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Healthcare systems around the world have set ambitious targets to design and deliver more environmentally sustainable healthcare. To achieve these targets, individuals, teams, organisations, and whole systems will have to change current attitudes, practices and processes. Change management theory advocates for early identification of the influencing forces to change, so that actions can be taken to overcome the barriers and strengthen the facilitators to increase the likelihood of success. This project undertook a forcefield analysis exercise to identify the barriers and facilitators to the design and delivery of sustainable healthcare in Scotland. The exercise identified 12 facilitators and 12 barriers to sustainable change and formulated ten recommendations to strengthen the former and overcome the latter. It is hoped that the results will raise awareness of the factors that influence the design and delivery of sustainable healthcare and will inform what actions can be taken to increase the likelihood of success., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12-17 and 18-24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations.

Objective: To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection., Design: Systematic review and meta-analysis., Data Sources: Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022., Study Selection: Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine., Data Extraction and Synthesis: Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model., Results: Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82)., Conclusion: Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk., Competing Interests: Competing interests: KW is a co-founder and Chief Scientific Officer of CAN Immunize Inc. (www.canimmunize.ca). He served on the Independent Data Monitoring Committee for Medicago, and is a member of the Moderna Global Advisory Core Consultancy Group. DK serves as Chief Risk Scientist (www.risksciences.com) and has conducted work on vaccines for public sector clients., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A number of investigators have explored the use of value of information (VOI) analysis to evaluate alternative information collection procedures in diverse decision-making contexts. This paper presents an analytic framework for determining the value of toxicity information used in risk-based decision making. The framework is specifically designed to explore the trade-offs between cost, timeliness, and uncertainty reduction associated with different toxicity-testing methodologies. The use of the proposed framework is demonstrated by two illustrative applications which, although based on simplified assumptions, show the insights that can be obtained through the use of VOI analysis. Specifically, these results suggest that timeliness of information collection has a significant impact on estimates of the VOI of chemical toxicity tests, even in the presence of smaller reductions in uncertainty. The framework introduces the concept of the expected value of delayed sample information, as an extension to the usual expected value of sample information, to accommodate the reductions in value resulting from delayed decision making. Our analysis also suggests that lower cost and higher throughput testing also may be beneficial in terms of public health benefits by increasing the number of substances that can be evaluated within a given budget. When the relative value is expressed in terms of return-on-investment per testing strategy, the differences can be substantial., (© 2022 Risk Sciences International. Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

There have been reports of cases of myocarditis and pericarditis as rare complications following mRNA COVID-19 vaccinations among young adults. While most reported cases are mild, this potential vaccine safety signal should be closely monitored. Using data from the CDC and the Vaccine Adverse Event Reporting System (VAERS), we calculated the combined reporting rate of myocarditis and pericarditis stratified by age group, sex, vaccine dose, and manufacturer, and compared these rates to the crude background incidence rates. Compared to the general population prior to the administration of the first COVID-19 vaccines in December 2020, we identified a higher-than-expected reporting rate of myocarditis and pericarditis following mRNA vaccination; the risk was higher after a second vaccine dose, higher in males than in females, and decreased with age. The highest risk was seen in males 12-17 years of age with approximately 6 cases per 100,000 second doses. Our findings suggest an increased risk of myocarditis and pericarditis in young males following a second dose of an mRNA COVID-19 vaccine. Since these findings are based on safety signals derived from passive surveillance data, confirmatory epidemiological studies should be undertaken.

Exposure-response assessment methods have shifted towards more quantitative approaches, with health risk assessors exploring more statistically driven techniques. These assessments, however, usually rely on one critical health effect from a single key study. Categorical regression addresses this limitation by incorporating data from all relevant studies – including human, animal, and mechanistic studies – thereby including a broad spectrum of health endpoints and exposure levels for exposure-response analysis in an objective manner. Categorical regression requires the establishment of ordered response categories corresponding to increasingly severe adverse health outcomes and the availability of a comprehensive database that summarizes all data on different outcomes from different studies, including the exposure or dose at which these out-comes are observed and their severity. It has found application in the risk assessment of essential nutrients and trace metals. Since adverse effects may arise from either deficient or excess exposure, the exposure-response curve is U-shaped, which provides a basis for determining optimal intake levels that minimize the joint risks of deficiency and excess. This article provides an overview of the use of categorical regression fit exposure-response models incorporating data from multiple evidence streams. An extension of categorical regression that permits the simultaneous analysis of excess and deficiency toxicity data is presented and applied to comprehensive databases on copper and manganese. Future applications of cat-egorical regression will be able to make greater use of diverse data sets developed using new approach methodologies, which can be expected to provide valuable information on toxic responses of varying severity.

