Age- and sex-related variations in platelet count in Italy: a proposal of reference ranges based on 40987 subjects' data

BACKGROUND AND OBJECTIVES: Although several studies demonstrated that platelet count is higher in women, decreases with age, and is influenced by genetic background, most clinical laboratories still use the reference interval 150-400×10(9) platelets/L for all subjects. The present study was to identify age- and sex-specific reference intervals for platelet count. METHODS: We analysed electronic records of subjects enrolled in three population-based studies that investigated inhabitants of seven Italian areas including six geographic isolates. After exclusion of patients with malignancies, liver diseases, or inherited thrombocytopenias, which could affect platelet count, reference intervals were estimated from 40,987 subjects with the non parametric method computing the 2.5° and 97.5° percentiles. RESULTS: Platelet count was similar in men and women until the age of 14, but subsequently women had steadily more platelets than men. The number of platelets decreases quickly in childhood, stabilizes in adulthood, and further decreases in oldness. The final result of this phenomenon is that platelet count in old age was reduced by 35% in men and by 25% in women compared with early infancy. Based on these findings, we estimated reference intervals for platelet count ×10(9)/L in children (176-452), adult men (141-362), adult women (156-405), old men (122-350) and, old women (140-379). Moreover, we calculated an extended reference interval that takes into account the differences in platelet count observed in different geographic areas. CONCLUSIONS: The age-, sex-, and origin-related variability of platelet count is very wide, and the patient-adapted reference intervals we propose change the thresholds for diagnosing both thrombocytopenia and thrombocytosis in Italy

Relative seismic and tsunami risk assessment for Stromboli Island (Italy)

An innovative method of estimating the relative risk of buildings exposed to seismic and tsunami hazards in volcanic islands is applied to Stromboli (Italy), a well-known stratovolcano affected by moderate earthquakes and mass-flow-induced tsunamis. The method uses a pre-existing quali-quantitative analysis to assess the relative risk indices of buildings, which provide comparative results useful for prioritisation purposes, in combination with a historical-geographical settlement analysis consistent with the ‘territorialist’ approach to the urban and regional planning and design. The quali-quantitative analysis is based on a new proposed survey-sheet model, useful to collect building information necessary for the relative risk estimation, whereas the historical-geographical investigation is based on the multi-temporal comparison of aerial and satellite images. The proposal to combine two consolidated methods represents an innovation in estimating relative risk. Considering that Stromboli Island had never been subjected to similar analyses, the results of the relative seismic risk assessment are novel and moreover identify buildings with a fairly-low and spatially-uniform relative risk. The results of the relative tsunami risk assessment are consistent with results of similar past studies, identifying buildings with a higher relative risk index on the northern coast of the island. The combined use of a building-by-building survey with a multi-temporal analysis of settlements allows obtaining a higher detail than previously available for the region. If adequately modified, the proposed combination of methods allows assessing relative risk also considering other geo-environmental hazards and their cascading effects, in a multi-hazard risk assessment perspective

Environmental aftermath of the 2019 Stromboli eruption

This study focuses on the July-August 2019 eruption-induced wildfires at the Stromboli island (Italy). The analysis of land cover (LC) and land use (LU) changes has been crucial to describe the environmental impacts concerning endemic vegetation loss, damages to agricultural heritage, and transformations to landscape patterns. Moreover, a survey was useful to collect eyewitness accounts aimed to define the LU and to obtain detailed information about eruption-induced damages. Detection of burnt areas was based on PLÉIADES-1 and Sentinel-2 satellite imagery, and field surveys. Normalized Burn Ratio (NBR) and Relativized Burn Ratio (RBR) allowed mapping areas impacted by fires. LC and LU classification involved the detection of new classes, following the environmental units of landscape, being the result of the intersection between CORINE Land Cover project (CLC) and local landscape patterns. The results of multi-temporal comparison show that fire-damaged areas amount to 39% of the total area of the island, mainly affecting agricultural and semi-natural vegetated areas, being composed by endemic Aeolian species and abandoned olive trees that were cultivated by exploiting terraces up to high altitudes. LC and LU analysis has shown the strong correlation between land use management, wildfire severity, and eruption-induced damages on the island

Rare coding variants and X-linked loci associated with age at menarche

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait

Changes in the eruptive style of Stromboli Volcano before the 2019 paroxysmal phase discovered through SOM clustering of seismo-acoustic features compared with camera images and GBInSAR data

Two paroxysmal explosions occurred at Stromboli on 3 July and 28 August 2019, the first of which caused the death of a young tourist. After the first paroxysm an effusive activity began from the summit vents and affected the NW flank of the island for the entire period between the two paroxysms. We carried out an unsupervised analysis of seismic and infrasonic data of Strombolian explosions over 10 months (15 November 2018–15 September 2019) using a Self-Organizing Map (SOM) neural network to recognize changes in the eruptive patterns of Stromboli that preceded the paroxysms. We used a dataset of 14,289 events. The SOM analysis identified three main clusters that showed different occurrences with time indicating a clear change in Stromboli’s eruptive style before the paroxysm of 3 July 2019. We compared the main clusters with the recordings of the fixed monitoring cameras and with the Ground-Based Interferometric Synthetic Aperture Radar measurements, and found that the clusters are associated with different types of Strombolian explosions and different deformation patterns of the summit area. Our findings provide new insights into Strombolian eruptive mechanisms and new perspectives to improve the monitoring of Stromboli and other open conduit volcanoes

A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans

Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10−8 of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10−9), 7q11 (rs13236689, CD36, p = 2.8×10−9), 10q21 (rs7896518, JMJD1C, p = 2.3×10−12), 11q13 (rs477895, BAD, p = 4.9×10−8), and 20q13 (rs151361, SLMO2, p = 9.4×10−9). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10−8, two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation