricular mass index (91.4 ± 24.6 versus 73.4 ± 17.3 g/m2, P = 0.017) than those in the control group. There were no significant differences in PAT (refractory hyperemia index, 1.86 ± 0.43 versus 1.99 ± 0.59, P = 0.48) and brachio-ankle pulse wave velocity between the two groups.Vascular dysfunction in r-CoA patients, particularly endothelial dysfunction, tends to occur more significantly in conduit arteries than in resistance arteries.

Single focus on breast magnetic resonance imaging: diagnosis based on kinetic pattern and patient age.

Background Because of its small size, a focus in breast magnetic resonance imaging (MRI) must be evaluated on the basis of characteristics other than morphologic features. Patient-related factors including patient age, in conjunction with lesion-related factors, could be useful for decision-making. Purpose To assess the probability of malignant foci based on both lesion- and patient-related factors, and to propose a relevant decision-making method. Material and Methods Foci in our breast MRI database dating from April 2006 to June 2013 were retrospectively identified and analyzed. A Fisher's exact test or a Mann-Whitney U test were performed for univariate analyses, and factors that showed a significant association with outcome in the univariate analyses were subjected to multivariate analysis using a logistic regression model. A decision tree was then drawn using the significant predictors confirmed by multivariate analysis. Results In total, 184 foci (168 benign, 16 malignant) in 184 patients were analyzed in our study. The presence of a washout pattern and older age were found to be significant predictors of malignancy ( P < 0.0001; odds ratio [OR], 17.8; P = 0.021; OR, 1.1, respectively). The main decisive node on the decision tree was the presence of a washout pattern, followed by whether the patient's age was >63 years. Conclusion An enhancing focus showing a washout pattern, especially in older patients, may warrant immediate biopsy rather than short-interval follow-up.

Diffusion-weighted imaging can correctly identify false-positive lymph nodes on positron emission tomography in non-small cell lung cancer.

PURPOSES: One of the limitations of fluorodeoxyglucose-positron emission tomography (PET) for N-staging in non-small cell lung cancer (NSCLC) is false-positive results due to lymphadenitis. This study was performed to examine whether DWI can correctly identify false-positive nodes on PET in NSCLC. METHODS: Both PET and DWI were performed in 157 patients before surgery, which involved dissection of 1033 nodal stations. Of the 157 patients, 26 patients had pathological N1 or N2 disease. Each nodal station was classified as positive or negative on PET and DWI according to the cutoff value determined by the receiver operating characteristic curve. Short-axis diameters of lymph nodes were measured on computed tomography. RESULTS: While hilar nodes did not show significant differences in the number of false-positives between PET and DWI, DWI showed fewer false-positives than PET in the mediastinum (p = 0.011). Of the 43 false-positive mediastinal nodes on PET, 35 (81 %) were negative on DWI. The mean size of the 43 false-positive nodes on PET was 9 ± 1 mm, which was significantly larger than mean size of 7 ± 3 mm of the 24 false-positive nodes on DWI (p = 0.002). CONCLUSIONS: DWI can correctly identify false-positive nodes on PET in the mediastinum. The larger size of false-positive nodes on PET could be due to enlargement by lymphadenitis.

Comparing diffusion-weighted imaging and positron emission tomography for pulmonary nodules measuring from 1 to 3 cm in size.

