Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines

The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMAPaediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private–public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of offpatent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes

Longitudinal tear protein changes correlate with ocular chronic gvhd development in allogeneic hematopoietic stem cell transplant patients

Ocular graft-versus-host disease (oGVHD) is a manifestation of chronic GVHD, frequently occurring in patients after allogeneic hematopoietic stem cell transplant (HSCT). We analyzed tear protein changes before and after allogeneic HSCT, and correlated their levels with the oGVHD development. This retrospective study included 102 patients, and data were recorded before the conditioning treatment, and after 3 to 6 months postoperatively. Tear protein analysis was performed with the Agilent-2100 Bioanalyzer on individual tears sampled by aspiration. Total protein (TP), Lysozyme-C (LYS-C), Lactoferrin (LACTO), Lipocalin-1 (LIPOC-1), Transferrin (TRANSF), Albumin (ALB), and Zinc-alpha-2-glycoprotein (ZAG-2) levels were retrieved and statistically analyzed. Following HSCT forty-three patients developed oGVHD. TP, LACTO, LYS-C, and ZAG-2 levels significantly decreased post-HSCT as compared to pre HSCT levels. In univariate analysis, TP, LACTO, and ZAG-2 decrease was associated with an increased development of oGVHD (OR = 4.49; 95% CI, 1.9 to 10.5; p < 0.001; OR = 3.08; 95% CI 1.3 to 7.6; p = 0.01; OR = 11.1; 95% CI 2.7 to 46.6; p < 0.001, respectively). TRANSF post-HSCT levels significantly increased (OR 15.7; 95% CI, 4.1 to 52.2; p = 0.0001). No pre-post-HSCT changes were shown in ALB and LIPOC-1 levels. Data suggest that TP content, LACTO, TRANSF, and ZAG-2 pre-post changes might be significant predictors of oGVHD development

Near-infrared spectroscopy as a tool for in vivo analysis of human muscles

Recent advances in materials and fabrication techniques provided portable, performant, sensing optical spectrometers readily operated by user-friendly cabled or wireless systems. Such systems allow rapid, non-invasive, and not destructive quantitative analysis of human tissues. This proof-of-principle investigation tested whether infrared spectroscopy techniques, currently utilized in a variety of areas, could be applied in living humans to categorize muscles. Using an ASD FieldSpec\uae 4 Standard-Res Spectroradiometer with a spectral sampling capability of 1.4 nm at 350\u20131000 nm and 1.1 nm at 1001\u20132500 nm, we acquired reflectance spectra in visible short-wave infra-red regions (350\u20132500 nm) from the upper limb muscles (flexors and extensors) of 20 healthy subjects (age 25\u201389 years, 9 women). Spectra off-line analysis included preliminary preprocessing, Principal Component Analysis, and Partial Least-Squares Discriminant Analysis. Near-infrared (NIR) spectroscopy proved valuable for noninvasive assessment of tissue optical properties in vivo. In addition to the non-invasive detection of tissue oxygenation, NIR spectroscopy provided the spectral signatures (ie, \u201cfingerprints\u201d) of upper limb flexors and extensors, which represent specific, accurate, and reproducible measures of the overall biological status of these muscles. Thus, non-invasive NIR spectroscopy enables more thorough evaluation of the muscular system and optimal monitoring of the effectiveness of therapeutic or rehabilitative interventions

Diagnostic Role of Bronchoalveolar Lavage in Patients with Suspected SARS-CoV-2 Pneumonia and Negative Upper Respiratory Tract Swab: A Systematic Review and Meta-Analysis

The added role of bronchoalveolar lavage (BAL) in SARS-CoV-2 detection in hospitalized patients with suspected COVID-19 pneumonia and at least one negative nasopharyngeal swab (NPS) has yet to be definitively established. We aimed to provide a systematic review and meta-analysis to summarize data from the literature on the diagnostic yield of BAL in this context. We searched Medline and Embase for all studies reporting outcomes of interest published up to October 2021. Two authors reviewed all titles/abstracts and retrieved the selected full texts according to predefined selection criteria. The summary estimate was derived using the random-effects model. Thirteen original studies, involving 868 patients, were included. The summary estimate of proportions of SARS-CoV-2 positivity in BAL fluid in patients with at least one previous negative NPS was 20% (95% confidence interval [CI]; 11–30%). Moreover, microbiological tests of BAL fluid led to the identification of other pathogens, mainly bacteria, in up to two-thirds of cases. BAL plays a crucial role in the diagnostic work-up of patients with clinical suspicion of COVID-19 and previous negative NPS, as it allowed to detect the infection in a significant proportion of subjects, who would have been otherwise misclassified, with relevant implications in the prevention of disease spread, especially in hospital settings

