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The aim of the article is to solve the scientific problem of outlining the issue of protection of patent law objects created using artificial intelligence technologies, and to establish whether it is possible to recognize artificial intelligence technologies as inventor at the present stage of development of legal systems. Philosophical, comparative-legal and system-structural methods were used in the research process. Based on the analysis of the European Patent Convention, the main generally accepted conditions of patentability of the invention are determined: novelty, inventive step, industrial applicability. It has been established that inventions created by artificial intelligence technologies will meet such criteria provided that certain requirements are met. In the context of the study, the case of the invention of artificial intelligence «DABUS» is analyzed and the results of its consideration in the European Patent Organization, the United Kingdom and the United States are summarized. In particular, it has been established that artificial intelligence technologies are currently not considered as inventors in either the Romano-Germanic or Anglo-Saxon legal systems.

Nowadays dental caries and periodontal diseases are among the most pressing problems in Paediatric Dentistry. Young patients with psychoneurological disorders are a special category among children with somatic pathology. At the same time, the issue of providing dental care to such children is underrepresented. Today, traditional schemes used for the prevention and treatment of caries and periodontal disease in children with mental retardation requires further improvement taking into account the clinical status of children with particular forms of mental retardation, including oligophrenia. Thus, the aim of our study was to develop and evaluate the effectiveness of a complex of measures to prevent dental caries in children with oligophrenia. To assess the effectiveness of the elaborated preventive complex, 56 children aged 12 years with the diagnosis of oligophrenia of I degree of severity (mild mental backwardness) were under observation during 2 years; 27 children received the complex we developed. The group of comparison included 29 children; caries prevention measures for these children were based on regional protocols (hygienic education, keeping oral hygiene, use of fluoride toothpastes). The effectiveness of the developed preventive complex was evaluated 6, 12 and 24 months after the beginning of its implementation according to the following criteria: the growth of dental caries intensity; reduction in the growth of dental caries intensity; level of oral hygiene (OHI-S index); changes in the biocenosis of the oral cavity (in 1 and 6 months of the observation). The results of the examination after the 6 month observation period have shown the dental caries intensity in children of the main group is 6.65 ± 0.45 teeth that is 1.02 times lower than in the children of the comparison group (6.79 ± 0.26 teeth, p ˃0.05). Thus, the growth of dental caries intensity in the children of the main group is, on average, 0.41 ± 0.05 tooth, which is significantly lower than in children of the comparison group (0.58 ± 0.06 tooth, p

Summary. The aim of the study. To improve the results of patients with tumors and non-neoplastic diseases of the colon treatment, to introduce into clinical practice the original surgical technique and methods of creating of colon anastomoses, which were tested in experiment. Materials and methods. Original methods of invaginational ileo-transverse and colon anastomoses creating were developed in the experiment on rabbits. Taking into account the obtained positive results, the methods of anastomoses formation were transferred to the surgical clinic and patents of Ukraine were obtained. In 2020, ileo-transverse and colonic anastomoses were formed in 134 patients on the basis of Transcarpathian Antitumor Center: one-row invaginational anastomosis according to the developed method in 22 patients (16.4 %), two-row manual — in 58 (43.3 %), circular stapler — in 36 (26.9 %), linear stapler anastomosis — in 4 (3 %), laparoscopic (linear stapler) — in 14 (10.4 %). Results and discussion. The most of complications occurred in the group with manual two-row anastomosis (16), in two cases the anastomotic leakage was recorded. When using a circular stapler suture, anastomotic leakage was observed in 1 patient, and anastomositis — in 4. When using linear stapler anastomoses, postoperative wound suppuration was observed in 1 patient. Conclusions. The most of early postoperative complications was observed after using a two-row manual colonic anastomosis (27.5 %). When using a circular stapler suture, the number of early postoperative complications was less than with a two-row manual anastomosis (22.2 % vs. 27.5 %, respectively). The least number of complications was recorded after the creation of a one-row invaginational anastomosis in the proposed original technique.

Objective. To establish the impact of intraintestinal pressure on the intestinal anastomosis integrity and to propose a prophylactic measures of its insufficiency in surgical treatment of the colon diseases. Materials and methods. Intraintestinal pressure was measured in 30 patients, using Waldman method during 72 h postoperatively - before and after the transanal lavage (every 4 h). Primary operation - resection of sigmoid colon with formation of a one-barrel colostomy. The restoration intervention was performed in 3 mo with formation of a large-bowel anastomosis in accordance to the method elaborated (n=17), hand-made two-layered large-bowel anastomosis (n=3), and the apparatus large-bowel anastomosis (n=10). Results. There was noted the intraintestinal pressure raising during first 24 - 36 h up to (5.3 ± 0.1) mm Hg with its further lowering during 12 - 20 h down to (2.1 ± 0.3) mm Hg. In 20 min after the transanal drain lavage the intraintestinal pressure have lowered by (3.0 ± 1.3) mm Hg, and in 3 - 5 h - gradually raised. While application of a hand-made two-layered large-bowel anastomosis its insufficiency was observed (n=1) and anastomositis (n=1); and in the apparatus large-bowel anastomosis formation - anastomositis (n=1). While disorder of the intestinal suture healing the intraintestinal pressure have raised in 16 - 60 h up to (11.4 ± 0.2) mm Hg with peak at (16.3 - 17.1) mm Hg, which persisted 12 -18 h. Prophylactic measures were directed towards lowering of intraintestinal pressure and elimination of unfavorable local and general factors. Conclusion. While persisting noncorrected, the intraintestinal pressure in the 16.3 - 17.1 mm Hg borders during 12 - 18 h leads to complicated course of postoperative period. Direct and nondirect methods of decompression of the interintestinal anastomoses constitutes a basic prophylactic principle for it.

