Severe abnormal behavior incidence after administration of neuraminidase inhibitors using the national database of medical claims.

An earlier study using the number of abnormal behaviors reported to the study group as the numerator and the number of influenza patient prescribed each neuraminidase inhibitor (NI) estimated by respective pharmaceutical companies found no significant difference among incidence rates of the most severe abnormal behaviors by type of NI throughout Japan. However, the dataset for the denominator used in that earlier study was the estimated number of prescriptions. In the present study, to compare the incidence rates of abnormal behavior more precisely among influenza patients administered several sorts of NI or administered no NI, we used data obtained from the National Database of Electronic Medical Claims (NDBEMC) as the denominator to reach a definitive conclusion. Results show that patients not administered any NI (hereinafter un-administered) or those administered peramivir sometimes showed higher risk of abnormal behavior than those administered oseltamivir, zanamivir, or laninamivir. However, the un-administered or peramivir patients were fewer than those taking other NI. Therefore, accumulation of data through continued research is expected to be necessary to reach a definitive conclusion about the relation between abnormal behavior and NI in influenza patients. Since severe abnormal behaviors with all types of NI or of un-administered patients have been reported, there are some risks in the administration of NI or even in un-administered cases. Therefore, we infer that the policy mandating package inserts in all types of NI.

Genetic variants related to gap junctions and hormone secretion influence conception rates in cows.

The recent decline in fertility is a serious problem in the dairy industry. To overcome this problem, we performed a genome-wide association study using 384 Holsteins and identified four loci associated with conception rates. Two of them contained gap junction-related genes: PKP2 and CTTNBP2NL. Further analysis confirmed that PKP2 increased connexin 43, a gap junction protein, whereas CTTNBP2NL dephosphorylated connexin 43. Knockdown of PKP2 or overexpression of CTTNBP2NL inhibited embryo implantation in mice. The other two loci contained neuroendocrine-related genes: SETD6 and CACNB2. Additional experiments indicated that SETD6 is involved in the transcriptional regulation of gonadotropin-releasing hormone, whereas CACNB2 controlled the secretion of follicle-stimulating hormone in cattle. The total allele substitution effect of these genes on conception rate was 3.5%. Our findings reveal important roles for gap junction communication and the neuroendocrine system in conception and suggest unique selection methods to improve reproductive performance in the livestock industry.

Proposition of real-time precise prediction model of infectious disease patients from Prescription Surveillance using the National Database of Electronic Medical Claims.

The incidence of common pediatric infectious diseases has been monitored officially at sentinel medical institutions in Japan. However, the numbers of affected patients are not provided. Prescription Surveillance (PS), which infers the number of patients with influenza, varicella, and gastrointestinal infections from data related to prescriptions at external pharmacies, provides estimates to the public the following morning. This study assessed the prediction ability of the incidence of common pediatric infectious diseases from PS information using the National Database of Electronic Medical Claims (NDBEMC): the number of patients prescribed neuraminidase inhibitors, anti-herpes virus drugs, antibiotic drugs, antipyretic analgesics, and multi-ingredient cold medications. The diseases include RS virus infection, pharyngoconjunctival fever, hand, foot and mouth disease, erythema infectiosum, exanthem subitum, pertussis, herpangina, influenza, varicella, and gastrointestinal infection. For comparison, we used the estimated number of patients who were prescribed neuraminidase inhibitor in PS, which had been confirmed already for precision, and provided estimates to the general public via the internet. The discrepancy rates of all considered diseases between the reported number in NDBEMC and the predicted numbers of patients from PS were less than the value in NI counts and the coefficients of determination in the estimation were from .8109 to .9825. These predictions were sufficiently precise to provide to the general public.

Prolonging hypothermic storage (4 C) of bovine embryos with fish antifreeze protein.

Embryos obtained via superovulation are necessary for mammalian artificial reproduction, and viability is a key determinant of success. Nonfreezing storage at 4 C is possible, but currently used storage solutions can maintain embryo viability for only 24-48 h. Here we found that 10 mg/ml antifreeze protein (AFP) dissolved in culture medium 199 with 20% (v/v) fetal bovine serum and 25 mM HEPES could keep bovine embryos alive for 10 days at 4 C. We used a recombinant AFP isolated from the notched-fin eelpout (Zoarces elongatus Kner). Photomicroscopy indicated that the AFP-embryo interaction was enhanced at 37 C. Embryos pre-warmed with the AFP solution at 37 C for 60 min maintained high viability, whereas those that were not pre-warmed could live no longer than 7 days. Thus, short-term storage of bovine embryos was achieved by a combination of AFP-containing medium and controlled pre-warming.

