Distribution of tuberculosis in migrant children and young people in Europe: a retrospective database analysis of European data.

OBJECTIVE: The burden of tuberculosis (TB) in migrant children and young people (CYP) is commonly overlooked, despite the increasing incidence of TB in migrant populations in the European region. This study aimed to examine the distribution and disease characteristics of TB among migrant and native-born CYP through analysis of data from the European Centre for Disease Prevention and Control (ECDC) surveillance system (TESSy). STUDY DESIGN: Retrospective database analysis. METHODS: A retrospective database analysis was conducted on all CYP TB cases (0-17 years) reported to TESSy (1995-2017), exploring distribution, site of TB, and presence of MDR-TB using multivariate analysis in R statistical software. RESULTS: Of the 73,176 CYP TB cases reported in the EU/EFTA (1995-2017), 24.4% (n = 17,879) occurred in migrant CYP and 75.6% (n = 55,297) occurred in native-born CYP. Migrant CYP were more likely (P < 0.001) to have pulmonary TB (OR: 1.90; 95% CI: 1.74-2.09) and unsuccessful treatment outcomes (OR: 2.05; 95% CI: 1.74-2.40) compared to native-born CYP. The proportion of extrapulmonary TB, compared to pulmonary TB across total CYP cases was higher than the existing evidence base. CONCLUSIONS: Overall, there were significant differences in the site of TB and treatment outcomes between migrant and native-born CYP. To improve outcomes, TB screening and detection practices should focus on facilitating care in migrant CYP. However, to better understand the implications of these findings on broader TB control, TB among CYP should be addressed more frequently in reports and research.

International Program to Monitor Cat Flea Populations for Susceptibility to Imidacloprid.

An international team of scientists and veterinarians was assembled in 1999 to develop a monitoring program to determine the susceptibility of cat fleas, Ctenocephalides felis felis (Bouché) (Siphonaptera: Pulicidae), to imidacloprid. Cat flea eggs were collected, shipped to laboratories, and tested for their susceptibility to imidacloprid. Over 3,000 C. felis populations were collected from 2002 to 2017 from 10 different countries. Of these, 66.3% were collected from cats and 33.7% from dogs. C. f. felis populations (n = 2,200) were bioassayed by exposing cat flea eggs and the emerging larvae to a Diagnostic Dose (DD) of 3 ppm imidacloprid in larval rearing medium. Flea eggs hatched and developed in the untreated controls in 1,837 of the isolates (83.5%) bioassayed. Flea isolates (n = 61) that had ≥5% survival at the DD of 3 ppm were retested with a second DD of 3 ppm. None of them had ≥5% survival to the second dose of 3 ppm. Of the 1,837 valid C. felis isolates tested, there has been no evidence of a decreased susceptibility to imidacloprid over the past 17 yr. The methods outlined in this article should provide an acceptable protocol for testing many of the new active ingredients that have been registered for cat flea control.

From Molecules to Patients: The Clinical Applications of Translational Bioinformatics.

OBJECTIVE: In order to realize the promise of personalized medicine, Translational Bioinformatics (TBI) research will need to continue to address implementation issues across the clinical spectrum. In this review, we aim to evaluate the expanding field of TBI towards clinical applications, and define common themes and current gaps in order to motivate future research. METHODS: Here we present the state-of-the-art of clinical implementation of TBI-based tools and resources. Our thematic analyses of a targeted literature search of recent TBI-related articles ranged across topics in genomics, data management, hypothesis generation, molecular epidemiology, diagnostics, therapeutics and personalized medicine. RESULTS: Open areas of clinically-relevant TBI research identified in this review include developing data standards and best practices, publicly available resources, integrative systemslevel approaches, user-friendly tools for clinical support, cloud computing solutions, emerging technologies and means to address pressing legal, ethical and social issues. CONCLUSIONS: There is a need for further research bridging the gap from foundational TBI-based theories and methodologies to clinical implementation. We have organized the topic themes presented in this review into four conceptual foci - domain analyses, knowledge engineering, computational architectures and computation methods alongside three stages of knowledge development in order to orient future TBI efforts to accelerate the goals of personalized medicine.

American Association of Veterinary Parasitologists' review of veterinary fecal flotation methods and factors influencing their accuracy and use--is there really one best technique?