The aim of the article is to describe the principles of cloud technology and the scope of its use at a lesson of the Russian language in a polylingual class. Following the analysis of scientific and methodological literature on digital education, new technologies are suggested which have been introduced in a new type of handbook – a course navigator. The authors present a model to construct a course «Theatrical readings» for primary and secondary schoolchildren. The methodical constructor is oriented not only on reading as a kind of speech activity but also on material visualization and audio perception. The system of tasks reflects the specific nature of teaching Russian by means of fiction texts, teaching reading strategies and fiction understanding with the application of differential, problem search methods of teaching. When constructing the educational navigator the resources of the Google Network were used, which is a useful instrument for a teacher of Russian. This service allows for a favorable combination of various forms of tasks which form a motivation for cognitive activity. The article concludes that cloud technology as an element of digital learning in the modern educational process should emerge as a set of teaching tools to create methodical products contributing to the effective study of Russian linguistic culture.

In recent years, digital communications have rapidly entered the lives of modern people. Globalization of digital technologies is solved in Russia at the state level – Federal programs of digitalization are created and implemented. They are aimed at the inclusion a person in the virtual space since the very childhood which undoubtedly affects many aspects of the human life. Thus, children developing in the context of the global spread of digital technologies have been called “generation Z”. Of course, this category of children could not go unnoticed by many domestic and foreign scientists. In this article, the authors provide an overview of studies devoted to the study of the “digital generation”.

Prevention of hard dental tissue diseases and periodontal diseases in children is one of the urgent issues of pediatric dentistry. This is especially true for the category of children with psychoneurological pathology. Due to the high prevalence of dental diseases, decreased immunity, and sometimes difficult assess to dental care for children with mental retardation, dental disease prevention is the most effective measure to maintain the normal functioning of the dentofacial apparatus. The results obtained by examining the children with oligophrenia allowed us to work up an algorithm for therapeutic and preventive measures aimed at preventing the development of oral tissue diseases in these children. The algorithm included measures for primary and secondary prevention of periodontal diseases. To assess the efficacy of the algorithm, the study involved a group of 55 mentally impaired children. The control group consisted of 50 children with oligophrenia, who were treated by traditional methods. Taking into account the burdened mental status of the children when developing the individual hygiene regimens, a motivational approach was worked out in co-operation with a psychiatrist and a paediatrician. Evaluation of treatment outcomes in the groups was performed in 1 month after the completion of the full course of treatment and prevention and in long-term intervals, in 6 and 12 months. Clinical evaluation of treatment efficacy was performed according to the following criteria: "normalization", "improvement", "progression". In one month following the regimen proposed, the "normalization" of the affected tissues was diagnosed in 40 children of the main group (72,73 ± 6,06%), p

Background Primary spontaneous pneumothorax is a common disorder occurring in young adults without underlying lung disease. Although tobacco smoking is a well-documented risk factor for spontaneous pneumothorax, an association between electronic cigarette use (that is, vaping) and spontaneous pneumothorax has not been noted. We report a case of spontaneous pneumothoraces correlated with vaping. Case presentation An 18-year-old Caucasian man presented twice with recurrent right-sided spontaneous pneumothoraces within 2 weeks. He reported a history of vaping just prior to both episodes. Diagnostic testing was notable for a right-sided spontaneous pneumothorax on chest X-ray and computed tomography scan. His symptoms improved following insertion of a chest tube and drainage of air on each occasion. In the 2-week follow-up visit for the recurrent episode, he was asymptomatic and reported that he was no longer using electronic cigarettes. Conclusions Providers and patients should be aware of the potential risk of spontaneous pneumothorax associated with electronic cigarettes.

