Complete Sequence, Analysis and Organization of the Orgyia leucostigma Nucleopolyhedrovirus Genome

The complete genome of the Orgyia leucostigma nucleopolyhedrovirus (OrleNPV) isolated from the whitemarked tussock moth (Orgyia leucostigma, Lymantridae: Lepidoptera) was sequenced, analyzed, and compared to other baculovirus genomes. The size of the OrleNPV genome was 156,179 base pairs (bp) and had a G+C content of 39%. The genome encoded 135 putative open reading frames (ORFs), which occupied 79% of the entire genome sequence. Three inhibitor of apoptosis (ORFs 16, 43 and 63), and five baculovirus repeated ORFs (bro-a through bro-e) were interspersed in the OrleNPV genome. In addition to six direct repeat (drs), a common feature shared among most baculoviruses, OrleNPV genome contained three homologous regions (hrs) that are located in the latter half of the genome. The presence of an F-protein homologue and the results from phylogenetic analyses placed OrleNPV in the genus Alphabaculovirus, group II. Overall, OrleNPV appears to be most closely related to group II alphabaculoviruses Ectropis obliqua (EcobNPV), Apocheima cinerarium (ApciNPV), Euproctis pseudoconspersa (EupsNPV), and Clanis bilineata (ClbiNPV)

Complications from Surgeries Related to Ovarian Cancer Screening

The aim of this study was to evaluate complications of surgical intervention for participants in the Kentucky Ovarian Cancer Screening Program and compare results to those of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. A retrospective database review included 657 patients who underwent surgery for a positive screen in the Kentucky Ovarian Cancer Screening Program from 1988–2014. Data were abstracted from operative reports, discharge summaries, and office notes for 406 patients. Another 142 patients with incomplete records were interviewed by phone. Complete information was available for 548 patients. Complications were graded using the Clavien–Dindo (C–D) Classification of Surgical Complications and considered minor if assigned Grade I (any deviation from normal course, minor medications) or Grade II (other pharmacological treatment, blood transfusion). C–D Grade III complications (those requiring surgical, endoscopic, or radiologic intervention) and C–D Grade IV complications (those which are life threatening) were considered “major”. Statistical analysis was performed using SAS 9.4 software. Complications were documented in 54/548 (10%) subjects. For women with malignancy, 17/90 (19%) had complications compared to 37/458 (8%) with benign pathology (p \u3c 0.003). For non-cancer surgery, obesity was associated with increased complications (p = 0.0028). Fifty patients had minor complications classified as C–D Grade II or less. Three of 4 patients with Grade IV complications had malignancy (p \u3c 0.0004). In the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, 212 women had surgery for ovarian malignancy, and 95 had at least one complication (45%). Of the 1080 women with non-cancer surgery, 163 had at least one complication (15%). Compared to the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, the Kentucky Ovarian Cancer Screening Program had significantly fewer complications from both cancer and non-cancer surgery (p \u3c 0.0001 and p = 0.002, respectively). Complications resulting from surgery performed as a result of the Kentucky Ovarian Cancer Screening Program were infrequent and significantly fewer than reported in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Complications were mostly minor (93%) and were more common in cancer versus non-cancer surgery

Symptoms Relevant to Surveillance for Ovarian Cancer

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and \u3e 9500 women completed it more than one four times for \u3e 43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p \u3c 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p \u3c 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported

Europe-wide expansion and eradication of multidrug-resistant Neisseria gonorrhoeae lineages: a genomic surveillance study