[Association between Diarrheal Infectious Diseases and Antidiarrheal Drugs Assessed with Prescription Surveillance].

OBJECT: It appears to be possible to measure the outbreak of infectious diseases with accompanying diarrhea by early detection of an outbreak. However, because some diseases are reported weekly from sentinel medical institutions, early detection of outbreaks might be inadequate. In this study, we examined the number of patients with diarrhea assessed with prescription surveillance and validated its association with the number of patients who have infectious diseases with diarrhea. METHODS: The number of patients who were prescribed an antidiarrheal drug or intestinal drug was estimated for each prefecture using the prescription surveillance system from April 1, 2011 through March 31, 2014. Moreover, we examined the association between the prevalence of diarrhea in prescription surveillance and the number of patients with diarrheal infectious diseases. RESULTS: Results showed a positive correlation between the prevalence of diarrhea in prescription surveillance and the number of reported cases per sentinel with gastrointestinal infections. However, no positive correlation was found with the others infectious diseases. CONCLUSION: Estimation of the number of patients with diarrhea in prescription surveillance might facilitate early detection of an outbreak of gastrointestinal infections.

[Evaluation of the Number of Varicella Patients Estimated by Prescription Surveillance].

OBJECT: It is important to know the precise number of varicella patients infected for evaluation of routine immunization and anti-bioterrorism attack using smallpox. Prescription Surveillance (PS) has been providing the estimated number of varicella patients up to the present. However, the estimated number of varicella patients cannot be validated because to date there has been no other comparable precise method of estimation. Recently, all electronic medical claims nationwide (NDB) have been disclosed. In this paper, we compare the number of varicella patients estimated by PS with NDB data, and adjust the number estimated with PS, if necessary. METHOD: For both NDB and PS, we used the monthly data from April, 2010 to March, 2013. The estimation of the number of varicella patients from the PS data was adjusted by the proportion of estimated number based on PS to the one based on NDB in the entire study period. Moreover, we adjusted it month by month, if the former method may not be enough to compensate for the discrepancy between the two datasets. RESULTS: The average discrepancy between NDB and PS was 48.00% in three years. By the adjustment using NDB in the three years, the discrepancy was improved to 11.49%. However, seasonal patterns of overestimation or underestimation were found. Conversely, by the adjustment using NDB month by month, the discrepancy was greatly reduced to 4.33%. Moreover, the seasonal patterns of overestimation or underestimation disappeared. CONCLUSION: The number of patients based on NDB would appear the most precise number, however, there may be a delay of about one year before it becomes available. On the other hand, PS data are updated every day and provide us with the up-to-date situation. This paper found that combining the timeliness of the PS data and preciseness of the NDB data will provide substantial benefit for public health.

Abnormal behavior during influenza in Japan during the last seven seasons: 2006-2007 to 2012-2013.

A few mortalities and cases of severe abnormal behavior have been reported after oseltamivir administration for influenza, thus increasing medical and public concerns regarding the drug's safety. We investigated the association between oseltamivir and abnormal behavior for seven years. All outpatient clinics and hospitals all over the country were requested to report severe abnormal behavior that could have resulted in a fatality if nobody intervened, such as abrupt running outside the home or intention of jumping off a building. The survey was performed prospectively between the 2007-2008 and 2012-2013 seasons, and retrospectively for the 2006-2007 season. As the result of the investigation, eight-hundred fifty-eight cases were reported and among of them 95.7% were positive by the influenza rapid diagnosis test. The epidemic curve of severe abnormal behavior showed a pattern similar to influenza-like illness. The same pattern was observed regardless of age group, gender, or timing of the incidents after waking. Consequently, specific association between the types of medications used or the types of antiviral and abnormal behavior was not observed clearly. The reported abnormal behaviors include fatal cases that would have died if nobody had stopped. This suggested that patients with influenza should be observed with caution for possible abnormal behavior whether taking oseltamivir or other neuraminidase inhibitor anti-influenza drugs.

Quality assessment methods for 3D protein structure models based on a residue-residue distance matrix prediction.

In the absence of experimentally determined three dimensional (3D) structures of proteins, the prediction of protein structures using computational methods is a standard alternative approach in bioinformatics. When using the predicted protein models to compute the native structure of an unknown target protein, estimating the actual quality of the protein models is important for selecting the best or near-best model. Moreover, estimates of the differences between the protein models and the native protein structure are obviously useful to end users who can then decide on the utility of the models for their specific problems. This article describes two new single-model quality assessment (QA) programs, pure single-model QA method (psQA) and a template based QA method (tbQA), that we developed. psQA is a pure single-model QA program that uses a neural network method to predict residue-residue distance matrices of the native protein structures. tbQA is a quasi-single-model QA program that mainly uses target-template sequence alignments and template structures. The performance of these two model QA programs was analyzed in a data set of 24022 models for 94 targets from the 10th critical assessment of protein structure prediction (CASP10) experiment.