The American Academy of Pediatrics published expanded guidelines for infant safe sleep in 2011, expanding the definition from “back to sleep” to “safe to sleep,” more fully describing risk factors and guidelines. In 2016, the guidelines were revised to promote “providers modeling safe sleep behavior” to the highest level of recommendation. Previous studies have addressed the difficulty in creating clear, consistent communication between health care providers and families during an infant’s inpatient stay. This institutional update describes an interprofessional and family-centered quality improvement project to improve sleep safety for hospitalized infants through a multimodal approach. Five family-centered interventions were designed: a designated safe sleep web page, a clear bedside guide to safe sleep, additional training for nursing staff in motivational interviewing, a Kamishibai card audit system, and electronic health record smart phrases. These coordinated interventions reflect advantages of an interprofessional and family-centered approach: building rapport and achieving improvements to infant sleep safety.

Background: Well characterized patient derived xenograft models (PDX) are becoming the preferred pre-clinical tool in translational cancer research for biologic understanding of the disease, development of new treatments, and identifying potential therapy predictive and resistant biomarkers. Characterization of PDX models using a multi-omic approach is most desirable, however such efforts can be expensive and technically demanding. Immunohistochemistry (IHC) has become an indispensable ancillary tool in the accurate classification of tumor types, determination of cell of origin, identification of biologic properties like growth and metastatic potential, and evaluation for the presence/absence of therapeutic or prognostic biomarkers. Methods: 43 IHC assays were validated on the Leica Bond RX automated staining platform to identify common inconsistencies in PDX development including markers for classifying carcinomas, lymphomas, sarcomas, murine tumors, and theragnostic biomarkers. Rabbit antibodies are used rather than mouse antibodies to prevent non-specific staining of murine tissue. Results: 1. IHC evaluation of models within NCI's Patient Derived Models Repository (pdmr.cancer.gov) led to re-classification or sub-classification of 12 tumor models in accordance with WHO guidelines. 2. IHC evaluation of theragnostic markers in 8 breast cancer PDX models showed concordant results throughout passaging, suggesting stability of these biomarkers in our models. 3. We observe malignant transformation of murine or transplanted benign human tissue at a rate of 2.5%. On IHC analysis, 52% were human lymphomas, 20% were murine lymphomas, and 28% were other murine tumors. Conclusions: IHC is a rapid, cost-effective tool that can be used for accurate tumor classification, identifying subclonal outgrowth and tumor evolution, assessing stability of biomarkers and identifying malignant transformation of benign tissue. Funded by NCI Contract No. HHSN261200800001E ANTIBODYCLONEVENDORANTIBODYCLONEVENDORAndrogen Receptor[EPR1535(2)]abcamGATA3[EPR16651]abcamB-Catenin[E247]abcamGCDFP-15[EPR1582Y]abcamCD19polyclonalabcamGFAPpolyclonalDAKO/AgilentCD3polyclonalabcamHER2 ErbB2[SP3]abcamCD20[SP32]abcamKi-67[D2H10]Cell SignalingCD34[EP373Y]abcamKu80[EPR3468]abcamCD45polyclonalabcamMGMTMT3.1MilliporeCD56 (NCAM1)[EPR2566]abcamMitochondria Marker (Biotin)MTC02abcamCD68[EPR20545]abcamMyogenin[EPR4789]abcamCDX2[EPR2764Y]abcamNAPSIN A[EPR6252]abcamChromogranin A[SP12]abcamp63polyclonalGeneTexCK7 (purified)[EPR1619Y]abcamPD-1[EPR4877(2)]abcamCK19[EPR1580Y]abcamPD-L1 (CD274)RBT-PDL1LifeSpan BiosciencesCK20[EPR1622Y]abcamProgesterone Receptor[SP2]abcamCytokeratin wide spectrumpolyclonalabcamProstate Specific Antigen (PSA)[EP1588Y]abcamDesmin[Y66]abcamS100[EPR19013]abcamEBV LMP1[D24-G]abcamSmooth Muscle Actin (SMA)polyclonalabcamERG[EPR3864]abcamSynaptophysin[SP11]abcamEstrogen Receptor[SP1]abcamTTF1[SP141]abcamFOXP1monoclonalLifeSpan BiosciencesVimentin[EPR3776]abcamFOXP3(5H10L18)Invitrogen Citation Format: Lindsay Dutko, Gloryvee Rivera, Erin Cantu, Vishnuprabha Rahulkannan, Kelly Benauer, Tiffanie Chase, Emily Delaney, Jesse Stottlemyer, Chelsea McGlynn, Howard Stotler, John Carter, Suzanne Borgel, Michelle M. Gottholm Ahalt, Michelle Eugeni, Melinda Hollingshead, Yvonne Evrard, Chris Karlovich, Biswajit Das, Mickey Williams, James H. Doroshow, Shahanawaz Jiwani. Applications of immunohistochemistry in characterization of patient derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3015.

