Fluconazole-Associated Birth Defects: A Comprehensive Review

Background: The August 2013 publication of a large historical cohort study in the New England Journal of Medicine has reignited interest in the potential teratogenic effects of fluconazole when used in pregnant females. Fluconazole is an effective and commonly-utilized antifungal medication. Thus, maternal and fetal exposure to fluconazole is expected in the general population, and pharmacists are expected to counsel patients regarding any risks to their prescribed treatment. Methods: A literature review of all published literature indexed to PubMed (January 1966 to October 2013) and International Pharmaceutical Abstracts (January 1975 to October 2013) including fluconazole and teratogenic effects and published in the English language was conducted. Results: Fourteen publications were included for analysis including case reports (n=7), cross-sectional research (n=2), and historical cohort studies (n=5). Conclusion: There appears to be little to no fetal risk resulting from a single dose or short duration antifungal therapy with fluconazole. However, prolonged high-dose fluconazole therapy has increased potential to confer teratogenic effects. In those cases, the risks of such therapy should be weighed against potential benefits

Detection of zoonotic pathogens and characterization of novel viruses carried by commensal Rattus norvegicus in New York City

Norway rats (Rattus norvegicus) are globally distributed and concentrate in urban environments, where they live and feed in closer proximity to human populations than most other mammals. Despite the potential role of rats as reservoirs of zoonotic diseases, the microbial diversity present in urban rat populations remains unexplored. In this study, we used targeted molecular assays to detect known bacterial, viral, and protozoan human pathogens and unbiased high-throughput sequencing to identify novel viruses related to agents of human disease in commensal Norway rats in New York City. We found that these rats are infected with bacterial pathogens known to cause acute or mild gastroenteritis in people, including atypical enteropathogenic Escherichia coli, Clostridium difficile, and Salmonella enterica, as well as infectious agents that have been associated with undifferentiated febrile illnesses, including Bartonella spp., Streptobacillus moniliformis, Leptospira interrogans, and Seoul hantavirus. We also identified a wide range of known and novel viruses from groups that contain important human pathogens, including sapoviruses, cardioviruses, kobuviruses, parechoviruses, rotaviruses, and hepaciviruses. The two novel hepaciviruses discovered in this study replicate in the liver of Norway rats and may have utility in establishing a small animal model of human hepatitis C virus infection. The results of this study demonstrate the diversity of microbes carried by commensal rodent species and highlight the need for improved pathogen surveillance and disease monitoring in urban environments. Importance: The observation that most emerging infectious diseases of humans originate in animal reservoirs has led to wide-scale microbial surveillance and discovery programs in wildlife, particularly in the developing world. Strikingly, less attention has been focused on commensal animals like rats, despite their abundance in urban centers and close proximity to human populations. To begin to explore the zoonotic disease risk posed by urban rat populations, we trapped and surveyed Norway rats collected in New York City over a 1-year period. This analysis revealed a striking diversity of known pathogens and novel viruses in our study population, including multiple agents associated with acute gastroenteritis or febrile illnesses in people. Our findings indicate that urban rats are reservoirs for a vast diversity of microbes that may affect human health and indicate a need for increased surveillance and awareness of the disease risks associated with urban rodent infestation

Gene expression levels assessed by oligonucleotide microarray analysis and quantitative real-time RT-PCR – how well do they correlate?

BACKGROUND: The use of microarray technology to assess gene expression levels is now widespread in biology. The validation of microarray results using independent mRNA quantitation techniques remains a desirable element of any microarray experiment. To facilitate the comparison of microarray expression data between laboratories it is essential that validation methodologies be critically examined. We have assessed the correlation between expression scores obtained for 48 human genes using oligonucleotide microarrays and the expression levels for the same genes measured by quantitative real-time RT-PCR (qRT-PCR). RESULTS: Correlations with qRT-PCR data were obtained using microarray data that were processed using robust multi-array analysis (RMA) and the MAS 5.0 algorithm. Our results indicate that when identical transcripts are targeted by the two methods, correlations between qRT-PCR and microarray data are generally strong (r = 0.89). However, we observed poor correlations between qRT-PCR and RMA or MAS 5.0 normalized microarray data for 13% or 16% of genes, respectively. CONCLUSION: These results highlight the complementarity of oligonucleotide microarray and qRT-PCR technologies for validation of gene expression measurements, while emphasizing the continuing requirement for caution in interpreting gene expression data

Full Genome Characterization of the Culicoides-Borne Marsupial Orbiviruses: Wallal Virus, Mudjinbarry Virus and Warrego Viruses

Viruses belonging to the species Wallal virus and Warrego virus of the genus Orbivirus were identified as causative agents of blindness in marsupials in Australia during 1994/5. Recent comparisons of nucleotide (nt) and amino acid (aa) sequences have provided a basis for the grouping and classification of orbivirus isolates. However, full-genome sequence data are not available for representatives of all Orbivirus species. We report full-genome sequence data for three additional orbiviruses: Wallal virus (WALV); Mudjinabarry virus (MUDV) and Warrego virus (WARV). Comparisons of conserved polymerase (Pol), sub-core-shell 'T2' and core-surface 'T13' proteins show that these viruses group with other Culicoides borne orbiviruses, clustering with Eubenangee virus (EUBV), another orbivirus infecting marsupials. WARV shares <70% aa identity in all three conserved proteins (Pol, T2 and T13) with other orbiviruses, consistent with its classification within a distinct Orbivirus species. Although WALV and MUDV share <72.86%/67.93% aa/nt identity with other orbiviruses in Pol, T2 and T13, they share >99%/90% aa/nt identities with each other (consistent with membership of the same virus species - Wallal virus). However, WALV and MUDV share <68% aa identity in their larger outer capsid protein VP2(OC1), consistent with membership of different serotypes within the species - WALV-1 and WALV-2 respectively