The principle of fecal flotation is based on the ability of a solution to allow less dense material (including parasite elements) to rise to the top. However, there are numerous factors that will influence the accuracy and use of such a theoretically simple technique. Whether or not centrifugation is used appears to have an impact on the ability to detect some parasites, but not others. Using a flotation solution with a relatively high specific gravity favors the simultaneous flotation of the diagnostic stages of many different parasites while, at the same time, making recognition of some more difficult because of distortion as well as the amount of debris in the preparation. Dilution methods tend to be less accurate because they require extrapolation; however, they are quicker to perform, in part, because of the cleaner preparation. Timing is a critical factor in the success of all flotation methods, as is technical ability of the personnel involved. Thus, simplicity, low costs and time savings have generally favored gravitational flotation techniques (including the McMaster technique and its modifications). How accurate the method needs to be is dependent upon the purpose of its use and choice of method requires an understanding of analytical sensitivity and expected levels of egg excretion. In some instances where the difference between, for example, 0 and 50 eggs per gram is insignificant with regards to management decisions, less accurate methods will suffice. In others, where the presence of a parasite means treatment of the animal regardless of the numbers of eggs present, methods with higher analytical sensitivities will be required, particularly for those parasites that pass few eggs. For other uses, such as the Fecal Egg Count Reduction Test, accuracy may become critical. Therefore, even though recommendations for standardized fecal flotation procedures have been promoted in the past, it is clear that the factors are too numerous to allow for the recommendation of one, or even a few, procedures for all purposes.

Ancestry-based pharmacogenomics, adverse reactions and carbamazepine: is the FDA warning correct?

In an effort to prevent potentially fatal adverse reactions to carbamazepine, the US Food and Drug Administration (FDA) issued an alert in 2007 containing pharmacogenomic information, which is still in effect today. The alert states that carbamazepine-induced skin reactions are significantly more common in patients with the human leukocyte antigen (HLA)-B*1502 allele and that these people are almost exclusively from 'broad areas of Asia, including South Asian Indians.' This study reviews the medical evidence relied upon by the FDA and finds that the alert does not accurately reflect the medical evidence relied upon in 2007 or evidence that has been generated over the last 5 years since the label was created. The FDA drug labeling should be modified to reflect current medical evidence.

TRIAD: The Translational Research Informatics and Data Management Grid.

OBJECTIVE: Multi-disciplinary and multi-site biomedical research programs frequently require infrastructures capable of enabling the collection, management, analysis, and dissemination of heterogeneous, multi-dimensional, and distributed data and knowledge collections spanning organizational boundaries. We report on the design and initial deployment of an extensible biomedical informatics platform that is intended to address such requirements. METHODS: A common approach to distributed data, information, and knowledge management needs in the healthcare and life science settings is the deployment and use of a service-oriented architecture (SOA). Such SOA technologies provide for strongly-typed, semantically annotated, and stateful data and analytical services that can be combined into data and knowledge integration and analysis "pipelines." Using this overall design pattern, we have implemented and evaluated an extensible SOA platform for clinical and translational science applications known as the Translational Research Informatics and Data-management grid (TRIAD). TRIAD is a derivative and extension of the caGrid middleware and has an emphasis on supporting agile "working interoperability" between data, information, and knowledge resources. RESULTS: Based upon initial verification and validation studies conducted in the context of a collection of driving clinical and translational research problems, we have been able to demonstrate that TRIAD achieves agile "working interoperability" between distributed data and knowledge sources. CONCLUSION: Informed by our initial verification and validation studies, we believe TRIAD provides an example instance of a lightweight and readily adoptable approach to the use of SOA technologies in the clinical and translational research setting. Furthermore, our initial use cases illustrate the importance and efficacy of enabling "working interoperability" in heterogeneous biomedical environments.

Large-scale monitoring of imidacloprid susceptibility in the cat flea, Ctenocephalides felis.

Although on-animal topical treatment with compounds such as imidacloprid has revolutionized the control of the cat flea, Ctenocephalides felis (Bouché) (Siphonaptera: Pulicidae), the development of insecticide resistance is a continuing threat. As part of a highly co-ordinated and unprecedented resistance monitoring programme for C. felis, 1437 flea isolates were collected by veterinary clinics in Australia, Germany, France, the U.K. and 29 states in the U.S.A. from 2002 to 2009. About 65% of the collections were made from June to October each year and 71% of the collections were from cats. Collections of flea eggs were sent to one of five different laboratories, where they were tested with a diagnostic dose of imidacloprid (3 p.p.m.) applied to larval flea-rearing medium. Of the 1437 collections received, 1064 contained adequate numbers of eggs for testing. Of these isolates, untreated eggs failed to hatch in 22.7% and were not considered valid bioassays. Survival rates >5% and development of adult fleas (a threshold for further testing) occurred in only 22 isolates. They were re-tested with the same diagnostic dose and none produced >5% adult emergence. Complete dose-response bioassays were performed on three of the isolates that had triggered a second test and produced slopes, intercepts and LC(50) values similar to those for existing susceptible laboratory strains. Results confirmed sustained susceptibility of C. felis to imidacloprid, despite its widespread use for over a decade.