Background: A major set of preclinical models derived from specimens acquired from rapid autopsy patients in the National Cancer Institute Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov) were from pancreatic adenocarcinoma (PAAD) patients, with metastatic specimens originating from liver, colon, omentum, and lung. Genomic characterization of these preclinical models provides a unique opportunity to study tumor heterogeneity and subclonality associated with the metastatic process and potential treatment resistance. Methods: To date, 30 rapid autopsy patient-derived xenograft (PDX)/patient-derived cell (PDC)/patient-derived organoid (PDOrg ) models derived from pancreatic adenocarcinoma patients (n = 9) have been sequenced using whole-exome sequencing (WES) and RNASeq. Tumor heterogeneity between primary and metastatic sites was studied based on somatic mutation, copy number alteration (CNA) and gene expression data. A bioinformatics workflow was developed to stably infer and visualize the tumor subclonality by integrating the tools of PyClone, SCHISM, and TIMESCAPE, using somatic mutations and site-specific copy number data of multiple samples generated from PDX models in primary and metastatic sites. Results: Among 30 rapid autopsy preclinical models from primary and metastatic sites, liver is the most common metastatic site in PAAD (9/19=47%) compared to other sites. Driver mutations are conserved in all preclinical model specimens derived from a given patient. KRAS p.G12D is present in 28 PDX/PDC/PDOrg models as well as the corresponding patient specimens, and BRAF p.V600E is present in other preclinical models. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n=18, mean=7.63%, sd=5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n=16, mean=19.47%, sd=9.69%). This indicates the presence of tumor heterogeneity between metastatic and primary sites. Site-specific subclones were identified in PDX models from two patients (521955 and 485368) and a phylogenetic tree of primary and metastasis sites indicates that one liver metastasis had a unique seeding event compared to the other metastatic sites for both patients. Conclusion: Tumor heterogeneity and subclonality was observed in preclinical models generated from PAAD patients in the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance. Citation Format: Li Chen, Biswajit Das, Yvonne A. Evrard, Chris A. Karlovich, Tomas Vilimas, Amanda Peach, Chapman Alyssa, Nikitha Nair, Anna L. Fong, Luis Romero, Ting-Chia Chang, Shahanawaz Jiwani, Lindsay Dutko, Kelly Benauer, Marianne Morton, Kelly Dougherty, Michelle A. Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow. Study of tumor heterogeneity and subclonality in primary pancreatic and metastatic sites from rapid autopsy patients in PDMR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3139.

Background There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Methods Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1–6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [

The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with 39 PDX models of rare cancers (mesothelioma, MPNST, osteosarcoma, Merkel cell carcinoma, etc) treated with 56 novel therapeutic combinations in an exploratory, n-of-4 arm, study design. Combinations that show promising responses (e.g., regression or durable inhibition of tumor growth) will be repeated along with the single agent arms to determine if the response is driven by the combination or only one of the agents. In order to do this in a timely fashion, relatively speaking, the PDX tumors are serially passaged and each passage is treated with a set of 8 combinations plus relevant vehicle control(s) while in parallel enough PDXs are retained to be expanded for the next passage and drug set. Every serial passage undergoes several quality control assessments that serve as go/no-go criteria including pathology assessment, human:mouse DNA content assessment, and low pass whole genome sequencing to determine the average fraction of genome changed compared to the original donor material. If there is a QC failure, the PDX model is restarted from early passage cryo-material (passage 1-2). An additional quality control effort is to bookend the combination studies with the first set of agents to see if tumor response is similar across passages. To date, most of the models have demonstrated a high degree of stability, though a couple of models have moved toward murine content and have been restarted from early passage material so all drug combinations can be tested. DNA and RNA are retained from all passages so a full NGS evaluation can be performed at a later date. This effort has been ongoing for over a year and the first bookend studies are beginning to be tested to determine if response at first and last passage of the study are consistent with each other, given the constraints of the inherent heterogeneity of the models themselves. Single agent studies of drug combinations that demonstrated a response in 30%-50% of the models tested are also underway to determine which combinations have a more than additive effect compared to the single agents. Promising combinations will be moved forward to early phase clinical trials for these rare cancers. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Biswajit Das, Sergio Y. Alcoser, Suzanne Borgel, Devynn Breen, John Carter, Tiffanie Chase, Alice Chen, Lily Chen, Kristen Cooley, Emily Delaney, Raymond Divelbiss, Lyndsay Dutko, Thomas Forbes, Kyle Georgius, Michelle Gottholm-Ahalt, Tara Grinnage-Pulley, Sierra Hoffman, Chris Karlovich, Shahanawaz Jiwani, Justine Mills, Malorie Morris, Michael Mullendore, Dianne Newton, Rajesh Patidar, Gloryvee Rivera, Howard Stotler, Jesse Stottlemyer, Savanna Styers, Debbie Trail, Shannon Uzelac, Thomas Vilimas, Abigail Walke, Thomas Walsh, Nicole Walters, Peng Wang, P. Mickey Williams, Melinda Hollingshead, James H. Doroshow. Quality control efforts in a large-scale, preclinical trial of rare cancer PDXs by the National Cancer Institute's patient-derived models repository (NCI PDMR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5056.

