Collagen Type IV-Related Nephropathies in Portugal: Pathogenic COL4A5 Mutations and Clinical Characterization of 22 Families

Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.info:eu-repo/semantics/publishedVersio

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Detrended Fluctuation Analysis in the prediction of type 2 diabetes mellitus in patients at risk: Model optimization and comparison with other metrics

[EN] Complexity analysis of glucose time series with Detrended Fluctuation Analysis (DFA) has been proved to be useful for the prediction of type 2 diabetes mellitus (T2DM) development. We propose a modified DFA algorithm, review some of its characteristics and compare it with other metrics derived from continuous glucose monitorization in this setting. Several issues of the DFA algorithm were evaluated: (1) Time windowing: the best predictive value was obtained including all time-windows from 15 minutes to 24 hours. (2) Influence of circadian rhythms: for 48-hour glucometries, DFA alpha scaling exponent was calculated on 24hour sliding segments (1-hour gap, 23-hour overlap), with a median coefficient of variation of 3.2%, which suggests that analysing time series of at least 24-hour length avoids the influence of circadian rhythms. (3) Influence of pretreatment of the time series through integration: DFA without integration was more sensitive to the introduction of white noise and it showed significant predictive power to forecast the development of T2DM, while the pretreated time series did not. (4) Robustness of an interpolation algorithm for missing values: The modified DFA algorithm evaluates the percentage of missing values in a time series. Establishing a 2% error threshold, we estimated the number and length of missing segments that could be admitted to consider a time series as suitable for DFA analysis. For comparison with other metrics, a Principal Component Analysis was performed and the results neatly tease out four different components. The first vector carries information concerned with variability, the second represents mainly DFA alpha exponent, while the third and fourth vectors carry essentially information related to the two "pre-diabetic behaviours" (impaired fasting glucose and impaired glucose tolerance). The scaling exponent obtained with the modified DFA algorithm proposed has significant predictive power for the development of T2DM in a high-risk population compared with other variability metrics or with the standard DFA algorithm.This study has been funded by Instituto de Salud Carlos III through the project PI17/00856 (Co-funded by the European Regional Development Fund, A way to make Europe). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Colás, A.; Vigil, L.; Vargas, B.; Cuesta Frau, D.; Varela, M. (2019). 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Altered Complexity and Correlation Properties of R-R Interval Dynamics Before the Spontaneous Onset of Paroxysmal Atrial Fibrillation. Circulation, 100(20), 2079-2084. doi:10.1161/01.cir.100.20.2079Wang, H., Naghavi, M., Allen, C., Barber, R. M., Bhutta, Z. A., Carter, A., … Coates, M. M. (2016). Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053), 1459-1544. doi:10.1016/s0140-6736(16)31012-1Saudek, C. D., Derr, R. L., & Kalyani, R. R. (2006). Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c. JAMA, 295(14), 1688. doi:10.1001/jama.295.14.1688Monnier, L., Colette, C., & Owens, D. R. (2008). Glycemic Variability: The Third Component of the Dysglycemia in Diabetes. Is it Important? How to Measure it? Journal of Diabetes Science and Technology, 2(6), 1094-1100. doi:10.1177/193229680800200618Abdul-Ghani, M. A., Tripathy, D., & DeFronzo, R. A. (2006). Contributions of  -Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose. Diabetes Care, 29(5), 1130-1139. doi:10.2337/dc05-2179(2017). 2. Classification and Diagnosis of Diabetes:Standards of Medical Care in Diabetes—2018. Diabetes Care, 41(Supplement 1), S13-S27. doi:10.2337/dc18-s002Tabák, A. G., Herder, C., Rathmann, W., Brunner, E. J., & Kivimäki, M. (2012). Prediabetes: a high-risk state for diabetes development. The Lancet, 379(9833), 2279-2290. doi:10.1016/s0140-6736(12)60283-9DeFronzo, R. A., Banerji, M. A., Bray, G. A., Buchanan, T. A., Clement, S., … Tripathy, D. (2009). Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study. Diabetologia, 53(3), 435-445. doi:10.1007/s00125-009-1614-2Nathan, D. M., Davidson, M. B., DeFronzo, R. A., Heine, R. J., Henry, R. R., Pratley, R., & Zinman, B. (2007). Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for care. Diabetes Care, 30(3), 753-759. doi:10.2337/dc07-9920Ogata, H., Tokuyama, K., Nagasaka, S., Tsuchita, T., Kusaka, I., Ishibashi, S., … Yamamoto, Y. (2012). The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus. Metabolism, 61(7), 1041-1050. doi:10.1016/j.metabol.2011.12.007Kohnert, K.-D. (2015). Utility of different glycemic control metrics for optimizing management of diabetes. World Journal of Diabetes, 6(1), 17. doi:10.4239/wjd.v6.i1.17García Maset, L., González, L. B., Furquet, G. L., Suay, F. M., & Marco, R. H. (2016). Study of Glycemic Variability Through Time Series Analyses (Detrended Fluctuation Analysis and Poincaré Plot) in Children and Adolescents with Type 1 Diabetes. Diabetes Technology & Therapeutics, 18(11), 719-724. doi:10.1089/dia.2016.0208Service, F. J., O’Brien, P. C., & Rizza, R. A. (1987). Measurements of Glucose Control. Diabetes Care, 10(2), 225-237. doi:10.2337/diacare.10.2.225Goldberger, A. L., Amaral, L. A. N., Hausdorff, J. M., Ivanov, P. C., Peng, C.-K., & Stanley, H. E. (2002). Fractal dynamics in physiology: Alterations with disease and aging. Proceedings of the National Academy of Sciences, 99(Supplement 1), 2466-2472. doi:10.1073/pnas.012579499Crenier, L., Lytrivi, M., Van Dalem, A., Keymeulen, B., & Corvilain, B. (2016). Glucose Complexity Estimates Insulin Resistance in Either Nondiabetic Individuals or in Type 1 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 101(4), 1490-1497. doi:10.1210/jc.2015-4035Rodríguez de Castro, C., Vigil, L., Vargas, B., García Delgado, E., García Carretero, R., Ruiz-Galiana, J., & Varela, M. (2016). Glucose time series complexity as a predictor of type 2 diabetes. Diabetes/Metabolism Research and Reviews, 33(2), e2831. doi:10.1002/dmrr.2831Weber, C., & Schnell, O. (2009). The Assessment of Glycemic Variability and Its Impact on Diabetes-Related Complications: An Overview. Diabetes Technology & Therapeutics, 11(10), 623-633. doi:10.1089/dia.2009.0043Pincus, S. M., Gladstone, I. M., & Ehrenkranz, R. A. (1991). A regularity statistic for medical data analysis. Journal of Clinical Monitoring, 7(4), 335-345. doi:10.1007/bf01619355Richman, J. S. (2007). Sample Entropy Statistics and Testing for Order in Complex Physiological Signals. Communications in Statistics - Theory and Methods, 36(5), 1005-1019. doi:10.1080/03610920601036481Platiša, M. M., Bojić, T., Pavlović, S. U., Radovanović, N. N., & Kalauzi, A. (2016). Generalized Poincaré Plots-A New Method for Evaluation of Regimes in Cardiac Neural Control in Atrial Fibrillation and Healthy Subjects. Frontiers in Neuroscience, 10. doi:10.3389/fnins.2016.00038García-Puig, J., Ruilope, L. M., Luque, M., Fernández, J., Ortega, R., & Dal-Ré, R. (2006). Glucose Metabolism in Patients with Essential Hypertension. The American Journal of Medicine, 119(4), 318-326. doi:10.1016/j.amjmed.2005.09.010Lepot, M., Aubin, J.-B., & Clemens, F. (2017). Interpolation in Time Series: An Introductive Overview of Existing Methods, Their Performance Criteria and Uncertainty Assessment. Water, 9(10), 796. doi:10.3390/w9100796Eke, A., Hermán, P., Bassingthwaighte, J., Raymond, G., Percival, D., Cannon, M., … Ikrényi, C. (2000). Physiological time series: distinguishing fractal noises from motions. Pflügers Archiv - European Journal of Physiology, 439(4), 403-415. doi:10.1007/s004249900135Eke, A., Herman, P., Kocsis, L., & Kozak, L. R. (2002). Fractal characterization of complexity in temporal physiological signals. Physiological Measurement, 23(1), R1-R38. doi:10.1088/0967-3334/23/1/201King, A. B., Philis-Tsimikas, A., Kilpatrick, E. S., Langbakke, I. H., Begtrup, K., & Vilsbøll, T. (2017). A Fixed Ratio Combination of Insulin Degludec and Liraglutide (IDegLira) Reduces Glycemic Fluctuation and Brings More Patients with Type 2 Diabetes Within Blood Glucose Target Ranges. Diabetes Technology & Therapeutics, 19(4), 255-264. doi:10.1089/dia.2016.0405Colas, A., Vigil, L., Rodríguez de Castro, C., Vargas, B., & Varela, M. (2018). New insights from continuous glucose monitoring into the route to diabetes. Diabetes/Metabolism Research and Reviews, 34(5), e3002. doi:10.1002/dmrr.3002Henriques, T., Munshi, M. N., Segal, A. R., Costa, M. D., & Goldberger, A. L. (2014). «Glucose-at-a-Glance». Journal of Diabetes Science and Technology, 8(2), 299-306. doi:10.1177/1932296814524095Hinton, P. R. (2004). Statistics Explained. doi:10.4324/9780203496787Van Cauter, E., Blackman, J. D., Roland, D., Spire, J. P., Refetoff, S., & Polonsky, K. S. (1991). Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. Journal of Clinical Investigation, 88(3), 934-942. doi:10.1172/jci115396Qian, J., & Scheer, F. A. J. L. (2016). Circadian System and Glucose Metabolism: Implications for Physiology and Disease. Trends in Endocrinology & Metabolism, 27(5), 282-293. doi:10.1016/j.tem.2016.03.00

