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Antidepressant Switching as a Proxy Phenotype for Drug Nonresponse:Investigating Clinical, Demographic, and Genetic Characteristics
Get PDFBACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI nonresponders.METHODS: In the UK Biobank (UKB) ( N = 38,813) and Generation Scotland ( N = 1777) datasets, SSRI switching was defined using ≤90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Nonswitchers were participants with ≥3 consecutive prescriptions for an SSRI. In the UKB, clinical, demographic, and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. RESULTS: In the UKB, 5133 (13.2%) SSRI switchers and 33,680 nonswitchers were defined. The mean time to switch was 28 days (interquartile range, 17-49). Switching patterns were consistent across the UKB and Generation Scotland ( n = 498 switchers). Higher annual income and educational levels (odds ratio [OR] [95% CI] for a university degree, 0.73 [0.67-0.79] compared with no qualifications) were associated with lower levels of switching. PGSs for nonremission, based on clinical studies, were associated with increased risk of switching (OR, 1.07 [1.02-1.12], p = .007). MDD PGSs and family history of depression were not significantly associated with switching. Using genome-wide complex trait Bayesian, the single nucleotide polymorphism-based heritability was approximately 4% (SE 0.016) on the observed scale. CONCLUSIONS: This study identified SSRI switching as a proxy for nonresponse, scalable across biobanks with electronic health records, capturing demographics and genetics of treatment nonresponse, and independent of MDD genetics.</p
Bilingualism, working memory, and relative clause comprehension in children
Get PDFBilingualism has sometimes been associated with cognitive boosts, particularly in working memory (WM). However, it remains unclear whether such benefits extend to the comprehension of syntactically complex structures. We investigated this through a gamified character-selection task assessing comprehension of subject-relative clauses and object-relative clauses among monolingual (n = 31) and bilingual (n = 28) French-speaking children, as well as monolingual (n = 45) and bilingual (n = 43) German-speaking children aged 3 to 12. We examined whether comprehension correlated with verbal WM, measured through a nonword repetition task, and interference resolution ability, assessed through a Simon task and an analysis of comprehension errors. The results indicated no bilingual advantage: object-relative clauses were more difficult than subject-relative clauses across all groups and languages. While interference-related errors – misinterpreting object-relative clauses as subject-relative clauses more frequently than vice versa – surfaced in all groups, verbal WM correlated with object-relative comprehension only in French. These findings are discussed in relation to current theories of bilingualism and WM in language comprehension
Data Resource Profile: Whole-Blood DNA Methylation Resource in Generation Scotland (MeGS)
Get PDFWe have generated whole-blood DNA methylation profiles from 18 869 Generation Scotland: Scottish Family Health Study (GS) participants, resulting in, at the time of writing, the largest single-cohort DNA methylation resource for basic biological and medical research: Methylation in Generation Scotland (MeGS). GS is a community- and family-based cohort, which recruited >24 000 participants from Scotland between 2006 and 2011.Comprehensive phenotype information, including detailed data on cognitive function, personality traits, and mental health, is available for all participants. The majority of GS participants (83%) have genome-wide single-nucleotide polymorphism genotype data (IlluminaHumanOmniExpressExome-8 array v1.0 and v1.2). Over 97% of GS participants have given consent for health record linkage and re-contact. At baseline, blood-based DNA methylation was characterized at �850 000 sites across four waves by using the Illumina EPICv1 array. MeGS participants were aged between 17 and 99 years at the time of enrolment in GS. Blood-based DNA methylation EPICv1 array profiles collected at a follow-up appointment that took place 4.3–12.2 years (mean ¼ 7.1 years) after baseline are also available for 796 MeGS participants. Access to MeGS for researchers and collaborators is via application to the GS Access Committee ([email protected])
Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201
Get PDFPURPOSE This study evaluated the efficacy and safety of avutometinib (rapidly acceleratedfibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK]clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor)in patients with recurrent low-grade serous ovarian cancer (LGSOC).METHODS In this phase II, open-label study, patients with recurrent, measurable LGSOCafter ≥1 line of platinum chemotherapy were stratified by tumor Kirsten ratsarcoma virus homolog (KRAS) mutation status and randomly assigned to oralavutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mgtwo times per week in combination with oral defactinib 200 mg two times perday. The combination was selected as the go-forward regimen for expansion.The primary end point was objective response rate (ORR) by blinded independentcentral review.RESULTS A total of 115 patients received the go-forward combination regimen. Patientshad a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%),bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR was 31% (95%CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI,14.8 to 31.1). ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts.The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2)overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to18.4) in KRAS-mutant and wild-type cohorts, respectively. The most frequentgrade ≥3 treatment-related adverse events (AEs) were elevated creatinephosphokinase (24%), diarrhea (8%), and anemia (5%). Ten percent of patientsdiscontinued because of AEs.CONCLUSION The efficacy and safety profile of avutometinib in combination with defactinibsupport this combination as a potential standard of care for recurrent LGSOC. Arandomized phase 3 study of avutometinib and defactinib versus investigator’schoice of therapy for women with recurrent LGSOC is currently enrolling(RAMP301; ClinicalTrials.gov identifier: NCT06072781)
A multicenter, retrospective analysis of long-term survival in 255 dogs with pheochromocytoma treated with alpha-adrenoreceptor antagonists or surgery (2010 – 2021)
Get PDFBackground: The survival of dogs with pheochromocytoma (PCC) treated with adrenoreceptor antagonists has not been described or compared to surgically managed cases. Hypothesis/Objectives: The objective of this study is to evaluate the survival of medically and surgically managed dogs with PCC and investigate factors associated with survival. Animals: Two hundred fifty-five dogs with PCC, treated with alpha-adrenoreceptor antagonists (AA) without adrenalectomy (Group 1, n = 75), adrenalectomy +/– AA (Group 2, n = 128), or neither treatment (Group 3, n = 52). Methods: Retrospective, multicenter review of medical records. Median overall survival time (OST) for Groups 1 and 2 combined was calculated using Kaplan–Meier estimates, and then compared between Group 1 and Group 2 using Log-Rank testing. Cox proportional hazard analysis identified factors associated with survival in Groups 1 and 2 individually and combined. Results: Median OST for all cases was 854 (95% CI: 572–1136) days. Median OST was lower in Group 1 (247 days, 95% CI: 76–418 days) than in Group 2 (927 days, 95% CI: 587–1267 days; p < 0.001). In Group 2, 88/92 dogs (97.8%) that received presurgical AA treatment survived to discharge compared to 23/27 (85.2%) that did not receive AA pretreatment (p = 0.03). Lack of clinical signs at presentation was associated with increased survival in both groups combined (HR 0.5; 95% CI 0.3–0.9; p = 0.02) and in Group 2 alone (HR 0.3; 95% CI 0.1–0.7; p = 0.01). Conclusions and Clinical Importance: Dogs with PCC treated with adrenalectomy have longer survival compared to those managed with AA without adrenalectomy.</p
Symbolic calculus for a class of pseudodifferential operators with applications to compactness
Get PDFWe prove a symbolic calculus for a class of pseudodifferential operators, and discuss its applications to L2-compactness via a compact version of the T(1) theorem.</p
Key action areas for transforming the UK food system: Insights from the Transforming UK Food Systems (TUKFS) Programme project portfolio
Get PDFThe UK food system is a driver of the public health crisis of non-communicable disease, is linked to the cost-of-living crisis, and contributes to climate change, biodiversity loss and soil degradation. The economy relies strongly on the health of its people and food businesses, while also impacting the livelihoods of food system actors. However, action towards more resilient, equitable and regenerative food systems remains too slow and unambitious to adequately address these challenges. The Transforming UK Food Systems Programme comprises a wide range of research projects which address these challenges in a novel place-based, co-produced and action-oriented way. We provide 27 suggested action areas for supporting food system transformation, grouped in five themes spanning production, manufacturing, supply chain and consumption. Among the suggestions, there is a strong emphasis on the importance of co-production with food system actors and affected citizens. We highlight the vital role of governance and policy in supporting these action areas in both a structural and financial way, noting that this needs both national policy and regional approaches to take into account geographically varying cultural circumstances and values, and to allow the high level of co-production necessary