Centre for Genomic Pathogen Surveillance and the Euro-GASP study group: Sonja Pleininger, Alexander Indra, Irith De Baetselier, Wim Vanden Berghe, Blaženka Hunjak, Tatjana Nemeth Blažić, Panayiota Maikanti-Charalambous, Despo Pieridou, Hana Zákoucká, Helena Žemličková, Steen Hoffmann, Susan Cowan, Lasse Jessen Schwartz, Rita Peetso, Jevgenia Epstein, Jelena Viktorova, Ndeindo Ndeikoundam, Beatrice Bercot, Cécile Bébéar, Florence Lot, Susanne Buder, Klaus Jansen, Vivi Miriagou, Georgios Rigakos, Vasilios Raftopoulos, Eszter Balla, Mária Dudás, Lena Rós Ásmundsdóttir, Guðrún Sigmundsdóttir, Guðrún Svanborg Hauksdóttir, Thorolfur Gudnason, Aoife Colgan, Brendan Crowley, Sinéad Saab, Paola Stefanelli, Anna Carannante, Patrizia Parodi, Gatis Pakarna, Raina Nikiforova, Antra Bormane, Elina Dimina, Monique Perrin, Tamir Abdelrahman, Joël Mossong, Jean-Claude Schmit, Friedrich Mühlschlegel, Christopher Barbara, Francesca Mifsud, Alje Van Dam, Birgit Van Benthem, Maartje Visser, Ineke Linde, Hilde Kløvstad, Dominique Caugant, Beata Młynarczyk-Bonikowska, Jacinta Azevedo, Maria-José Borrego, Marina Lurdes Ramos Nascimento, Peter Pavlik, Irena Klavs, Andreja Murnik, Samo Jeverica, Tanja Kustec, Julio Vázquez Moreno, Asuncion Diaz, Raquel Abad, Inga Velicko, Magnus Unemo, Helen Fifer, Jill Shepherd, Lynsey PattersonBackground: Genomic surveillance using quality-assured whole-genome sequencing (WGS) together with epidemiological and antimicrobial resistance (AMR) data is essential to characterise the circulating Neisseria gonorrhoeae lineages and their association to patient groups (defined by demographic and epidemiological factors). In 2013, the European gonococcal population was characterised genomically for the first time. We describe the European gonococcal population in 2018 and identify emerging or vanishing lineages associated with AMR and epidemiological characteristics of patients, to elucidate recent changes in AMR and gonorrhoea epidemiology in Europe. Methods: We did WGS on 2375 gonococcal isolates from 2018 (mainly Sept 1-Nov 30) in 26 EU and EEA countries. Molecular typing and AMR determinants were extracted from quality-checked genomic data. Association analyses identified links between genomic lineages, AMR, and epidemiological data. Findings: Azithromycin-resistant N gonorrhoeae (8·0% [191/2375] in 2018) is rising in Europe due to the introduction or emergence and subsequent expansion of a novel N gonorrhoeae multi-antigen sequence typing (NG-MAST) genogroup, G12302 (132 [5·6%] of 2375; N gonorrhoeae sequence typing for antimicrobial resistance [NG-STAR] clonal complex [CC]168/63), carrying a mosaic mtrR promoter and mtrD sequence and found in 24 countries in 2018. CC63 was associated with pharyngeal infections in men who have sex with men. Susceptibility to ceftriaxone and cefixime is increasing, as the resistance-associated lineage, NG-MAST G1407 (51 [2·1%] of 2375), is progressively vanishing since 2009-10. Interpretation: Enhanced gonococcal AMR surveillance is imperative worldwide. WGS, linked to epidemiological and AMR data, is essential to elucidate the dynamics in gonorrhoea epidemiology and gonococcal populations as well as to predict AMR. When feasible, WGS should supplement the national and international AMR surveillance programmes to elucidate AMR changes over time. In the EU and EEA, increasing low-level azithromycin resistance could threaten the recommended ceftriaxone-azithromycin dual therapy, and an evidence-based clinical azithromycin resistance breakpoint is needed. Nevertheless, increasing ceftriaxone susceptibility, declining cefixime resistance, and absence of known resistance mutations for new treatments (zoliflodacin, gepotidacin) are promising.This study was supported by the European Centre for Disease Prevention and Control, the Centre for Genomic Pathogen Surveillance, the Li Ka Shing Foundation (Big Data Institute, University of Oxford), the Wellcome Genome Campus, the Foundation for Medical Research at Örebro University Hospital, and grants from Wellcome (098051 and 099202). LSB was funded by Conselleria de Sanitat Universal i Salut Pública, Generalitat Valenciana (Plan GenT CDEI-06/20-B), Valencia, Spain, and Ministry of Science, Innovation and Universities (PID2020–120113RA-I00), Spain, at the time of analysing and writing this manuscript.info:eu-repo/semantics/publishedVersio