Acute ischemic heart disease and interventional cardiology: a time for pause

BACKGROUND: A major change has occurred in the last few years in the therapeutic approach to patients presenting with all forms of acute coronary syndromes. Whether or not these patients present initially to tertiary cardiac care centers, they are now routinely referred for early coronary angiography and increasingly undergo percutaneous revascularization. This practice is driven primarily by the angiographic image and technical feasibility. Concomitantly, there has been a decline in expectant or ischemia-guided medical management based on specific clinical presentation, response to initial treatment, and results of noninvasive stratification. This 'tertiarization' of acute coronary care has been fuelled by the increasing sophistication of the cardiac armamentarium, the peer-reviewed publication of clinical studies purporting to show the superiority of invasive cardiac interventions, and predominantly supporting (non-peer-reviewed) editorials, newsletters, and opinion pieces. DISCUSSION: This review presents another perspective, based on a critical reexamination of the evidence. The topics addressed are: reperfusion treatment of ST-elevation myocardial infarction; the indications for invasive intervention following thrombolysis; the role of invasive management in non-ST-elevation myocardial infarction and unstable angina; and cost-effectiveness and real world considerations. A few cases encountered in recent practice in community and tertiary hospitals are presented for illustrative purposes The numerous and far-reaching scientific, economic, and philosophical implications that are a consequence of this marked change in clinical practice as well as healthcare, decisional and conflict of interest issues are explored. SUMMARY: The weight of evidence does not support the contemporary unfocused broad use of invasive interventional procedures across the spectrum of acute coronary clinical presentations. Excessive and unselective recourse to these procedures has deleterious implications for the organization of cardiac health care and undesirable economic, scientific and intellectual consequences. It is suggested that there is need for a new equilibrium based on more refined clinical risk stratification in the treatment of patients who present with acute coronary syndromes

Functional redundancy and sensitivity of fish assemblages in European rivers, lakes and estuarine ecosystems