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.

Background Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation. Methods Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis. Results Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines. Conclusion The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.

International Liver Congress (ILC) of the European-Association-for-the-Study-of-the-Liver (EASL), Paris, FRANCE, APR 11-15, 2018; International audience

BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3.METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720.FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection.FUNDING: Merck & Co, Inc.

Prevention, diagnosis and treatment of lesions of the maxillofacial area is one of the most urgent modern medical and social problems, the signifi cance of which is determined by the constant increase in the frequency of maxillofacial injuries, which averages from 6.0 to 16.4 % of all traumas of peacetime.The aim of the study – to learn the individual immunological parameters in patients with fractures of the jaws against the background of generalized periodontitis.Materials and Methods. The article presents the analysis of individual parameters of cellular factors (phagocytic index, phagocytic count, phagocytosis completeness, NK-cells) and humoral immunity (total protein, globulin fractions, albumin, C-reactive protein, titre of lysozyme, immunoglobulins A, G, M) in serum in patients with jaw fractures on the background of generalized periodontitis (GP) (group A) and in patients with traumatic jaw lesions without periodontal tissue pathology (group B). The obtained values were compared with the data of the average norm.Results and Discussion. Investigation of changes in cellular factors of congenital immunity was performed in 45 patients with fractures of the jaws against the background of generalized periodontitis II-III stages (group A) and 41 patients with jaw fractures without concomitant periodontal pathology (group B). The obtained results were compared with the data of the average norm. The obtained results were processed statistically.Conclusions. As a result of the studies of the main parts of non-specifi c immunity in patients with jaw fractures, certain violations of humoral and cellular factors, which manifested themselves both in decreasing and dangerous increase of most of the studied parameters, were found, and in the patients with traumatic jaw lesions on the background of GP this tendency was worn more pronounced character.

Prevention of major dental diseases in children is one of the most urgent problems of dentistry in childhood. This is especially true in the category of children with central nervous system (CNS) disorders. It is known that deviations in the psychological development of children are often accompanied by somatic diseases. The literature highlights the dependence of dental status on somatic health. The aim of the study – to conduct an analysis of the somatic status of children with oligophrenic patients. Materials and Methods. The data presented during the examination of 263 children aged 12–18 years. The choice of this age group was subordinated to WHO (1997) requirements to obtain a reliable characterization of the state of solid dental tissues (group of children 12 years old) and periodontal tissues (group of children 15 years). A group of children 18 years old was selected to study the disease of hard tissues of teeth and periodontal tissues in the dynamics. Dental examination of this contingent of children was carried out at the psycho-neurological dispensary of the city of Lviv. The diagnosis of "oligophrenia" was established by a specialist of this specialty (psychiatrist). The control group included 99 students from several secondary schools in Lviv, of the same age, without psychoneurological abnormalities. Results and Discussion. Having conducted a detailed analysis of these indicators among the children of the main group, we have established their direct dependence on the severity of the underlying disease. According to the results of the research, in the main group there is a high percentage of children who were ill with infectious diseases (50 ± 3.9 %), indicating a decrease in the protective immune forces of the organism. Prevalent in the main group of children are diseases of the gastrointestinal tract. A significant number of children with oligophrenia who had a respiratory tract pathology (34.76 ± 3.72 %) were found. In addition to the general factors contributing to the occurrence of pathological processes in the tissues of the oral cavity, there are local, such as: anomalies of bite, dental arches, buckling of teeth, and the like. Conclusions. Some general and local risk factors for dental diseases characteristic of children with oligophrenia have been identified: pathological changes in the respiratory system (34.76 ± 3.72 %) and the gastrointestinal tract (32.32 ± 3.65 %) are more frequent than in mentally healthy children. Oral respiration is on the first place of the local factor of the occurrence of dental diseases in this contingent of children (59.15 ± 3.84 %). Particular weight is occupied by buccal pathology and teething brittleness (40.85 ± 3.84 %). We have also established the dependence of the general state of health of children-oligophrenic patients on the degree of reduction of their intelligence.

Aims and objectives This study aimed to determine the interobserver reliability between bedside nurses and attending physicians for a paediatric respiratory score as part of an asthma Integrated Care Pathway implementation. Background An Integrated Care Pathway is one approach to improving quality of care for children hospitalised with asthma. Prior to implementation of the integrated care pathway, it was necessary to train nursing staff on the use of a respiratory assessment tool and to evaluate the interobserver reliability use of this tool. Design Prospective study using a convenience sample of children hospitalised for a respiratory illness in an academic medical centre. Methods The respiratory assessment used was the Paediatric Asthma Score. Bedside nurse-attending physician (27 different RNs and three attending paediatric hospitalists) pairs performed 71 simultaneous patient assessments on 20 patients. Intraclass correlation coefficient and kappa statistics were used to assess interobserver reliability. Results The overall intraclass correlation coefficient was nearly perfect where κ = 0·95, 95% CI (0·92, 0·97) and overall kappa for reliability based on clinically relevant score breakpoints was also high with κ = 0·82, 95% CI (0·75, 0·90). The majority of subgroup analyses revealed substantial to almost perfect agreement across a variety of diagnoses, age ranges, and individual score components. Conclusions Bedside nurses, with support and training from attending physicians, can perform respiratory assessments that agree almost perfectly with those of attending physicians. Relevance to clinical practice The use of an Integrated Care Pathway allows for optimal interprofessional collaboration between bedside nurses and attending physicians.