Mathematical modelling of ionic electrodiffusion and water movement is emerging as a powerful avenue of investigation to provide a new physiological insight into brain homeostasis. However, in order to provide solid answers and resolve controversies, the accuracy of the predictions is essential. Ionic electrodiffusion models typically comprise non-trivial systems of non-linear and highly coupled partial and ordinary differential equations that govern phenomena on disparate time scales. Here, we study numerical challenges related to approximating these systems. We consider a homogenized model for electrodiffusion and osmosis in brain tissue and present and evaluate different associated finite element-based splitting schemes in terms of their numerical properties, including accuracy, convergence and computational efficiency for both idealized scenarios and for the physiologically relevant setting of cortical spreading depression (CSD). We find that the schemes display optimal convergence rates in space for problems with smooth manufactured solutions. However, the physiological CSD setting is challenging: we find that the accurate computation of CSD wave characteristics (wave speed and wave width) requires a very fine spatial and fine temporal resolution., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications.)

A phenomenological free energy model is proposed to describe the behavior of smectic liquid crystals, an intermediate phase that exhibits orientational order and layering at the molecular scale. Advantageous properties render the functional amenable to numerical simulation. The model is applied to a number of scenarios involving geometric frustration, leading to emergent structures such as focal conic domains and oily streaks and enabling detailed elucidation of the very rich energy landscapes that arise in these problems.

Within this work, we describe the design and synthesis of a range of novel chromanones and quinolinones, based on natural products reported to possess anti-leishmanial action. The core heterocycles were obtained either via classical or ionic liquid mediated Kabbe condensation in the case of chromanones, or aqueous Sonogashira based alkynylation followed by acid-catalysed cyclisation in the case of quinolinones. Upon testing in promastigotes, axenic amastigotes and Leishmania -infected macrophages, compound 13c was identified as displaying interesting activity, inhibiting axenic amastigotes and intracellular amastigotes with IC 50 s of 25.3 and 24.6μM respectively., (© 2020 The Authors.)

A flow cytometry-based assay was developed to assess the infective titer of two recombinant viruses: a recombinant herpes simplex type 2 (rHSV-2) and a recombinant canary pox (rALVAC.gfp). This method uses granularity of infected Vero and QT-35 cells, respectively, and correlates this to the infectious titer of virus samples. The percent of the cell populations with a high level of granularity could accurately be correlated to viral titers obtained through a traditional plaque assay, with R 2 values greater than 0.8 using a semi-logarithmic scale. This approach offers a rapid, high-throughput method for infectious virus titration with similar accuracy to a traditional plaque assay., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Misclassification of a binary outcome can introduce bias in estimation of the odds-ratio associated with an exposure of interest in pharmacoepidemiology research. It has been previously demonstrated that utilizing information from an internal randomly selected validation sample can help mitigate this bias., Methods: Using a Monte Carlo simulation-based approach, we study the properties of misclassification bias-adjusted odds-ratio estimators in a contingency table setting. We consider two methods of internal validation sampling; namely, simple random sampling and sampling conditional on the original (possibly incorrect) outcome status. Additional simulation studies are conducted to investigate these sampling approaches in a multi-table setting., Results: We demonstrate that conditional validation sampling, across a range of subsampling fractions, can produce better estimates than those based on an unconditional simple random sample. This approach allows for greater flexibility in the chosen categorical composition of the validation data, as well as the potential for obtaining a more efficient estimator of the odds-ratio. We further demonstrate that this relationship holds for the Mantel-Haenszel misclassification bias-adjusted odds-ratio in stratified samples. Recommendations for the choice of validation subsampling fraction are also provided., Conclusions: Careful consideration when choosing the sampling scheme used to draw internal validation samples can improve the properties of the outcome misclassification bias-adjusted odds-ratio estimator in a (multiple) contingency table., (© 2019 John Wiley & Sons, Ltd.)

