Collaborative Practices and Multidisciplinary Research : The Dialogue Between Entrepreneurship, Management, and Data Science

Author's accepted version (post-print).Available from 06/06/2020.acceptedVersio

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcome

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.

OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised

Quantification and visualization of cardiovascular 4D velocity mapping accelerated with parallel imaging or k-t BLAST: head to head comparison and validation at 1.5 T and 3 T

<p>Abstract</p> <p>Background</p> <p>Three-dimensional time-resolved (4D) phase-contrast (PC) CMR can visualize and quantify cardiovascular flow but is hampered by long acquisition times. Acceleration with SENSE or k-t BLAST are two possibilities but results on validation are lacking, especially at 3 T. The aim of this study was therefore to validate quantitative in vivo cardiac 4D-acquisitions accelerated with parallel imaging and k-t BLAST at 1.5 T and 3 T with 2D-flow as the reference and to investigate if field strengths and type of acceleration have major effects on intracardiac flow visualization.</p> <p>Methods</p> <p>The local ethical committee approved the study. 13 healthy volunteers were scanned at both 1.5 T and 3 T in random order with 2D-flow of the aorta and main pulmonary artery and two 4D-flow sequences of the heart accelerated with SENSE and k-t BLAST respectively. 2D-image planes were reconstructed at the aortic and pulmonary outflow. Flow curves were calculated and peak flows and stroke volumes (SV) compared to the results from 2D-flow acquisitions. Intra-cardiac flow was visualized using particle tracing and image quality based on the flow patterns of the particles was graded using a four-point scale.</p> <p>Results</p> <p>Good accuracy of SV quantification was found using 3 T 4D-SENSE (r²= 0.86, -0.7 ± 7.6%) and although a larger bias was found on 1.5 T (r²= 0.71, -3.6 ± 14.8%), the difference was not significant (p = 0.46). Accuracy of 4D k-t BLAST for SV was lower (p < 0.01) on 1.5 T (r²= 0.65, -15.6 ± 13.7%) compared to 3 T (r²= 0.64, -4.6 ± 10.0%). Peak flow was lower with 4D-SENSE at both 3 T and 1.5 T compared to 2D-flow (p < 0.01) and even lower with 4D k-t BLAST at both scanners (p < 0.01). Intracardiac flow visualization did not differ between 1.5 T and 3 T (p = 0.09) or between 4D-SENSE or 4D k-t BLAST (p = 0.85).</p> <p>Conclusions</p> <p>The present study showed that quantitative 4D flow accelerated with SENSE has good accuracy at 3 T and compares favourably to 1.5 T. 4D flow accelerated with k-t BLAST underestimate flow velocities and thereby yield too high bias for intra-cardiac quantitative in vivo use at the present time. For intra-cardiac 4D-flow visualization, however, 1.5 T and 3 T as well as SENSE or k-t BLAST can be used with similar quality.</p

The Geography of Fear: A Latitudinal Gradient in Anti-Predator Escape Distances of Birds across Europe

All animals flee from potential predators, and the distance at which this happens is optimized so the benefits from staying are balanced against the costs of flight. Because predator diversity and abundance decreases with increasing latitude, and differs between rural and urban areas, we should expect escape distance when a predator approached the individual to decrease with latitude and depend on urbanization. We measured the distance at which individual birds fled (flight initiation distance, FID, which represents a reliable and previously validated surrogate measure of response to predation risk) following a standardized protocol in nine pairs of rural and urban sites along a ca. 3000 km gradient from Southern Spain to Northern Finland during the breeding seasons 2009–2010. Raptor abundance was estimated by means of standard point counts at the same sites where FID information was recorded. Data on body mass and phylogenetic relationships among bird species sampled were extracted from the literature. An analysis of 12,495 flight distances of 714 populations of 159 species showed that mean FID decreased with increasing latitude after accounting for body size and phylogenetic effects. This decrease was paralleled by a similar cline in an index of the abundance of raptors. Urban populations had consistently shorter FIDs, supporting previous findings. The difference between rural and urban habitats decreased with increasing latitude, also paralleling raptor abundance trends. Overall, the latitudinal gradient in bird fear was explained by raptor abundance gradients, with additional small effects of latitude and intermediate effects of habitat. This study provides the first empirical documentation of a latitudinal trend in anti-predator behavior, which correlated positively with a similar trend in the abundance of predators.TG was supported by the Human Frontier Science Program (RGY69/07) and MSM6198959212. JJ was supported by the EU Regional Development Foundation for the project (A31026). MD was funded by the project RISKDISP (CGL2009-08430) of the Spanish Ministerio de Ciencia e Innovación. GM was supported by TÁMOP-4.2.1./B-09/1-KMR-2010-0005 and TÁMOP-4.2.2./B-10/1-2010-0023 grants

CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD

BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear. METHODS AND FINDINGS: We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10(−12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10(−9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). CONCLUSION: Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD

Deliverable 3.6 zoning plan of case studies : evaluation of spatial management options for the case studies

Within MESMA, nine case studies (CS) represent discrete marine European spatial entities, at different spatial scales, where a spatial marine management framework is in place, under development or considered. These CS (described in more details below) are chosen in such a way (MESMA D. 3.1 ) that they encompass the complexity of accommodating the various user functions of the marine landscape in various regions of the European marine waters. While human activities at sea are competing for space, there is also growing awareness of the possible negative effects of these human activities on the marine ecosystem. As such, system specific management options are required, satisfying current and future sectoral needs, while safeguarding the marine ecosystem from further detoriation. This integrated management approach is embedded in the concept of ecosystem based management (EBM). The goal of marine EBM is to maintain marine ecosystems in a healthy, productive and resilient condition, making it possible that they sustain human use and provide the goods and services required by society (McLeod et al. 2005). Therefore EBM is an environmental mangagement approach that recognises the interactions within a marine ecosystem, including humans. Hence, EBM does not consider single issues, species or ecosystems good and services in isolation. Operationalisation of EBM can be done through place-based or spatial management approaches (Lackey 1998), such as marine spatial planning (MSP). MSP is a public process of analysing and allocating the spatial and temporal distribution of human activities aiming at achieving ecological, economic and social objectives. These objectives are usually formulated through political processes (Douvere et al. 2007, Douvere 2008). Within MESMA, a spatially managed area (SMA) is then defined as “a geographical area within which marine spatial planning initiatives exist in the real world”. Marine spatial planning initiatives refer to existing management measures actually in place within a defined area, or in any stage of a process of putting management in place, e.g. plans or recommendations for a particular area. Management can include management for marine protection (e.g. in MPAs), or management for sectoral objectives (e.g. building a wind farm to meet renewable energy objectives). Within MESMA, SMAs can have different spatial scales. A SMA can be a small, specific area that is managed/planned to be managed for one specific purpose, but it can also be a larger area within which lots of plans or ‘usage zones’ exist. This definition is different from the definition mentioned in the DoW (page 60). The original definition was adapted during a CS leader workshop (2-4 May 2012 in Gent, Belgium) and formally accepted by the MESMA ExB during the ExB meeting in Cork (29-30 May 2012). MSP should result in a marine spatial management plan that will produce the desired future trough explicit decisions about the location and timing of human activities. Ehler & Douvere (2009) consider this spatial management as a beginning toward the the implementation of desired goals and objectives. They describe the spatial management plan as a comprehensive, strategic document that provides the framework and direction for marine spatial management decisions. The plan should identify when, where and how goals and objectives will be met. Zoning (the development of zoning plans) is often an important management measure to implement spatial management plans. The purpose of a zoning plan (Ehler & Douvere 2009) is: To provide protection for biologically and ecologically important habitats, ecosystems, and ecological processes. To seperate conflicting human activities, or to combine compatible activities. To protect the natural values of the marine management area (in MESMA terminology: the SMA) while allowing reasonable human uses of the area. To allocate areas for reasonable human uses while minimising the effects of these human uses on each other, and nature. To preserve some areas of the SMA in their natural state undisturbed by humans except for scientific and educational purposes.peer-reviewe

The Highly Virulent 2006 Norwegian EHEC O103:H25 Outbreak Strain Is Related to the 2011 German O104:H4 Outbreak Strain

In 2006, a severe foodborne EHEC outbreak occured in Norway. Seventeen cases were recorded and the HUS frequency was 60%. The causative strain, Esherichia coli O103:H25, is considered to be particularly virulent. Sequencing of the outbreak strain revealed resemblance to the 2011 German outbreak strain E. coli O104:H4, both in genome and Shiga toxin 2-encoding (Stx2) phage sequence. The nucleotide identity between the Stx2 phages from the Norwegian and German outbreak strains was 90%. During the 2006 outbreak, stx2-positive O103:H25 E. coli was isolated from two patients. All the other outbreak associated isolates, including all food isolates, were stx-negative, and carried a different phage replacing the Stx2 phage. This phage was of similar size to the Stx2 phage, but had a distinctive early phage region and no stx gene. The sequence of the early region of this phage was not retrieved from the bacterial host genome, and the origin of the phage is unknown. The contaminated food most likely contained a mixture of E. coli O103:H25 cells with either one of the phages

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists’ free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among &gt;75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by &gt;67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if &gt;75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was &gt;95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.Instituto de Estudios Inmunológicos y Fisiopatológico