Detection of a Fourth Orbivirus Non-Structural Protein

The genus Orbivirus includes both insect and tick-borne viruses. The orbivirus genome, composed of 10 segments of dsRNA, encodes 7 structural proteins (VP1–VP7) and 3 non-structural proteins (NS1–NS3). An open reading frame (ORF) that spans almost the entire length of genome segment-9 (Seg-9) encodes VP6 (the viral helicase). However, bioinformatic analysis recently identified an overlapping ORF (ORFX) in Seg-9. We show that ORFX encodes a new non-structural protein, identified here as NS4. Western blotting and confocal fluorescence microscopy, using antibodies raised against recombinant NS4 from Bluetongue virus (BTV, which is insect-borne), or Great Island virus (GIV, which is tick-borne), demonstrate that these proteins are synthesised in BTV or GIV infected mammalian cells, respectively. BTV NS4 is also expressed in Culicoides insect cells. NS4 forms aggregates throughout the cytoplasm as well as in the nucleus, consistent with identification of nuclear localisation signals within the NS4 sequence. Bioinformatic analyses indicate that NS4 contains coiled-coils, is related to proteins that bind nucleic acids, or are associated with membranes and shows similarities to nucleolar protein UTP20 (a processome subunit). Recombinant NS4 of GIV protects dsRNA from degradation by endoribonucleases of the RNAse III family, indicating that it interacts with dsRNA. However, BTV NS4, which is only half the putative size of the GIV NS4, did not protect dsRNA from RNAse III cleavage. NS4 of both GIV and BTV protect DNA from degradation by DNAse. NS4 was found to associate with lipid droplets in cells infected with BTV or GIV or transfected with a plasmid expressing NS4

Patient Care Teams in treatment of diabetes and chronic heart failure in primary care: an observational networks study

Contains fulltext : 97203.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Patient care teams have an important role in providing medical care to patients with chronic disease, but insight into how to improve their performance is limited. Two potentially relevant determinants are the presence of a central care provider with a coordinating role and an active role of the patient in the network of care providers. In this study, we aimed to develop and test measures of these factors related to the network of care providers of an individual patient. METHODS: We performed an observational study in patients with type 2 diabetes or chronic heart failure, who were recruited from three primary care practices in The Netherlands. The study focused on medical treatment, advice on physical activity, and disease monitoring. We used patient questionnaires and chart review to measure connections between the patient and care providers, and a written survey among care providers to measure their connections. Data on clinical performance were extracted from the medical records. We used network analysis to compute degree centrality coefficients for the patient and to identify the most central health professional in each network. A range of other network characteristics were computed including network centralization, density, size, diversity of disciplines, and overlap among activity-specific networks. Differences across the two chronic conditions and associations with disease monitoring were explored. RESULTS: Approximately 50% of the invited patients participated. Participation rates of health professionals were close to 100%. We identified 63 networks of 25 patients: 22 for medical treatment, 16 for physical exercise advice, and 25 for disease monitoring. General practitioners (GPs) were the most central care providers for the three clinical activities in both chronic conditions. The GP's degree centrality coefficient varied substantially, and higher scores seemed to be associated with receiving more comprehensive disease monitoring. The degree centrality coefficient of patients also varied substantially but did not seem to be associated with disease monitoring. CONCLUSIONS: Our method can be used to measure connections between care providers of an individual patient, and to examine the association between specific network parameters and healthcare received. Further research is needed to refine the measurement method and to test the association of specific network parameters with quality and outcomes of healthcare

Labour intensity of guidelines may have a greater effect on adherence than GPs' workload

Background: Physicians' heavy workload is often thought to jeopardise the quality of care and to be a barrier to improving quality. The relationship between these has, however, rarely been investigated. In this study quality of care is defined as care 'in accordance with professional guidelines'. In this study we investigated whether GPs with a higher workload adhere less to guidelines than those with a lower workload and whether guideline recommendations that require a greater time investment are less adhered to than those that can save time. Methods: Data were used from the Second Dutch National survey of General Practice (DNSGP- 2). This nationwide study was carried out between April 2000 and January 2002. A multilevel logistic-regression analysis was conducted of 170,677 decisions made by GPs, referring to 41 Guideline Adherence Indicators (GAIs), which were derived from 32 different guidelines. Data were used from 130 GPs, working in 83 practices with 98,577 patients. GP-characteristics as well as guideline characteristics were used as independent variables. Measures include workload (number of contacts), hours spent on continuing medical education, satisfaction with available time, practice characteristics and patient characteristics. Outcome measure is an indicator score, which is 1 when a decision is in accordance with professional guidelines or 0 when the decision deviates from guidelines. Results: On average, 66% of the decisions GPs made were in accordance with guidelines. No relationship was found between the objective workload of GPs and their adherence to guidelines. Subjective workload (measured on a five point scale) was negatively related to guideline adherence (OR = 0.95). After controlling for all other variables, the variation between GPs in adherence to guideline recommendations showed a range of less than 10%. 84% of the variation in guideline adherence was located at the GAI-level. Which means that the differences in adherence levels between guidelines are much larger than differences between GPs. Guideline recommendations that require an extra time investment during the same consultation are significantly less adhered to: (OR = 0.46), while those that can save time have much higher adherence levels: OR = 1.55). Recommendations that reduce the likelihood of a follow-up consultation for the same problem are also more often adhered to compared to those that have no influence on this (OR = 3.13). Conclusion: No significant relationship was found between the objective workload of GPs and adherence to guidelines. However, guideline recommendations that require an extra time investment are significantly less well adhered to while those that can save time are significantly more often adhered to.