Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of ...coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.
A common assumption of data analysis in clinical trials is that the patient population, as well as treatment effects, do not vary during the course of the study. However, when trials enroll patients ...over several years, this hypothesis may be violated. Ignoring variations of the outcome distributions over time, under the control and experimental treatments, can lead to biased treatment effect estimates and poor control of false positive results. We propose and compare two procedures that account for possible variations of the outcome distributions over time, to correct treatment effect estimates, and to control type‐I error rates. The first procedure models trends of patient outcomes with splines. The second leverages conditional inference principles, which have been introduced to analyze randomized trials when patient prognostic profiles are unbalanced across arms. These two procedures are applicable in response‐adaptive clinical trials. We illustrate the consequences of trends in the outcome distributions in response‐adaptive designs and in platform trials, and investigate the proposed methods in the analysis of a glioblastoma study.
This article reviews an instrument used in cross-national research with dementia family caregivers-the Revised Scale for Caregiving Self-Efficacy (RSCSE). Although the RSCSE has been translated into ...multiple languages, few studies have examined scale performance across samples. We examine congruence of psychometric, reliability, and validity data to inform research and practice.
We conducted citation searches using Scopus, Google Scholar, Web of Science, and PsycINFO. Identified dementia caregiving studies cited the original RSCSE article and described results of English and/or non-English translations of the scale.
Peer-reviewed published studies (N = 58) of dementia family caregivers included data for Arabic, Chinese, English, French, Italian, and Spanish translations of the RSCSE; the majority (72%) reported use of non-English translations. Studies utilizing confirmatory factor analytic approaches reported findings consistent with the original development study. Internal consistency, convergent/discriminant validity, and criterion validity indices were congruent across diverse cross-national caregiving samples assessed with different translations. Data supported the RSCSE's sensitivity to change following specific psychosocial caregiving interventions.
The reliability and validity of different translations of the RSCSE support continued use with cross-national samples of dementia family caregivers. Limitations of the scale point to the need for further self-efficacy measurement development within caregiving domains. Consistent with Bandura's discussion of social cognitive theory in cultural contexts, personal agency for caregiving challenges remains generalizable to cross-national populations. This review discusses the implications for cross-cultural research and practice.
Planetary Boundaries Rockström, Johan; Steffen, Will; Noone, Kevin ...
Ecology and society,
01/2009, Letnik:
14, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Anthropogenic pressures on the Earth System have reached a scale where abrupt global environmental change can no longer be excluded. We propose a new approach to global sustainability in which we ...define planetary boundaries within which we expect that humanity can operate safely. Transgressing one or more planetary boundaries may be deleterious or even catastrophic due to the risk of crossing thresholds that will trigger non-linear, abrupt environmental change within continental- to planetary-scale systems. We have identified nine planetary boundaries and, drawing upon current scientific understanding, we propose quantifications for seven of them. These seven are climate change (CO₂ concentration in the atmosphere <350 ppm and/or a maximum change of +1 W m−2in radiative forcing); ocean acidification (mean surface seawater saturation state with respect to aragonite ≥ 80% of pre-industrial levels); stratospheric ozone (<5% reduction in O₃ concentration from pre-industrial level of 290 Dobson Units); biogeochemical nitrogen (N) cycle (limit industrial and agricultural fixation of N₂ to 35 Tg N yr−1) and phosphorus (P) cycle (annual P inflow to oceans not to exceed 10 times the natural background weathering of P); global freshwater use (<4000 km³ yr−1of consumptive use of runoff resources); land system change (<15% of the ice-free land surface under cropland); and the rate at which biological diversity is lost (annual rate of <10 extinctions per million species). The two additional planetary boundaries for which we have not yet been able to determine a boundary level are chemical pollution and atmospheric aerosol loading. We estimate that humanity has already transgressed three planetary boundaries: for climate change, rate of biodiversity loss, and changes to the global nitrogen cycle. Planetary boundaries are interdependent, because transgressing one may both shift the position of other boundaries or cause them to be transgressed. The social impacts of transgressing boundaries will be a function of the social–ecological resilience of the affected societies. Our proposed boundaries are rough, first estimates only, surrounded by large uncertainties and knowledge gaps. Filling these gaps will require major advancements in Earth System and resilience science. The proposed concept of “planetary boundaries” lays the groundwork for shifting our approach to governance and management, away from the essentially sectoral analyses of limits to growth aimed at minimizing negative externalities, toward the estimation of the safe space for human development. Planetary boundaries define, as it were, the boundaries of the “planetary playing field” for humanity if we want to be sure of avoiding major human-induced environmental change on a global scale.
