Epidemiology-driven approaches to surveillance in HPAI-vaccinated poultry flocks aiming to demonstrate freedom from circulating HPAIV.

Incursion pressure of high pathogenicity avian influenza viruses (HPAIV) by secondary spread among poultry holdings and/or from infected migratory wild bird populations increases worldwide. Vaccination as an additional layer of protection of poultry holdings using appropriately matched vaccines aims at reducing clinical sequelae of HPAIV infection, disrupting HPAIV transmission, curtailing economic losses and animal welfare problems and cutting exposure risks of zoonotic HPAIV at the avian-human interface. Products derived from HPAIV-vaccinated poultry should not impose any risk of virus spread or exposure. Vaccination can be carried out with zero-tolerance for infection in vaccinated herds and must then be flanked by appropriate surveillance which requires tailoring at several levels: (i) Controlling appropriate vaccination coverage and adequate population immunity in individual flocks and across vaccinated populations; (ii) assessing HPAI-infection trends in unvaccinated and vaccinated parts of the poultry population to provide early detection of new/re-emerged HPAIV outbreaks; and (iii) proving absence of HPAIV circulation in vaccinated flocks ideally by real time-monitoring. Surveillance strategies, i.e. selecting targets, tools and random sample sizes, must be accommodated to the specific epidemiologic and socio-economic background. Methodological approaches and practical examples from three countries or territories applying AI vaccination under different circumstances are reviewed here.

Carbon fiber reinforced polymers for implantable medical devices.

Carbon fibers reinforced polymers (CFRPs) are prolifically finding applications in the medical field, moving beyond the aerospace and automotive industries. Owing to its high strength-to-weight ratio, lightness and radiolucency, CFRP-based materials are emerging to replace traditional metal-based medical implants. Numerous types of polymers matrices can be incorporated with carbon fiber using various manufacturing methods, creating composites with distinct properties. Thus, prior to biomedical application, comprehensive evaluation of material properties, biocompatibility and safety are of paramount importance. In this study, we systematically evaluated a series of novel CFRPs, aiming at analyzing biocompatibility for future development into medical implants or implantable drug delivery systems. These CFRPs were produced either via Carbon Fiber-Sheet Molding Compound or Fused Deposition Modelling-based additive manufacturing. Unlike conventional methods, both fabrication processes afford high production rates in a time-and cost-effective manner. Importantly, they offer rapid prototyping and customization in view of personalized medical devices. Here, we investigate the physicochemical and surface properties, material mutagenicity or cytotoxicity of 20 CFRPs, inclusive of 2 surface finishes, as well as acute and sub-chronic toxicity in mice and rabbits, respectively. We demonstrate that despite moderate in vitro physicochemical and surface changes over time, most of the CFRPs were non-mutagenic and non-cytotoxic, as well as biocompatible in small animal models. Future work will entail extensive material assessment in the context of orthopedic applications such as evaluating potential for osseointegration, and a chronic toxicity study in a larger animal model, pigs.

Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.

PURPOSE: Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. METHODS AND MATERIALS: We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. RESULTS: The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. CONCLUSIONS: Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.

Emerging technologies for local cancer treatment.

The fundamental limitations of systemic therapeutic administration have prompted the development of local drug delivery platforms as a solution to increase effectiveness and reduce side effects. By confining therapeutics to the site of disease, local delivery technologies can enhance therapeutic index. This review highlights recent advances and opportunities in local drug delivery strategies for cancer treatment in addition to challenges that need to be addressed to facilitate clinical translation. The benefits of local cancer treatment combined with technological advancements and increased understanding of the tumor microenvironment, present a prime breakthrough opportunity for safer and more effective therapies.

Chronic constipation in infants and children.

