| 1. |
- Ahluwalia, T. S., et al.
(författare)
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Genome-wide association study of circulating interleukin 6 levels identifies novel loci
- 2021
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:5, s. 393-409
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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| 2. |
- Medina-Gomez, C., et al.
(författare)
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Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis
- 2023
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Ingår i: Communications Biology. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n similar to 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
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| 3. |
- Hakkaart, C, et al.
(författare)
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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1061-
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
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| 4. |
- Santoro, V., et al.
(författare)
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HighNESS conceptual design report: Volume I
- 2024
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Ingår i: Journal of Neutron Research. - 1023-8166 .- 1477-2655. ; 25:3-4, s. 85-314
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Tidskriftsartikel (refereegranskat)abstract
- The European Spallation Source, currently under construction in Lund, Sweden, is a multidisciplinary international laboratory. Once completed to full specifications, it will operate the world’s most powerful pulsed neutron source. Supported by a 3 million Euro Research and Innovation Action within the EU Horizon 2020 program, a design study (HighNESS) has been completed to develop a second neutron source located below the spallation target. Compared to the first source, designed for high cold and thermal brightness, the new source has been optimized to deliver higher intensity, and a shift to longer wavelengths in the spectral regions of cold (CN, 2–20 Å), very cold (VCN, 10–120 Å), and ultracold (UCN, >500 Å) neutrons. The second source comprises a large liquid deuterium moderator designed to produce CN and support secondary VCN and UCN sources. Various options have been explored in the proposed designs, aiming for world-leading performance in neutronics. These designs will enable the development of several new instrument concepts and facilitate the implementation of a high-sensitivity neutron-antineutron oscillation experiment (NNBAR). This document serves as the Conceptual Design Report for the HighNESS project, representing its final deliverable.
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| 5. |
- Santoro, V., et al.
(författare)
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HighNESS conceptual design report: Volume II. the NNBAR experiment.
- 2024
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Ingår i: Journal of Neutron Research. - 1023-8166 .- 1477-2655. ; 25:3-4, s. 315-406
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Tidskriftsartikel (refereegranskat)abstract
- A key aim of the HighNESS project for the European Spallation Source is to enable cutting-edge particle physics experiments. This volume presents a conceptual design report for the NNBAR experiment. NNBAR would exploit a new cold lower moderator to make the first search in over thirty years for free neutrons converting to anti-neutrons. The observation of such a baryon-number-violating signature would be of fundamental significance and tackle open questions in modern physics, including the origin of the matter-antimatter asymmetry. This report shows the design of the beamline, supermirror focusing system, magnetic and radiation shielding, and anti-neutron detector necessary for the experiment. A range of simulation programs are employed to quantify the performance of the experiment and show how background can be suppressed. For a search with full background suppression, a sensitivity improvement of three orders of magnitude is expected, as compared with the previous search. Civil engineering studies for the NNBAR beamline are also shown, as is a costing model for the experiment.
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| 6. |
- Schiller, D, et al.
(författare)
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The Human Affectome
- 2024
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Ingår i: Neuroscience and biobehavioral reviews. - 1873-7528. ; 158, s. 105450-
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Alexander, Stephen P. H., et al.
(författare)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
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Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 8. |
- Christopoulos, Arthur, et al.
(författare)
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- 2021
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Ingår i: British journal of pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 178 Suppl 1
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Forskningsöversikt (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 9. |
- Tobias, J. H., et al.
(författare)
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Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
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| 10. |
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| 11. |
- Forgetta, V., et al.
(författare)
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Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N= 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r(2)= 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. Author summaryWhy was this study done? Osteoporosis screening identifies only a small proportion of the screened population to be eligible for intervention. The prediction of heritable risk factors using polygenic risk scores could decrease the number of screened individuals by reassuring those with low genetic risk. We investigated whether the genetic prediction of heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-could be incorporated into an established screening guideline to identify individuals at low risk for osteoporosis. What did the researchers do and find? Using UK Biobank, we developed a polygenic risk score (gSOS) consisting of 21,717 genetic variants that was strongly correlated with SOS ( = 23.2%). Using the National Osteoporosis Guideline Group clinical assessment guidelines in 5 validation cohorts, we estimate that reassuring individuals with a high gSOS, rather than doing further assessments, could reduce the number of clinical-risk-factor-based Fracture Risk Assessment Tool (FRAX) tests and bone-density-measurement-based FRAX tests by 37% and 41%, respectively, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. What do these findings mean? We show that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. Therefore, the potential exists to improve the efficiency of osteoporosis screening programs without large losses in sensitivity or specificity to identify individuals who should receive an intervention. Further translational studies are needed to test the clinical applications of this polygenic risk score; however, our work shows how such scores could be tested in the clinic.