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification

Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease

Part I: Total Synthesis of Novel Dihydroceramids from the Dental Pathogen Porphyromonas gingivalis Part II: Application of Conducting Polymers as Green-Chemistry Reagents in Organic Reactions Part III: Synthesis of Imidazole-Indocyanine Green Conjugates

Part I: Porphyromonas gingivalis is a known periodontal pathogen that produced four classes of novel dihydroceramides with biological activity ranging from inducing pro-inflammatory responses to gingival tissue and bone degeneration. It has been shown that these compounds are capable of induction of multiple sclerosis in mice model systems. GCMS and NMR analysis of these active compounds revealed that a mixture of dihydroceramides existed whose composition was dihydrosphinganine base with an amide linkage to a β-hydroxy fatty acid. The dihydrosphinganine portion contained two stereocenters, odd-carbon chains (C17 and C19), and a terminal isobranch moiety. The β-hydroxy fatty acid had a chain length of C17, a single stereocenter and a terminal isobranch. Due to the complexity of the lipid extracts we have not been able to isolate individual lipid components in pure form, directly from P.gingivalis by using chromatographic method, making their synthesis essential. Apart from the synthesis and verification of the structure, our work is focused on determining the absolute and relative stereochemistry of the most active dihydroceramide. ^ Part II: Conducting polymers are rarely thought of as chemical reagents that promote chemical transformations. Poly(3,4-ethylenedioxythiophene) or PEDOT and Polypyrrole (PP) are some of the most widely used conducting polymers and can be prepared via oxidative chemical using FeCl3 or electrochemical polymerization with a triflate counterion. Chemical reactions induced by PEDOT and PP alone have not been reported prior to our work. The commercial importance of PEDOT, along with the ease of preparation and handling, stability to air and solvents, and its conductive properties led us to choose it for our studies.^ Work in our laboratory disproves the common assumption of chemical inertness by showing that these polymers are capable of facilitating a variety of chemical reactions. Upon exposure to PEDOT or polypyrrole, alcohols are converted to ethers or undergo Friedel-Crafts alkylation. Polyols and ketohexoses undergo cyclodehydrations, dienones undergo Nazarov cyclization, 1,2-diols go through Pinacol rearrangements, and acid-sensitive alcohol and ketone protecting groups can be removed. Their use as a chemical reagent in organic reactions has proved to not only generate equivalent yields when compared to standard literature precedent but also able to complete reactions previously inaccessible by conventional methods.^ Part III: Cancerous solid tumors generate a specific environment that are characterized by a low oxygen partial pressure and low pH. This microenvironment is recognized as a critical factor that makes conventional anti-cancer treatment ineffective while also rapidly advancing the malignant progression. This condition is known as tumor hypoxia. Currently non-invasive imaging methods include Magnetic Resonance Imaging (MRI) and Positron emission tomography (PET). The issue with these methods is the large expense and short half-life of radioactive isotopes required for imaging that is required during chemotherapy treatment. Hence a new, non-invasive, lost cost method to repeatedly monitor changes to hypoxia tumor size and characteristics is an attractive goal. Near-infrared (NIR) fluorescence diffuse optical tomography (FDOT) is low-cost and highly effective technique used to image tumors. However the technique is dependent on an internal fluorochrome to generate a fluorescent signal. Our goal was to combine a biologically safe fluorescent dye (indocyanine green), that could be easily detectable by a topical imaging probe, with a molecule which has an affinity for low-pH, hypoxic areas (2-nitroimidazoles). This involved the formation these new indocyanine green dye conjugates that would specifically target hypoxic tumor and supply imaging at that site. Our work synthesized four generations of dye conjugates with each subsequent generation improving on the previous.

