| 1. |
- Austin, Thomas R, et al.
(författare)
-
Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.
- 2024
-
Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 1523-4681.
-
Tidskriftsartikel (refereegranskat)abstract
- Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P<1.0×10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.
|
|
| 2. |
- Babucci, Melike, et al.
(författare)
-
Unraveling the individual influences of supports and ionic liquid coatings on the catalytic properties of supported iridium complexes and iridium clusters
- 2020
-
Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 387, s. 186-195
-
Tidskriftsartikel (refereegranskat)abstract
- Supported iridium complexes were synthesized by the reaction of Ir(CO)(2) (acac) (acac = acetylacetonato) with SiO2, gamma-Al2O3, and MgO. Extended X-ray absorption fine structure (EXAFS) and infrared (IR) spectra demonstrate that the iridium was present as atomically dispersed species anchored to each support. The samples were treated in flowing H-2 at 673 K to form supported iridium clusters. EXAFS spectra and highangle annular dark-field scanning transmission electron microscopy images demonstrate that the average diameter of the iridium clusters on each support was approximately 1.2 nm. The catalysts before and after cluster formation were coated with each of a family of 1,3-dialkylimidazolium ionic liquids (ILs) having varying electron-donor tendencies probed by their nu(C2H) frequencies determined by IR spectroscopy. The coated and uncoated samples were tested as catalysts for partial hydrogenation of 1,3-butadiene in a flow reactor at 333 K, with turnover frequencies determined from differential conversions. The individual influences of the IL coatings and supports on the catalyst performance were found to depend strongly on whether the iridium was site-isolated complexes or present in clusters. The IL coatings as ligands exerted dominant effects on the clusters as catalysts, whereas the supports exerted dominant effects on the isolated iridium atoms. The results indicate how to tune the effects of metal nuclearity, IL coatings, and supports on the electronic environments and catalytic properties of the metals
|
|
| 3. |
- Christmas, Matthew, et al.
(författare)
-
Evolutionary constraint and innovation across hundreds of placental mammals
- 2023
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
-
Tidskriftsartikel (refereegranskat)abstract
- Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (similar to 10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
|
|
| 4. |
- Ercan, Ayse Bahar, et al.
(författare)
-
Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
-
Ingår i: The Lancet. Oncology. - 1474-5488. ; 25:5, s. 668-682
-
Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
|
|
| 5. |
- Kalaria, Raj, et al.
(författare)
-
The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.
- 2024
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279.
-
Tidskriftsartikel (refereegranskat)abstract
- Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.
|
|
| 6. |
- Krasnoselskikh, Vladimir, et al.
(författare)
-
ICARUS : in-situ studies of the solar corona beyond Parker Solar Probe and Solar Orbiter
- 2022
-
Ingår i: Experimental astronomy. - : Springer Nature. - 0922-6435 .- 1572-9508. ; 54:2-3, s. 277-315
-
Tidskriftsartikel (refereegranskat)abstract
- The primary scientific goal of ICARUS (Investigation of Coronal AcceleRation and heating of solar wind Up to the Sun), a mother-daughter satellite mission, proposed in response to the ESA “Voyage 2050” Call, will be to determine how the magnetic field and plasma dynamics in the outer solar atmosphere give rise to the corona, the solar wind, and the entire heliosphere. Reaching this goal will be a Rosetta Stone step, with results that are broadly applicable within the fields of space plasma physics and astrophysics. Within ESA’s Cosmic Vision roadmap, these science goals address Theme 2: “How does the Solar System work?” by investigating basic processes occurring “From the Sun to the edge of the Solar System”. ICARUS will not only advance our understanding of the plasma environment around our Sun, but also of the numerous magnetically active stars with hot plasma coronae. ICARUS I will perform the first direct in situ measurements of electromagnetic fields, particle acceleration, wave activity, energy distribution, and flows directly in the regions in which the solar wind emerges from the coronal plasma. ICARUS I will have a perihelion altitude of 1 solar radius and will cross the region where the major energy deposition occurs. The polar orbit of ICARUS I will enable crossing the regions where both the fast and slow winds are generated. It will probe the local characteristics of the plasma and provide unique information about the physical processes involved in the creation of the solar wind. ICARUS II will observe this region using remote-sensing instruments, providing simultaneous, contextual information about regions crossed by ICARUS I and the solar atmosphere below as observed by solar telescopes. It will thus provide bridges for understanding the magnetic links between the heliosphere and the solar atmosphere. Such information is crucial to our understanding of the plasma physics and electrodynamics of the solar atmosphere. ICARUS II will also play a very important relay role, enabling the radio-link with ICARUS I. It will receive, collect, and store information transmitted from ICARUS I during its closest approach to the Sun. It will also perform preliminary data processing before transmitting it to Earth. Performing such unique in situ observations in the area where presumably hazardous solar energetic particles are energized, ICARUS will provide fundamental advances in our capabilities to monitor and forecast the space radiation environment. Therefore, the results from the ICARUS mission will be extremely crucial for future space explorations, especially for long-term crewed space missions.
