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| 2. |
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| 3. |
- Bousquet, J, et al.
(author)
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Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
- 2020
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In: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 10:1, s. 58-
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Journal article (peer-reviewed)abstract
- There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
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| 4. |
- Patel, Y., et al.
(author)
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Virtual Ontogeny of Cortical Growth Preceding Mental Illness
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 92:4, s. 299-313
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Journal article (peer-reviewed)abstract
- Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
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| 5. |
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| 6. |
- Silventoinen, K., et al.
(author)
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Educational attainment of same-sex and opposite-sex dizygotic twins : An individual-level pooled study of 19 twin cohorts
- 2021
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In: Hormones and Behavior. - : Elsevier. - 0018-506X .- 1095-6867. ; 136
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Journal article (peer-reviewed)abstract
- Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = −0.05 educational years, 95% CI −0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.
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| 7. |
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| 8. |
- Bohm, E. R., et al.
(author)
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Collection and Reporting of Patient-reported Outcome Measures in Arthroplasty Registries: Multinational Survey and Recommendations
- 2021
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In: Clinical Orthopaedics and Related Research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-921X .- 1528-1132. ; 479:10, s. 2151-2166
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Journal article (peer-reviewed)abstract
- Background Patient-reported outcome measures (PROMs) are validated questionnaires that are completed by patients. Arthroplasty registries vary in PROM collection and use. Current information about registry collection and use of PROMs is important to help improve methods of PROM data analysis, reporting, comparison, and use toward improving clinical practice. Questions/purposes To characterize PROM collection and use by registries, we asked: (1) What is the current practice of PROM collection by arthroplasty registries that are current or former members of the International Society of Arthroplasty Registries, and are there sufficient similarities in PROM collection between registries to enable useful international comparisons that could inform the improvement of arthroplasty care? (2) How do registries differ in PROM administration and demographic, clinical, and comorbidity index variables collected for case-mix adjustment in data analysis and reporting? (3) What quality assurance methods are used for PROMs, and how are PROM results reported and used by registries? (4) What recommendations to arthroplasty registries may improve PROM reporting and facilitate international comparisons? Methods An electronic survey was developed with questions about registry structure and collection, analysis, reporting, and use of PROM data and distributed to directors or senior administrators of 39 arthroplasty registries that were current or former members of the International Society of Arthroplasty Registries. In all, 64% (25 of 39) of registries responded and completed the survey. Missing responses from incomplete surveys were captured by contacting the registries, and up to three reminder emails were sent to nonresponding registries. Recommendations about PROM collection were drafted, revised, and approved by the International Society of Arthroplasty Registries PROMs Working Group members. Results Of the 25 registries that completed the survey, 15 collected generic PROMs, most frequently the EuroQol-5 Dimension survey; 16 collected joint-specific PROMs, most frequently the Knee Injury and Osteoarthritis Outcome Score and Hip Disability and Osteoarthritis Outcome Score; and 11 registries collected a satisfaction item. Most registries administered PROM questionnaires within 3 months before and 1 year after surgery. All 16 registries that collected PROM data collected patient age, sex or gender, BMI, indication for the primary arthroplasty, reason for revision arthroplasty, and a comorbidity index, most often the American Society of Anesthesiologists classification. All 16 registries performed regular auditing and reporting of data quality, and most registries reported PROM results to hospitals and linked PROM data to other data sets such as hospital, medication, billing, and emergency care databases. Recommendations for transparent reporting of PROMs were grouped into four categories: demographic and clinical, survey administration, data analysis, and results. Conclusion Although registries differed in PROM collection and use, there were sufficient similarities that may enable useful data comparisons. The International Society of Arthroplasty Registries PROMs Working Group recommendations identify issues that may be important to most registries such as the need to make decisions about survey times and collection methods, as well as how to select generic and joint-specific surveys, handle missing data and attrition, report data, and ensure representativeness of the sample.
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| 9. |
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| 10. |
- Ruggeri, Kai, et al.
(author)
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The globalizability of temporal discounting
- 2022
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In: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 6:10, s. 1386-1397
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Journal article (peer-reviewed)abstract
- Economic inequality is associated with preferences for smaller, immediate gains over larger, delayed ones. Such temporal discounting may feed into rising global inequality, yet it is unclear whether it is a function of choice preferences or norms, or rather the absence of sufficient resources for immediate needs. It is also not clear whether these reflect true differences in choice patterns between income groups. We tested temporal discounting and five intertemporal choice anomalies using local currencies and value standards in 61 countries (N = 13,629). Across a diverse sample, we found consistent, robust rates of choice anomalies. Lower-income groups were not significantly different, but economic inequality and broader financial circumstances were clearly correlated with population choice patterns. Ruggeri et al. find in a study of 61 countries that temporal discounting patterns are globally generalizable. Worse financial environments, greater inequality and high inflation are associated with extreme or inconsistent long-term decisions.