The Power Manager for the LHCb On-Line Farm

The Power Manager is a tool of the LHCb FMC (Farm Monitoring and Control System) which allows - in an OS-independent manner and without requiring expensive network-controlled power distributors - to switch the farm nodes on and off, and to monitor their physical condition: power status (on/off), temperatures, fan speeds and voltages. The Power Manager can operate on farm nodes whose motherboards and network interface cards implement the IPMI (Intelligent Platform Management Interface) specifications, version 1.5 or subsequent, and copes with several IPMI limitations

BN-Doped Metal–Organic Frameworks: Tailoring 2D and 3D Porous Architectures through Molecular Editing of Borazines

Building on the MOF approach to prepare porous materials, herein we report the engineering of porous BN-doped materials using tricarboxylic hexaarylborazine ligands, which are laterally decorated with functional groups at the full-carbon ‘inner shell’. Whilst an open porous 3D entangled structure could be obtained from the double interpenetration of two identical metal frameworks derived from the methyl substituted borazine, the chlorine-functionalised linker undergoes formation of a porous layered 2D honeycomb structure, as shown by single-crystal X-ray diffraction analysis. In this architecture, the borazine cores are rotated by 60° in alternating layers, thus generating large rhombohedral channels running perpendicular to the planes of the networks. An analogous unsubstituted full-carbon metal framework was synthesised for comparison. The resulting MOF revealed a crystalline 3D entangled porous structure, composed by three mutually interpenetrating networks, hence denser than those obtained from the borazine linkers. Their microporosity and CO2 uptake were investigated, with the porous 3D BN-MOF entangled structure exhibiting a large apparent BET specific surface area (1091 m2 g−1) and significant CO2 reversible adsorption (3.31 mmol g−1) at 1 bar and 273 K

The Process Controller for the LHCb On-LIne Farm

The Process Controller is a tool of the LHCb FMC (Farm Monitoring and Control System) in charge of keeping a list of applications up and running on the farm nodes. It tipically runs on a few control PCs each one watching ~200 farm nodes and performs its task by maintaining the list of scheduled applications for each controlled farm node and by interacting with the Task Manager Servers running on the farm nodes to start processes, to obtain the notification of process termination, to re-spawn the terminated processes (if requested) and to stop processes. Processes can be added to or removed from the scheduled application list for one or more nodes by means of DIM commands, while DIM services provide the list of scheduled applications for each controlled farm node together with their properties, the number of re-spawns and the re-spawn times

