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Rationale, design and baseline characteristics of participants in the OCEANIC-STROKE trial of FXIa inhibition for secondary stroke prevention
No full textIntroduction Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. Patients and methods Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS <= 15) or high-risk TIA (ABCD(2 )6 or 7) within 72 h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. Results Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. Conclusion OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA
Priorities for conservation rely heavily on discovery and assessments
No full textThe Red List is one of the most important and widely used sources of biodiversity information, providing conservation assessments for nearly 160,000 species. Here, we assess how the change in available Red List data can influence the selection of spatial conservation priorities and which regions are identified as most critical for conservation. We mapped biodiversity importance based on species ranges and threat status at ∼25 km, ∼50 km, and ∼ 100 km resolutions for two time points: 2010 and 2023. We then analyzed shifts in the top 10 % and 25 % most important areas for biodiversity at global and national levels between the two time points. We find that, globally, conservation priorities shifted over time from higher-income to lower-income countries. Nationally, priority areas in 2010 and 2023 were on average 60 % retained and over 40 % of countries experienced a shift in over half of their priority areas between the two years. Beyond showing large shifts within countries of which areas would be the most important to preserve, our analysis highlights an increasing focus on biodiversity research in developing nations. These shifts showcase the uneven global sampling of biodiversity, which skews our understanding of where to invest to efficiently conserve nature. We recommend increased funding for geographically representative field data collection, and the inclusion of explicit guidelines for regular updates in biodiversity frameworks to ensure conservation strategies remain effective.</p
The relationship between genotype- and phenotype-based estimates of genetic liability to psychiatric disorders, in practice and in theory
No full textGenetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation between individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, such as polygenic scores, but unlike in agriculture, there is an emerging consensus that family variables act nearly independently of genotypes in models of human disease. However, there is insufficient theoretical treatment of these scores, especially guiding our understanding of how and why scores derived from different sources of data may combine. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the Integrative Psychiatric Research (iPSYCH)2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that the low correlation between current phenotype- and genotype-based genetic instruments is caused by both being noisy measures of additive genetic liability. We expect they should remain complementary over the near future and therefore expect approaches integrating both sources of information to achieve more power for genetic inference.</p
Pubertal development and mental health:A population-based cohort study on self-rated health, psychotropic medication, and psychiatric diagnoses
No full textPurposeEarlier age at menarche may influence mental health but less is known of other measures of pubertal development. We aimed to investigate general mental health consequences of altered timing and tempo of several pubertal milestones in adolescents from the population-based Danish National Birth Cohort (DNBC).MethodsInformation on pubertal development (Tanner stages, age at menarche, age at first ejaculation, and voice break), was provided half-yearly throughout puberty in 6941 adolescent females and 6267 adolescent males. Timing (earlier, average, later) and tempo (faster, average, slower) of puberty were derived using non-linear mixed effect growth models and analysed as categorical and continuous variables. Outcomes included self-rated health obtained from the DNBC 18-year follow-up, and redemption of any prescribed psychotropic medication or any psychiatric diagnosis obtained from the Danish registers up to age 19 years. Adjusted odds ratios were estimated using logistic regression.ResultsEarlier pubertal timing and faster pubertal tempo were associated with higher odds, whereas later pubertal timing and slower pubertal tempo were associated with lower odds of the mental health outcomes, ranging from poor self-rated health to redeeming any psychotropic medication and receiving a psychiatric diagnosis. Associations were strongest in female adolescents.ConclusionsAltered pubertal development was associated with all unfavorable mental health outcomes. Vulnerable adolescents at increased risk of poor mental health due to earlier pubertal timing or faster pubertal tempo should be identified with the potential to introduce earlier interventions and support preventive actions for these adolescents.Purpose Earlier age at menarche may influence mental health but less is known of other measures of pubertal development. We aimed to investigate general mental health consequences of altered timing and tempo of several pubertal milestones in adolescents from the population-based Danish National Birth Cohort (DNBC). Methods Information on pubertal development (Tanner stages, age at menarche, age at first ejaculation, and voice break), was provided half-yearly throughout puberty in 6941 adolescent females and 6267 adolescent males. Timing (earlier, average, later) and tempo (faster, average, slower) of puberty were derived using non-linear mixed effect growth models and analysed as categorical and continuous variables. Outcomes included self-rated health obtained from the DNBC 18-year follow-up, and redemption of any prescribed psychotropic medication or any psychiatric diagnosis obtained from the Danish registers up to age 19 years. Adjusted odds ratios were estimated using logistic regression. Results Earlier pubertal timing and faster pubertal tempo were associated with higher odds, whereas later pubertal timing and slower pubertal tempo were associated with lower odds of the mental health outcomes, ranging from poor self-rated health to redeeming any psychotropic medication and receiving a psychiatric diagnosis. Associations were strongest in female adolescents. Conclusions Altered pubertal development was associated with all unfavorable mental health outcomes. Vulnerable adolescents at increased risk of poor mental health due to earlier pubertal timing or faster pubertal tempo should be identified with the potential to introduce earlier interventions and support preventive actions for these adolescents.</p