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| 11. |
- Abé, Christoph, et al.
(author)
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Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.
- 2022
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In: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 91:6, s. 582-592
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD.Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables.Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18
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| 12. |
- Ambaw, Y. A., et al.
(author)
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Tailored polymer-based selective extraction of lipid mediators from biological samples
- 2021
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In: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 11:8
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Journal article (peer-reviewed)abstract
- Lipid mediators, small molecules involved in regulating inflammation and its resolution, are a class of lipids of wide interest as their levels in blood and tissues may be used to monitor health and disease states or the effect of new treatments. These molecules are present at low levels in biological samples, and an enrichment step is often needed for their detection. We describe a rapid and selective method that uses new low-cost molecularly imprinted (MIP) and non-imprinted (NIP) polymeric sorbents for the extraction of lipid mediators from plasma and tissue samples. The extraction process was carried out in solid-phase extraction (SPE) cartridges, manually packed with the sorbents. After extraction, lipid mediators were quantified by liquid chromatography–tandem mass spectrometry (LC–MSMS). Various parameters affecting the extraction efficiency were evaluated to achieve optimal recovery and to reduce non-specific interactions. Preliminary tests showed that MIPs, designed using the prostaglandin biosynthetic precursor arachidonic acid, could effectively enrich prostaglandins and structurally related molecules. However, for other lipid mediators, MIP and NIP displayed comparable recoveries. Under optimized conditions, the recoveries of synthetic standards ranged from 62% to 100%. This new extraction method was applied to the determination of the lipid mediators concentration in human plasma and mouse tissues and compared to other methods based on commercially available cartridges. In general, the methods showed comparable performances. In terms of structural specificity, our newly synthesized materials accomplished better retention of prostaglandins (PGs), hydroxydocosahexaenoic acid (HDoHE), HEPE, hydroxyeicosatetraenoic acids (HETE), hydroxyeicosatrienoic acid (HETrE), and PUFA compounds, while the commercially available Strata-X showed a higher recovery for dihydroxyeicosatetraenoic acid (diHETrEs). In summary, our results suggest that this new material can be successfully implemented for the extraction of lipid mediators from biological samples. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 13. |
- Anderzen, J., et al.
(author)
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International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study
- 2020
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In: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 21:4, s. 621-627
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Journal article (peer-reviewed)abstract
- Objectives To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. Subjects 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. Methods Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. Results Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P < .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P < .001) in seven out of eight countries. Conclusions In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.
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| 14. |
- Bergemalm, Daniel, 1977-, et al.
(author)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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In: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Journal article (peer-reviewed)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 15. |
- Bohm, Eric R., et al.
(author)
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Collection and Reporting of Patient-reported Outcome Measures in Arthroplasty Registries: Multinational Survey and Recommendations
- 2021
-
In: Clinical Orthopaedics and Related Research. - 0009-921X. ; 479:10, s. 2151-2166
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Patient-reported outcome measures (PROMs) are validated questionnaires that are completed by patients. Arthroplasty registries vary in PROM collection and use. Current information about registry collection and use of PROMs is important to help improve methods of PROM data analysis, reporting, comparison, and use toward improving clinical practice. QUESTIONS/PURPOSES: To characterize PROM collection and use by registries, we asked: (1) What is the current practice of PROM collection by arthroplasty registries that are current or former members of the International Society of Arthroplasty Registries, and are there sufficient similarities in PROM collection between registries to enable useful international comparisons that could inform the improvement of arthroplasty care? (2) How do registries differ in PROM administration and demographic, clinical, and comorbidity index variables collected for case-mix adjustment in data analysis and reporting? (3) What quality assurance methods are used for PROMs, and how are PROM results reported and used by registries? (4) What recommendations to arthroplasty registries may improve PROM reporting and facilitate international comparisons? METHODS: An electronic survey was developed with questions about registry structure and collection, analysis, reporting, and use of PROM data and distributed to directors or senior administrators of 39 arthroplasty registries that were current or former members of the International Society of Arthroplasty Registries. In all, 64% (25 of 39) of registries responded and completed the survey. Missing responses from incomplete surveys were captured by contacting the registries, and up to three reminder emails were sent to nonresponding registries. Recommendations about PROM collection were drafted, revised, and approved by the International Society of Arthroplasty Registries PROMs Working Group members. RESULTS: Of the 25 registries that completed the survey, 15 collected generic PROMs, most frequently the EuroQol-5 Dimension survey; 16 collected joint-specific PROMs, most frequently the Knee Injury and Osteoarthritis Outcome Score and Hip Disability and Osteoarthritis Outcome Score; and 11 registries collected a satisfaction item. Most registries administered PROM questionnaires within 3 months before and 1 year after surgery. All 16 registries that collected PROM data collected patient age, sex or gender, BMI, indication for the primary arthroplasty, reason for revision arthroplasty, and a comorbidity index, most often the American Society of Anesthesiologists classification. All 16 registries performed regular auditing and reporting of data quality, and most registries reported PROM results to hospitals and linked PROM data to other data sets such as hospital, medication, billing, and emergency care databases. Recommendations for transparent reporting of PROMs were grouped into four categories: demographic and clinical, survey administration, data analysis, and results. CONCLUSION: Although registries differed in PROM collection and use, there were sufficient similarities that may enable useful data comparisons. The International Society of Arthroplasty Registries PROMs Working Group recommendations identify issues that may be important to most registries such as the need to make decisions about survey times and collection methods, as well as how to select generic and joint-specific surveys, handle missing data and attrition, report data, and ensure representativeness of the sample. CLINICAL RELEVANCE: By collecting PROMs, registries can provide patient-centered data to surgeons, hospitals, and national entities to improve arthroplasty care.
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| 16. |
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| 17. |
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| 18. |
- Dahlin, Lars B., et al.
(author)
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Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.
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| 19. |
- de Boniface, J., et al.
(author)
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Omitting axillary dissection in breast cancer with sentinel-node metastases
- 2024
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 390:13, s. 1163-1175
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Journal article (peer-reviewed)abstract
- BACKGROUND Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups.METHODS We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44.RESULTS Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy–only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy–only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin.CONCLUSIONS The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).
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| 20. |
- Eap, C. B., et al.
(author)
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Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests) : focus on antidepressants
- 2021
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In: World Journal of Biological Psychiatry. - : Taylor & Francis Group. - 1562-2975 .- 1814-1412. ; 22:8, s. 561-628
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Research review (peer-reviewed)abstract
- Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient. Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug. Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.
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| 21. |
- Ebrahimi-Fakhari, Darius, et al.
(author)
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
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In: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Journal article (peer-reviewed)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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| 22. |
- Ittermann, T., et al.
(author)
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Standardized Map of Iodine Status in Europe
- 2020
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In: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 30:9
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Journal article (peer-reviewed)abstract
- Background:Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods:We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results:In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 mu g/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 mu g/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC Conclusions:We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.
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| 23. |
- Mollehave, L. T., et al.
(author)
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Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration
- 2022
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In: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 11:3
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Journal article (peer-reviewed)abstract
- ObjectiveRegisters of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. DesignRegister-based cross-sectional study. MethodsNational register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. ResultsRegister data on >= 1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. ConclusionsThe collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Silventoinen, Karri, et al.
(author)
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Genetic and environmental variation in educational attainment : an individual-based analysis of 28 twin cohorts
- 2020
-
In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
-
Journal article (peer-reviewed)abstract
- We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural–geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41–0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30–0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900–1949 (a2 = 0.44; 0.41–0.46) than in the later cohorts born in 1950–1989 (a2 = 0.38; 0.36–0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29–0.33 and c2 = 0.34; 0.32–0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
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| 28. |
- Silventoinen, Karri, et al.
(author)
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Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts
- 2022
-
In: Scientific Reports. - : Nature Portfolio. - 2045-2322. ; 12:1
-
Journal article (peer-reviewed)abstract
- We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.
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| 29. |
- Sofiev, M., et al.