United3D: a protein model quality assessment program that uses two consensus based methods.

In protein structure prediction, such as template-based modeling and free modeling (ab initio modeling), the step that assesses the quality of protein models is very important. We have developed a model quality assessment (QA) program United3D that uses an optimized clustering method and a simple Cα atom contact-based potential. United3D automatically estimates the quality scores (Qscore) of predicted protein models that are highly correlated with the actual quality (GDT_TS). The performance of United3D was tested in the ninth Critical Assessment of protein Structure Prediction (CASP9) experiment. In CASP9, United3D showed the lowest average loss of GDT_TS (5.3) among the QA methods participated in CASP9. This result indicates that the performance of United3D to identify the high quality models from the models predicted by CASP9 servers on 116 targets was best among the QA methods that were tested in CASP9. United3D also produced high average Pearson correlation coefficients (0.93) and acceptable Kendall rank correlation coefficients (0.68) between the Qscore and GDT_TS. This performance was competitive with the other top ranked QA methods that were tested in CASP9. These results indicate that United3D is a useful tool for selecting high quality models from many candidate model structures provided by various modeling methods. United3D will improve the accuracy of protein structure prediction.

Intrauterine administration of peripheral blood mononuclear cells enhances early development of the pre-implantation bovine embryo.

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) prior to bovine embryo transfer (ET) was previously shown to improve the pregnancy rate. To better understand how PBMCs improve the pregnancy rate, we examined gene expression in the cells from uterine lumen and evaluated the morphology of bovine pre-attachment embryos in utero following intrauterine administration of PBMCs. On day 3 of the estrous cycle (day 0 = estrous), bovine PBMCs were isolated and suspended in RPMI 1640, and were incubated for 24 hr. The cultured PBMCs were administered non-surgically to the uterine horn ipsilateral to the corpus luteum on day 4 of the estrous cycle (PBMC group). On day 9, endometrial-luminal lymphoid cells from uterine lumen ipsilateral to the corpus luteum were collected by uterine flushing. Transcripts for macrophage-colony stimulating factor in the lymphoid cells were more abundant in the PBMC group than in the control group (P < 0.05). On day 7 (of the separate experiments), five blastocysts were each transferred to the luminal area, to which PBMCs had been administered on day 4. These embryos were allowed to develop in utero until day 15 of gestation, when embryos were non-surgically retrieved from the uterus. The average length of trophoblasts recovered from the PBMC group was significantly longer than that of the control group (51.6 ± 7.8 vs. 27.4 ± 6.0 mm, P < 0.05). Our results strongly suggest that intrauterine administration of PBMCs improves endometrial environment, which promotes early development of pre-attachment conceptuses.

Irinotecan hydrochloride (CPT-11) in dialysis patients with gastrointestinal cancer.

We investigated changes in drug disposition and toxicities with CPT-11 in 15 dialysis patients with gastrointestinal cancers to clarify whether CPT-11 could be administered safely in such patients. For comparison, the same parameters were also investigated in 10 cancer patients not undergoing dialysis. Items investigated included (1) plasma concentrations of SN-38, SN-38G and CPT-11 at 0, 1, 12, 24, 36, 48 and 72 h after administration, together with a comparison of mean AUC values for 3 dose levels of CPT-11 (50, 60 and 70 mg/m2) in dialysis patients and controls; and (2) occurrence of adverse events. Several findings emerged from this study: (1) No significant difference was observed in the AUC for SN-38 or CPT-11 between the dialysis and control groups; (2) The AUC for SN-38G at each dose was significantly higher in dialysis patients; and (3) Grade 1-4 leucopenia was observed in 11 of the dialysis patients. One patient developed grade 4 leucopenia and died due to sepsis. Anorexia, diarrhea, nausea, alopecia and interstitial pneumonia occurred in 6 dialysis patients. We found changes in drug dispositions of CPT-11, SN-38 and SN-38G in dialysis patients, suggesting that hepatic excretion, especially that of SN-38G, was increased. No significant difference in occurrence of adverse events was observed between the 2 groups. This indicates that CPT-11 can be administered safely in patients on dialysis.

Clinical analysis of false-negative fine needle aspiration cytology of head and neck cancers.