Constipation is common in infants and children. Helping parents understand the vicious cycle of childhood chronic constipation is the key to successful management. Weaning, toilet training, transitions to kindergarten/school, a bout of febrile illness and overseas holidays are common life milestones that may be associated with an increased risk of constipation. A detailed history and targeted physical examination can rule out most organic causes of chronic constipation. Infrequent defecation (≤ 2 per week), faecal incontinence, retentive posturing, painful or hard bowel movements or large diameter of stool suggest functional constipation. The Bristol stool chart is a free, useful tool for parents or caregivers to report and monitor the child's stools. Red flags in constipation include delayed passage of meconium beyond 48 hours of life, associated intestinal obstruction symptoms, developmental delays, behavioural problems and frequent soiling of underwear. Behavioural modifications should be considered in primary care, together with pharmacotherapy such as laxatives.

Applying Bidirectional Transformations to the Design of Interoperable EMR Systems.

Interoperability between heterogeneous health information systems has remained an elusive goal despite decades of exchange standards development and implementation initiatives. Empirical studies have shown that in many cases, implemented interoperability interfaces fail to function correctly. Unfortunately, the health informatics literature provides little guidance on how to best design and assure interoperability interfaces. Still, healthcare is not the only industry that requires the exchange of highly complex semantic data structures. Similar requirements can be observed in the engineering industry, where complex data models maintained by various types of development tools and environments must be synchronized over a product's life cycle. Research on how to best address this challenge has led to the development of the concept of bidirectional transformations (BX) and associated design theories, methods, and tools. While BX approaches have received little attention in e-Health interoperability applications to date, we believe that they can also facilitate the implementation and assurance of interoperability in that domain. In this paper, we cast the health information exchange (HIE) challenge as a BX problem, review applicable BX theories, and discuss their practical applications from the perspective of software engineers who are tasked with constructing and assuring bidirectional interoperability interfaces for health information systems. We further design a proof-of-concept interoperability interface using BX design methods in the context of a real-world interoperability standard initiative. We compare the new BX-based interoperability interface with a preexisting, conventionally designed implementation. We find that the BX design offers similar runtime performance while providing improved maintainability, testability, and modularity.

Patient-, software-, and observer-related factors associated with the time required for semi-automated measurements of the maxillary sinus volume using cone beam computed tomography (CBCT)

This study aimed to evaluate patient-, software-, and observer-related factors influencing the time required for volumetric measurements of maxillary sinuses using cone beam computed tomography (CBCT) and a commercially available software. The volumes of healthy bilateral maxillary sinuses of adult patients from CBCT images taken during a 15-month study period were measured using dedicated software by two observers. The time required for volumetric assessments was evaluated statistically with respect to the potential influence of gender, age, sinus side, sinus volume, sequence of measurement, and selection threshold of the software. The resulting average sinus volume of the 174 sinuses from 87 patients was 16.9 cm3. The average time required to measure one sinus volume was 91.8 s. Sinuses from male patients required a longer time (median of 95.5 s) for the measurements than their female counterparts (median of 87.5 s). Measurement time increased with increasing age, sinus volume and selection threshold based on calculated grey values provided by the software. The volumetric measurements and measurement times exhibited a high intra-observer agreement. The volumetric measurements were highly reproducible. Each measurement was completed within 4 minutes, though there was a marked difference in the mean measurement time between the two observers. Semi-automated volumetric measurement of the maxillary sinus with commercially available software is feasible, efficient, and reproducible. Based on these favorable findings, practitioners might consider using such volumetric instead of linear measurements to plan and analyse outcomes of sinus grafting procedures in daily clinical practice.

A Retrospective Evaluation of Factors Influencing the Volume of Healthy Maxillary Sinuses Based on CBCT Imaging.