Carbon footprint of a sample of clinical trials for people with neurological disorders: cross-sectional analysis
Get PDFOBJECTIVE: To quantify the carbon footprint of a sample of clinical trials for neurological disorders.DESIGN: Cross-sectional study.METHOD: Two clinical trial registries were searched on 29 December 2022 for phase 2-4 randomised controlled trials led from and recruiting in the UK, enrolling people with any of the 15 neurological disorders with the highest global burden, that had started recruitment or been registered in the preceding 5 years. Eligible trials were invited to share data to estimate emissions in each of the 10 modules of the Low Carbon Clinical Trials footprinting guidance. The primary outcome measure was kg of carbon dioxide equivalent (CO 2e). RESULTS: 318 randomised controlled trials were found, nine were eligible and six shared data (three completed and three ongoing). The module with the highest estimated CO 2e for each trial was the Clinical Trial Unit staff emissions (median 24 126 kg CO2e, IQR 10 395-78,867; range 45-79% of overall emissions of each trial); commuting accounted for >50% of CO 2e in this module. The second and third highest modules were trial-specific participant assessments (median 11 497 kg CO2e, IQR 825-15,682) and trial supplies and equipment (median 1161 kg CO 2e, IQR 226-6632). The total carbon footprint of these six trials involving 2248 participants at 239 sites was 2 63 215 kg CO 2e. CONCLUSIONS: Emissions by Clinical Trials Unit staff were the top modifiable carbon hotspot in six randomised controlled trials for people with neurological disorders, which had a total carbon footprint equivalent to 1364 passengers' return aeroplane journeys between London and Edinburgh.</p
Protocol:Bereavement interventions for children and adolescents: An evidence and gap map of primary studies and systematic reviews
Get PDFThis is the protocol for a Campbell evidence and gap map. The objectives are as follows: (1) To identify and map all existing primary studies and systematic reviews (published and unpublished) on bereavement interventions/programmes for children and adolescents to create a live, searchable and publicly available EGM; (2) Provide a comprehensive descriptive overview of psychosocial outcomes targeted by bereavement interventions for children and adolescents; (3) Determine the characteristics of bereavement interventions targeted at children and adolescents, including age, location, duration, delivery, underlying theories, evaluation and target death.</p
Extensive fluvial surfaces at the East Antarctic margin have modulated ice-sheet evolution
Get PDFAntarctic bed topography influences how the overlying ice sheet responds to climate change and provides a record of long-term glacial history. However, knowledge of the processes that governed the development of the landscape before glacial inception and how this modulated subsequent ice-sheet evolution remains limited. Here we use radio-echo sounding to reveal extensive flat surfaces beneath the ice margin between Princess Elizabeth Land and George V Land, East Antarctica. When their elevations are isostatically adjusted for unloading of the present-day ice load, these surfaces cluster at 200–450 metres above sea level and dip gently in an offshore direction. We show that the surfaces are fragments of a once-contiguous coastal plain formed by fluvial erosion, which dates from between the separation of East Antarctica from Australia (~100–80 Ma) and the onset of Southern Hemisphere ice-sheet glaciation (~34 Ma). The preservation of these landforms indicates a lack of intense, selective erosion of the surfaces throughout Antarctica’s glacial history. Fast-flowing ice has instead been directed through inherited tectonic structures and fluvial valleys, leading to the incision of overdeepened subglacial troughs between the flat surfaces and thus modulating the responsiveness of the ice sheet to climate change
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