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| 12. |
- Steinthorsdottir, V, et al.
(författare)
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Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5976-
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Tidskriftsartikel (refereegranskat)abstract
- Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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| 13. |
- Al-Khalili, F, et al.
(författare)
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Clinical and echocardiographic characteristics of individuals aged 75/76 years old with screening-detected elevated NT-proBNP levels
- 2020
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Ingår i: Open heart. - : BMJ. - 2053-3624. ; 7:1, s. e001200-
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Tidskriftsartikel (refereegranskat)abstract
- High plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) indicate increased probability of congestive heart failure (CHF) and atrial fibrillation (AF) and are associated with poor prognosis.ObjectiveWe aimed to describe the clinical and echocardiographic characteristics of a population of individuals aged 75/76 years old with NT-proBNP ≥900 ng/L without previously known CHF or AF.MethodsAll individuals aged 75/76 years in the Stockholm region were randomised to a screening study for AF. Half of them were invited to screening. Of those invited, 49.5% agreed to participate. Individuals with NT-proBNP ≥900 ng/L without known CHF were invited for further clinical evaluation.ResultsAmong 6315 participants without AF who had NT-proBNP sampled, 102 without previously known CHF had ≥900 ng/L. Of these, 93 completed further clinical investigations. In the population that was clinically investigated, 53% were female, and the median NT-proBNP was 1200 ng/L. New AF was found in 28 (30%). The NT-proBNP value in this group was not significantly different from those where AF was not detected (median 1285 vs 1178 ng/L). Patients with newly detected AF had larger left atrial volume and higher pulmonary artery pressure than those without AF. Preserved left ventricular ejection fraction (≥50%) was found in 86% of the participants, mid-range ejection fraction (40%–49%) in 3.2% and reduced ejection fraction (<40%) in 10.8%. Thirteen patients (14%) had other serious cardiac disorders that required medical attention.ConclusionElderly individuals with NT-proBNP levels ≥900 ng/L constitute a population at high cardiovascular risk even in the absence of diagnosed CHF or AF, and therefore merit further investigation.
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| 14. |
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| 15. |
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| 16. |
- de la Fuente, Eduardo, et al.
(författare)
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Ultracompact H II regions with extended emission: the case of G43.89-0.78 and its molecular environment
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 497:4, s. 4436-4447
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Tidskriftsartikel (refereegranskat)abstract
- The Karl Jansky Very Large Array (VLA), Owens Valley Radio Observatory (OVRO), Atacama Large Millimetric Array (ALMA), and the infrared Spitzer observatories are powerful facilities to study massive star formation regions and related objects such as ultra-compact (UC) H II regions, molecular clumps, and cores. We used these telescopes to study the UC H II region G43.89-0.78. The morphological study at arcminute scales using NVSS and Spitzer data shows that this region is similar to those observed in the bubble-like structures revealed by Spitzer observations. With this result, and including a physical characterization based on 3.6 cm data, we suggest G43.89-0.78 be classified as an UC H II region with Extended Emission because it meets the operational definition given in this paper comparing radio continuum data at 3.6 and 20 cm. For the ultra-compact component, we use VLA data to obtain physical parameters at 3.6 cm confirming this region as an UC H II region. Using ALMA observations, we detect the presence of a dense (2.6 x 10(7) cm(-3)) and small (similar to 2.0 arcsec; 0.08 pc) molecular clump with a mass of 220 M-circle dot and average kinetic temperature of 21 K, located near to the UC H II region. In this clump, catalogued as G43.890-0.784, water masers also exist, possibly tracing a bipolar outflow. We discover in this vicinity two additional clumps which we label as G43.899-0.786 (T-d = 50 K; M = 11 M-circle dot) and G43.888-0.787 (T-d = 50 K; M = 15 M-circle dot).