PURPOSES: To examine whether diffusion-weighted magnetic resonance imaging (DWI) is as useful as fluorodeoxyglucose positron emission tomography (FDG-PET) for discriminating between malignant and benign pulmonary nodules measuring less than 3 cm in size, as well as for predicting tumor aggressiveness. METHODS: PET and DWI were carried out on 87 pulmonary nodules measuring from 1 to 3 cm in size (66 NSCLCs and 21 benign nodules). The signal intensity (SI) of DWI was measured by the contrast ratio (CR) between the lesions and spinal cord, i.e., SI-CR. The maximum standard uptake value (SUV) of PET was measured by CR between the lesions and contralateral lung, i.e., SUV-CR. RESULTS: DWI and PET showed sensitivities of 0.86 and 0.71, and specificities of 0.90 and 0.81, respectively. While there was no significant difference in the specificity between the two, DWI showed a significantly higher sensitivity than PET (p = 0.013). While the difference in the sensitivity was significant in lung adenocarcinoma (p = 0.012), there was no difference in the other histological types. Both the SI-CR and SUV-CR were significantly higher in the tumors with either histological invasiveness or lymphatic metastasis than in those without. CONCLUSIONS: DWI is thus considered to be useful, not only to diagnose NSCLCs, especially in lung adenocarcinoma, but also for predicting tumor aggressiveness as well as FDG-PET.

A novel type of hemocytes localizing melanization with high-spreading behavior in Mythimna separata.

Lepidopteran larvae show a cellular response to invading foreign substances that are larger than hemocytes, for example, parasitoid eggs or larvae. This response is called hemocyte encapsulation and is often accompanied by phenoloxidase (PO)-catalyzed melanization. In the present study, we artificially transplanted endoparasitoid larvae and small glass fragments into the hemocoel of the common armyworm, Mythimna separata. We observed that the host larva showed a cellular response and that, 2-4 h after transplantation, melanin formation was spatially confined to the surface of the encapsulated substances. We further noted that specific morphological hemocytes surrounded by melanin formation became attached to the surface of the foreign substances. We designated these hemocytes hyperspread cells (HSCs) on the basis of their specific characteristics and circumferential spread. We confirmed the occurrence of prophenoloxidase (PPO)/phenoloxidase (PO) on the periphery of the HSCs and in the substance secreted around the HSCs by using anti-PPO antibody. We were unable to detect PPO-mRNA in HSCs by using in situ hybridization, although we showed that oenocytoids contained PPO-mRNA and PPO protein. We used light microscopy and scanning electron microscopy to discriminate five main types of circulating M. separata hemocytes. We observed that HSCs differed from plasmatocytes, but spread out well. Further, during the encapsulation process, HSCs appeared to provide a localized melanization spot on the surface of foreign invaders.

Modified procedures of subcutaneous implantable cardioverter defibrillator implantation for a child with small body size.

Modified procedures of subcutaneous implantable cardioverter defibrillator (S-ICD) implantation for a child with a small body size are presented. This report demonstrates the feasibility of novel diagonal S-ICD lead implantation method.

Radical Nitrososulfonation of Propargyl Alcohols: Thiazolidine-2,4-dione-Assisted Synthesis of 5-Alykyl-4-sulfonylisoxazoles.

In this study, we discover a good NO/HNO precursor, N-hydroxypyridinesulfonamide, and the regioselective radical nitrososulfonylation reaction of propargyl alcohols. Direct and unique isoxazole synthesis afforded a good-to-high yield of 5-alkyl-3-aryl-4-pyridinesulfonylisoxazoles. Copper-catalyzed aerobic oxidation could efficiently proceed in the presence of thiazolidine-2,4-dione. This work provides a powerful method for the synthesis and functionalization of alkyl-substituted isoxazoles and explores a new investigation route for drug-drug discovery.

Improving image quality using the pause function combination to PROPELLER sequence in brain MRI: a phantom study.

While some MRI systems offer a "pause" function, combining it with the PROPELLER method for image quality improvement remains underexplored. This study investigated whether repositioning the head after pausing during PROPELLER imaging enhances image quality. All brain phantom images in this study were obtained using a 3.0 T MRI and acquired using the fast spin-echo T2WI-based PROPELLER with motion correction. By combining the angle of rotational motion of the head phantom and the number of repositioning after a pause, two studies including seven trials were performed. Increasing the rotation angle decreased the image quality; however, pausing the image and repositioning the head phantom to the original angle improved the image quality. A similar result was obtained by repositioning the angle closer to its original angle. Experiments with multiple head movements showed that pausing the scan and repositioning the phantom with each movement improved image quality.

Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections.

Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients.