Individuals with acute venous thromboembolism (VTE) constitute a heterogeneous group of patients with diverse clinical characteristics and outcome.
To identify endotypes of individuals with acute VTE ...based on clinical characteristics at presentation through unsupervised cluster analysis and to evaluate their molecular proteomic profile and clinical outcome.
Data from 591 individuals from the Genotyping and Molecular phenotyping of Venous thromboembolism (GMP-VTE) project were explored. Hierarchical clustering was applied to 58 variables to define VTE endotypes. Clinical characteristics, three-year incidence of thromboembolic events or death, and acute-phase plasma proteomics were assessed.
Four endotypes were identified, exhibiting different patterns of clinical characteristics and clinical course. Endotype 1 (n = 300), comprising older individuals with comorbidities, had the highest incidence of thromboembolic events or death (HR 95 % CI: 3.76 1.96–7.19), followed by endotype 4 (n = 127) (HR 95 % CI: 2.55 1.26–5.16), characterised by men with history of VTE and provoking risk factors, and endotype 3 (n = 57) (HR 95 % CI: 1.57 0.63–3.87), composed of young women with provoking risk factors, vs. reference endotype 2 (n = 107). The reference endotype was constituted by individuals diagnosed with PE without comorbidities, who had the lowest incidence of the investigated endpoint. Differentially expressed proteins associated with the endotypes were related to distinct biological processes, supporting differences in molecular pathophysiology. The endotypes had superior prognostic ability compared to existing risk stratifications such as provoked vs unprovoked VTE and D-dimer levels.
Four endotypes of VTE were identified by unsupervised phenotype-based clustering that diverge in clinical outcome and plasmatic protein signature. This approach might support the future development of individualized treatment in VTE.
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•Unsupervised clustering of clinical features identified four endotypes in acute VTE.•Endotypes differed in recurrence of VTE, arterial events, death and bleeding.•Plasma protein profiling by immuno-PCR suggests pathomechanistic diversity.•The endotyping outperformed traditional tools for VTE risk stratification.
Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These ...findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line-derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genetic variants of interest, by recruiting carriers of such variants for further phenotyping. RbG ...approaches pose major ethical and legal challenges related to the disclosure of possibly unwanted genetic information. The Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study based in South Tyrol, Italy. Demand has grown for CHRIS study participants to be enrolled in RbG studies, thus making the design of a suitable ethical framework a pressing need. We here report upon the design of a pilot RbG study conducted with CHRIS study participants. By reviewing the literature and by consulting relevant stakeholders (CHRIS participants, clinical geneticists, ethics board, GPs), we identified key ethical issues in RbG approaches (e.g. complexity of the context, communication of genetic results, measures to further protect participants). The design of the pilot was based on a feasibility assessment, the selection of a suitable test case within the ProtectMove Research Unit on reduced penetrance of hereditary movement disorders, and the development of appropriate recruitment and communication strategies. An empirical study was embedded in the pilot study with the aim of understanding participants' views on RbG. Our experience with the pilot study in CHRIS allowed us to contribute to the development of best practices and policies for RbG studies by drawing recommendations: addressing the possibility of RbG in the original consent, implementing tailored communication strategies, engaging stakeholders, designing embedded empirical studies, and sharing research experiences and methodology.
Primary focal dystonia (PFD) is characterised by motor symptoms. Frequent co-occurrence of abnormal mental conditions has been mentioned for decades but is less well defined. In this study, ...prevalence rates of psychiatric disorders, personality disorders and traits in a large cohort of patients with PFD were evaluated.
Prevalence rates of clinical psychiatric diagnoses in 86 PFD patients were compared with a population based sample (n = 3943) using a multiple regression approach. Furthermore, participants were evaluated for personality traits with the 5 Factor Personality Inventory.
Lifetime prevalence for any psychiatric or personality disorder was 70.9%. More specifically, axis I disorders occurred at a 4.5-fold increased chance. Highest odds ratios were found for social phobia (OR 21.6), agoraphobia (OR 16.7) and panic disorder (OR 11.5). Furthermore, an increased prevalence rate of 32.6% for anxious personality disorders comprising obsessive-compulsive (22.1%) and avoidant personality disorders (16.3%) were found. Except for social phobia, psychiatric disorders manifested prior to the occurrence of dystonia symptoms. In the self-rating of personality traits, PFD patients demonstrated pronounced agreeableness, conscientiousness and reduced openness.
Patients with PFD show distinct neuropsychiatric and personality profiles of the anxiety spectrum. PFD should therefore be viewed as a neuropsychiatric disorder rather than a pure movement disorder.
Purpose
Infective endocarditis (IE) is a serious complication of bacteremia and is most often caused by Gram positive cocci. We investigated the prevalence of IE in patients where echocardiography ...was encouraged when bacteremia with Gram positive cocci was present.
Methods
The study included patients with Gram positive cocci bacteremia hospitalized at two Danish hospitals between March and December 2016. Information concerning echocardiography, demographics and bacterial species was collected from the patients’ medical files. Patients without echocardiography were followed for 6 months in order to confirm or reject possible IE.
Results
The study included 585 patients with Gram positive cocci bacteremia, and echocardiography was performed in 414 (71%) of them. The prevalence of IE in patients with high risk bacteremia, i.e.
Staphylococcus aureus,
non-beta-hemolytic streptococci,
Enterococcus faecalis,
and coagulase-negative staphylococci was 16%. Patients with
Enterococcus faecalis
had the highest prevalence of IE (33%) followed by non-beta-hemolytic streptococci (23%) and
Staphylococcus aureus
(12%). Among low risk bacteremia the prevalence of IE was 1%. The mean age of patients with IE was 74 years (SD 12.9) and 71% were male.
Conclusion
These findings strongly support routine echocardiography in patients with high risk bacteremia and non-performance of echocardiography in patients with low risk bacteremia.
The COVID-19 pandemic remains a significant challenge to global health despite the application of vaccines to approximately 70% of the world's population 1. Unresolved questions include the duration ...of immunity after infection and vaccination, the effectiveness of vaccines against new virus variants, the relationship between antibody levels and immunity, re-infection risk, and long-term consequences of infection, including Long- and Post-COVID-syndrome. Thus, there is an unmet need for long-term, prospective epidemiological studies addressing these issues in the post-vaccination era.
Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic ...model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment. Notably, relatively few studies specifically addressed NMS in genetic PD and missing data ranged from 42% to 100%. Diagnostic criteria and examination methods were variable and cases differed widely for age at onset, disease duration, ethnicity, treatment, and comorbidity. Although in comparison to IPD, SNCA duplication carriers have the most similar course of disease, even for duplication carriers the frequencies of dementia, hallucinations, and depression seem higher than in IPD. Supporting the notion that LRRK2-linked PD has a similar course to iPD but is slightly more benign, the frequency of dementia is below that of iPD. For Parkin, the frequency of cognitive decline falls within the range of the general population above the age of 65 years. GBA mutations are associated with a distinct profile of cognitive impairment and a greater prevalence of depression. Despite the current data gaps, NMS should be considered as an important and often treatable concomitant feature of genetic parkinsonism.
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