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| 17. |
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| 18. |
- Fielding, J. James, et al.
(författare)
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Tracing lake pollution, eutrophication and partial recovery from the sediments of Windermere, UK, using geochemistry and sediment microfabrics
- 2020
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 722
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Tidskriftsartikel (refereegranskat)abstract
- Many lakes undergo anthropogenically driven eutrophication and pollution leading to decreasedwater and sediment quality. These effects can enhance seasonally changing lake redox conditions that may concentrate potentially toxic elements. Here we report the results of a multi-method geochemical and sediment microfabric analysis applied to reconstruct the history of cultural eutrophication and pollution of the North and South Basins of Windermere, UK. Eutrophication developed from the mid-19th to the earliest 20th centuries. Enhanced lake productivity is indicated by increased sedimentary delta C-13, and increased pollution by a higher concentration of metals (Pb, Hg, and As) in the sediment, likely enhanced by incorporation and adsorption to settling diatom aggregates, preserved as sedimentary laminae. In the South Basin, increasing sediment delta N-15 values occur in step with Zn, Hg, and Cu, linking metal enrichment to isotopically heavy nitrate (N) from anthropogenic sources. From around 1930, decreases in Mn and Fe-rich laminae indicate reduced deep-water ventilation, whereas periods of sediment anoxia increased, being most severe in the deeper North Basin. Strongly reducing sediment conditions promoted Fe and Mn reduction and Pb-bearing barite formation, hitherto only described from toxic minewastes and contaminated soils. From 1980 there was an increase in indicators of bottomwater oxygenation, although not to before 1930. But in the South Basin, the continued impacts of sewage are indicated by elevated sediment delta N-15. Imaging and X-ray microanalysis using scanning electron microscopy has shown seasonal-scale redoxmineralisation of Mn, Fe, and Ba related to intermittent sediment anoxia. Elevated concentrations of these metals and As also occur in the surficial sediment and provide evidence for dynamic redox mobilisation of potentially toxic elements to the lake water. Concentrations of As (up to 80 ppm), exceed international Sediment Quality Standards. This process may become more prevalent in the future with climate change driving lengthened summer stratification.
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| 19. |
- Gallo, V., et al.
(författare)
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Concussion and long-term cognitive function among rugby players-The BRAIN Study
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:6, s. 1164-1176
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Tidskriftsartikel (refereegranskat)abstract
- Objective The BRAIN Study was established to assess the associations between self-reported concussions and cognitive function among retired rugby players. Methods Former elite-level male rugby union players (50+ years) in England were recruited. Exposure to rugby-related concussion was collected using the BRAIN-Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. Results A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby-related concussion(s). No association was found between concussion and PACC (beta -0.03 [95% confidence interval (CI): -1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (beta -1.04 [95% CI: -1.62, -0.47]). Conclusions Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants.
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| 20. |
- Impellizzeri, Franco M., et al.
(författare)
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Patient-reported outcome measures for hip-related pain : A review of the available evidence and a consensus statement from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:14, s. 848-857
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Forskningsöversikt (refereegranskat)abstract
- Hip-related pain is a well-recognised complaint among active young and middle-aged active adults. People experiencing hip-related disorders commonly report pain and reduced functional capacity, including difficulties in executing activities of daily living. Patient-reported outcome measures (PROMs) are essential to accurately examine and compare the effects of different treatments on disability in those with hip pain. In November 2018, 38 researchers and clinicians working in the field of hip-related pain met in Zurich, Switzerland for the first International Hip-related Pain Research Network meeting. Prior to the meeting, evidence summaries were developed relating to four prioritised themes. This paper discusses the available evidence and consensus process from which recommendations were made regarding the appropriate use of PROMs to assess disability in young and middle-aged active adults with hip-related pain. Our process to gain consensus had five steps: (1) systematic review of systematic reviews; (2) preliminary discussion within the working group; (3) update of the more recent high-quality systematic review and examination of the psychometric properties of PROMs according to established guidelines; (4) formulation of the recommendations considering the limitations of the PROMs derived from the examination of their quality; and (5) voting and consensus. Out of 102 articles retrieved, 6 systematic reviews were selected and assessed for quality according to AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews). Two showed moderate quality. We then updated the most recent review. The updated literature search resulted in 10 additional studies that were included in the qualitative synthesis. The recommendations based on evidence summary and PROMs limitations were presented at the consensus meeting. The group makes the following recommendations: (1) the Hip and Groin Outcome Score (HAGOS) and the International Hip Outcome Tool (iHOT) instruments (long and reduced versions) are the most appropriate PROMs to use in young and middle-aged active adults with hip-related pain; (2) more research is needed into the utility of the HAGOS and the iHOT instruments in a non-surgical treatment context; and (3) generic quality of life measures such as the EuroQoL-5 Dimension Questionnaire and the Short Form Health Survey-36 may add value for researchers and clinicians in this field. We conclude that as none of the instruments shows acceptable quality across various psychometric properties, more methods studies are needed to further evaluate the validity of these PROMS-the HAGOS and iHOT-as well as the other (currently not recommended) PROMS.