(author)
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Designing an automatic pollen monitoring network for direct usage of observations to reconstruct the concentration fields
- 2023
-
In: SCIENCE OF THE TOTAL ENVIRONMENT. - 0048-9697. ; 900
-
Journal article (peer-reviewed)abstract
- We consider several approaches to a design of a regional-to-continent-scale automatic pollen monitoring network in Europe. Practical challenges related to the arrangement of such a network limit the range of possible solutions. A hierarchical network is discussed, highlighting the necessity of a few reference sites that follow an extended observations protocol and have corresponding capabilities. Several theoretically rigorous approaches to a network design have been developed so far. However, before starting the process, a network purpose, a criterion of its performance, and a concept of the data usage should be formalized. For atmospheric composition monitoring, developments follow one of the two concepts: a network for direct representation of concentration fields and a network for model-based data assimilation, inverse problem solution, and forecasting. The current paper demonstrates the first approach, whereas the inverse problems are considered in a follow-up paper. We discuss the approaches for the network design from theoretical and practical standpoints, formulate criteria for the network optimality, and consider practical constraints for an automatic pollen network. An application of the methodology is demonstrated for a prominent example of Germany's pollen monitoring network. The multi-step method includes (i) the network representativeness and (ii) redundancy evaluation followed by (iii) fidelity evaluation and improvement using synthetic data.
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| 30. |
- Beam, Christopher R., et al.
(author)
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Estimating Likelihood of Dementia in the Absence of Diagnostic Data : A Latent Dementia Index in 10 Genetically Informed Studies
- 2022
-
In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:3, s. 1187-1201
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. OBJECTIVE: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results. METHODS: Using 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available. RESULTS: Results indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis. CONCLUSION: This latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges.
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| 31. |
- Boisen, Gabriella, et al.
(author)
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Limosilactobacillus reuteri inhibits the acid tolerance response in oral bacteria
- 2023
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In: Biofilm. - : Elsevier. - 2590-2075. ; 6
-
Journal article (peer-reviewed)abstract
- Probiotic bacteria show promising results in prevention of the biofilm-mediated disease caries, but the mechanisms are not fully understood. The acid tolerance response (ATR) allows biofilm bacteria to survive and metabolize at low pH resulting from microbial carbohydrate fermentation. We have studied the effect of probiotic strains: Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus on ATR induction in common oral bacteria. Communities of L. reuteri ATCC PTA5289 and Streptoccus gordonii, Streptococcus oralis, Streptococcus mutans or Actinomyces naeslundii in the initial stages of biofilm formation were exposed to pH 5.5 to allow ATR induction, followed by a low pH challenge. Acid tolerance was evaluated as viable cells after staining with LIVE/ DEAD & REG;BacLightTM. The presence of L. reuteri ATCC PTA5289 caused a significant reduction in acid tolerance in all strains except S. oralis. When S. mutans was used as a model organism to study the effects of additional probiotic strains (L. reuteri SD2112, L. reuteri DSM17938 or L. rhamnosus GG) as well as L. reuteri ATCC PTA5289 supernatant on ATR development, neither the other probiotic strains nor supernatants showed any effect. The presence of L. reuteri ATCC PTA5289 during ATR induction led to down-regulation of three key genes involved in tolerance of acid stress (luxS, brpA and ldh) in Streptococci. These data suggest that live cells of probiotic L. reuteri ATCC PTA5289 can interfere with ATR development in common oral bacteria and specific strains of L. reuteri may thus have a role in caries prevention by inhibiting development of an acid-tolerant biofilm microbiota.
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| 32. |
- Brooks, Samantha, et al.
(author)
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A neuroinflammatory compulsivity model of anorexia nervosa (NICAN)
- 2024
-
In: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 159
-
Research review (peer-reviewed)abstract
- Anorexia nervosa (AN) is an eating disorder often highly resistant to treatment, characterised by restrictive eating and/or compensatory behaviours such as purging or excessive exercising, leading to low body weight and dysregulated appetite. The recovery rate is low for those with AN in standard treatment, including cognitive behavioural therapy (CBT), enhanced-CBT, and anti-depressant medication, and risk of relapse is high (Muratore, Attia, 2021; Monteleone et al., 2022; Dalle Grave et al., 2023) estimated at around an annual global rate of 50% (Steinhausen, 2002, Frostad et al., 2022). Moreover, longitudinal studies show that for those with over twenty years lived experience of AN, recovery rate is only 40–63% (Eddy et al., 2017, Fichter et al., 2017). And for the last five years in the UK (2017–2022), an alarming 84% rise in AN admissions to the National Health Service was reported (Royal College of Psychiatrists, 2022), a rise echoed around the world, especially in high-income countries (Zipfel et al., 2022). Given this alarming rise, some clinicians are dividing opinion by suggesting palliative care and medically assisted death for treatment resistant AN (Royal College of Psychiatrists, 2023). Considering the dangerous nature of AN and heightened risk of death, new approaches are urgently needed to examine novel neurobiological mechanisms maintaining the disorder that may improve global treatment resistance.
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| 33. |
- Båth, Petra, 1988, et al.
