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- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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- Beger, Richard D., et al.
(författare)
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Metabolomics enables precision medicine : "A White Paper, Community Perspective"
- 2016
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Ingår i: Metabolomics. - : Springer. - 1573-3882 .- 1573-3890. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.OBJECTIVES OF WHITE PAPER—EXPECTED TREATMENT OUTCOMES AND METABOLOMICS ENABLING TOOL FOR PRECISION MEDICINE: We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.CONCLUSIONS KEY SCIENTIFIC CONCEPTS AND RECOMMENDATIONS FOR PRECISION MEDICINE: Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.
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- Gavin, Michael C., et al.
(författare)
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Toward a Mechanistic Understanding of Linguistic Diversity
- 2013
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Ingår i: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 63:7, s. 524-535
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Tidskriftsartikel (refereegranskat)abstract
- Our species displays remarkable linguistic diversity. Although the uneven distribution of this diversity demands explanation, the drivers of these patterns have not been conclusively determined. We address this issue in two steps: First, we review previous empirical studies whose authors have suggested environmental, geographical, and sociocultural drivers of linguistic diversification. However, contradictory results and methodological variation make it difficult to draw general conclusions. Second, we outline a program for future research. We suggest that future analyses should account for interactions among causal factors, the lack of spatial and phylogenetic independence of the data, and transitory patterns. Recent analytical advances in biogeography and evolutionary biology, such as simulation modeling of diversity patterns, hold promise for testing four key mechanisms of language diversification proposed here: neutral change, population movement, contact, and selection. Future modeling approaches should also evaluate how the outcomes of these processes are influenced by demography, environmental heterogeneity, and time.
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- Bohm, Eric R., et al.
(författare)
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Collection and Reporting of Patient-reported Outcome Measures in Arthroplasty Registries: Multinational Survey and Recommendations
- 2021
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Ingår i: Clinical Orthopaedics and Related Research. - 0009-921X. ; 479:10, s. 2151-2166
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Tidskriftsartikel (refereegranskat)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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- Dunn, Jennifer A, et al.
(författare)
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Toward Consensus in Assessing Upper Limb Muscle Strength and Pinch and Grip Strength in People With Tetraplegia Having Upper Limb Reconstructions.
- 2021
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Ingår i: Topics in spinal cord injury rehabilitation. - : American Spinal Injury Association. - 1945-5763 .- 1082-0744. ; 27:3, s. 70-82
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Tidskriftsartikel (refereegranskat)abstract
- To reach agreement on standardized protocols for assessing upper limb strength and grip and pinch force for upper limb reconstructive surgery for tetraplegia.Selected members of an expert panel composed of international therapists formed at the 2018 International Congress for Upper Limb Surgery for Tetraplegia conducted a literature review of current practice that identified gaps and inconsistencies in measurement protocols and presented to workshop attendees. To resolve discrepancies, a set of questions was presented to workshop attendees who voted electronically. Consensus was set at 75% agreement.For manual muscle testing, consensus was reached for using the Medical Research Council scale, without plus or minus, and the use of resistance through range when testing grade 4 and grade 5 strength. Pectoralis major and serratus anterior should be routinely tested, however there was no consensus on other shoulder muscles. Grip and pinch strength should be tested according to the American Society of Hand Therapists positioning. For grip strength, either the Jamar or Biometrics dynamometer expressed in kilograms should be used. For grip and pinch strength, three measurements should be performed at each testing. No consensus was reached on a device for pinch strength.This work is an important step to enable comparable data in the future. Further consensus methods will work toward developing more comprehensive guidelines in this population. Building international consensus for pre- and postoperative measures of function supports objective evaluation of novel therapies and interpretation of multicenter studies.
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- Muraro, Antonella, et al.
(författare)
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Managing food allergy: GA2LEN guideline 2022.
- 2022
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Ingår i: The World Allergy Organization journal. - : Elsevier BV. - 1939-4551. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Food allergy affects approximately 2-4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.