Policymakers have dedicated increasing attention to whether Americans have access to healthful food. As a result, various methods for measuring food store access at the national level have been developed to identify areas that lack access. However, these methods face definitional, data, and methodological limitations. The focus on neighborhoods instead of individuals underestimates the barriers that some individuals face in accessing healthy food, and overestimates the problem in other neighborhoods. This paper reviews and critiques currently available national-level measures of food access. While multiple measures of food access are needed to understand the problem, we recommend greater attention be paid to individual measures of food store access.

Background: Patient-derived tumor xenografts (PDX) are powerful tools to study cancer biology, cancer genomics and developmental therapeutics. A common problem in the development of PDX models is proliferation of atypical lymphocytes at the implantation site, which often overtake or limit the growth of the original tumor. This atypical lymphocyte proliferation has been described as XABLD in our PDX models. In this study, we characterized XABLD cases by morphology, immunophenotyping and genomic profiling. We hypothesize that XABLD tumors are morphologically and phenotypically similar to EBV-driven post-transplant lymphoproliferative disease (PTLD) and diffuse large B cell lymphoma (DLBCL). XABLD is a surrogate model to study EBV-driven PTLD and DLBCL. Materials and Methods: Models were generated from patient tissue collected under NCI Tissue Procurement Protocol (clinicaltrials.gov: NCT00900198) and CIRB Tissue Procurement Protocol 9846 for development of models for NCI’s Patient-Derived Models Repository (https://pdmr.cancer.gov). Specimens were implanted subcutaneously in NOD/SCID/IL2Rg null (NSG) mice and animal health was monitored throughout the study. Tumors in mice with suspected XABLD were harvested and reviewed by histology and immunohistochemical analysis for CD45, B and T cell markers, EBV status, B-cell clonality assay. All samples were also classified by the Lymph2Cx NanoString cell of origin assay and transcriptome profiling. Results: XABLD cases were found to originate from both solid tumor and circulating tumor cell implants. XABLD is a rapidly growing tumor positive for CD45, CD20, and LMP1 stains, 36 of 42 cases are strongly positive for PD-L1 stain. 39 of 42 cases exhibited an activated B cell (ABC) phenotype with evidence of elevated NF-kB signaling. Most cases were monoclonal for IGK/IGH and contained high numbers of tumor infiltrating CD8-positive T-cells with associated high mRNA expression of activated T cell markers. Conclusion: The clinical presentation, morphology and molecular characteristics of XABLD cases were similar to EBV-driven DLBCL. As the XABLD models exhibited frequent PD-L1 expression and marked infiltration of CD8-positive T cells, they may be useful for in vitro evaluation of checkpoint inhibitor response and T cell antitumor activity. Grant Support: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Citation Format: Tomas Vilimas, Gloryvee Rivera, Brandie Fullmer, Wiem Lassoued, Lindsay Dutko, Amanda Peach, Corinne Camalier, Li Chen, Rajesh Patidar, Suzanne Borgel, John Carter, Howard Stotler, Raymond Divelbiss, Jesse Stottlemyer, Michelle M. Gottholm-Ahalt, Michelle Crespo-Eugeni, Sean McDermott, William Jacob, Liqiang Xi, Pallavi Galera, Yvonne A. Evrard, Melinda G. Hollingshead, Elaine S. Jaffe, Mark Raffeld, Biswajit Das, Chris Karlovich, Vivekananda Datta, James H. Doroshow, P. Mickey Williams. Xenograft-associated B cell lymphoproliferative disease (XABLD) as a surrogate model to study Epstein-Barr virus (EBV) driven B cell Diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1056.

Background Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary funding source Merck & Co.