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| 21. |
- Kemp, Joanne L., et al.
(författare)
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Physiotherapist-led treatment for young to middle-aged active adults with hip-related pain : Consensus recommendations from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:9, s. 504-511
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Tidskriftsartikel (refereegranskat)abstract
- The 1st International Hip-related Pain Research Network meeting discussed four prioritised themes concerning hip-related pain in young to middle-aged adults: (1) diagnosis and classification of hip-related pain; (2) patient-reported outcome measures for hip-related pain; (3) measurement of physical capacity for hip-related pain; (4) physiotherapist-led treatment for hip-related pain. Thirty-eight expert researchers and clinicians working in the field of hip-related pain attended the meeting. This manuscript relates to the theme of physiotherapist-led treatments for hip-related pain. A systematic review on the efficacy of physiotherapist-led interventions for hip-related pain (published separately) was conducted and found that strong evidence for physiotherapist-led treatments was lacking. Prior to the meeting, draft consensus recommendations for consideration in the meeting were also developed based on the systematic review. The draft consensus recommendations were presented to all of the meeting participants via email, at least 1 week prior to the meeting. At the meeting, these recommendations were discussed, revised and voted on. Six recommendations for clinical practice and five recommendations for research were included and all gained consensus. Recommendations for clinical practice were that (i) Exercise-based treatments are recommended for people with hip-related pain. (ii) Exercise-based treatment should be at least 3 months duration. (iii) Physiotherapist-led rehabilitation after hip surgery should be undertaken. (iv) Patient-reported outcome measures, measures of physical impairment and measures of psychosocial factors should be used to monitor response to treatment. (v) Physical activity (that may include sport) is recommended for people with hip-related pain. (vi) Clinicians should discuss patient expectations, use shared-decision making and provide education. Recommendations for research were (i) Reporting of exercise programmes: Exercise descriptors such as load magnitude, number of repetitions and sets, duration of whole programme, duration of contractile element of exercise, duration of one repetition, time under tension, rest between repetitions, range of motion through which the exercise is performed, and rest between exercise sessions should be reported. (ii) Research should investigate the optimal frequency, intensity, time, type, volume and progression of exercise therapy. (iii) Research should examine the effect of patient education in people with hip-related pain. (iv) Research should investigate the effect of other treatments used in people with hip-related pain (for example: manual therapy, medications, injections). (v) Research should examine the impact of comorbidities and social determinants on treatment effectiveness in people with hip-related pain. Clinicians and researchers working with young to middle-aged active adults with hip-related pain may use these consensus recommendations to guide, develop, test and implement individualised, evidence-based physiotherapist-led rehabilitation programmes.
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| 22. |
- Lee, Man K.S., et al.
(författare)
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Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis
- 2022
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Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 61
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis.Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice.Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs.Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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| 23. |
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| 24. |
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| 25. |
- Mosler, Andrea Britt, et al.