The aim of this study was to evaluate the factors influencing the volume of healthy maxillary sinuses by means of cone beam computed tomography (CBCT). The sinus volumes in bilateral CBCT images of healthy maxillary sinuses of patients aged 18 years or older were evaluated using dedicated 3D volumetric software. Differences in volume based on gender, age, sinus side, and dental status were analyzed statistically. The study included 174 healthy maxillary sinuses in 87 patients (60 women and 27 men) aged between 18 to 82 years with a mean age of 29.5 years. There were 73 dentate sinuses and 101 partially dentate or edentulous sinuses. Males had significantly larger maxillary sinus volumes compared to females. Subjects below the median age of 24.3 years had a significantly larger sinus volume than older subjects. There was no difference in sinus volume between left and right sides. When partially dentate and edentulous cases were pooled together and compared to dentate cases, there was no difference in sinus volume. Gender and age influence healthy maxillary sinus volume, while sinus side and dental status do not. Neither tooth loss nor increasing age could be correlated with ongoing pneumatization of the maxillary sinus in the present population. Thus, the reported increase of the maxillary sinus volume over life and following extraction of posterior teeth in the upper jaw might be considered a misconception. To prove this hypothesis, prospective studies comparing sinus volumes using standardized time intervals before and after tooth extraction in the posterior maxilla are needed.

Movement time and guidance accuracy in teleoperation of robotic vehicles.

Two experiments are reported on the steering of a tracked vehicle through straight-line courses and corners to determine the relationships between movement time and control accuracy with the geometry of the course, such as the vehicle width, the track width and the type of corner. For straight line tracking, Drury's law in which movement time (MT) is linear with the tracking task difficulty measure [A/(W - d)] is found to hold, where A is the distance traveled, 'W' is the track width and 'd' is the vehicle width. Performance in three types of corners (right angle, cut angle and circular) varied little, with the most important factor being the clearance (W - d) available to the operator. Collisions with boundary walls were also highly related to this factor. The reported research has strong relevance to the training of operators for urban search and rescue robots. Practitioner summary: Data for steering a real vehicle in a simulated environment of straight paths and different corner geometries showed that Drury's law holds for straight line tracking and the clearance between the widths of vehicle and track is important in steering corners. Data show clear need for training of USAR (Urban Search and Rescue) operators.

First case report of fatal Nocardia nova infection in yellow-bibbed lory (Lorius chlorocercus) identified by multilocus sequencing.

BACKGROUND: Nocardiosis is often a multi-systemic disease in humans and other mammals. Nocardiosis in birds is uncommon. Laboratory identification of Nocardia to the species level is difficult by traditional phenotypic methods based on biochemical reactions and hydrolysis tests, and is most accurately performed by sequencing multiple gene targets. CASE PRESENTATION: We report the first case of fatal Nocardia nova infection in a yellow-bibbed lory nestling in an oceanarium diagnosed by multilocus sequencing. Necropsy examination showed effacement of normal sternal musculature with yellowish, firm aberrant material, and diffuse infiltration of the lungs with nodular, tan to yellow foci. Histologically, severe granulomatous inflammation with marked necrosis was observed in the lung, spleen and sternal musculature. Fine, sometimes Gram-positive, 0.5-1 µm wide, branching and beaded filamentous organisms were visible within the lesions. They were acid-fast on Fite-Faraco stain. Tissue samples obtained from the sternum, liver, right lung and right kidney recovered Nocardia species. Sequencing of four gene loci and phylogenetic analysis of concatenated (gyrB-16S-secA1-hsp65) sequences revealed that the isolate was N. nova. CONCLUSIONS: We report the first case of N. nova infection in yellow-bibbed lorry (Lorius chlorocercus). The present case is the first one of which the species identity of the isolate was determined by multilocus sequencing. Molecular diagnosis is important for identifying the Nocardia to species level and understanding the epidemiology of nocardiosis in birds.

Nanofluidic microsystem for sustained intraocular delivery of therapeutics.

Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis.

The mechanism of action of Lipiburn on fat metabolism.