(author)
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Lipidic cubic phase serial femtosecond crystallography structure of a photosynthetic reaction centre
- 2022
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In: Acta Crystallographica Section D-Structural Biology. - : International Union of Crystallography (IUCr). - 2059-7983. ; 78, s. 698-708
-
Journal article (peer-reviewed)abstract
- Serial crystallography is a rapidly growing method that can yield structural insights from microcrystals that were previously considered to be too small to be useful in conventional X-ray crystallography. Here, conditions for growing microcrystals of the photosynthetic reaction centre of Blastochloris viridis within a lipidic cubic phase (LCP) crystallization matrix that employ a seeding protocol utilizing detergent-grown crystals with a different crystal packing are described. LCP microcrystals diffracted to 2.25 angstrom resolution when exposed to XFEL radiation, which is an improvement of 0.15 angstrom over previous microcrystal forms. Ubiquinone was incorporated into the LCP crystallization media and the resulting electron density within the mobile Q(B) pocket is comparable to that of other cofactors within the structure. As such, LCP microcrystallization conditions will facilitate time-resolved diffraction studies of electron-transfer reactions to the mobile quinone, potentially allowing the observation of structural changes associated with the two electron-transfer reactions leading to complete reduction of the ubiquinone ligand.
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| 34. |
- Dahl, Martin, 1984-, et al.
(author)
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A 2,000-Year Record of Eelgrass (Zostera marina L.) : Colonization Shows Substantial Gains in Blue Carbon Storage and Nutrient Retention
- 2024
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In: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 38:3
-
Journal article (peer-reviewed)abstract
- Assessing historical environmental conditions linked to habitat colonization is important for understanding long-term resilience and improving conservation and restoration efforts. Such information is lacking for the seagrass Zostera marina, an important foundation species across cold-temperate coastal areas of the Northern Hemisphere. Here, we reconstructed environmental conditions during the last 14,000 years from sediment cores in two eelgrass (Z. marina) meadows along the Swedish west coast, with the main aims to identify the time frame of seagrass colonization and describe subsequent biogeochemical changes following establishment. Based on vegetation proxies (lipid biomarkers), eelgrass colonization occurred about 2,000 years ago after geomorphological changes that resulted in a shallow, sheltered environment favoring seagrass growth. Seagrass establishment led to up to 20- and 24-fold increases in sedimentary carbon and nitrogen accumulation rates, respectively. This demonstrates the capacity of seagrasses as efficient ecosystem engineers and their role in global change mitigation and adaptation through CO2 removal, and nutrient and sediment retention. By combining regional climate projections and landscape models, we assessed potential climate change effects on seagrass growth, productivity and distribution until 2100. These predictions showed that seagrass meadows are mostly at risk from increased sedimentation and hydrodynamic changes, while the impact from sea level rise alone might be of less importance in the studied area. This study showcases the positive feedback between seagrass colonization and environmental conditions, which holds promise for successful conservation and restoration efforts aimed at supporting climate change mitigation and adaptation, and the provision of several other crucial ecosystem services. © 2024. The Authors.
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| 35. |
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| 36. |
- Dods, Robert, 1989, et al.
(author)
-
Ultrafast structural changes within a photosynthetic reaction centre.
- 2021
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 589:7841, s. 310-314
-
Journal article (peer-reviewed)abstract
- Photosynthetic reaction centres harvest the energy content of sunlight by transporting electrons across an energy-transducing biological membrane. Here we use time-resolved serial femtosecond crystallography1 using an X-ray free-electron laser2 to observe light-induced structural changes in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds. Structural perturbations first occur at the special pair of chlorophyll molecules of the photosynthetic reaction centre that are photo-oxidized by light. Electron transfer to the menaquinone acceptor on the opposite side of the membrane induces a movement of this cofactor together with lower amplitude protein rearrangements. These observations reveal how proteins use conformational dynamics to stabilize the charge-separation steps of electron-transfer reactions.
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| 37. |
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| 38. |
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| 39. |
- Heggebo, L. C., et al.
(author)
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Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden
- 2023
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In: Bmj Open. - : BMJ. - 2044-6055. ; 13:3
-
Journal article (peer-reviewed)abstract
- IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).
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| 40. |
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| 41. |
- Husby, A, et al.
(author)
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Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study
- 2023
-
In: BMJ medicine. - : BMJ. - 2754-0413. ; 2:1, s. e000373-
-
Journal article (peer-reviewed)abstract
- To investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis.DesignPopulation based cohort study.SettingNationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022.ParticipantsThe Nordic myocarditis cohort; 7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden.Main outcome measuresHeart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared.ResultsIn 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis; the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20).ConclusionsCompared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.