(författare)
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Standardised measurement of physical capacity in young and middle-aged active adults with hip-related pain : Recommendations from the first International Hip-related Pain Research Network (IHiPRN) meeting, Zurich, 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:12, s. 702-710
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Tidskriftsartikel (refereegranskat)abstract
- Hip-related pain can significantly impact quality of life, function, work capacity, physical activity and family life. Standardised measurement methods of physical capacity of relevance to young and middle-aged active adults with hip-related pain are currently not established. The aim of this consensus paper was to provide recommendations for clinical practice and research on standardised measurement methods of physical capacity in young and middle-aged active adults with hip-related pain. Four areas of importance were identified: (1) clinical measures (range of motion, muscle strength, functional impairments), (2) laboratory-based measures (biomechanics and muscle function (muscle activity, size and adiposity)), (3) physical activity, and (4) return to sport/performance. The literature was reviewed, and a summary circulated to the working group to inform discussion at the consensus meeting. The working group developed clinical and research recommendations from the literature review, which were further discussed and modified within the working group at the consensus meeting. These recommendations were then presented to all 38 International Hip-related Pain Research Network (IHiPRN) participants for further discussion, refinement and consensus voting. Therefore, the recommendations voted on were based on a combination of current evidence and expert opinion. The consensus meeting voted on 13 recommendations, six of which were clinically orientated, and seven more research specific. We recommended that clinicians working with young and middle-aged active adults with hip-related pain assess strength using objective methods of measurement, and clinically assess performance of functional tasks, including walking and running. Physical activity should be quantified using both self-reported and objective measures, and patient expectations of recovery should be quantified prior to treatment. It was recommended that return to physical activity (including sport and occupation) be quantified, and sport-specific activities should be assessed prior to return to sport. The IHiPRN participants were uncertain regarding recommendations for range of motion assessment. Research recommendations were that the measurement properties of range of motion, strength and functional performance tests be investigated, reported and improved in both clinical and research settings. Reporting of movement-related parameters (biomechanics and muscle function) should be standardised and the relationship among movement-related parameters, symptoms, function, quality of life, and intra-articular and imaging findings should be investigated. Quantification of return to physical activity (including sport and occupational demands) is required in future research, and the return to sport continuum should be used. Future research is required to determine the best criteria for rehabilitation progression and return to physical activity following hip-related pain management.
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| 26. |
- Reiman, Michael P., et al.
(författare)
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Consensus recommendations on the classification, definition and diagnostic criteria of hip-related pain in young and middle-aged active adults from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:11, s. 631-641
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Forskningsöversikt (refereegranskat)abstract
- There is no agreement on how to classify, define or diagnose hip-related pain-a common cause of hip and groin pain in young and middle-aged active adults. This complicates the work of clinicians and researchers. The International Hip-related Pain Research Network consensus group met in November 2018 in Zurich aiming to make recommendations on how to classify, define and diagnose hip disease in young and middle-aged active adults with hip-related pain as the main symptom. Prior to the meeting we performed a scoping review of electronic databases in June 2018 to determine the definition, epidemiology and diagnosis of hip conditions in young and middle-aged active adults presenting with hip-related pain. We developed and presented evidence-based statements for these to a panel of 37 experts for discussion and consensus agreement. Both non-musculoskeletal and serious hip pathological conditions (eg, tumours, infections, stress fractures, slipped capital femoral epiphysis), as well as competing musculoskeletal conditions (eg, lumbar spine) should be excluded when diagnosing hip-related pain in young and middle-aged active adults. The most common hip conditions in young and middle-aged active adults presenting with hip-related pain are: (1) femoroacetabular impingement (FAI) syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without a distinct osseous morphology (labral, chondral and/or ligamentum teres conditions), and that these terms are used in research and clinical practice. Clinical examination and diagnostic imaging have limited diagnostic utility; a comprehensive approach is therefore essential. A negative flexion-adduction-internal rotation test helps rule out hip-related pain although its clinical utility is limited. Anteroposterior pelvis and lateral femoral head-neck radiographs are the initial diagnostic imaging of choice-advanced imaging should be performed only when requiring additional detail of bony or soft-tissue morphology (eg, for definitive diagnosis, research setting or when planning surgery). We recommend clear, detailed and consistent methodology of bony morphology outcome measures (definition, measurement and statistical reporting) in research. Future research on conditions with hip-related pain as the main symptom should include high-quality prospective studies on aetiology and prognosis. The most common hip conditions in active adults presenting with hip-related pain are: (1) FAI syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without distinct osseous morphology including labral, chondral and/or ligamentum teres conditions. The last category should not be confused with the incidental imaging findings of labral, chondral and/or ligamentum teres pathology in asymptomatic people. Future research should refine our current recommendations by determining the clinical utility of clinical examination and diagnostic imaging in prospective studies.