Migratory birds like endangered whooping cranes (Grus americana) require suitable nocturnal roost sites during twice annual migrations. Whooping cranes primarily roost in shallow surface water wetlands, ponds, and rivers. All these features have been greatly impacted by human activities, which present threats to the continued recovery of the species. A portion of one such river, the central Platte River, has been identified as critical habitat for the survival of the endangered whooping crane. Management intervention is now underway to rehabilitate habitat form and function on the central Platte River to increase use and thereby contribute to the survival of whooping cranes. The goal of our analyses was to develop habitat selection models that could be used to direct riverine habitat management activities (i.e., channel widening, tree removal, flow augmentation, etc.) along the central Platte River and throughout the species' range. As such, we focused our analyses on two robust sets of whooping crane observations and habitat metrics the Platte River Recovery Implementation Program (Program or PRRIP) and other such organizations could influence. This included channel characteristics such as total channel width, the width of channel unobstructed by dense vegetation, and distance of forest from the edge of the channel and flow-related metrics like wetted width and unit discharge (flow volume per linear meter of wetted channel width) that could be influenced by flow augmentation or reductions during migration. We used 17 years of systematic monitoring data in a discrete-choice framework to evaluate the influence these various metrics have on the relative probability of whooping crane use and found the width of channel unobstructed by dense vegetation and distance to the nearest forest were the best predictors of whooping crane use. Secondly, we used telemetry data obtained from a sample of 38 birds of all ages over the course of seven years, 2010-2016, to evaluate whooping crane use of riverine habitat within the North-central Great Plains, USA. For this second analysis, we focused on the two metrics found to be important predictors of whooping crane use along the central Platte River, unobstructed channel width and distance to nearest forest or wooded area. Our findings indicate resource managers, such as the Program, have the potential to influence whooping crane use of the central Platte River through removal of in-channel vegetation to increase the unobstructed width of narrow channels and through removal of trees along the bank line to increase unforested corridor widths. Results of both analyses also indicated that increases in relative probability of use by whooping cranes did not appreciably increase with unobstructed views ≥200 m wide and unforested corridor widths that were ≥330 m. Therefore, managing riverine sites for channels widths >200 m and removing trees beyond 165 m from the channel's edge would increase costs associated with implementing management actions such as channel and bank-line disking, removing trees, augmenting flow, etc. without necessarily realizing an additional appreciable increase in use by migrating whooping cranes., Competing Interests: The Platte River Recovery Implementation Program provided support in the form of salaries for authors DMB, PDF, JMF, and CBS, Western Ecosystems Technology provided support in the form of salaries for author SH, and the United States Geological Survey provided support in the form of salaries for author ATP, but none of the funding agencies had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Patient electronic health records, viewed as continuous-time right-censored survival data, can be used to estimate adverse drug reaction risk. Temporal outcome misclassification may occur as a result of errors in follow-up. These errors can be due to a failure to observe the incidence time of the adverse event of interest (due to misdiagnosis or nonreporting, etc) or an actual misdiagnosis of a competing adverse event. As the misclassifying event is often unobservable in the original data, we apply an internal validation sampling approach to produce consistent estimation in the presence of such errors. We introduce a univariate survival model and a cause-specific hazards model in which misclassification may also manifest as a diagnosis of an alternate adverse health outcome other than that of interest. We develop a method of maximum likelihood estimation of the model parameters and establish consistency and asymptotic normality of the estimators using standard results. We also conduct simulation studies to numerically investigate the finite sample properties of these estimators and the impact of ignoring the misclassification error., (© 2018 John Wiley & Sons, Ltd.)

The Flow-Sediment-Mechanical approach is one of two management strategies presented in the Platte River Recovery Implementation Program's (Program) Adaptive Management Plan to create and maintain suitable riverine habitat (≥200 m wide unobstructed channels) for whooping cranes ( Grus americana ). The Program's Flow-Sediment-Mechanical management strategy consists of sediment augmentation, mechanical vegetation clearing and channel widening, channel consolidation, and short duration high flow releases of 142-227 m 3 /s for three to five days in two out of three years in order to increase the unvegetated width of the main channel and, by extension, create and maintain suitable habitat for whooping crane use. We examined the influence of a range of hydrologic and physical metrics on total unvegetated channel width (TUCW) and maximum unobstructed channel width (MUOCW) during the period of 2007-2015 and applied those findings to assess the performance of the Flow-Sediment-Mechanical management strategy for creating and maintaining whooping crane roosting habitat. Our investigation highlights uncertainties that are introduced when exploring the relationship between physical process drivers and species habitat metrics. We identified a strong positive relationship between peak flows and TUCW and MUOCW within the Associated Habitat Reach of the central Platte River. However, the peak discharge magnitude and duration needed to create highly favorable whooping crane roosting habitat within our study area are much greater than short duration high flow releases, as currently envisioned. We also found disking in combination with herbicide application to vegetated portions of the channel are effective for creating and maintaining highly favorable unobstructed channel widths for whooping cranes in all but the very driest years. As such, resource managers could prioritize the treatment of mid-channel islands that are vegetated to increase the suitability of roosting habitat for whooping cranes.

The decade of the 1950s is well known among historians of psychiatry for the unprecedented shift toward psychopharmacological solutions to mental health problems. More psychiatric medications were introduced than ever before or since (Healy, 2002). While psychiatric researchers later credited these drugs, in part, for controlling psychotic, depressive, and anxious symptoms-and subsequently for emptying decaying psychiatric institutions throughout the Western world-psychiatrists also produced a number of other theories that relied on a more delicate and nuanced blending of psychotherapy and psychopharmacology. Canadian-based researchers were at the forefront of experiments combining mescaline, LSD, and psychoactive substances later described as "psychedelics." From a relatively isolated setting on the Canadian prairies, in one of the most notorious mental hospitals in North America, this blending of traditions generated a unique approach. A close look at the correspondence between the psychiatrist Humphry Osmond and his friend, the writer Aldous Huxley, who shared interests in psychoactive substances and their effects on perception, and the stimulation of empathy, gives us an opportunity to explore how they developed their psychedelic approach to therapy in the 1950s. The combination of working in an isolated hospital, far from the main research powers in North America, produced a sense of regional incubation and required Osmond to look for collaborators well beyond his own field of psychiatry. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