Paeoniflorin (PF) is the active ingredient in Lipiburn, a fat loss supplement. PF is a component in Paeonia Lactiflora with multiple medicinal uses. Here, we studied the effect of Lipiburn on fat metabolism in differentiated 3T3-L1 adipocytes. Adipocytes exposed to Lipiburn exhibited significant increase in expression of beta-adrenergic receptors, HSL levels, and cAMP and exhibited increase in glycerol release. The data show that Lipiburn affects fat metabolism through the cAMP route by activating HSL which in turn breaks down triglycerides into glycerol and fatty acids.

Crystal structure and biochemical properties of putrescine carbamoyltransferase from Enterococcus faecalis: Assembly, active site, and allosteric regulation.

Putrescine carbamoyltransferase (PTCase) catalyzes the conversion of carbamoylputrescine to putrescine and carbamoyl phosphate (CP), a substrate of carbamate kinase (CK). The crystal structure of PTCase has been determined and refined at 3.2 Å resolution. The trimeric molecular structure of PTCase is similar to other carbamoyltransferases, including the catalytic subunit of aspartate carbamoyltransferase (ATCase) and ornithine carbamoyltransferase (OTCase). However, in contrast to other trimeric carbamoyltransferases, PTCase binds both CP and putrescine with Hill coefficients at saturating concentrations of the other substrate of 1.53 ± 0.03 and 1.80 ± 0.06, respectively. PTCase also has a unique structural feature: a long C-terminal helix that interacts with the adjacent subunit to enhance intersubunit interactions in the molecular trimer. The C-terminal helix appears to be essential for both formation of the functional trimer and catalytic activity, since truncated PTCase without the C-terminal helix aggregates and has only 3% of native catalytic activity. The active sites of PTCase and OTCase are similar, with the exception of the 240's loop. PTCase lacks the proline-rich sequence found in knotted carbamoyltransferases and is unknotted. A Blast search of all available genomes indicates that 35 bacteria, most of which are Gram-positive, have an agcB gene encoding PTCase located near the genes that encode agmatine deiminase and CK, consistent with the catabolic role of PTCase in the agmatine degradation pathway. Sequence comparisons indicate that the C-terminal helix identified in this PTCase structure will be found in all other PTCases identified, suggesting that it is the signature feature of the PTCase family of enzymes.

Reducing malaria misdiagnosis: the importance of correctly interpreting Paracheck Pf® "faint test bands" in a low transmission area of Tanzania.

BACKGROUND: Although malaria rapid diagnostic tests (RDTs) have been extensively evaluated since their introduction in the early 1990's, sensitivity and specificity vary widely limiting successful integration into clinical practice. This paper reviews specific issues surrounding RDT use in field settings and presents results of research investigating how to interpret "faint test bands" on ParaCheck Pf® in areas of low transmission in order to reduce malaria misdiagnosis. METHODS: A multi-phase cross-sectional study was conducted at a remote hospital in the northern Tanzanian highlands. Capillary blood samples were taken from consenting participants (n = 319) for blood smear and ParaCheck Pf® testing. Primary outcome variables were sensitivity, specificity and proportion misdiagnosed by ParaCheck Pf® and local microscopy. ParaCheck Pf® "faint bands" were classified as both true positives or true negatives during evaluation to determine appropriate clinical interpretation. Multivariate logistic regression adjusted for age and gender was conducted to determine odds of misdiagnosis for local microscopy and ParaCheck Pf®. RESULTS: Overall, 23.71% of all ParaCheck Pf® tests resulted in a "faint band" and 94.20% corresponded with true negatives. When ParaCheck Pf® "faint bands" were classified as positive, specificity was 75.5% (95% CI = 70.3%-80.6%) as compared to 98.9% (95% CI = 97.0%-99.8%) when classified as negative. The odds of misdiagnosis by local microscopy for those > 5 years as compared to those ≤ 5 years are 0.370 (95% CI = 0.1733-0.7915, p = 0.010). In contrast, even when ParaCheck Pf® faint bands are considered positive, the odds of misdiagnosis by ParaCheck Pf® for those > 5 years as compared to those ≤ 5 years are 0.837 (95% CI = 0.459-1.547, p = 0.5383). CONCLUSIONS: We provide compelling evidence that in areas of low transmission, "faint bands" should be considered a negative test when used to inform clinical decision-making. Correct interpretation of RDT test bands in a clinical setting plays a central role in successful malaria surveillance, appropriate patient management and most importantly reducing misdiagnosis.