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors ...(HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.
Objective
Adult drug‐resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the ...peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well‐controlled epilepsy (WCE).
Methods
Peripheral blood mononuclear cells and serum from >120 age‐ and sex‐matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.
Results
Using a data‐driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)‐17A, IL‐22, tumor necrosis factor, interferon‐γ, and granulocyte‐macrophage colony–stimulating factor, but not anti‐inflammatory cytokines IL‐10 and IL‐4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17‐related circulating proinflammatory cytokines are elevated, but Th2‐related cytokine IL‐4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.
Significance
Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.
The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to ...assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).
A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).
We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval CI = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC.
Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
Abstract
The European Heart Journal—Cardiovascular Imaging with its over 10 years existence is an established leading multi-modality cardiovascular imaging journal. Pertinent publications including ...original research, how-to papers, reviews, consensus documents, and in our journal from 2022 have been highlighted in two reports. Part I focuses on cardiomyopathies, heart failure, valvular heart disease, and congenital heart disease and related emerging techniques and technologies.
Hemolysis is associated with increased mortality in patients with sepsis, ARDS, or therapy with extracorporeal membrane oxygenation (ECMO). To quantify a critical threshold of hemolysis in patients ...with ARDS and treatment with veno-venous ECMO, we aimed to identify cutoff values for cell-free hemoglobin (CFH) and haptoglobin (Hp) plasma concentrations associated with a significant increase in ICU mortality.
Patients with ARDS admitted to a tertiary ARDS referral center between 01/2007 and 12/2018 and treatment with veno-venous ECMO were included. Cutoff values for mean CFH (mCFH) and mean Hp (mHp) plasma concentrations dividing the cohort into groups with significantly different ICU mortalities were calculated and patient characteristics were compared. A multiple logistic regression model with stepwise backward variable selection was included. In addition, cutoff values for vulnerable relative timespans for the respective CFH and Hp concentrations were calculated.
A quantitative cutoff value of 11 mg/dl for mCFH separated the cohort (n = 442) regarding ICU mortality (mCFH ≤ 11 mg/dl: 38%, 95%-CI: 32.22-43.93 (n = 277) vs. mCFH > 11 mg/dl: 70%, 61.99-76.47 (n = 165), p < 0.001). Analogously, a mHp cutoff value ≤ 0.39 g/l was associated with a significant increase in ICU mortality (mHp ≤ 0.39 g/l: 68.7%, 60.91-75.61 (n = 163) vs. mHp > 0.39 g/l: 38.7%, 33.01-44.72 (n = 279), p < 0.001). The independent association of ICU mortality with CFH and Hp cutoff values was confirmed by logistic regression adjusting for confounders (CFH Grouping: OR 3.77, 2.51-5.72, p < 0.001; Hp Grouping: OR 0.29, 0.19-0.43, p < 0.001). A significant increase in ICU mortality was observed when CFH plasma concentration exceeded the limit of 11 mg/dl on 13.3% of therapy days (≤ 13.3% of days with CFH > 11 mg/dl: 33%; 26.81-40.54 (n = 192) vs. > 13.3% of days with CFH > 11 mg/dl: 62%; 56.05-68.36 (n = 250), p < 0.001). Analogously, a mortality increase was detected when Hp plasma concentration remained ≤ 0.39 g/l for > 18.2% of therapy days (≤ 18.2% days with Hp ≤ 0.39 g/l: 27%; 19.80-35.14 (n = 138) vs. > 18.2% days with Hp ≤ 0.39 g/l: 60%; 54.43-65.70 (n = 304), p < 0.001).
Moderate hemolysis with mCFH-levels as low as 11 mg/dl impacts mortality in patients with ARDS and therapy with veno-venous ECMO. Furthermore, a cumulative dose effect should be considered indicated by the relative therapy days with CFH-concentrations > 11 mg/dl. In addition, also Hp plasma concentrations need consideration when the injurious effect of elevated CFH is evaluated.
PDF