The Federally endangered interior least tern ( Sterna antillarum athalassos ) and threatened piping plover ( Charadrius melodus ) nest on emergent sandbars in several braided rivers in the USA. Previous habitat selection and geomorphic investigations identified a relationship between channel width and nesting incidence. Species-centric analyses indicate selection for the widest available channels whereas geomorphic-centric analyses indicate the probability of species occurrence was higher in narrow channels that better supported suitable sandbar habitat. Given the disparate conclusions from each of these perspectives, we examined species use in relation to channel-width metrics across segments of the Platte, Niobrara, and Loup Rivers from both perspectives. We found the probability of nesting incidence increased with increased maximum unvegetated channel width in all river segments. However, maximum unvegetated width decreased with increased total channel width once total width exceeded 300 m in the central Platte River and 500 m in all other river segments as did the probability that the channel was free of permanently-vegetated islands. Channels within the Lower Platte, Loup and Niobrara River systems with total widths of 500-800 m appear to be both wide enough to have a high probability of nesting incidence and narrow enough to be free of vegetated islands. Actions that affect channels with total, bank-to-bank widths of <500 m and >800 m would likely have a small influence on species use while actions that change the width characteristics of 500-800 m channels could have a strong negative or positive influence on species use. Integrating species- and geomorphic-centric views into a single analysis provided a fuller picture of the relationship between species use and channel-width metrics.

Essential elements such as copper and manganese may demonstrate U-shaped exposure-response relationships due to toxic responses occurring as a result of both excess and deficiency. Previous work on a copper toxicity database employed CatReg, a software program for categorical regression developed by the U.S. Environmental Protection Agency, to model copper excess and deficiency exposure-response relationships separately. This analysis involved the use of a severity scoring system to place diverse toxic responses on a common severity scale, thereby allowing their inclusion in the same CatReg model. In this article, we present methods for simultaneously fitting excess and deficiency data in the form of a single U-shaped exposure-response curve, the minimum of which occurs at the exposure level that minimizes the probability of an adverse outcome due to either excess or deficiency (or both). We also present a closed-form expression for the point at which the exposure-response curves for excess and deficiency cross, corresponding to the exposure level at which the risk of an adverse outcome due to excess is equal to that for deficiency. The application of these methods is illustrated using the same copper toxicity database noted above. The use of these methods permits the analysis of all available exposure-response data from multiple studies expressing multiple endpoints due to both excess and deficiency. The exposure level corresponding to the minimum of this U-shaped curve, and the confidence limits around this exposure level, may be useful in establishing an acceptable range of exposures that minimize the overall risk associated with the agent of interest., (© 2016 Society for Risk Analysis.)

Introduction: Manganese is an essential nutrient which can cause adverse effects if ingested to excess or in insufficient amounts, leading to a U-shaped exposure-response relationship. Methods have recently been developed to describe such relationships by simultaneously modeling the exposure-response curves for excess and deficiency. These methods incorporate information from studies with diverse adverse health outcomes within the same analysis by assigning severity scores to achieve a common response metric for exposure-response modeling., Objective: We aimed to provide an estimate of the optimal dietary intake of manganese to balance adverse effects from deficient or excess intake., Methods: We undertook a systematic review of the literature from 1930 to 2013 and extracted information on adverse effects from manganese deficiency and excess to create a database on manganese toxicity following oral exposure. Although data were available for seven different species, only the data from rats was sufficiently comprehensive to support analytical modelling. The toxicological outcomes were standardized on an 18-point severity scale, allowing for a common analysis of all available toxicological data. Logistic regression modelling was used to simultaneously estimate the exposure-response profile for dietary deficiency and excess for manganese and generate a U-shaped exposure-response curve for all outcomes., Results: Data were available on the adverse effects of 6113 rats. The nadir of the U-shaped joint response curve occurred at a manganese intake of 2.70mg/kgbw/day with a 95% confidence interval of 2.51-3.02. The extremes of both deficient and excess intake were associated with a 90% probability of some measurable adverse event., Conclusion: The manganese database supports estimation of optimal intake based on combining information on adverse effects from systematic review of published experiments. There is a need for more studies on humans. Translation of our results from rats to humans will require adjustment for interspecies differences in sensitivity to manganese., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A simple "off-the-shelf" fed-batch approach to aerobic bacterial cultivation for recombinant protein subunit vaccine manufacturing is presented. In this approach, changes in the dissolved oxygen levels are used to adjust the nutrient feed rate (DO-stat), so that the desired dissolved oxygen level is maintained throughout cultivation. This enables high Escherichia coli cell densities and recombinant protein titers. When coupled to a kLa-matched scale-down model, process performance is shown to be consistent at the 2L, 20L, and 200L scales for two recombinant E. coli strains expressing different protein subunit vaccine candidates. Additionally, by mining historical DO-stat nutrient feeding data, a method to transition from DO-stat to a pre-determined feeding profile suitable for larger manufacturing scales without using feedback control is demonstrated at the 2L, 20L, and 200L scales., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: We compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4(+) T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8(+) T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine., Importance: The finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

