| 1. |
- Anthon, Carl Thomas, et al.
(author)
-
Platelet transfusions in adult ICU patients with thrombocytopenia : A sub-study of the PLOT-ICU inception cohort study
-
In: Acta Anaesthesiologica Scandinavica. - 0001-5172.
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown.STUDY DESIGN AND METHODS: Sub-study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 10 9/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. RESULTS: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1-4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180-308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 10 11 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 10 11 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (-1 to 8) × 10 9/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. CONCLUSIONS: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.
|
|
| 2. |
- Anthon, Carl Thomas, et al.
(author)
-
Thrombocytopenia and platelet transfusions in ICU patients : an international inception cohort study (PLOT-ICU)
- 2023
-
In: Intensive Care Medicine. - 0342-4642. ; 49:11, s. 1327-1338
-
Journal article (peer-reviewed)abstract
- PURPOSE: Thrombocytopenia (platelet count < 150 × 10 9/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. METHODS: We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses.RESULTS: We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4-46.1) had thrombocytopenia; 23.4% (20-26) had thrombocytopenia at ICU admission, and 19.8% (17.6-22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19-2.42).CONCLUSION: Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.
|
|
| 3. |
- Gersing, Sarah K., et al.
(author)
-
Mapping the degradation pathway of a disease-linked aspartoacylase variant
- 2021
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:4
-
Journal article (peer-reviewed)abstract
- Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets. Author summary Canavan disease is a fatal neurodegenerative disorder which is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene. Although the molecular mechanism of most disease-causing substitutions remains to be examined, some variants have been suggested to cause the loss-of-function phenotype by perturbing the structural stability of ASPA. So far the cellular fate of these variants have not been examined. Here we examine the stability and degradation pathways of the disease-causing ASPA variant C152W. In yeast cells, ASPA C152W showed decreased steady-state protein levels as a result of increased proteasomal turnover. Our molecular dynamics simulations showed that the C152W substitution did not globally perturb the native structure of ASPA. Instead we propose that ASPA C152W is targeted by the protein quality control system during de novo folding. Specifically, we found that the molecular chaperone Hsp70, its co-chaperone Hsp110, and the E3 ubiquitin-protein ligase Ubr1 promote degradation of ASPA C152W. When we expressed ASPA C152W in cultured human cells, we found that Hsp70 and Hsp110 similarly mediated degradation. Therefore, we propose that Hsp110 should be further examined as a potential therapeutic target in Canavan disease and other protein misfolding diseases.
|
|
| 4. |
- Olsson, Tina M., et al.
(author)
-
Study protocol for a non-randomized controlled trial of the effects of internet-based parent training as a booster to the preschool edition of PATHS® : Universal edition of the Parent Web
- 2023
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:4, s. e0284926-e0284926
-
Journal article (peer-reviewed)abstract
- Well implemented, universal parental support is often effective in families with younger children, but research on their effects on families with adolescent children is scarce. In this study, a trial of the universal parent training intervention “Parent Web” in early adolescence is added to the social emotional learning intervention Promoting Alternative Thinking Strategies (PATHS®), completed in early childhood. The Parent Web is a universal online parenting intervention based on social learning theory. The intervention aims to promote positive parenting and family interaction through five weekly modules completed over 6–8 weeks.The main hypothesis is that participants in the intervention group will exhibit significant pre to post- intervention-related benefits relative participants in the comparison group.The aims of this study are: 1) provide Parent Web as a booster aimed at improving parenting support and practices at the transition into adolescence to a cohort of parents whose children have previously participated in preschool PATHS, and 2) examine the effects of the universal edition of Parent Web. The study has a quasi-experimental design with pre- and post-testing.The incremental effects of this internet-delivered parent training intervention are tested in parents of early adolescents (11–13 years) who participated in PATHS when 4–5 years old compared to a matched sample of adolescents with no prior experience of PATHS. The primary outcomes are parent reported child behavior and family relationships. Secondary outcomes include self-reported parent health and stress. The proposed study is one of the few trials to test the effects of universal parental support in families of early adolescents and will therefore contribute to the understanding of how mental health in children and young people can be promoted across developmental periods through a continuum of universal measures.Trial registration: Clinical trials.gov (NCT05172297), prospectively registered on December 29, 2021.
|
|
| 5. |
- Reuten, Raphael, et al.
(author)
-
Basement membrane stiffness determines metastases formation
- 2021
-
In: Nature Materials. - : Springer Science and Business Media LLC. - 1476-4660 .- 1476-1122.
-
Journal article (peer-reviewed)abstract
- The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of ‘normal’ BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.
|
|