Effects of lifestyle interventions in pregnancy on gestational diabetes:individual participant data and network meta-analysis
No full textOBJECTIVES: To assess the effects of lifestyle interventions on gestational diabetes, determine whether the effects vary by maternal body mass index, age, parity, ethnicity, education level, or intervention, and rank interventions by effectiveness.DESIGN: Individual participant data (IPD) and network meta-analysis.DATA SOURCES: Major electronic databases (January 1990 to April 2025).METHODS: This meta-analysis included randomised trials on the effects of lifestyle interventions (physical activity based, diet based, or mixed) in pregnancy on gestational diabetes. Main outcomes were gestational diabetes defined by any criteria and by UK NICE (National Institute for Health and Care Excellence) criteria; other outcomes included IADPSG (International Association of Diabetes in Pregnancy Study Group) and modified IADPSG defined gestational diabetes. A two stage IPD meta-analysis estimated summary odds ratios and 95% confidence intervals and interactions (subgroup effects), along with absolute risk reduction estimates. Aggregate data from non-IPD trials were added to the meta-analysis when possible. Intervention effects were ranked using network meta-analysis.RESULTS: 104 randomised trials (35 993 women) were included, with IPD for 68% of participants (24 391 women; 54 studies). Lifestyle interventions reduced gestational diabetes defined by any criteria by 10% in IPD trials (odds ratio 0.90, 95% confidence interval (CI) 0.80 to 1.02; absolute risk reduction 1.3%, 95% CI -0.3% to 2.6%), and by 20% when combining IPD and non-IPD trials (odds ratio 0.80, 95% CI 0.73 to 0.88; absolute risk reduction 2.6%, 95% CI 1.6% to 3.6%), and no reduction was observed using NICE criteria (odds ratio 0.98, 95% CI 0.84to 1.13). Lifestyle interventions reduced gestational diabetes defined using IADPSG criteria by 14% in IPD trials (odds ratio 0.86, 95% CI 0.75 to 0.97; absolute risk reduction 2.7%, 95% CI 0.6% to 5.0%) and by 18% when combining IPD and non-IPD trials (odds ratio 0.82, 95% CI 0.72 to 0.93; absolute risk reduction 3.5%, 95% CI 1.3% to 5.7%). Effects did not vary by maternal characteristics, except for education. Although women of all educational levels benefited from the intervention, the benefit was less in those with low education (low v middle interaction: odds ratio 0.68, 95% CI 0.51 to 0.90; low v high interaction: odds ratio 0.71, 95% CI 0.54 to 0.93). Benefits did not vary by intervention characteristics, except for greater effectiveness with group format (odds ratio 0.81, 95% CI 0.68 to 0.97; absolute risk reduction 2.5%, 95% CI 0.4% to 4.3%) and newly trained facilitators (odds ratio 0.82, 95% CI 0.69 to 0.96; absolute risk reduction 2.4%, 95% CI 0.5% to 4.2%). Physical activity based interventions ranked highest (mean rank 1.1, 95% CI 1 to 2) in preventing gestational diabetes.CONCLUSIONS: Lifestyle interventions in pregnancy are likely to prevent gestational diabetes, with effects varying according to diagnostic criteria. Implementation strategies should address inequalities by maternal education, and consider group formats, provider training, and physical activity based interventions to prevent gestational diabetes.STUDY REGISTRATION: PROSPERO CRD42020212884.</p
Kan Trump købe Grønland?
No full textEt formelt køb af Grønland er juridisk udelukket – men politisk pres og økonomiske muskler kan gør spørgsmålet uomgængelig
A neutralizing APOA5 monoclonal antibody reduces amounts of lipoprotein lipase in capillaries and triggers hypertriglyceridemia
No full textApolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformation of lipoprotein lipase (LPL). LPL unfolding results in loss of catalytic activity and the detachment of LPL from the surface of cells. An APOA5 truncation mutation (identified in two patients with hypertriglyceridemia) had suggested that the last 35 amino acids of APOA5 are important for its function. We reasoned that a monoclonal antibody (mAb) against carboxyl-terminal sequences in APOA5 could clarify functionally important amino acid residues in APOA5 and assist in elucidating the mechanism by which APOA5 regulates plasma triglyceride metabolism. Because carboxyl-terminal APOA5 sequences are evolutionarily conserved, we began by screening a human Fab bacteriophage library for binders of carboxyl-terminal APOA5 sequences. We identified one such binder and used phage DNA sequences to build a chimeric IgG1 mAb (IBA707) against APOA5. The binding of IBA707 to APOA5 was abolished by nonconservative amino acid substitutions in conserved sequences (residues L337–I348) within a C-terminal α-helix in APOA5. The same substitutions disrupted APOA5’s ability to bind and inhibit ANGPTL3/8 activity. IBA707-mediated blockade of APOA5 function reduced intracapillary LPL levels and triggered elevated plasma levels of triglycerides and ANGPTL3/8 in both fasted and refed mice. IBA707 was cleared rapidly from the plasma in Apoa5+/+ mice but slowly in Apoa5–/– mice. Our studies identified functionally important amino acids in APOA5 and revealed that APOA5 controls plasma triglyceride metabolism in part by modulating plasma levels of ANGPTL3/8.</p