BACKGROUND: Fine-needle aspiration (FNA) cytology is frequently used for initial and/or preoperative diagnosis of tumors in the head and neck region. However, false-negative results can lead to misdiagnosis. The aim of this study was to investigate the diagnostic results of FNA in the head and neck region and the reasons for false-negative cases. METHODS: The study population comprised 1,341 patients with pathologically confirmed head and neck tumors in whom FNA was performed before surgery or biopsy in the Otolaryngology Department at Numazu City Hospital between 2002 and 2016. We evaluated the false-negative FNA cytology rate as well as the site of the primary nodule, patient age and sex, sensitivity, accuracy, specificity, positive predictive value, negative predictive value, and the pathologic diagnosis after resection. RESULTS: The rate of false-negative FNA results was 5.9% (78/1,315 cases). The main sites of false-negative cases were the thyroid gland (n = 50), the lymph nodes (n = 16), and the salivary glands (n = 9). The sensitivity of FNA for head and neck tumors was 82.0%, with specificity and accuracy rates of 94% and 92.0%, respectively. CONCLUSIONS: We have assessed the quality of preoperative FNA cytology in head and neck tumors. To avoid misdiagnosis by FNA, it is important that the target tumor is punctured accurately. If the specimen obtained is too small, FNA should be repeated.

Tumor lysis syndrome following cabazitaxel administration for metastatic castration-resistant prostate cancer: A case report.

INTRODUCTION: Tumor lysis syndrome is a rare and potentially fatal complication of oncological treatment. It is characterized by biochemical changes associated with the rapid lysis of malignant cells, usually after chemotherapy. Tumor lysis syndrome is typically noted in patients with hematological malignancies, and it rarely occurs in patients with solid tumors. CASE PRESENTATION: We report a case of tumor lysis syndrome after cabazitaxel administration for metastatic castration-resistant prostate cancer. To our knowledge, tumor lysis syndrome after cabazitaxel therapy has not been reported previously. The patient was a 77-year-old man who developed clinical tumor lysis syndrome after a single dose of cabazitaxel for metastatic castration-resistant prostate cancer. He was treated with hydration and the recombinant uricolytic agent rasburicase, and his condition improved. CONCLUSION: It is extremely important to assess the risk factors for tumor lysis syndrome and to perform active prevention procedures in order to avoid fatal outcomes. It may be beneficial to use rasburicase in patients with established tumor lysis syndrome.

Welfare analysis of a zero-smoking policy - A case study in Japan.

Smoking cessation efforts in Japan reduce smoking rates. A future zero-smoking policy would completely prohibit smoking (0% rate). We therefore analyzed the social welfare of smokers and non-smokers under a hypothetical zero-smoking policy. The demand curve for smoking from 1990 to 2014 was estimated by defining quantity as the number of cigarettes smoked and price as total tobacco sales/total cigarettes smoked by the two-stage least squares method using the tax on tobacco as the instrumental variable. In the estimation equation (calculated using the ordinary least squares method), the price of tobacco was the dependent variable and tobacco quantity the explanatory variable. The estimated constant was 31.90, the estimated coefficient of quantity was - 0.0061 (both, p < 0.0004), and the determinant coefficient was 0.9187. Thus, the 2015 consumer surplus was 1.08 trillion yen (US$ 9.82 billion) (95% confidence interval (CI), 889 billion yen (US$ 8.08 billion) - 1.27 trillion yen (US$ 11.6 billion)). Because tax revenue from tobacco in 2011 was 2.38 trillion yen (US$ 21.6 billion), the estimated deadweight loss if smoking were prohibited in 2014 was 3.31 trillion yen (US$ 30.2 billion) (95% CI, 3.13 trillion yen (US$ 28.5 billion) - 3.50 trillion yen (US$ 31.8 billion)), representing a deadweight loss about 0.6 trillion yen (US$ 5.45 billion) below the 2014 disease burden (4.10-4.12 trillion yen (US$ 37.3-37.5 billion)). We conclude that a zero-smoking policy would improve social welfare in Japan.

Evaluation of estimated number of influenza patients from national sentinel surveillance using the national database of electronic medical claims.

Officially, the national official sentinel surveillance of infectious diseases (NOSSID) has been used to estimate the number of influenza patients nationwide; NOSSID is based on the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law). Prescription Surveillance (PS) has also provided a numerical estimate of influenza patients. This study compared these 2 estimations using NOSSID and PS with the numbers of influenza patients from all electronic medical claims (NDBEMC), which had the nearly-comprehensive data from surveys. Results showed that the estimate from NOSSID was about twice the estimate from the NDBEMC. However, the estimated number from the PS was almost equivalent to that from the NDBEMC. The estimated number of patients from NOSSID might not be precise, but NOSSID itself may be useful to monitor influenza trends.