Defining the host mucosal and gut microflora interactions in Crohn\u27s disease using redundancy analysis on microarray datasets

Introduction: Crohn’s disease (CD) is an inflammatory bowel disease that is characterised by chronic relapsing inflammation of the digestive tract. There is a significant body of evidence that suggests the intestinal mucosal microbiome interacts with the immune response to produce pathological inflammation and together these factors play a major role in the pathogenesis of CD. The aim of this study is to investigate interactions between the human intestinal mucosal transcriptome and mucosal microbiome using multivariate redundancy analysis on microarray datasets. Methods: DNA and RNA were extracted from the same mucosal biopsies collected from CD patients (terminal ileum: n=5 from sites with active disease, n=4 from inactive sites (tissue with normal histology); colon: n=8 from active and n=6 from inactive sites). RNA was used to study the human intestinal mucosal transcriptome (Affymetrix GeneChip® Exon 1.0 ST arrays) and DNA was used to study the resident microbiota using a custom phylogenetic microarray. The latter was designed using published gastrointestinal microbiota 16S rRNA sequences with ~ 40-mer oligonucleotides targeting 765 bacterial species. Through examining the expression arrays, 30 differentially expressed inflammatory response genes of interest were selected. Correlations between expression patterns for these genes were assessed. Representatives (TNFRSF1B, IL2RA, IL8) of three groups of inflammatory genes with highly correlated expression and three uncorrelated genes of interest (CXCL11, IL- 13RA1 and TIRAP) were used. Multivariate relationships between the expression of the six representative inflammatory response genes and the abundance of microbial species in colon or terminal ileum, in patients with active or inactive disease was examined using redundancy analysis using the vegan package in R1. Correlations between the expression of individual inflammatory response genes and the abundance of individual microbes were also investigated. Results: There appears to be a significant relationship between changes in the abundance of some microbial species in intestinal mucosa with active disease and the expression of the six representative inflammatory response genes. However, this was not the case in the normal (inactive) mucosa of these patients. Where there was active disease the expression of the six genes were predicted by members of the sulfite-reducing bacteria Clostridia class (p-value 0.02-0.005) in the colon, and the Betaproteobacteria (p-value 0.02) and Clostridia (p-value 0.03) class members in the ileum. In the normal (inactive) mucosa of CD patients, there were no bacterial species that significantly predicted the expression of inflammatory immune response genes. There was also some evidence that the expression of the pro-inflammatory cytokine, IL8, predicted changes in the abundance of microbes in inactive colon (p-value 0.04) and that TIRAP (toll-Il1 receptor domain containing adaptor protein), involved in the innate immune system’s recognition of microbial pathogens, was predictive of the pattern of microbial abundance in active ileum (p-value 0.05). Conclusions: Our findings begin to define the unique hostmicrobial responses associated with CD

Management of Pediatric Skin Abscesses in Pediatric, General Academic and Community Emergency Departments

Objectives: To compare the evaluation and management of pediatric cutaneous abscess patients at three different emergency department (ED) settings.Method: We conducted a retrospective cohort study at two academic pediatric hospital EDs, a general academic ED and a community ED in 2007, with random sampling of 100 patients at the three academic EDs and inclusion of 92 patients from the community ED. Eligible patients were ≤18 years who had a cutaneous abscess. We recorded demographics, predisposing conditions, physical exam findings, incision and drainage procedures, therapeutics and final disposition. Laboratory data were reviewed for culture results and antimicrobial sensitivities. For subjects managed as outpatients from the ED, we determined where patients were instructed to follow up and, using electronic medical records, ascertained the proportion of patients who returned to the ED for further management.Result: Of 392 subjects, 59% were female and the median age was 7.7 years. Children at academic sites had larger abscesses compared to community patients, (3.5 versus 2.5 cm, p=0.02). Abscess incision and drainage occurred in 225 (57%) children, with the lowest rate at the academic pediatric hospital EDs (51%) despite the relatively larger abscess size. Procedural sedation and the collection of wound cultures were more frequent at the academic pediatric hospital and the general academic EDs. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence did not differ among sites; however, practitioners at the academic pediatric hospital EDs (92%) and the general academic ED (86%) were more likely to initiate empiric MRSA antibiotic therapy than the community site (71%), (p<0.0001). At discharge, children who received care at the community ED were more likely to be given a prescription for a narcotic (23%) and told to return to the ED for ongoing wound care (65%). Of all sites, the community ED also had the highest percentage of follow-up visits (37%).Conclusion: Abscess management varied among the three settings, with more conservative antibiotic selection and greater implementation of procedural sedation at academic centers and higher prescription rates for narcotics, self-referrals for ongoing care and patient follow-up visits at the community ED. [West J Emerg Med. 2011;12(2):159-167.