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Progressive obstructive pulmonary disease is the primary life-shortening complication in people with Cystic Fibrosis (CF); improvement in life expectancy has led to increased prevalence of non-pulmonary complications. Patients with CF are considered to be at low risk for coronary artery disease (CAD). We report here a case series of six patients with CF with and without known cystic fibrosis related diabetes (CFRD) who had acute myocardial infarction (AMI) requiring coronary stent placement. This was a heterogeneous group of patients, without a clear pattern of consistent risk factors. Interestingly, most patients in this cohort had low LDL. In this review, we discuss risk factors of cardiovascular disease (CVD) that may apply to the CF population. While CAD is rare in people with CF, it does occur. We postulate that the risk will grow with increased longevity and the increased prevalence of co-morbidities such as obesity and dyslipidemia.

There is mounting evidence of SARS-CoV-2 spillover from humans into many domestic, companion, and wild animal species. Research indicates that humans have infected white-tailed deer, and that deer-to-deer transmission has occurred, indicating that deer could be a wildlife reservoir and a source of novel SARS-CoV-2 variants. We examined the hypothesis that the Omicron variant is actively and asymptomatically infecting the free-ranging deer of New York City. Between December 2021 and February 2022, 155 deer on Staten Island, New York, were anesthetized and examined for gross abnormalities and illnesses. Paired nasopharyngeal swabs and blood samples were collected and analyzed for the presence of SARS-CoV-2 RNA and antibodies. Of 135 serum samples, 19 (14.1%) indicated SARS-CoV-2 exposure, and 11 reacted most strongly to the wild-type B.1 lineage. Of the 71 swabs, 8 were positive for SARS-CoV-2 RNA (4 Omicron and 4 Delta). Two of the animals had active infections and robust neutralizing antibodies, revealing evidence of reinfection or early seroconversion in deer. Variants of concern continue to circulate among and may reinfect US deer populations, and establish enzootic transmission cycles in the wild: this warrants a coordinated One Health response, to proactively surveil, identify, and curtail variants of concern before they can spill back into humans.

Abstract Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.

Background: Lithium is a drug with a narrow therapeutic range and has been associated with a number of serious adverse effects. This study aimed to characterise primary care lithium-related patient safety incidents submitted to the National Reporting and Learning System (NRLS) database with respect to incident origin, type, contributory factors and outcome. The intention was to identify ways to minimise risk to future patients by examining incidents with a range of harm outcomes. Methods: A mixed methods analysis of patient safety incident reports related to lithium was conducted. Data from healthcare organisations in England and Wales were extracted from the NRLS database. An exploratory descriptive analysis was undertaken to characterise the most frequent incident types, the associated chain of events and other contributory factors. Results: A total of 174 reports containing the term ‘lithium’ were identified. Of these, 41 were excluded and, from the remaining 133 reports, 138 incidents were identified and coded. Community pharmacies reported 100 incidents (96 dispensing related, two administration, two other), general practitioner (GP) practices filed 22 reports and 16 reports originated from other sources. A total of 99 dispensing-related incidents were recorded, 39 resulted from the wrong medication dispensed, 31 the wrong strength, 8 the wrong quantity and 21 other. A total of 128 contributory factors were identified overall; for dispensing incidents, the most common related to medication storage/packaging ( n = 41), and ‘mistakes’ ( n = 22), whereas no information regarding contributory factors was provided in 41 reports. Conclusion: Despite the established link between medication packaging and the risk of dispensing errors, our study highlighted storage and packaging as the most commonly described contributory factors to dispensing errors. The absence of certain relevant data limited the ability to fully characterise a number of reports. This highlighted the need to include clear and complete information when submitting reports. This, in turn, may help to better inform the further development of interventions designed to reduce the risk of incidents and improve patient safety. Lay Summary A characterisation of lithium-related patient safety incidents in primary care Lithium is an effective treatment for certain mental illnesses, but has a number of harmful side effects. Safety incidents related to medicines in the UK are reported to the National Reporting and Learning System database (NRLS), and concerns relating to lithium have previously been highlighted. This study aimed to characterise lithium incidents reported to the NRLS that occurred in a primary care setting. Reports relating to lithium and submitted between 2002 and 2013 were reviewed, and the information coded. A total of 174 reports containing the term ‘lithium’ were identified. Of these, 41 were excluded and, from the remaining 133 reports, 138 incidents were identified and coded with respect to incident origin, type, contributory factors and outcome. A total of 100 incidents were reported by community pharmacies (96 of which related to medicine dispensing), general practitioner (GP) practices filed 22 reports and 16 reports originated from other sources. Of the dispensing-related incidents, 39 resulted from the wrong medication dispensed, 31 the wrong strength, 8 the wrong quantity and 21 other. A total of 128 contributory factors were identified overall; for dispensing incidents, the most common related to medication storage/packaging ( n = 41), and ‘mistakes’ ( n = 22) whereas no information regarding contributory factors was provided in 41 reports. Despite the established link between medication packaging and the risk of dispensing errors, our study highlighted storage and packaging as the most commonly cited contributory factors to dispensing errors. The absence of certain relevant data limited the ability to fully characterise a number of reports. This highlighted the need to include clear and complete information when submitting reports. This, in turn, may help to better inform the further development of interventions designed to reduce incident numbers and improve patient safety.