Life-Threatening Abnormal Behavior Incidence in 10-19 Year Old Patients Administered Neuraminidase Inhibitors.

Much discussion has surrounded the association between the administration of neuraminidase inhibitors (NI) and severe abnormal behaviors, including sudden running away and jumping from a high place, which can be life-threatening if no one intervenes. Using data on the number of abnormal behaviors and patients who had been prescribed NI in Japan, we calculated the incidence rate of severe abnormal behaviors among influenza patients who had been prescribed NI. Then, we evaluated the relative risk between the four types of NI on severe abnormal behavior. We found no significant difference in the incidence rates of abnormal behavior by the type of NI. Results implicate that the current policy of package inserts, which warn physicians that patients who were administered ANY type of NI might exhibit abnormal behavior, seems to be appropriate.

Enhanced Surveillance for the Sports Festival in Tokyo 2013: Preparation for the Tokyo 2020 Olympic and Paralympic Games.

Enhanced surveillance was conducted during the Sports Festival in Tokyo 2013 (September 28-October 14, 2013) for early detection of outbreaks of infectious diseases and other health emergencies. Through this enhanced surveillance, 15 cases were found that required additional gathering of information outside the routine process of creating/evaluating the Daily Report. However, none of these was assessed as critical. Through the enhanced surveillance, we structured a framework that allows for earlier response when detecting aberrations. It includes the role of the Tokyo Metropolitan Government in communications and contacts with relevant parties such as public health centers, as well as in monitoring of surveillance data. However, some issues need to be further considered toward the Tokyo 2020 Olympic and Paralympic Games, such as establishing the criteria for additional response steps, increasing the number of participating bodies in syndromic surveillance, and strengthening of cooperation with related departments, including those for crisis management assuming potential biological/chemical terrorism.

Examination of prognostic factors in patients undergoing surgery for colorectal perforation: a case controlled study.

OBJECTIVE: To determine if the POSSUM, SOFA, MPI, and SAS scores provide a better measure of severity for patients with prognostic factors undergoing surgery for colorectal perforation. SUBJECTS: Fifty-nine patients who underwent surgery between 1996 and 2012. METHODS: We retrospectively reviewed background factors, blood and physiological test results, and intraoperative findings of patients who survived and those who died. We also compared the POSSUM, SOFA, MPI, and SAS scores. Multivariate analysis was performed for factors that were significant by univariate analysis, and selected factors were used to produce a predictive prognostic model. RESULTS: Univariate analysis revealed significant differences in age, anticoagulant/steroid administration, serum creatinine level, PF ratio, base excess (BE), chest radiography, pulse rate, and severity of peritoneal soiling. Age, serum creatinine level, pulse rate, and severity of peritoneal soiling were selected for multivariate analysis; only pulse rate was significantly different. There were significant differences between the two groups in POSSUM PS, OSS, SOFA, and MPI scores, and a comparison in terms of the ROC curve showed that our model had the highest peak; the area under the curve was 94.8% compared with 70-80% for the other systems, suggesting that our model is better than those systems. CONCLUSIONS: POSSUM and SOFA are valid methods of evaluating risk from colorectal perforation, but our study revealed addition risk factors: (1) the PF ratio and BE, which are not included in POSSUM; (2) the pulse rate and severity of peritonitis, which are not included in SOFA; and (3) anticoagulant/steroid hormone administration.

Fluorescent-based methods for gene knockdown and functional cardiac imaging in zebrafish.

A notable advantage of zebrafish as a model organism is the ease of gene knockdown using morpholino antisense oligonucleotide (MO). However, zebrafish morphants injected with MO for a target protein often show heterogeneous phenotypes, despite controlling the injection volume of the MO solution in all embryos. We developed a method for estimating the quantity of MO injected into each living morphant, based on the co-injection of a control MO labeled with the fluorophore lissamine. By applying this method for knockdown of cardiac troponin T (tnnt2a) in zebrafish, we could efficiently select the partial tnnt2a-depleted zebrafish with a decreased heart rate and impairment of cardiac contraction. To investigate cardiac impairment of the tnnt2a morphant, we performed fluorescent cardiac imaging using Bodipy-ceramide. Cardiac image analysis showed moderate reduction of tnnt2a impaired diastolic distensibility and decreased contraction and relaxation velocities. To the best of our knowledge, this is the first report to analyze the role of tnnt2a in cardiac function in tnnt2a-depleted living animals. Our combinatorial approach can be applied for analyzing the molecular function of any protein associated with human cardiac diseases.