A high level of norleucine misincorporation was detected in a recombinant methionine-rich protein vaccine candidate expressed in E. coli K12. An investigation was conducted to evaluate a simple remediation strategy to reduce norleucine misincorporation and to determine if the phenomenon was either (a) due to the depletion of methionine during fermentation, (b) a result of the cultivation environment, or (c) a strain-specific effect. While supplementation with exogenous methionine improved product quality, the undesirable biosynthesis of non-standard amino acids such as norleucine and norvaline persisted. In contrast, non-standard amino acid biosynthesis was quickly minimized upon selection of an appropriate fed-batch process control strategy, fermentation medium, and nutrient feed. By expressing the same protein in E. coli BL21(DE3), it was determined that the biosynthesis of norleucine and norvaline, and the misincorporation of norleucine into the protein were primarily attributed to the use of E. coli K12 as the host for protein expression.

Lewis Carroll's English word game Doublets is represented as a system of networks with each node being an English word and each connectivity edge confirming that its two ending words are equal in letter length, but different by exactly one letter. We show that this system, which we call the Doublets net, constitutes a complex body of linguistic knowledge concerning English word structure that has computable multiscale features. Distributed morphological, phonological and orthographic constraints and the language's local redundancy are seen at the node level. Phonological communities are seen at the network level. And a balancing act between the language's global efficiency and redundancy is seen at the system level. We develop a new measure of intrinsic node-to-node distance and a computational algorithm, called community geometry, which reveal the implicit multiscale structure within binary networks. Because the Doublets net is a modular complex cognitive system, the community geometry and computable multi-scale structural information may provide a foundation for understanding computational learning in many systems whose network structure has yet to be fully analyzed.

Pharmacovigilance aims to identify adverse drug reactions using postmarket surveillance data under real-world conditions of use. Unlike passive pharmacovigilance, which is based on largely voluntary (and hence incomplete) spontaneous reports of adverse drug reactions with limited information on patient characteristics, active pharmacovigilance is based on electronic health records containing detailed information about patient populations, thereby allowing consideration of modifying factors such as polypharmacy and comorbidity, as well as sociodemographic characteristics. With the present shift toward active pharmacovigilance, statistical methods capable of addressing the complexities of such data are needed. We describe four such methods here, and demonstrate their application in the analysis of a large retrospective cohort of diabetics taking anti-hyperglycemic medications that may increase the risk of adverse cardiovascular events.

A simple technique to enhance the humoral immune response to intracellular protein antigens in genetic immunizations is demonstrated in mice. In this approach, the intracellular protein is intentionally secreted from expressing cells as a chimeric protein, comprising an N-terminal secreted protein fused to the intracellular protein antigen. Using the Leishmania chagasi Ldccys1 cysteine protease (411CP) as an example of an intracellular protein antigen and both human and murine granulocyte colony stimulating factor (GMCSF) as examples of N-terminal secretion competent fusion partners in chimeric proteins, a humoral response in plasmid DNA immunized mice could only be detected by Western blotting when the expressed 411CP was secreted., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Management of a pediatric airway can be a challenge, especially for the non-pediatric anesthesiologists. Structured algorithms for an unexpected difficult pediatric airway have been missing so far. A recent step wise algorithm, based on the Difficult Airway society (DAS) adult protocol, is a step in the right direction. There have been some exciting advances in development of pediatric extra-glottic devices for maintaining ventilation, and introduction of pediatric versions of new 'non line of sight' laryngoscopes and optical stylets. The exact role of these devices in routine and emergent situations is still evolving. Recent advances in simulation technology has become a valuable tool in imparting psychomotor and procedural skills to trainees and allied healthcare workers. Moving toward the goal of eliminating serious adverse events during the management of routine and difficult pediatric airway, authors propose that institutions develop a dedicated Difficult Airway Service comprising of a team of experts in advanced airway management., (© 2012 Blackwell Publishing Ltd.)

A simple approach to the development of an aerobic scaled-down fermentation model is presented to obtain more consistent process performance during the scale-up of recombinant protein manufacture. Using a constant volumetric oxygen mass transfer coefficient (k(L)a) for the criterion of a scale-down process, the scaled-down model can be "tuned" to match the k(L)a of any larger-scale target by varying the impeller rotational speed. This approach is demonstrated for a protein vaccine candidate expressed in recombinant Escherichia coli, where process performance is shown to be consistent among 2-L, 20-L, and 200-L scales. An empirical correlation for k(L)a has also been employed to extrapolate to larger manufacturing scales., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

One of the most important aspects of profiling healthcare providers or services is constructing a model that is flexible enough to allow for random variation. At the same time, we wish to identify those institutions that clearly deviate from the usual standard of care. Here, we propose a hierarchical Bayes model to study the choice of surgical procedure for rectal cancer using data previously analysed by Simons et al.(1) Using hospitals as random effects, we construct a computationally simple graphical method for determining hospitals that are outliers; that is, they differ significantly from other hospitals of the same type in terms of surgical choice.