Surface-initiated ring-opening metathesis polymerization of 5-(perfluorohexyl)norbornene on carbon paper electrodes.

Hydrophobic coatings on carbon paper electrodes are known to provide effective water management, superior gas transfer, and improved mechanical stability of the paper in fuel cell applications. Here, we describe the surface-initiated ring-opening metathesis polymerization (ROMP) of 5-(perfluorohexyl)norbornene (NBF6) to prepare fluorocarbon-rich films on carbon paper substrates that were pre-treated with O(2) plasma. For our reaction scheme, the growth of the pNBF6 films is dependent on the concentration of hydroxyl groups on the carbon paper substrate. X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) were used to determine the required time for O(2) plasma exposure to saturate the surface with hydroxyl-termini. Complete, conformal pNBF6 films were grown on carbon paper electrodes exposed to O(2) plasma for at least 45 s. These films exhibit hydrophobic and oleophobic surface properties and serve as insulative barriers to the diffusion of aqueous ions to the conductive carbon fibers.

Surface-initiated growth of ionomer films from pt-modified gold electrodes.

The ability to chemically wire ionomer films to electrode surfaces can promote transport near interfaces and impact a host of energy-related applications. Here, we demonstrate proof-of-concept principles for the surface-initiated ring-opening metathesis polymerization (SI-ROMP) of norbornene (NB), 5-butylnorbornene (NBH4), and 5-perfluorobutylnorbornene (NBF4) from Pt-modified gold substrates and the subsequent sulfonation of olefins along the polymer backbones to produce ultrathin sulfonated polymer films. Prior to sulfonation, the films are hydrophobic and exhibit large barriers against ion transport, but sulfonation dramatically reduces the resistance of the films by providing pathways for proton diffusion. Sulfonated films derived from NBF4 and NBH4 yield more anodic potentials for oxygen reduction than those derived from NB or unfunctionalized electrodes. These improvements are consistent with hydrophobic structuring by the fluorocarbon or hydrocarbon side groups to minimize interfacial flooding and generate pathways for enhanced O(2) permeation near the interface. Importantly, we demonstrate that the sulfonated polymer chains remain anchored to the surface during voltammetry for oxygen reduction whereas short-chain thiolates that do not tether polymer are removed from the substrate. This approach, which we extend to unmodified gold electrodes at neutral pH, presents a method of cleaning the ionomer/electrode interface to remove molecular components that may hamper the performance of the electrode.

Efficacy of fipronil (9.8% w/w) + (S)-methoprene (8.8% w/w) and imidacloprid (8.8% w/w) + permethrin (44% w/w) against Dermacentor variabilis (American dog tick) on dogs.

This study evaluated overall efficacy, percentage of dogs free of live ticks, retention of ticks, and efficacy against retained ticks of fipronil (9.8% w/w) + (S)-methoprene (8.8% w/w) and imidacloprid (8.8% w/w) + permethrin (44% w/w) spot-on topical solutions against Dermacentor variabilis-infested dogs. Tick control was significantly greater (P < .05) on dogs treated with fipronil + (S)-methoprene than on control dogs for the entire 30-day study period. Conversely, the combination product of imidacloprid + permethrin demonstrated activity significantly (P < .05) different from that seen on control dogs only up to day 23. Significantly (P < .05) more dogs treated with fipronil + (S)-methoprene were free of live ticks compared with controls on days 3, 9, and 16. There was never a significant difference (P > .05) between control and imidacloprid + permethrin-treated dogs in numbers of dogs free of live ticks. After the initial 10-minute tick exposure, lower numbers of ticks were retained on the imidacloprid + permethrin-treated dogs than on the fipronil + (S)-methoprene-treated dogs. However, when evaluating the effectiveness of the acaricides on "retained ticks," it appears that while some of the ticks were rapidly knocked down on the imidacloprid + permethrin-treated dogs, efficacy against ticks still retained at 10 minutes was never greater than 50%.

Evaluation of an imidacloprid (8.8% w/w)--permethrin (44.0% w/w) topical spot-on and a fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w) topical spot-on to repel, prevent attachment, and kill adult Ixodes scapularis and Amblyomma americanum ticks on dogs.