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| 42. |
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| 43. |
- Ingelsrud, L. H., et al.
(author)
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How do Patient-reported Outcome Scores in International Hip and Knee Arthroplasty Registries Compare?
- 2022
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In: Clinical orthopaedics and related research. - 1528-1132 .- 0009-921X. ; 480:10, s. 1884-1896
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Patient-reported outcome measures (PROMs) are the only systematic approach through which the patient's perspective can be considered by surgeons (in determining a procedure's efficacy or appropriateness) or healthcare systems (in the context of value-based healthcare). PROMs in registries enable international comparison of patient-centered outcomes after total joint arthroplasty, but the extent to which those scores may vary between different registry populations has not been clearly defined. QUESTIONS/PURPOSES: (1) To what degree do mean change in general and joint-specific PROM scores vary across arthroplasty registries, and to what degree is the proportion of missing PROM scores in an individual registry associated with differences in the mean reported change scores? (2) Do PROM scores vary with patient BMI across registries? (3) Are comorbidity levels comparable across registries, and are they associated with differences in PROM scores? METHODS: Thirteen national, regional, or institutional registries from nine countries reported aggregate PROM scores for patients who had completed PROMs preoperatively and 6 and/or 12 months postoperatively. The requested aggregate PROM scores were the EuroQol-5 Dimension Questionnaire (EQ-5D) index values, on which score 1 reflects "full health" and 0 reflects "as bad as death." Joint-specific PROMs were the Oxford Knee Score (OKS) and the Oxford Hip Score (OHS), with total scores ranging from 0 to 48 (worst-best), and the Hip Disability and Osteoarthritis Outcome Score-Physical Function shortform (HOOS-PS) and the Knee Injury and Osteoarthritis Outcome Score-Physical Function shortform (KOOS-PS) values, scored 0 to 100 (worst-best). Eligible patients underwent primary unilateral THA or TKA for osteoarthritis between 2016 and 2019. Registries were asked to exclude patients with subsequent revisions within their PROM collection period. Raw aggregated PROM scores and scores adjusted for age, gender, and baseline values were inspected descriptively. Across all registries and PROMs, the reported percentage of missing PROM data varied from 9% (119 of 1354) to 97% (5305 of 5445). We therefore graphically explored whether PROM scores were associated with the level of data completeness. For each PROM cohort, chi-square tests were performed for BMI distributions across registries and 12 predefined PROM strata (men versus women; age 20 to 64 years, 65 to 74 years, and older than 75 years; and high or low preoperative PROM scores). Comorbidity distributions were evaluated descriptively by comparing proportions with American Society of Anesthesiologists (ASA) physical status classification of 3 or higher across registries for each PROM cohort. RESULTS: The mean improvement in EQ-5D index values (10 registries) ranged from 0.16 to 0.33 for hip registries and 0.12 to 0.25 for knee registries. The mean improvement in the OHS (seven registries) ranged from 18 to 24, and for the HOOS-PS (three registries) it ranged from 29 to 35. The mean improvement in the OKS (six registries) ranged from 15 to 20, and for the KOOS-PS (four registries) it ranged from 19 to 23. For all PROMs, variation was smaller when adjusting the scores for differences in age, gender, and baseline values. After we compared the registries, there did not seem to be any association between the level of missing PROM data and the mean change in PROM scores. The proportions of patients with BMI 30 kg/m 2 or higher ranged from 16% to 43% (11 hip registries) and from 35% to 62% (10 knee registries). Distributions of patients across six BMI categories differed across hip and knee registries. Further, for all PROMs, distributions also differed across 12 predefined PROM strata. For the EQ-5D, patients in the younger age groups (20 to 64 years and 65 to 74 years) had higher proportions of BMI measurements greater than 30 kg/m 2 than older patients, and patients with the lowest baseline scores had higher proportions of BMI measurements more than 30 kg/m 2 compared with patients with higher baseline scores. These associations were similar for the OHS and OKS cohorts. The proportions of patients with ASA Class at least 3 ranged across registries from 6% to 35% (eight hip registries) and from 9% to 42% (nine knee registries). CONCLUSION: Improvements in PROM scores varied among international registries, which may be partially explained by differences in age, gender, and preoperative scores. Higher BMI tended to be associated with lower preoperative PROM scores across registries. Large variation in BMI and comorbidity distributions across registries suggest that future international studies should consider the effect of adjusting for these factors. Although we were not able to evaluate its effect specifically, missing PROM data is a recurring challenge for registries. Demonstrating generalizability of results and evaluating the degree of response bias is crucial in using registry-based PROMs data to evaluate differences in outcome. Comparability between registries in terms of specific PROMs collection, postoperative timepoints, and demographic factors to enable confounder adjustment is necessary to use comparison between registries to inform and improve arthroplasty care internationally. LEVEL OF EVIDENCE: Level III, therapeutic study. Copyright © 2022 by the Association of Bone and Joint Surgeons.