Despite substantial growth in the field of conservation planning, the speed and success with which conservation plans are converted into conservation action remains limited. This gap between science and action extends beyond conservation planning into many other applied sciences and has been linked to complexity of current societal problems, compartmentalization of knowledge and management sectors, and limited collaboration between scientists and decision makers. Transdisciplinary approaches have been proposed as a possible way to address these challenges and to bridge the gap between science and action. These approaches move beyond the bridging of disciplines to an approach in which science becomes a social process resolving problems through the participation and mutual learning of stakeholders. We explored the principles of transdisciplinarity, in light of our experiences as conservation-planning researchers working in South Africa, to better understand what is required to make conservation planning transdisciplinary and therefore more effective. Using the transdisciplinary hierarchy of knowledge (empirical, pragmatic, normative, and purposive), we found that conservation planning has succeeded in integrating many empirical disciplines into the pragmatic stakeholder-engaged process of strategy development and implementation. Nevertheless, challenges remain in engagement of the social sciences and in understanding the social context of implementation. Farther up this knowledge hierarchy, at the normative and purposive levels, we found that a lack of integrated land-use planning and policies (normative) and the dominant effect of national values (purposive) that prioritize growth and development limit the effectiveness and relevance of conservation plans. The transdisciplinary hierarchy of knowledge highlighted that we need to move beyond bridging the empirical and pragmatic disciplines into the complex normative world of laws, policies, and planning and become engaged in the purposive processes of decision making, behavior change, and value transfer. Although there are indications of progress in this direction, working at the normative and purposive levels requires time, leadership, resources, skills that are absent in conservation training and practice, and new forms of recognition in systems of scientific reward and funding.

Multivariate Bayesian models trained with machine learning, in conjunction with rule-based time-series statistical techniques, are explored for the purpose of improving patient monitoring. Three vital sign data streams and known outcomes for 36 intensive care unit (ICU) patients were captured retrospectively and used to train a set of Bayesian net models and to construct time-series models. Models were validated on a reserved dataset from 16 additional patients. Receiver operating characteristic (ROC) curves were calculated. Area under the curve (AUC) was 91% for predicting improving outcome. The model's AUC for predicting declining outcome increased from 70% to 85% when the model was indexed to personalized baselines for each patient. The rule-based trending and alerting system was accurate 100% of the time in alerting a subsequent decline in condition. These techniques promise to improve the monitoring of ICU patients with high-sensitivity alerts, fewer false alarms, and earlier intervention.

A likelihood ratio test is proposed for the detection of an ordered group effect on bivariate responses where one response is binary and the other is continuous. The procedure is based on a conditional logistic model for the binary response given the continuous outcome. We also develop a likelihood ratio test for simultaneously determining the goodness of fit of the ordering assumption on both responses. Our approach is motivated by a particular toxicity study application involving laboratory animals that focused on the effect of a food color additive on the development of reticuloendothelial (RE) tumors. A brief discussion on extensions to the methodology introduced here is also given, along with a comparison of the approach with a marginal strategy where the presence of an ordered group effect is assessed independently for each of the two responses., ((c) 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Background: We need a sensor to measure the convective heat transfer coefficient during ablation of the heart or liver., Methods: We built a minimally invasive instrument to measure the in vivo convective heat transfer coefficient, h in animals, using a Wheatstone-bridge circuit, similar to a hot-wire anemometer circuit. One arm is connected to a steerable catheter sensor whose tip is a 1.9 mm x 3.2 mm thin film resistive temperature detector (RTD) sensor. We used a circulation system to simulate different flow rates at 39 degrees C for in vitro experiments using distilled water, tap water and saline. We heated the sensor approximately 5 degrees C above the fluid temperature. We measured the power consumed by the sensor and the resistance of the sensor during the experiments and analyzed these data to determine the value of the convective heat transfer coefficient at various flow rates., Results: From 0 to 5 L/min, experimental values of h in W/(m2.K) were for distilled water 5100 to 13000, for tap water 5500 to 12300, and for saline 5400 to 13600. Theoretical values were 1900 to 10700., Conclusion: We believe this system is the smallest, most accurate method of minimally invasive measurement of in vivo h in animals and provides the least disturbance of flow.