This study evaluated the effectiveness of two topical spot-on formulations -- imidacloprid(8.8% w/w)-permethrin (44.0% w/w) and fipronil (9.8% w/w)-(S)-methoprene (8.8% w/w)--to repel, prevent the attachment of, and kill adult Ixodes scapularis and Amblyomma americanum on dogs. Twelve purpose-bred beagles were distributed into three groups of four dogs each; one group served as untreated controls, and each of the other two groups received one of the test products. Dogs were exposed to 25 adult ticks of each species for 10 minutes on posttreatment days 3, 7, 14, 21, and 28. Unattached or repelled ticks were collected and evaluated for viability, and on-dog tick counts were conducted at 3, 24, and 48 hours after tick exposure. The imidacloprid-permethrin formulation provided significant repellency against I. scapularis for up to 3 weeks after treatment, and both formulations provided good overall control of I. scapularis and A. americanum during the study period.

Evaluation of an imidacloprid (8.8% w/w)--permethrin (44.0% w/w) topical spot-on and a fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w) topical spot-on to repel, prevent attachment, and kill adult Rhipicephalus sanguineus and Dermacentor variabilis ticks on dogs.

This study evaluated the effectiveness of two topical spot-on formulations, imidacloprid (8.8% w/w)--permethrin (44.0% w/w) and fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w), to repel, prevent the attachment of, and kill adult Rhipicephalus sanguineus and Dermacentor variabilis on dogs. Twelve purpose-bred beagles were distributed into three groups of four dogs each; one group served as untreated controls and each of the other two groups received one of the test products. Dogs were exposed to 25 adult ticks of each species for 10 minutes on posttreatment days 3, 7, 14, 21, and 28. Nonattached or repelled ticks were collected and evaluated for viability, and on-dog tick counts were conducted at 3, 24, and 48 hours after tick exposure. The imidacloprid-permethrin formulation provided significant repellency of R. sanguineus and D. variabilis for up to 3 and 4 weeks after treatment, respectively; and provided good overall control for R. sanguineus and D. variabilis during the study period. The fipronil--(S)-methoprene formulation provided good overall tick control during the study period.

Efficacy of imidacloprid (8.8% w/w) plus permethrin (44% w/w) spot-on topical solution against Amblyomma americanum infesting dogs using a natural tick exposure model.

This study evaluated the efficacy of an imidacloprid 8.8% w/w + permethrin 44% w/w spot-on topical solution (K9 Advantix, Bayer Animal Health) against Amblyomma americanum using a natural field exposure model. Sixteen beagles were divided into two groups of eight dogs each. One group of dogs was treated with K9 Advantix and the other group served as untreated controls. On day -1 and at 3, 7, 14, 21 and 28 days after treatment, the dogs were walked for 80 minutes in an A. americanum-infested habitat at the Konza Prairie Biological Station in Northeastern Kansas. Postexposure tick counts (efficacy evaluations) were conducted on each dog at 3 and 48 hours after exposure. At 3 days after treatment, the efficacy of K9 Advantix within 3 hours of natural tick exposure was 88.0% and declined slowly during the study. The 48-hour postexposure efficacy remained above 93.5% throughout the study.

Accurate diagnosis of Giardia spp and proper fecal examination procedures.

A series of investigations evaluated the ability of different testing methods - a swing-head centrifugation technique using two flotation solutions (1.18-specific gravity zinc sulfate and 1.27-specific gravity Sheather's sugar solution), a passive commercial flotation technique, and the SNAP Giardia Test Kit from IDEXX Laboratories - to identify Giardia-positive dogs and recover the eggs of other intestinal parasites. It was determined that the SNAP Giardia test can improve a practice's ability to identify Giardia-infected dogs. Because of its higher specific gravity, the sugar solution was better for recovering heavy parasite eggs, such as Taenia spp, and thus is the flotation solution of choice when conducting routine centrifugation fecal examinations.

Comparative speed of kill of selamectin, imidacloprid, and fipronil-(S)-methoprene spot-on formulations against fleas on cats.

The speed of kill of selamectin, imidacloprid, and fipronil-(S)-methoprene against Ctenocephalides felis infestations on cats for one month following a single treatment was evaluated. Eighty cats were randomly allocated so that there were 20 cats in four different treatment groups. On Days -2, 7, 14, 21, and 28, each cat was infested with 100 adult C. felis from the Kansas 1 flea strain. Following initial application only imidacloprid had caused a significant reduction in adult fleas on treated cats within 6 hours, but by 24 hours all three formulations had killed 96.7% of the fleas. At 7 days post treatment, all three formulations reduced flea populations within 6 and 24 hours by 68.4% and 99.4%, respectively. At 21 and 28 days after treatment, none of the formulations killed significant numbers of fleas as compared to controls within 6 hours of infestation. At 28 days after treatment, selamectin, fipronil-(S)-methoprene, and imidacloprid had killed 99.0%, 86.4%, and 72.6% of the fleas within 48 hours of infestation, respectively. This study demonstrates that the speed of kill of residual flea products on cats decreases throughout the month following application. It also demonstrated that selamectin provided the highest level of residual activity on cats against the Kansas 1 flea strain.