|
|
| 7. |
- Oodit, Ravi, et al.
(författare)
-
Guidelines for Perioperative Care in Elective Abdominal and Pelvic Surgery at Primary and Secondary Hospitals in Low-Middle-Income Countries (LMIC's) : Enhanced Recovery After Surgery (ERAS) Society Recommendation
- 2022
-
Ingår i: World Journal of Surgery. - : Springer. - 0364-2313 .- 1432-2323. ; 46:8, s. 1826-1843
-
Forskningsöversikt (refereegranskat)abstract
- Background: This is the first Enhanced Recovery After Surgery (ERAS (R)) Society guideline for primary and secondary hospitals in low-middle-income countries (LMIC's) for elective abdominal and gynecologic care.Methods: The ERAS LMIC Guidelines group was established by the ERAS (R) Society in collaboration with different representatives of perioperative care from LMIC's. The group consisted of seven members from the ERAS (R) Society and eight members from LMIC's. An updated systematic literature search and evaluation of evidence from previous ERAS (R) guidelines was performed by the leading authors of the Colorectal (2018) and Gynecologic (2019) surgery guidelines (Gustafsson et al in World J Surg 43:6592-695, Nelson et al in Int J Gynecol Cancer 29(4):651-668). Meta-analyses randomized controlled trials (RCTs), prospective and retrospective cohort studies from both HIC's and LMIC's were considered for each perioperative item. The members in the LMIC group then applied the current evidence and adapted the recommendations for each intervention as well as identifying possible new items relevant to LMIC's. The Grading of Recommendations, Assessment, Development and Evaluation system (GRADE) methodology was used to determine the quality of the published evidence. The strength of the recommendations was based on importance of the problem, quality of evidence, balance between desirable and undesirable effects, acceptability to key stakeholders, cost of implementation and specifically the feasibility of implementing in LMIC's and determined through discussions and consensus.Results: In addition to previously described ERAS (R) Society interventions, the following items were included, revised or discussed: the Surgical Safety Checklist (SSC), preoperative routine human immunodeficiency virus (HIV) testing in countries with a high prevalence of HIV/AIDS (CD4 and viral load for those patients that are HIV positive), delirium screening and prevention, COVID 19 screening, VTE prophylaxis, immuno-nutrition, prehabilitation, minimally invasive surgery (MIS) and a standardized postoperative monitoring guideline.Conclusions: These guidelines are seen as a starting point to address the urgent need to improve perioperative care and to effect data-driven, evidence-based care in LMIC's.
|
|
| 8. |
- Steer, Philippe, et al.
(författare)
-
Earthquake statistics changed by typhoon-driven erosion
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Tectonics and climate-driven surface processes govern the evolution of Earth’s surface topography. Topographic change in turn influences lithospheric deformation, but the elementary scale at which this feedback can be effective is unclear. Here we show that it operates in a single weather-driven erosion event. In 2009, typhoon Morakot delivered ~ 3 m of precipitation in southern Taiwan, causing exceptional landsliding and erosion. This event was followed by a step increase in the shallow (< 15 km depth) earthquake frequency lasting at least 2.5 years. Also, the scaling of earthquake magnitude and frequency underwent a sudden increase in the area where mass wasting was most intense. These observations suggest that the progressive removal of landslide debris by rivers from southern Taiwan has acted to increase the crustal stress rate to the extent that earthquake activity was demonstrably affected. Our study offers the first evidence of the impact of a single weather-driven erosion event on tectonics.
|
|