Reversible post-translational carboxylation modulates the enzymatic activity of N-acetyl-L-ornithine transcarbamylase.

N-Acetyl-l-ornithine transcarbamylase (AOTCase), rather than ornithine transcarbamylase (OTCase), is the essential carbamylase enzyme in the arginine biosynthesis of several plant and human pathogens. The specificity of this unique enzyme provides a potential target for controlling the spread of these pathogens. Recently, several crystal structures of AOTCase from Xanthomonas campestris (xc) have been determined. In these structures, an unexplained electron density at the tip of the Lys302 side chain was observed. Using (13)C NMR spectroscopy, we show herein that Lys302 is post-translationally carboxylated. The structure of wild-type AOTCase in a complex with the bisubstrate analogue N(delta)-(phosphonoacetyl)-N(alpha)-acetyl-l-ornithine (PALAO) indicates that the carboxyl group on Lys302 forms a strong hydrogen bonding network with surrounding active site residues, Lys252, Ser253, His293, and Glu92 from the adjacent subunit either directly or via a water molecule. Furthermore, the carboxyl group is involved in binding N-acetyl-l-ornithine via a water molecule. Activity assays with the wild-type enzyme and several mutants demonstrate that the post-translational modification of lysine 302 has an important role in catalysis.

Barriers in phase I cancer clinical trials referrals and enrollment: five-year experience at the Princess Margaret Hospital.

BACKGROUND: There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to identify obstacles in the recruitment process. METHODS: A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded. RESULTS: A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots. CONCLUSION: This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates.

Preoperative chemo-radiation-induced ulceration in patients with esophageal cancer: a confounding factor in tumor response assessment in integrated computed tomographic-positron emission tomographic imaging.

HYPOTHESIS: Positron emission tomography can be useful in predicting response of esophageal cancer after preoperative chemo-radiation therapy (CRT). We evaluated the use of integrated computed tomography (CT)-PET among patients with esophageal cancer being considered for resection after CRT. METHODS: Three reviewers blinded to clinical and pathologic staging retrospectively reviewed the CT-PET scans of patients with esophageal cancer after preoperative CRT who underwent esophagectomy. [F]-fluoro-2-deoxy-D-glucose uptake for residual malignancy was determined by visual analysis and semi-quantitatively when standardized uptake value (SUV) was > or =4. RESULTS: Forty-two patients underwent esophageal resection. Using visual analysis, CT-PET had a sensitivity of 47% and specificity of 58% in detecting residual malignancy. Using semi-quantitative analysis, 19 patients had a SUV > or =4 in the region of the primary esophageal tumor and were interpreted as having residual malignancy (sensitivity 43%, specificity 50%). Of these 19, six had complete pathologic response to CRT. These false-positive results, due to therapy-induced ulceration detected at endoscopy, limit the use of CT-PET alone in detecting residual malignancy. Similarly, sensitivity (25%) and specificity (73%) of endoscopy/biopsy in detecting residual malignancy were poor. However, the accuracy of CT-PET in detecting residual malignancy was improved when combined with endoscopic findings. In the absence of ulceration at endoscopy, 8 of 8 patients with SUV > or =4 after chemo-radiation had residual malignancy at surgery. CONCLUSIONS: CRT-induced ulceration results in false-positive results on CT-PET and precludes accurate detection of residual esophageal tumor. However, CT-PET in combination with endoscopy is useful in identifying patients with a high risk of residual tumor post-CRT.