Impact of Interbeef on national beef cattle evaluations

Submitted 2020-07-02 | Accepted 2020-08-22 | Available 2020-12-01https://doi.org/10.15414/afz.2020.23.mi-fpap.144-155International evaluation models for beef cattle allow to compare animals’ estimated breeding values (EBV) across different countries, thanks to sires having offspring in more than one country. In this study we aimed to provide an up-to-date picture of the Interbeef international beef cattle evaluations from a national perspective, considering both large and small populations. Limousin age-adjusted weaning weight (AWW) phenotypes were available for 3,115,598 animals from 10 European countries, born between 1972 and 2017. EBV and reliabilities were obtained using a multi-trait animal model including maternal effects where AWW from different countries are modelled as different traits. We investigated the country of origin of the sires with internationally publishable EBV and, among them, the country of origin of the top 100 sires for each country scale. All countries had 20 to 28,557 domestic sires whose EBV were publishable, according to Interbeef’s rules, on the scale of other countries. All countries, except one, had domestic sires that ranked among the top 100 sires on other country scales. Across countries, inclusion of information from relatives recorded in other countries increased the reliability of EBV for domestic animals on average by 9.6 percentage points for direct EBV, and 8.3 percentage points for maternal EBV. In conclusion, international evaluations provide small countries access to a panel of elite foreign sires with EBV on their country scale and a more accurate estimation of EBV of domestic animals, while large countries obtain EBV for their sires on the scale of different countries which helps to better promote them.Keywords: international breeding values, genotype-by-environment interaction, Interbeef, reliabilities, weaning weightReferencesBonifazi, R., Vandenplas, J., Napel, J. ten, Matilainen, K., Veerkamp, R. F., & Calus, M. P. L. (2020). Impact of sub-setting the data of the main Limousin beef cattle population on the estimates of across-country genetic correlations. Genetics Selection Evolution, 52(1), 32. https://doi.org/10.1186/s12711-020-00551-9Bouquet, A., Venot, E., Laloë, D., Forabosco, F., Fogh, A., Pabiou, T., Coffey, M., Eriksson, J-A., Renand, G., & Phocas, F. (2009). Genetic Structure of the European Limousin Cattle Metapopulation Using Pedigree Analyses. Interbull Bullettin, 40, 98–103.Durr, J., & Philipsson, J. (2012). International cooperation: The pathway for cattle genomics. Animal Frontiers, 2(1), 16–21. https://doi.org/10.2527/af.2011-0026Fikse, W. F., & Philipsson, J. (2007). Development of international genetic evaluations of dairy cattle for sustainable breeding programs. Animal Genetic Resources, (41), 29–43. https://doi.org/10.1017/S1014233900002315Goddard, M. (1985). A method of comparing sires evaluated in different countries. Livestock Production Science, 13(4), 321–331. https://doi.org/10.1016/0301-6226(85)90024-7Interbeef. (2020). Interbeef Working Group, ICAR. Retrieved August 20, 2020, from https://www.icar.org/index.php/technical-bodies/working-groups/interbeef-working-group/Jorjani, H., Emanuelson, U., & Fikse, W. F. (2005). Data Subsetting Strategies for Estimation of Across-Country Genetic Correlations. Journal of Dairy Science, 88(3), 1214–1224. https://doi.org/10.3168/jds.S0022-0302(05)72788-0Journaux, L., Wickham, B., Venot, E., & Pabiou, T. (2006). Development of Routine International Genetic Evaluation Services for Beef Cattle as an Extension of Interbull ’s Services. Interbull Bulletin, 35(1), 146–152.MiX99 Development Team. (2017). MiX99: A software package for solving large mixed model equations. Release XI/2017.Moore, S. G., & Hasler, J. F. (2017). A 100-Year Review: Reproductive technologies in dairy science. Journal of Dairy Science, 100(12), 10314–10331. https://doi.org/10.3168/jds.2017-13138Mrode, R. A., & Thompson, R. (2005). Linear models for the prediction of animal breeding values: Second Edition. In Linear Models For the Prediction of Animal Breeding Values: Second Edition.Philipsson, J. (2011). Interbull Developments, Global Genetic Trends and Role in the Era of Genomics. Interbull Bulletin, 44, i–xiii.Phocas, F., Donoghue, K., & Graser, H. U. (2005). Investigation of three strategies for an international genetic evaluation of beef cattle weaning weight. Genetics Selection Evolution, 37(4), 361–380. https://doi.org/10.1051/gse:2005006Quintanilla, R., Laloë, D., & Renand, G. (2002a). Heterogeneity of variances across regions for weaning weight in Charolais breed. 7th World Congress on Genetics Applied to Livestock Production, 19–23. Montpellier, France.Quintanilla, R., Laloë, D., & Renand, G. (2002b). Heteroskedasticity and genotype by environment interaction across European countries for weaning weight in Charolais breed. Proceedings of the 33rd Biennial Session of ICAR, 147–150. Interlaken, Switzerland: EAAP publication N. 107, 2003.Renand, G., Laloë, D., Quintanilla, R., & Fouilloux, M. N. (2003). A first attempt of an international genetic evaluation of beef breeds in Europe. Interbull Bulletin, 31, 151–155.Robinson, G. K. (1986). That BLUP Is a Good Thing: The Estimation of Random Effects. Statistical Science, 6(1), 15–51.Schaeffer, L. R. (1994). Multiple-Country Comparison of Dairy Sires. Journal of Dairy Science, 77(9), 2671–2678. https://doi.org/10.3168/jds.S0022-0302(94)77209-XTier, B., & Meyer, K. (2004). Approximating prediction error covariances among additive genetic effects within animals in multiple-trait and random regression models. Journal of Animal Breeding and Genetics, 121(2), 77–89. https://doi.org/10.1111/j.1439-0388.2003.00444.xVenot, E., Fouilloux, M. N., Forabosco, F., Fogh, A., Pabiou, T., Moore, K., Eriksson, J-A., Renand, G., Laloë, D.(2009). Interbeef genetic evaluation of Charolais and Limousine weaning weights. Interbull Bulletin, 40, 61–67.Venot, E., Pabiou, T., Hjerpe, E., Nilforooshan, M. M. A., Launay, A., & Wickham, B. W. W. (2014). Benefits ofInterbeef international genetic evaluations for weaning weight. 10th World Congress of Genetics Applied to Livestock Production.Venot, E, Pabiou, T., Guerrier, J., Cromie, A., Journaux, L., Flynn, J., & Wickham, B. (2007). Interbeef in Practice: Example of a Joint Genetic Evaluation between France, Ireland and United Kingdom for Pure Bred Limousine Weaning Weights. Interbull Bulletin, 36, 41–47.Venot, E, Pabiou, T., Wickham, B., & Journaux, L. (2006). First Steps Towards a European Joint Genetic Evaluation of the Limousine Breed. Interbull Bulletin, 35, 141–145.Venot, Eric, Fouilloux, M. N., Sullivan, P., & Laloë, D. (2008). Level of Connectedness and Reliability in International Beef Evaluation. Interbull Bulletin, 38(June 2008), 3–7.Vishwanath, R. (2003). Artificial insemination: The state of the art. Theriogenology, 59(2), 571–584. https://doi.org/10.1016/S0093-691X(02)01241-4Wickham, B. W., & Durr, J. W. (2011). A new international infrastructure for beef cattle breeding. Animal Frontiers, 1(2), 53–59. https://doi.org/10.2527/af.2011-0019Wilmink, J. B. M., Meijering, A., & Engel, B. (1986). Conversion of breeding values for milk from foreign populations. Livestock Production Science, 14(3), 223–229. https://doi.org/10.1016/0301-6226(86)90081-3