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- Pile, Victoria, et al.
(författare)
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A brief early intervention for adolescent depression that targets emotional mental images and memories : protocol for a feasibility randomised controlled trial (IMAGINE trial).
- 2018
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Ingår i: Pilot and Feasibility Studies. - : Springer Science and Business Media LLC. - 2055-5784. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adolescent depression is common and impairing. There is an urgent need to develop early interventions to prevent depression becoming entrenched. However, current psychological interventions are difficult to access and show limited evidence of effectiveness. Schools offer a promising setting to enhance access to interventions, including reducing common barriers such as time away from education. Distressing negative mental images and a deficit in positive future images, alongside overgeneral autobiographical memories, have been implicated in depression across the lifespan, and interventions targeting them in adults have shown promise. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This feasibility randomised controlled trial will test the feasibility and acceptability of delivering this imagery-based cognitive behavioural intervention in schools.Methods/design: Fifty-six adolescents (aged 16-18) with high symptoms of depression will be recruited from schools. Participants will be randomly allocated to the imagery-based cognitive behavioural intervention (ICBI) or the control intervention, non-directive supportive therapy (NDST). Data on feasibility and acceptability will be recorded throughout, including data on recruitment, retention and adherence rates as well as adverse events. In addition, symptom assessment will take place pre-intervention, post-intervention and at 3-month follow-up. Primarily, the trial aims to establish whether it is feasible and acceptable to carry out this project in a school setting. Secondary objectives include collecting data on clinical measures, including depression and anxiety, and measures of the mechanisms proposed to be targeted by the intervention. The acceptability of using technology in assessment and treatment will also be evaluated.Discussion: Feasibility, acceptability and symptom data for this brief intervention will inform whether an efficacy randomised controlled trial is warranted and aid planning of this trial. If this intervention is shown in a subsequent definitive trial to be safe, clinically effective and cost-effective, it has potential to be rolled out as an intervention and so would significantly extend the range of therapies available for adolescent depression. This psychological intervention draws on cognitive mechanism research suggesting a powerful relationship between emotion and memory and uses imagery as a cognitive target in an attempt to improve interventions for adolescent depression.Trial registration: ISRCTN85369879.
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- Pile, Victoria, et al.
(författare)
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A feasibility randomised controlled trial of a brief early intervention for adolescent depression that targets emotional mental images and memory specificity (IMAGINE)
- 2021
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Ingår i: Behaviour Research and Therapy. - : Elsevier. - 0005-7967 .- 1873-622X. ; 143
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Tidskriftsartikel (refereegranskat)abstract
- Brief, evidence-based interventions for adolescent depression are urgently required, particularly for schoolsettings. Cognitive mechanisms research suggests dysfunctional mental imagery and overgeneral memory could be promising targets to improve mood. This feasibility randomised controlled trial with parallel symptomatic groups (n = 56) compared a novel imagery-based cognitive behavioural intervention (ICBI) to nondirective supportive therapy (NDST) in school settings. Blind assessments (of clinical symptoms and cognitive mechanisms) took place pre-intervention, post-intervention and follow-up three months later. The trial aimed to evaluate the feasibility and acceptability of the methodology and interventions, and estimate the likely range of effects of the intervention on self-reported depression. The pre-defined criteria for proceeding to a definitive RCT were met: full recruitment occurred within eleven months; retention was 89%; ICBI acceptability was above satisfactory; and no harm was indicated. Intention-to-treat analysis found large effects in favour of ICBI (relative to NDST) at post-intervention in reducing depressive symptoms (d = -1.34, 95% CI [-1.87, -0.80]) and improving memory specificity (d = 0.79 [0.35, 1.23]), a key cognitive target. The findings suggest that ICBI may not only improve mood but also strengthen abilities associated with imagining and planning the future, critical skills at this life stage. A fully powered evaluation of ICBI is warranted. Trial Registration: https://www.isrctn.com/; ISRCTN85369879.
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