Background: Convection heating shows most promise in maintaining children's core temperatures under anesthesia. We have previously shown that a modified convection heating technique worked in a mannequin model and sought to establish its safety and effectiveness in a clinical study., Methods: Children were recruited who were having elective surgery under general anesthesia lasting >90 min. The children were anesthetized and maintained in a room temperature of 21 degrees C. Warming was performed by a 'Bair Hugger' attached to a heat dissipation box, producing turbulent air from multiple outlet holes on its face. A plastic sheet covered the child, was attached to the top of the box, tucked into the sides of the bed and left open at the head end. Temperatures at various sites (air, skin, and core) were continuously monitored using thermistors connected to a datalogger and laptop. Analysis was performed using Excel., Results: The study comprised 40 children ranging in age from 2 days to 12.5 years and weigh 2.5-73 kg. Operations were 'peripheral' (e.g. urethroplasty) lasting 90 min to major laparotomy lasting 590 min. Body surface area uncovered was 5-25%. Skin temperatures rose to a maximum of c. 40 degrees C. Core temperatures rose after a 12-min lag by 0.01-0.04 degrees C x min(-1). In children who became hyperthermic, cooling was readily achieved by turning the heating off and leaving the fan running., Conclusions: The technique is safe and effective for children throughout the pediatric range. The practice of increasing room temperature above 21 degrees C for elective cases should be abandoned. Continuous monitoring of core temperature is necessary to prevent hyperthermia.

Objectives: The purpose of this study is to present 2 clinical case studies in which large herniated disks were not detected on magnetic resonance imaging (MRI), leading to false negative results, and discuss some issues regarding potential shortcomings of MRI., Clinical Features: Cases of cervical and lumbar herniated nucleus pulposus (HNP) are presented. Each patient had severe pain and neurological deficit. The patients had positive physical examination findings suggestive of HNP despite the negative MRI scans. Both subsequently underwent myelography and computed tomography to arrive at the final and definitive diagnosis of HNP., Intervention and Outcome: Both patients failed a course of conservative care that included manual and mechanical traction, manual mobilization, myofascial release techniques, epidural steroid injections, oral steroid and narcotic medications, and rehabilitative exercises. Both patients eventually required surgical decompression., Conclusion: False negative MRI results in these cases of large HNPs emphasize the importance of case history and physical examination findings as the basis for ordering diagnostic tests. The conclusion of this article is simple; no single diagnostic test should be considered as 100% accurate, as false negative studies may occur that may mislead the patient and clinician.

Recent work on Bayesian inference of disease mapping models discusses the advantages of the fully Bayesian (FB) approach over its empirical Bayes (EB) counterpart, suggesting that FB posterior standard deviations of small-area relative risks are more reflective of the uncertainty associated with the relative risk estimation than counterparts based on EB inference, since the latter fail to account for the variability in the estimation of the hyperparameters. In this article, an EB bootstrap methodology for relative risk inference with accurate parametric EB confidence intervals is developed, illustrated, and contrasted with the hyperprior Bayes. We elucidate the close connection between the EB bootstrap methodology and hyperprior Bayes, present a comparison between FB inference via hybrid Markov chain Monte Carlo and EB inference via penalized quasi-likelihood, and illustrate the ability of parametric bootstrap procedures to adjust for the undercoverage in the "naive" EB interval estimates. We discuss the important roles that FB and EB methods play in risk inference, map interpretation, and real-life applications. The work is motivated by a recent analysis of small-area infant mortality rates in the province of British Columbia in Canada.

Methodology to rapidly express milligram quantities of recombinant proteins through the Lipofectin-mediated transfection of insect cells in small-scale, protein-free suspension culture is presented. The transfection phase in suspension culture was first optimized using the green fluorescence protein coupled with FACs analysis to examine the effect of variables such as the transfection media, duration, and cell density on transfection efficiency and expression level. The recombinant protein production phase was optimized using secreted alkaline phosphatase (SEAP) as a reporter protein to evaluate the cell seeding density and harvest time. Using this method, 5 secreted, 2 intracellular, and 1 chimeric protein were expressed at levels ranging from 6 to 50 mg/L. Furthermore, the ability to purify over 2 mg of His(6)-tagged SEAP by immobilized metal affinity chromatography from 50 mL insect cell culture medium to greater than 95% purity was also demonstrated. This method is suitable for scale-up and high-throughput applications.

Reovirus serotype 3 Dearing (T3D) has shown potential as a novel cancer therapy. To support the increasing demand for reovirus, a two-stage perfusion mode scheme is proposed for cell growth and reovirus production. Mouse L-929 cells were used as the host for reovirus infection due to their ability to grow well in suspension culture. Several L-929 cell growth and reovirus infection characteristics were investigated and optimized in spinner flask batch cultures. For the growth of L-929 cells, a balanced nutrient-fortification of SMEM medium increased the maximum cell density by 30%, compared to normal SMEM; however, ammonia and lactate accumulations were found to inhibit further cell growth. For the production of reovirus, approximately 90% increase in viral yield resulted when the infection temperature was reduced from 37 to 33 degrees C. Infectious reovirus particles were shown to be stable in conditioned medium at 37 and 33 degrees C. The final virus titer was dependent on the multiplicity of infection (MOI) and the host cell density at the time of infection. A combination of an MOI of 0.1 pfu/cell and an initial host cell density of 1.0 x 10(6) cells/mL in fortified medium resulted in a maximum virus titer of (4.59 +/- 0.16) x 10(9) pfu/mL and a specific yield of (2.34 +/- 0.08) x 10(3) pfu/cell. At an optimal harvest time of the infection process, 99% of the virus was associated with the cellular debris. Finally, the presence of 5.0 mM ammonia in the culture medium was shown to seriously inhibit the reovirus yield, whereas lactate concentrations up to 20 mM had no effect., (Copyright 2004 Wiley Periodicals, Inc.)