A structured approach to electronic authentication assurance level derivation

We envisage a fine-grained access control solution that allows a user's access privilege to be linked to the confidence level (hereafter referred to as the assurance level) in identifying the user. Such a solution would be particularly attractive to a large-scale distributed resource sharing environment, where resources are likely to be more diversified and may have varying levels of sensitivity and resource providers may wish to adjust security protection levels to adapt to resource sensitivity levels or risk levels in the underlying environment. However, existing electronic authentication systems largely identify users through the verification of their electronic identity (ID) credentials. They take into account neither assurance levels of the credentials, nor any other factors that may affect the assurance level of an authentication process, and this binary approach to access control may not provide cost-effective protection to resources with varying sensitivity levels. To realise the vision of assurance level linked access control, there is a need for an authentication framework that is able to capture the confidence level in identifying a user, expressed as an authentication Level of Assurance (LoA), and link this LoA value to authorisation decision-making. This research investigates the feasibility of estimating a user's LoA at run-time by designing, prototyping and evaluating an authentication model that derives an LoA value based upon not only users' ID credentials, but also other factors such as access location, system environment and authentication protocol used. To this aim, the thesis has identified and analysed authentication attributes, processes and procedures that may influence the assurance level of an authentication environment. It has examined various use-case scenarios of authentication in Grid environments (a well-known distributed system) and investigated the relationships among the attributes in these scenarios. It has then proposed an authentication model, namely a generic e-authentication LoA derivation model (GEA-LoADM). The GEA-LoADM takes into account multiple authentication attributes along with their relationships, abstracts the composite effect by the multiple attributes into a generic value called the authentication LoA, and provides algorithms for the run-time derivation of LoA values. The algorithms are tailored to reflect the relationships among the attributes involved in an authentication instance. The model has a number of valuable properties, including flexibility and extensibility; it can be applied to different application contexts and supports easy addition of new attributes and removal of obsolete ones. The prototypes of the algorithms and the model have been developed. The performance and security properties of the LoA derivation algorithms and the model are analysed here and evaluated based on the prototypes. The performance costs of the GEA-LoADM are also investigated and compared against conventional authentication mechanisms, and the security of the model is tested against various attack scenarios. A case study has also been conducted using a live system, the Multi-Agency Information Sharing (MAIS) system.EThOS - Electronic Theses Online ServiceSchool of Computer Science, The University of ManchesterGBUnited Kingdo

Deep shower interpretation of the cosmic ray events observed in excess of the Greisen-Zatsepin-Kuzmin energy

We consider the possibility that the ultra-high-energy cosmic ray flux has a small component of exotic particles which create showers much deeper in the atmosphere than ordinary hadronic primaries. It is shown that applying the conventional AGASA/HiRes/Auger data analysis procedures to such exotic events results in large systematic biases in the energy spectrum measurement. SubGZK exotic showers may be mis-reconstructed with much higher energies and mimick superGZK events. Alternatively, superGZK exotic showers may elude detection by conventional fluorescence analysis techniques.Comment: 22 pages, 5 figure