Direct-acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C-SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C-SWIFT was an open-label, single-center trial in treatment-naive patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4-12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA

Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%).With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

In the USA, the US Department of Agriculture's Food Safety and Inspection Service (FSIS) conducts the National Residue Program designed to monitor veterinary drug and other chemical residues in beef and other slaughtered food animals. Currently, FSIS uses a 7-plate bioassay in the laboratory to screen for antimicrobial drugs in bovine kidneys from those animals tested positive by inspectors in the slaughter establishments. The microbial inhibition bioassay has several limitations in terms of monitoring scope, sensitivity, selectivity, and analysis time. Ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS) has many advantages over the bioassay for this application, and this study was designed to develop, evaluate, and validate a fast UHPLC-MS/MS method for antibiotics and other high-priority veterinary drugs in bovine kidney. Five existing multi-class, multi-residue methods from the literature were tested and compared, and each performed similarly. Experiments with incurred samples demonstrated that a 5-min shake of 2 g homogenized kidney with 10 ml of 4/1 (v/v) acetonitrile/water followed by simultaneous clean-up of the initial extract with 0.5 g C18 and 10 ml hexane gave a fast, simple, and effective sample preparation method for the

Background: Patient-derived tumor xenografts (PDX) are powerful tools to study cancer biology, cancer genomics and developmental therapeutics. A common problem in the development of PDX models is proliferation of atypical lymphocytes at the implant site, which often overtake or limit the growth of the original tumor. This atypical proliferation has been described as Xenograft-Associated B cell Lymphoproliferative Disease (XABLD) in our PDX models. In this study, we characterized XABLD cases by morphology, immunophenotyping and genomic profiling. We hypothesize that XABLD tumors are morphologically and phenotypically similar to EBV-driven lymphoma of the elderly and may function as a surrogate model for that lymphoma. Materials and Methods: Models were generated from patient tissue collected under NCI Tissue Procurement Protocol (clincialtrials.gov: NCT00900198) and CIRB Tissue Procurement Protocol 9846 for development of models for NCI's Patient-Derived Models Repository (https://pdmr.cancer.gov). Specimens were implanted subcutaneously in NOD/SCID/IL2Rg null (NSG) mice and animal health was monitored throughout the study. Tumors in mice with suspected XABLD were harvested and reviewed by histology and immunohistochemical analysis for CD45, B and T cell markers and EBV status. All samples in this study were classified by the Lymph2Cx NanoString cell of origin assay and transcriptome profiling. Results: XABLD-associated mice had rapidly growing CD45-positive tumors at the implantation site. Histopathological features were consistent with EBV-driven diffuse large B-cell lymphoma (DLBCL) primarily of polymorphous subtype. All XABLD specimens were diffusely positive for CD20 and EBNA, and most cases contained tumor infiltrating CD8-positive T-cells. Out of 42 cases, 36 were PD-L1-positive and 26 were PD-1-positive by IHC. 39 cases exhibited an activated B cell (ABC) phenotype, which is predominant in EBV-positive DLBCL. Conclusion: XABLD development has been seen across multiple patient histologies from both solid tumor and circulating tumor cells tissues of origin. The clinical presentation, morphology and molecular characteristics of XABLD cases were similar to EBV-driven DLBCL. As DLBCL is an aggressive disease with limited treatment options, our early-passage XABLD models may be useful in the preclinical evaluation of new therapies for EBV-positive DLBCL. Grant Support: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Citation Format: Tomas Vilimas, Gloryvee Rivera, Brandie Fullmer, Wiem Lassoued, Lindsay Dutko, William Walsh, Amanda Peach, Corinne Camalier, Li Chen, Rajesh Patidar, Suzanne Borgel, John Carter, Howard Stotler, Raymond Divelbiss, Jesse Stottlemyer, Margaret Defreytas, Michelle M. Gottholm-Ahalt, Michelle A. Crespo-Eugeni, Sean McDermott, Yvonne A. Evrard, Melinda G. Hollingshead, Biswajit Das, Chris Karlovich, Vivekananda Datta, James H. Doroshow, P. Mickey Williams. Xenograft-associated B cell lymphoproliferative disease as a surrogate model to study Epstein-Barr virus (EBV) driven lymphoma of the elderly [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1038.

Purpose Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. Methods These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. Findings Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. Implications The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).

BACKGROUND The American Academy of Pediatrics (AAP) published expanded safe sleep guidelines in 2011. OBJECTIVE The purpose of this quality improvement project was to promote the AAP safe sleep recommendations and provide appropriate role modeling of these recommendations for hemodynamically stable infants throughout their hospital stay. DESIGN AND INTERVENTION A safe sleep educational initiative for parents and hospital staff included an observation of infant sleep practice before and after the initiative and a pre- and posteducation questionnaire of nurses' knowledge, attitudes, and opinions. SETTING AND PARTICIPANTS A Magnet-designated urban hospital that included 72 pediatric beds, a 60-bed NICU, and 41 mother-baby beds; and 658 pediatric and obstetric nurses. RESULTS One-hundred percent of nurses received the educational intervention. Observations noted an improvement from 70% to 90% (p< 0.01) of infants in a safe sleep position when comparing pre- and postintervention results. There were some improvements in knowledge of and agreement with the AAP guidelines after the educational intervention, but not as much as expected. CONCLUSIONS There was inconsistency between nursing knowledge and practice about safe infant sleep. Nurses were aware of the AAP recommendations, but it took time to achieve close to full compliance in changing clinical practice. Observation was an important part of this initiative to reinforce knowledge and role model best practice for parents.