Background: Core temperature drops in all children having general anaesthesia. Convection heating may be useful, but its effectiveness in the paediatric setting is not established. Additionally, its utility in many paediatric situations is limited by blanket design., Methods: Using a mannequin model in a sham operation, we assessed the likely safety and effectiveness of a draping technique in association with a 'Bair Hugger' and a heat dissipation unit (HDU). In Part 1 of the study, the influence of ambient temperature was assessed. In Part 2, a simulated laparotomy was set up and a more detailed assessment of air temperatures around the mannequin was made. In addition, the effect of a change in the HDU design was assessed., Results: Part 1: the technique achieved 'near-plateau' temperature within 5-10 min. A difference of 8 degrees C in ambient temperature (between 18 and 26 degrees C) translated only to a 2-3 degrees C difference under the drapes. Part 2: the technique produced sidestream cooler zones at the head and shoulders. Air temperature at these sites was 28-34 degrees C, whereas at other points (irrespective of their distance from the heat source), it was 37-40 degrees C. Warm air reached sufficient skin sites to anticipate adequate heat transfer in the clinical situation. Air temperature at 'skin' surface stayed below 40 degrees C over the 90-min study period., Conclusions: A customized HDU used in association with a 'Bair Hugger' unit and a careful surgical draping technique provides stable, safe and consistent air temperatures around a mannequin. Net heat gain by a child's body should occur with this arrangement. Further evaluation in a clinical study is underway.

Foreign body aspiration is a leading cause of death in children 1-3 years old, although mortality is low for children who reach the hospital. Presenting symptoms of an inhaled foreign body depends on time since aspiration. Immediately after inhalation the child starts to cough, wheeze, or have laboured breathing. If the early signs are missed, the child usually presents with fever and other signs and symptoms of chest infection. A plain chest X-ray has relatively low sensitivity and specificity for inhaled foreign body. The gold standard for diagnosis and management of this condition is rigid open tube bronchoscopy under general anaesthesia. For late presentations, time should be taken to fast the child and complete a thorough evaluation before bronchoscopy. The procedure should be performed in a well-equipped room with at least two anaesthesiologists, one with paediatric experience, in attendance. Most experienced anaesthesiologists prefer inhalational rather than intravenous induction of anaesthesia and a ventilating bronchoscope rather than intubation. Equally good results have been reported with spontaneous ventilation or positive pressure ventilation; jet ventilation is not advocated for foreign body removal in children.

Dicubyl disulfide (1) has been prepared in six steps from commercially available dimethyl-1,4-cubanedicarboxylate in 47% overall yield. In the final step, the previously unknown cubanethiol 2 was oxidized to disulfide 1. X-ray crystallography for 1 reveals the shortest tetragonal C-S bond on record (1.771 A). In contrast to previous generalizations, density functional theory calculations predict a low S-S rotation barrier similar to that for t-BuSSBu-t. Low-temperature (13)C NMR (600 MHz) confirms the prediction.

For the first time, we report the genomic organization and characterization of Cathepsin L-like cysteine protease gene cluster from the members of Leishmania donovani complex. The cysteine protease gene cluster of Leishmania chagasi has five copies of tandemly arranged genes. The first gene (Ldccys1A) is identical to Ldccys1 cDNA and is predominantly expressed in promastigotes. The last gene (Ldccys1E) is identical to Ldccys1A with a 13 amino acids deletion in the mature domain, including one of the active site histidine residues and a truncated carboxyl terminal extension. It has a diverged 3' untranslated region and is also constitutively expressed in the parasite. Results from rapid amplification of cDNA ends (RACE) suggest that there are three different types of 3' untranslated regions, one of them is identical to that of Ldccys1A whereas another to Ldccys1E. The third one is also identical to Ldccys1A, but has a 154 nucleotides deletion near the polyA region and this gene is constitutively expressed. Gene organization and expression in L. donovani cluster is similar to that of L. chagasi. However, the last gene (Lddcys1F) is different from Ldccys1E as it lacks 13 amino acid deletions. Also, L. donovani possesses an additional copy of the gene (Lddcys1E), which is located away from the cluster. Furthermore, for the first time we have expressed full-length cysteine protease genes in an insect expression system. Ldccys1A and Ldccys1F cleaved gelatin whereas Ldccys1E was found to be inactive in gelatin assays.