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

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations:the EUROSPAN project

We set out to identify common genetic determinants of the length of the RR and QT intervals in 2325 individuals from isolated European populations.We analyzed the heart rate at rest, measured as the RR interval, and the length of the corrected QT interval for association with 318 237 single-nucleotide polymorphisms. The RR interval was associated with common variants within GPR133, a G-protein-coupled receptor (rs885389, P=3.9 x 10(-8)). The QT interval was associated with the earlier reported NOS1AP gene (rs2880058, P=2.00 x 10(-10)) and with a region on chromosome 13 (rs2478333, P=4.34 x 10(-8)), which is 100 kb from the closest known transcript LOC730174 and has previously not been associated with the length of the QT interval.Our results suggested an association between the RR interval and GPR133 and confirmed an association between the QT interval and NOS1AP

Return of research results (RoRR) to the healthy CHRIS cohort: designing a policy with the participants

Legal, financial and organizational challenges and the absence of coherent international guidelines and legal frameworks still discourage many genetic studies to share individual research results with their participants. Studies and institutions deciding to return genetic results will need to design their own study-specific return policy after due consideration of the ethical responsibilities. The Cooperative Health Research in South Tyrol (CHRIS) study, a healthy cohort study, did not foresee the return of individual genomic results during its baseline phase. However, as it was expected that the follow-up phase would generate an increasing amount of reliable genetic results, an update of the return of research results (RoRR) policy became necessary. To inform this revision, an empirical study using mixed methods was developed to investigate the views of CHRIS research participants (20), local general practitioners (3) and the local genetic counselling service (1). During the interviews, three different examples of potential genetic results with a very diverse potential impact on participants were presented: breast cancer, Parkinson disease and Huntington disease. The CHRIS participants also completed a short questionnaire, collecting personal information and asking for a self-evaluation of their knowledge about genetics. This study made it clear that research participants want to make autonomous decisions on the disclosure or non-disclosure of their results. While the motivations for participants' decisions were very diverse, we were able to identify several common criteria that had a strong influence on their choices. Providing information on these factors is crucial to enable participants to make truly informed decisions. [Abstract copyright: © 2021. The Author(s).

Localising Loci underlying Complex Trait Variation Using Regional Genomic Relationship Mapping

The limited proportion of complex trait variance identified in genome-wide association studies may reflect the limited power of single SNP analyses to detect either rare causative alleles or those of small effect. Motivated by studies that demonstrate that loci contributing to trait variation may contain a number of different alleles, we have developed an analytical approach termed Regional Genomic Relationship Mapping that, like linkage-based family methods, integrates variance contributed by founder gametes within a pedigree. This approach takes advantage of very distant (and unrecorded) relationships, and this greatly increases the power of the method, compared with traditional pedigree-based linkage analyses. By integrating variance contributed by founder gametes in the population, our approach provides an estimate of the Regional Heritability attributable to a small genomic region (e.g. 100 SNP window covering ca. 1 Mb of DNA in a 300000 SNP GWAS) and has the power to detect regions containing multiple alleles that individually contribute too little variance to be detectable by GWAS as well as regions with single common GWAS-detectable SNPs. We use genome-wide SNP array data to obtain both a genome-wide relationship matrix and regional relationship (“identity by state" or IBS) matrices for sequential regions across the genome. We then estimate a heritability for each region sequentially in our genome-wide scan. We demonstrate by simulation and with real data that, when compared to traditional (“individual SNP") GWAS, our method uncovers new loci that explain additional trait variation. We analysed data from three Southern European populations and from Orkney for exemplar traits – serum uric acid concentration and height. We show that regional heritability estimates are correlated with results from genome-wide association analysis but can capture more of the genetic variance segregating in the population and identify additional trait loci

Zum Ende des Studiums (k)eine Spur von Sicherheit(en)

Die vorliegende Arbeit untersucht die Zeit des Übergangs im Lebenslauf zwischen Studium und Beruf. Dabei wird auf das Konstrukt „Sicherheit(en)“ Bezug genommen und analysiert, inwiefern in dieser von Unsicherheiten und Risiken geprägten Lebensphase von Sicherheit(en) gesprochen werden kann sowie gesprochen wird. Während im theoretischen Teil der Arbeit eine angenommene Unterscheidung in „alte“ und „neue“ Sicherheit(en) geklärt wird, sollen geführte Gruppendiskussionen mit Studierenden, die sich im Übergang Studium-Beruf befinden, Erfahrungen zu und mit Sicherheit(en) sichtbar machen. Weiters werden zwei sozialpädagogische Perspektiven – sie sind gekennzeichnet mit: „den eigenen Lebensplan unter entgrenzten Voraussetzungen schreiben müssen beziehungsweise entwerfen dürfen“ – skizziert. Die Anbindung der Ergebnisse aus den Gruppendiskussionen an Überlegungen zu einer Sozialpädagogik des Übergangs geht davon aus, dass Sicherheit(en) als Voraussetzung für die Perspektive „entwerfen dürfen“ gedacht werden können. In diesem Bezug kann von einer Sozialpädagogik des Übergangs, die vom Etikett „Übergänge im Gefühl der Sicherheit entwerfen dürfen“ gekennzeichnet ist, gesprochen werden. Die Ergebnisse zeigen auf, dass Diskussionen hierzu eng an „Orientierung finden“ und an „Sich-Orientieren-Können“ gebunden sind.This paper focuses on the time of transition from university to the workplace. The construct, or notion of “security/-ies”, is the central aspect taken into account in this study, analysing if this notion can be and is spoken of in such an insecure and risky phase of life. While the theoretical part of this paper sets about to clarify a supposed distinction between “old” and “new” security/-ies, the practical part sheds light on the experience with and on “security/-ies” through group discussions with students who are in the middle of this transition from university to the job market. Furthermore, two perspectives of social pedagogy are sketched – formulated as “being forced to create or allowed to design your own life plan under de-bordered (/borderless) circumstances”. The output of the group discussions is tied onto reflections of a social pedagogy of transition, which supposes security/-ies as prerequisites for being able to “design” one’s own perspectives. In this regard, such a pedagogy of transition can be labelled as one where you are “allowed to design transitions with the feeling of security”