Twenty lactating dairy cattle were intravenously infused with either lipopolysaccharide (LPS) (n = 10) or sterile saline (n = 10). Five cattle in each group received three doses of flunixin meglumine administered by either intravenous infusion or intramuscular injection at 24 h intervals. Milk, urine, and tissues were collected. Thirty-six hours after the last flunixin administration, milk from six cows contained 5-hydroxyflunixin (5OHF) levels greater than the milk tolerance of 2 ng/mL; by 48 h, milk from two cows, a saline and a LPS-treated animal, had violative milk concentrations of 5OHF. A single animal treated with LPS and intramuscular flunixin contained violative flunixin residues in liver. The ratio of urinary flunixin/5OHF was correlated (P0.01; R(2) = 0.946) with liver flunixin residues in LPS-treated animals, but not (P = 0.96; R(2) = 0.003) in cows treated with saline in lieu of LPS. Violative residues of flunixin in dairy cattle may be related to LPS inhibition of flunixin metabolism.

Comment in New kids on the block--step by step to an ideal HCV therapy. [Lancet. 2015]; International audience; There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]). Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

Halofuginone (Hal) is a feed additive used worldwide to prevent coccidiosis in commercial poultry production. The current regulatory method for determining the action level of Hal residues in poultry involves measuring parent Hal in liver tissue by HPLC. A competitive enzyme-linked immunosorbent assay (cELISA) for Hal was evaluated with respect to HPLC in determining Hal in 473 samples of chicken liver tissue obtained from commercial poultry slaughterhouses. Chicken liver samples were divided, and analyzed by both the US Department of Agriculture, Food Safety and Inspection Service's(FSIS's) regulatory method, and by the US Department of Agriculture, Agricultural Research Service's (ARS's) cELISA method described here. The lower level of detection for Hal was 50 ppb by the FSIS HPLC method and 38 ppb by the ARS cELISA method. The lower cutoff limit for this study was 50 ppb as mandated by FSIS SOP. There was good agreement in the results obtained by HPLC and cELISA. In addition, the cELISA method does not...

International audience; BACKGROUND & AIMS:HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials.METHODS:Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring.RESULTS:Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with

Background & Aims MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. Methods We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. Results At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. Conclusions Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172–based regimens. ClinicalTrials.gov number: NCT01353911.

International audience; Background & AimsTreatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.MethodsPatients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).ResultsRates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received

International audience; BACKGROUND:Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1.AIM:To determine if medication adherence impacts efficacy [sustained virological response (SVR)] with triple therapy that includes boceprevir (BOC) plus P/R.METHODS:Adherence was determined in two Phase 3 clinical studies with BOC: SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R). Adherence to the assigned duration of the dosing regimen and adherence to the three times a day (t.d.s.) dosing interval of 7-9 h for BOC were assessed by the recording of data from patients' dosing diaries and by the amount of study drug dispensed and returned.RESULTS:Most patients (63-71%) adhered to ≥80% of their assigned treatment duration and achieved SVR rates of 86-90%. In contrast, patients who adhered to 80%) to the t.d.s. dosing interval (7-9 h) with BOC did not influence the SVR rates (SVR = 60-83%) with the exception of patients who failed previous treatment and adhered to 60% of t.d.s. dosing with boceprevir is important in patients who failed previous therapy.

Issues related to numerical integration of the Willam-Warnke version of the five-parameter model for concrete [K.J. Willam and E.P. Warnke, Constitutive model for triaxial behaviour of concrete. IABSE Seminar on Concrete Structures Subjected to Triaxial Stresses (1974)] are discussed. The constitutive equations are numerically integrated by an algorithm based on the operator split methodology. The cutting plane method and the full Newton-Raphson method are applied in the solution of the nonlinear set of equations in the plastic corrector stage and comparative analysis is performed. Attention is restricted to the perfectly plastic behaviour of compressed concrete under plane stress conditions. Accuracy analysis is performed via iso-error maps for a representative range of loading conditions. Numerical examples are presented to test the effectiveness of the solution scheme.

Nontraditional stores, including mass merchandisers, supercenters, club warehouse stores, and dollar stores, have increased their food offerings over the past 15 years and often promote themselves as lower priced alternatives to traditional supermarkets. How much lower are food prices at these stores? In order to better understand nontraditional stores’ impact on the cost of food, ERS analysts evaluate food price differences between nontraditional and traditional stores at the national and market level using 2004-06 Nielsen Homescan data. Findings show that nontraditional retailers offer lower prices than traditional stores even after controlling for brand and package size. Comparisons of identical items, at the Universal Product Code (UPC) level, show an expenditure-weighted average price discount of 7.5 percent, with differences ranging from 3 to 28 percent lower in nontraditional stores than in traditional stores. Nontraditional stores in metro areas where such stores have a higher-than-average market share have smaller and less frequent price discounts than those in areas where such stores have a lower market share.