Determining a diagnostic dose for imidacloprid susceptibility testing of field-collected isolates of cat fleas (Siphonaptera: Pulicidae).

The susceptibility of four laboratory strains of cat fleas, Ctenocephalides felis (Bouche), to imidacloprid was determined by three different laboratories, by using a standardized bioassay protocol. The probit lines generated by the different laboratories were very similar, with LC50 values ranging from 0.32 to 0.81 ppm. Based on these data, a diagnostic dose (DD) of 3 ppm imidacloprid in larval rearing media was provisionally identified for detecting shifts in tolerance, possibly as a consequence of incipient imidacloprid resistance. None of the larvae from the susceptible laboratory strains survived the DD. Eighteen field-collected isolates were evaluated for their susceptibility to imidacloprid and to validate a DD of 3 ppm. Probit lines from 18 field-collected isolates were very similar, with LC50 values ranging from 0.14 to 1.52 ppm. When exposed to the DD, between 3 and 10% of the exposed larvae emerged as adults from only three of the 18 isolates. All other field isolates gave 100% mortality at the DD. Under the criteria established (>5% survivorship at 3 ppm), two isolates would be established on mammalian hosts and more extensive tests conducted to exclude or confirm the presence of resistance. The DD of 3 ppm is robust enough to eliminate most of the susceptible isolates collected until today, yet low enough to identify possible isolates for further testing.

Comparison of common fecal flotation techniques for the recovery of parasite eggs and oocysts.

A variety of procedures are available to detect parasite eggs or oocysts in feces. This study compared the efficacy of simple flotation, a commercial assay, and various centrifugation techniques and three common flotation solutions. Results indicate that centrifugation consistently recovered more eggs than other methods. Proper technique is critical, including ensuring that the specific gravity of the flotation solution is correct and allowing the sample to stand for a sufficient amount of time before examining the coverslip. Because of the zoonotic health risks of many companion animal parasites, veterinarian and their staff should better utilize fecal examinations in their routine diagnostic plan.

Molecular phylogeny of isolates of Ctenocephalides felis and related species based on analysis of ITS1, ITS2 and mitochondrial 16S rDNA sequences and random binding primers.

The phylogenetic relationships among 31 different flea isolates representing seven different species were studied by nucleotide sequence comparison of the internal transcribed spacer 1 (ITS1), internal transcribed spacer 2 (ITS2) and/or mitochondrial 16S ribosomal RNA gene (mt16S-rDNA) to examine the patterns of variation. Results show that all regions are useful in discriminating among flea species. In Ctenocephalides felis and Tunga penetrans, some differences in these gene regions occurred among different isolates within the same species. In the latter case, the differences are in the mt16S-rDNA region, with one isolate showing 48% divergence in nucleotide sequence. The taxonomic implications of this result are unclear at present. The gene regions revealed differences between C. felis isolates only after DNA sequencing the PCR products. Further differentiation among C. felis isolates was obtained using four different random binding primers (decamers) and primers for mammalian aldolase to amplify narrow differences in the genome. Using these primers we were able to discriminate between different C. felis isolates and determine that some of the genetic variation coincided with minor differences in response to the control agent imidacloprid. However, overall findings do not support the existence of subspecies of C. felis.

Development of a larval bioassay for susceptibility of cat fleas (Siphonaptera: Pulicidae) to imidacloprid.

Strategies for controlling cat fleas, Ctenocephalidesfelisfelis (Bouché), have undergone dramatic changes in the past 5 yr. With the advent of on-animal treatments with residual activity the potential for the development of insecticide resistance increases. A larval bioassay was developed to determine the baseline susceptibility of field-collected strains of cat fleas to imidacloprid. All four laboratory strains tested showed a similar level of susceptibility to imidacloprid. Advantages of this bioassay are that smaller numbers of fleas are required because flea eggs are collected for the test. Insect growth regulators and other novel insecticides can also be evaluated. Using a discriminating dose, the detection of reduced susceptibility in field strains can be determined with as few as 40 eggs.