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| 27. |
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| 28. |
- Rodger, James G., et al.
(författare)
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Widespread vulnerability of flowering plant seed production to pollinator declines
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:42
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Tidskriftsartikel (refereegranskat)abstract
- Despite evidence of pollinator declines from many regions across the globe, the threat this poses to plant populations is not clear because plants can often produce seeds without animal pollinators. Here, we quantify pollinator contribution to seed production by comparing fertility in the presence versus the absence of pollinators for a global dataset of 1174 plant species. We estimate that, without pollinators, a third of flowering plant species would produce no seeds and half would suffer an 80% or more reduction in fertility. Pollinator contribution to plant reproduction is higher in plants with tree growth form, multiple reproductive episodes, more specialized pollination systems, and tropical distributions, making these groups especially vulnerable to reduced service from pollinators. These results suggest that, without mitigating efforts, pollinator declines have the potential to reduce reproduction for most plant species, increasing the risk of population declines.
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| 29. |
- Romero, Gustavo Q., et al.
(författare)
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Climate variability and aridity modulate the role of leaf shelters for arthropods : A global experiment
- 2022
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 28:11, s. 3694-3710
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Tidskriftsartikel (refereegranskat)abstract
- Current climate change is disrupting biotic interactions and eroding biodiversity worldwide. However, species sensitive to aridity, high temperatures, and climate variability might find shelter in microclimatic refuges, such as leaf rolls built by arthropods. To explore how the importance of leaf shelters for terrestrial arthropods changes with latitude, elevation, and climate, we conducted a distributed experiment comparing arthropods in leaf rolls versus control leaves across 52 sites along an 11,790 km latitudinal gradient. We then probed the impact of short- versus long-term climatic impacts on roll use, by comparing the relative impact of conditions during the experiment versus average, baseline conditions at the site. Leaf shelters supported larger organisms and higher arthropod biomass and species diversity than non-rolled control leaves. However, the magnitude of the leaf rolls' effect differed between long- and short-term climate conditions, metrics (species richness, biomass, and body size), and trophic groups (predators vs. herbivores). The effect of leaf rolls on predator richness was influenced only by baseline climate, increasing in magnitude in regions experiencing increased long-term aridity, regardless of latitude, elevation, and weather during the experiment. This suggests that shelter use by predators may be innate, and thus, driven by natural selection. In contrast, the effect of leaf rolls on predator biomass and predator body size decreased with increasing temperature, and increased with increasing precipitation, respectively, during the experiment. The magnitude of shelter usage by herbivores increased with the abundance of predators and decreased with increasing temperature during the experiment. Taken together, these results highlight that leaf roll use may have both proximal and ultimate causes. Projected increases in climate variability and aridity are, therefore, likely to increase the importance of biotic refugia in mitigating the effects of climate change on species persistence.
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| 30. |
- Velter, M. G.E., et al.
(författare)
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Sustainable business model innovation : The role of boundary work for multi-stakeholder alignment
- 2020
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Ingår i: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 247
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Tidskriftsartikel (refereegranskat)abstract
- This study focuses on the boundary-spanning nature of sustainable business model innovation, studying multi-stakeholder engagement and alignment. Drawing on the concept of boundary work, we explore the different types of organizational boundary changes between focal companies and their external stakeholders, investigating specifically the process of exploring, negotiating, disrupting and realigning organizational boundaries. Based on an exploratory study of nine different sustainable business model initiatives from for-profit and non-profit organizations, our analysis shows how actors involved need to find alignment at normative, instrumental and strategic dimensions in order to achieve sustainable value creation. However, complexity for alignment emerges through different understandings of value, diverging interests, division of risks and responsibilities, and existing processes and activities that limits actors’ openness to align. Mutual boundary changes are thus necessary in the process of multi-stakeholder engagement in order to enhance organizations’ understanding of value and to capture the envisioned value. This paper functions as an agenda-setting paper, presenting first insights on how the boundary work lens can advance our understanding of alignment processes between focal organizations and their external stakeholders, required for sustainable business model innovation.
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| 31. |
- Zheng, Jie, et al.
(författare)
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Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.
- 2023
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - 2326-5205. ; 75:10, s. 1781-1792
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β=0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
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