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| 44. |
- Ivarsson, Tord, 1946, et al.
(author)
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Remission and Relapse Across Three Years in Pediatric Obsessive-Compulsive Disorder Following Evidence-Based Treatments
- 2024
-
In: Journal of the American Academy of Child and Adolescent Psychiatry. - 0890-8567 .- 1527-5418. ; 63:5, s. 519-527
-
Journal article (peer-reviewed)abstract
- Objective: To examine relapse rates following remission in a 3-year follow-up study in pediatric patients with obsessive-compulsive disorder (OCD) treated with cognitive–behavioral therapy (CBT) in a first step, and either continued CBT or sertraline (randomized selection) in a second step. Method: Participants (N = 269) fulfilled DSM-IV OCD criteria with a mean severity on the Children's Yale–Brown Obsessive Compulsive Scale (CY-BOCS) of 24.6 (SD = 5.1) and were included in analyses according to intent-to-treat principles. CBT used manualized exposure and response prevention (ERP) during both steps 1 and 2, and step 2 sertraline medication used flexible dosing. The follow-up schedules were timed to 6, 12, 24, and 36 months following step 1 CBT. Remission was defined as a CY-BOCS score ≤10 and relapse as an elevated CY-BOCS score ≥16 in those who had remitted. Results: A good third of our patients were in stable and full remission at all examinations (n = 98, 36.4%). Further, some in remission following treatment (n = 36, 13.4%) had mild OCD at some examinations. Relapses during follow-up were not uncommon (n = 28, 10.4%), but in many patients these improved again (n = 10, 3.7%) and were in remission at the final 3-year follow-up. Furthermore, a considerable proportion (n = 50, 18.6%) of the patients were initial non-remitters to the treatment but achieved remission at some point during the follow-up. In addition, 11.5% (n = 31) had persistent OCD but reached remission by the last follow-up. Finally, a smaller segment of our sample (9.7%, n = 26), did not attain remission at any point during the study. Conclusion: Our outcome paints a more promising picture of pediatric OCD long-term outcome than previous studies have done. However, both relapse rates and the presence of initial non-remitters and persistent OCD show that treatments need improvement, particularly for those who respond slowly, partially, or not at all. The lack of a general psychiatric interview at follow-up is a marked limitation. Clinical trial registration information: Nordic Long-term Obsessive compulsive disorder (OCD) Treatment Study; https://www.isrctn.com; ISRCTN66385119
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| 45. |
- Jensen, S., et al.
(author)
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Distinct trajectories of long-term symptom severity in pediatric obsessive-compulsive disorder during and after stepped-care treatment
- 2020
-
In: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 61:9, s. 969-978
-
Journal article (peer-reviewed)abstract
- Background First-line treatments for pediatric obsessive-compulsive disorder (OCD) include exposure-based cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). No studies have thus far identified distinct classes and associated predictors of long-term symptom severity during and after treatment. Yet, these could form the basis for more personalized treatment in pediatric OCD. Method The study included 269 OCD patients aged 7-17 years from the Nordic Long-term OCD Treatment Study (NordLOTS). All participants received stepped-care treatment starting with 14 weekly sessions of manualized CBT. Nonresponders were randomized to either prolonged CBT or SSRIs. Symptom severity was assessed using the Children's Yale-Brown Obsessive-Compulsive Scale at seven time points from pre- to post-treatment and over a three-year follow-up. Latent class growth analysis (LCGA) was performed to identify latent classes of symptom severity trajectories. Univariate and multivariate analyses were used to detect differences between classes and identify predictors of trajectory class membership including several clinical and demographic variables. Trial registry: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; ; ISRCTN66385119. Results Three LCGA classes were identified: (a) acute, sustained responders (54.6%); (b) slow, continued responders (23.4%); and (c) limited long-term responders (21.9%). Class membership was predicted by distinct baseline characteristics pertaining to age, gender, symptom presentation, insight, avoidance, and comorbidity. Conclusions The LCGA suggests three distinct trajectory classes of long-term symptom severity during and after treatment in pediatric OCD with different clinical profiles at pretreatment. The results point to required clinical attention for adolescent patients with contamination/cleaning symptoms and reduced insight who do not show convincing responses to first-line treatment even though they may have reached the established cutoff for treatment response.