The impact of species loss on ecosystems functioning depends on the amount of trait similarity between species, i.e. functional redundancy, but it is also influenced by the order in which species are lost. Here we investigated redundancy and sensitivity patterns across fish assemblages in lakes, rivers and estuaries. Several scenarios of species extinction were simulated to determine whether the loss of vulnerable species (with high propensity of extinction when facing threats) causes a greater functional alteration than random extinction. Our results indicate that the functional redundancy tended to increase with species richness in lakes and rivers, but not in estuaries. We demonstrated that i) in the three systems, some combinations of functional traits are supported by non-redundant species, ii) rare species in rivers and estuaries support singular functions not shared by dominant species, iii) the loss of vulnerable species can induce greater functional alteration in rivers than in lakes and estuaries. Overall, the functional structure of fish assemblages in rivers is weakly buffered against species extinction because vulnerable species support singular functions. More specifically, a hotspot of functional sensitivity was highlighted in the Iberian Peninsula, which emphasizes the usefulness of quantitative criteria to determine conservation prioritiesinfo:eu-repo/semantics/publishedVersio

A framework for the development of a global standardised marine taxon reference image database (SMarTaR-ID) to support image-based analyses

Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem

High interannual variability in connectivity and genetic pool of a temperate clingfish matches oceanographic transport predictions

Adults of most marine benthic and demersal fish are site-attached, with the dispersal of their larval stages ensuring connectivity among populations. In this study we aimed to infer spatial and temporal variation in population connectivity and dispersal of a marine fish species, using genetic tools and comparing these with oceanographic transport. We focused on an intertidal rocky reef fish species, the shore clingfish Lepadogaster lepadogaster, along the southwest Iberian Peninsula, in 2011 and 2012. We predicted high levels of self-recruitment and distinct populations, due to short pelagic larval duration and because all its developmental stages have previously been found near adult habitats. Genetic analyses based on microsatellites countered our prediction and a biophysical dispersal model showed that oceanographic transport was a good explanation for the patterns observed. Adult sub-populations separated by up to 300 km of coastline displayed no genetic differentiation, revealing a single connected population with larvae potentially dispersing long distances over hundreds of km. Despite this, parentage analysis performed on recruits from one focal site within the Marine Park of Arrabida (Portugal), revealed self-recruitment levels of 2.5% and 7.7% in 2011 and 2012, respectively, suggesting that both long-and short-distance dispersal play an important role in the replenishment of these populations. Population differentiation and patterns of dispersal, which were highly variable between years, could be linked to the variability inherent in local oceanographic processes. Overall, our measures of connectivity based on genetic and oceanographic data highlight the relevance of long-distance dispersal in determining the degree of connectivity, even in species with short pelagic larval durations

Comparative analysis between mandibular positions in centric relation and maximum intercuspation by cone beam computed tomography (CONE-BEAM)

This research consisted of a quantitative assessment, and aimed to measure the possible discrepancies between the maxillomandibular positions for centric relation (CR) and maximum intercuspation (MI), using computed tomography volumetric cone beam (cone beam method). The sample of the study consisted of 10 asymptomatic young adult patients divided into two types of standard occlusion: normal occlusion and Angle Class I occlusion. In order to obtain the centric relation, a JIG device and mandible manipulation were used to deprogram the habitual conditions of the jaw. The evaluations were conducted in both frontal and lateral tomographic images, showing the condyle/articular fossa relation. The images were processed in the software included in the NewTom 3G device (QR NNT software version 2.00), and 8 tomographic images were obtained per patient, four laterally and four frontally exhibiting the TMA's (in CR and MI, on both sides, right and left). By means of tools included in another software, linear and angular measurements were performed and statistically analyzed by student t test. According to the methodology and the analysis performed in asymptomatic patients, it was not possible to detect statistically significant differences between the positions of centric relation and maximum intercuspation. However, the resources of cone beam tomography are of extreme relevance to the completion of further studies that use heterogeneous groups of samples in order to compare the results