Abstract Background The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment. Results We used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types. Conclusions We observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.

Cancer Immunotherapetics differ fundamentally from most cancer therapies in that they involve manipulation of the immune system to induce an anti-tumor response. This fundamental difference results in differences in the pre-clinical and clinical development of immunotherapeutics. Even the regulatory culture of developing one drug at a time and demonstrating that it, when added to standard therapy, prolongs patient survival, is often not suitable for the development of effective immunotherapy regimens. In this commentary, we explore some of these differences and describe novel clinical trial designs which may be useful in immunotherapeutics regimen development.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.

Cellular glycosylation processes are vital to cell functioning. In malignant cells, they are profoundly altered. We used time-course gene expression data from the NCI-60 cancer cell lines treated with 11 antitumor agents to analyze expression changes of genes involved in glycosylation pathways, genes encoding glycosylation targets or regulators, and members of cancer pathways affected by glycosylation. We also identified glycosylation genes for which pretreatment expression levels or changes after treatment were correlated with drug sensitivity. Their products are involved in N- glycosylation and O- glycosylation, fucosylation, biosynthesis of poly- N -acetyllactosamine, removal of misfolded proteins, binding to hyaluronic acid and other glycans, and cell adhesion. Tumor cell sensitivity to multiple agents was correlated with transcriptional response of C1GALT1C1, FUCA1, SDC1, MUC1 ; members of the MGAT, GALNT, B4GALT, B3GNT, MAN , and EDEM families; and other genes. These genes may be considered as potential candidates for drug targeting in combination therapy to enhance treatment response.

A numerical tool, called Hydro-Geosphere, was used to simulate unsaturated water flow and contaminants migration around an open pit filled with mining wastes. Numerical simulations had been carried out to assess the influence of various factors on water flow and solute transport in and around the surface openings including recharge, properties of the waste material and presence of fractures in the surrounding rock mass. The effect of the regional hydraulic gradient was also investigated. The analyses were conducted by simulating various 2D cases using experimentally obtained material properties and controlled boundary conditions. The effects of the hydrogeological properties of the filling material (i.e., water retention curve and hydraulic conductivity function), fracture network characteristics and conductivity of the joints were assessed. The results illustrate that fractures control water flow and contaminants transport around the waste disposal area. A fracture network can desaturate the system and improve the regional gradient effect. Keywords: Hydro-Geosphere, Numerical modelling, Unsaturated water flow, Contaminants transport, Tailings, Waste rocks

In the quality control of pharmaceutical products, it is of utmost importance that validated analytical methods are used to ensure the credibility of the results generated. At the time of the study, official monographs from the United States Pharmacopeia and National Formulary (USP-NF) for the quantification of Losartan potassium in tablets were unavailable, denoting the need for a validated analytical procedure for the analysis of the drug. The study adapted direct and first-derivative UV spectrophotometry methods proposed by Bonfilio and others (2010) for the assay of Losartan potassium in Losartan 50 mg. capsules, then modified and validated the said procedures for the assay of Losartan potassium in Losartan 100 mg. tablets following the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines on method validation for accuracy, precision, specificity, linearity, limit of detection, and limit of quantitation. Results demonstrated that all the performance characteristics of both methods were highly satisfactory and confirmed the possible application of the methods in routine analysis of Losartan potassium tablets.

There have been relatively few publications using linear regression models to predict a continuous response based on microarray expression profiles. Standard linear regression methods are problematic when the number of predictor variables exceeds the number of cases. We have evaluated three linear regression algorithms that can be used for the prediction of a continuous response based on high dimensional gene expression data. The three algorithms are the least angle regression (LAR), the least absolute shrinkage and selection operator (LASSO), and the averaged linear regression method (ALM). All methods are tested using simulations based on a real gene expression dataset and analyses of two sets of real gene expression data and using an unbiased complete cross validation approach. Our results show that the LASSO algorithm often provides a model with somewhat lower prediction error than the LAR method, but both of them perform more efficiently than the ALM predictor. We have developed a plug-in for BRB-ArrayTools that implements the LAR and the LASSO algorithms with complete cross-validation.