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| 46. |
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| 47. |
- Krackhardt, F., et al.
(author)
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Results from the "Me & My Heart" (eMocial) Study: a Randomized Evaluation of a New Smartphone-Based Support Tool to Increase Therapy Adherence of Patients with Acute Coronary Syndrome
- 2023
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In: Cardiovascular Drugs and Therapy. - : Springer Science and Business Media LLC. - 0920-3206 .- 1573-7241. ; 37:4, s. 729-741
-
Journal article (peer-reviewed)abstract
- Purpose This study evaluated whether patient support, administered via an electronic device-based app, increased adherence to treatment and lifestyle changes in patients with acute coronary syndrome (ACS) treated with ticagrelor in routine clinical practice. Methods Patients (aged >= 18 years) with diagnosed ACS treated with ticagrelor co-administered with low-dose acetylsalicylic acid were randomized into an active group (with support tool app for medication intake reminders and motivational messages) and a control group (without support tool app), and observed for 48 weeks (ClinicalTrials.gov Identifier: NCT02615704). Patients were asked to complete the 36-item Short-Form Health Survey (SF-36) and Lifestyle Changes Questionnaire (LSQ), and were assessed for blood pressure and body mass index (BMI) at baseline (visit 1) and at the end of the study (visit 2). Medication adherence was measured using the Brilique Adherence Questionnaire (BAQ). Results Patients (N = 676) were randomized to an active (n = 342) or a control (n = 334) group. BAQ data were available for 174 patients in the active group and 174 patients in the control group. Over the 48-week period, mean (standard deviation) adherence for the active and control groups was 96.4% (13.2%) and 91.5% (23.1%), respectively (effect of app intervention, p < 0.05). There were no significant differences in blood pressure and BMI between visits. General improvements in SF-36 and LSQ scores were observed for both groups. Conclusion The patient support tool app was associated with significant improvements in patient-reported treatment adherence compared with a data collection app alone in patients prescribed ticagrelor for ACS.
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| 48. |
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| 49. |
- Melin, Karin, 1964, et al.
(author)
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Treatment Gains Are Sustainable in Pediatric Obsessive-Compulsive Disorder: Three-Year Follow-Up From the NordLOTS
- 2020
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In: Journal of the American Academy of Child and Adolescent Psychiatry. - Amsterdam : Elsevier BV. - 0890-8567 .- 1527-5418. ; 59:2, s. 244-253
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Journal article (peer-reviewed)abstract
- © 2019 American Academy of Child and Adolescent Psychiatry Objective: This study evaluated the long-term outcomes of a stepped care treatment for pediatric obsessive-compulsive disorder (OCD) and investigated whether response to first-step cognitive-behavioral therapy (CBT) is an important indicator of 3-year outcomes. Method: This study is a part of the Nordic Long-term OCD Treatment Study (NordLOTS), in which 269 children and adolescents were treated with CBT. Nonresponders to CBT were randomized to extended treatment with continued CBT or pharmacotherapy with sertraline. Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores no higher than 15 and no higher than 10 were defined as treatment response and remission, respectively. Participants were assessed 2 and 3 years after first-step CBT. Linear mixed-effects models were used to analyze the outcomes. Results: Intent-to-treat analyses showed a significant decrease in CY-BOCS total score from baseline (24.6) to 3-year follow-up (5.0; p = .001), with a mean decrease of 5.9 from after treatment to 3-year follow-up. Three years after treatment, 90% (n = 242) of participants were rated as responders and 73% were in clinical remission. The duration of treatment did not influence the symptom level at 3-year follow-up (p = .998) and no significant difference was found (p = .169) between the extended treatment conditions. Conclusion: The results suggest that evidence-based treatment for pediatric OCD has long-term positive effects, whether a first step of manual-based CBT or extended treatment with CBT or sertraline. The improvements were maintained, and the symptoms decreased further during follow-up and were, after 3 years, similarly independent of treatment duration and form of extended treatment. Clinical trial registration information: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com; ISRCTN66385119.
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- Morcos, M. N. F., et al.
(author)
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Continuous mitotic activity of primitive hematopoietic stem cells in adult mice
- 2020
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 217:6
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Journal article (peer-reviewed)abstract
- The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.
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