The explosion of available microarray data on human cancer increases the urgency for developing methods for effectively sharing this data among clinical cancer investigators. Lack of a smooth interface between the databases and statistical analysis tools limits the potential benefits of sharing the publicly available microarray data. To facilitate the efficient sharing and use of publicly available microarray data among cancer investigators, we have built a BRB-ArrayTools Data Archive including over one hundred human cancer microarray projects for 28 cancer types. Expression array data and clinical descriptors have been imported into BRB-ArrayTools and are stored as BRB-ArrayTools project folders on the archive. The data archive can be accessed from: http://linus.nci.nih.gov/~brb/DataArchive.html Our BRB-ArrayTools data archive and GEO importer represent ongoing efforts to provide effective tools for efficiently sharing and utilizing human cancer microarray data.

BRB-ArrayTools is an integrated software system for the comprehensive analysis of DNA microarray experiments. It was developed by professional biostatisticians experienced in the design and analysis of DNA microarray studies and incorporates methods developed by leading statistical laboratories. The software is designed for use by biomedical scientists who wish to have access to state-of-the-art statistical methods for the analysis of gene expression data and to receive training in the statistical analysis of high dimensional data. The software provides the most extensive set of tools available for predictive classifier development and complete cross-validation. It offers extensive links to genomic websites for gene annotation and analysis tools for pathway analysis. An archive of over 100 datasets of published microarray data with associated clinical data is provided and BRB-ArrayTools automatically imports data from the Gene Expression Omnibus public archive at the National Center for Biotechnology Information.

In 2009, an outbreak of raccoon rabies in Central Park in New York City, New York, USA, infected 133 raccoons. Five persons and 2 dogs were exposed but did not become infected. A trap-vaccinate-release program vaccinated ≈500 raccoons and contributed to the end of the epizootic.

The explosion of available microarray data on human cancer increases the urgency for developing methods for effectively sharing this data among clinical cancer investigators. Lack of a smooth interface between the databases and statistical analysis tools limits the potential benefits of sharing the publicly available microarray data. To facilitate the efficient sharing and use of publicly available microarray data among cancer investigators, we have built a BRB-ArrayTools Data Archive including over one hundred human cancer microarray projects for 28 cancer types. Expression array data and clinical descriptors have been imported into BRB-ArrayTools and are stored as BRB-ArrayTools project folders on the archive. The data archive can be accessed from: http://www.linus.nci.nih.gov/~brb/DataArchive.html Our BRB-ArrayTools data archive and GEO importer represent ongoing efforts to provide effective tools for efficiently sharing and utilizing human cancer microarray data.

BRB-ArrayTools is an integrated software system for the comprehensive analysis of DNA microarray experiments. It was developed by professional biostatisticians experienced in the design and analysis of DNA microarray studies and incorporates methods developed by leading statistical laboratories. The software is designed for use by biomedical scientists who wish to have access to state-of-the-art statistical methods for the analysis of gene expression data and to receive training in the statistical analysis of high dimensional data. The software provides the most extensive set of tools available for predictive classifier development and complete cross-validation. It offers extensive links to genomic websites for gene annotation and analysis tools for pathway analysis. An archive of over 100 datasets of published microarray data with associated clinical data is provided and BRB-ArrayTools automatically imports data from the Gene Expression Omnibus public archive at the National Center for Biotechnology Information.

Propose/aim of study: Modafinil (MD) is a psychostimulant drug used off-label and cognitive dysfunction may be a significant emerging treatment target for this drug. The objective of this study was to evaluate the effect of MD on the neurochemical parameters and memory impairment of rats submitted to sepsis by cecal ligation and perforation (CLP). Material and method: Male Wistar rats (250–350g) were submitted to CLP, or sham as control, and divided into the sham + water, sham + MD (300 mg/kg), CLP + water, and CLP + MD (300 mg/kg) groups. Ten days after the administration of MD and CLP, the rats were submitted to a memory test by passive avoidance apparatus being sacrificed. The nitrite and nitrate (N/N) concentration, myeloperoxidase (MPO) and catalase (CAT) activity, lipid and protein oxidative damage, and brain-derived neurotrophic factor (BDNF) levels were measured in the prefrontal cortex and hippocampus. Results: The passive avoidance test verified an increase in the latency time compared training and test section in the groups sham + water and CLP + MD. Decreased N/N concentration and MPO activity were verified in the prefrontal cortex of rats submitted to CLP and MD treatment, as well as reduced protein and lipid oxidative damage in the hippocampus, which was accompanied by increased CAT activity and BDNF levels.Conclusion: Our data indicate the role of MD in attenuating oxidative stress parameters, the alteration of BDNF, and an improvement in memory impairment in rats ten days after induction of sepsis. [ABSTRACT FROM AUTHOR]