Blood biomarker profiles in young-onset neurocognitive disorders: A cohort study

Introduction: Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals \u3c65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses. Methods: Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer’s disease (n = 18), non-Alzheimer’s disease neurodegeneration (n = 23) or primary psychiatric disorders (n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181, apolipoprotein E genotype and late-onset Alzheimer’s disease polygenic risk scores were determined. Information-theoretic model selection identified discriminatory factors. Results: Neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181 levels were elevated in early-onset Alzheimer’s disease compared with other diagnostic categories. A multi-omic model selection identified that a combination of cognitive and blood biomarkers, but not the polygenic risk score, discriminated between early-onset Alzheimer’s disease and primary psychiatric disorders (area under the curve ⩾ 0.975, 95% confidence interval: 0.825–1.000). Phosphorylated-tau 181 alone significantly discriminated between early-onset Alzheimer’s disease and non-Alzheimer’s disease neurodegeneration causes (area under the curve = 0.950, 95% confidence interval: 0.877–1.00). Discussion: Discriminating between early-onset Alzheimer’s disease, non-Alzheimer’s disease neurodegeneration and primary psychiatric disorders causes of young-onset neurocognitive symptoms is possible by combining cognitive profiles with blood biomarkers. These results support utilizing blood biomarkers for the work-up of young-onset neurocognitive symptoms and highlight the need for the development of a young-onset Alzheimer’s disease-specific polygenic risk score

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

An Inquiry into Algorithmic Complexity

This is the first section in a proposed monograph on algorithmic complexity theory. Future sections shall include: information Theory as a Proof Technique; Algorithms Using Linear Form Inequalities; Some Probabilistic Analyses of Algorithms, etc. Comments, suggestions and corrections are welcomed. Please let me know what you think. This is not a limited distribution document, although I may wish to publish it later. Anyone who develops an idea based on this work to a more advanced state is welcome to publish first. I would be very eager to see any such result as soon as possible

Comment on 'Does replacing coal with wood lower CO2 emissions? Dynamic lifecycle analysis of wood bioenergy'

An analysis by Sterman et al (2018 Environ. Res. Lett. 13 015007) suggests that use of wood for bioenergy production results in a worse climate outcome than from using coal. However, many of the assumptions on which their primary wood bioenergy scenario is based are not realistic and therefore are not informative. Assumptions of uncharacteristically long rotations for southern pine plantations, no utilization of wood for longer-duration products, and a single harvest over 100 years understate the carbon performance of current forest management practices. We provide references that support realistic modeling of forest carbon dynamics that are reflective of current practice and therefore more informative

Community Culture Survey - Revised: Measuring neighborhood culture and exploring geographic, socioeconomic, and cultural determinants of health in samples across the United States and in Thailand.

OBJECTIVES: Research on links between social, geographic, and cultural determinants of health has been thwarted by inadequate measures of culture. The purpose of this study was to improve the measurement of community culture, defined as shared patterns of attitudes and behaviors among people within a neighborhood that distinguish it from others, and to examine dimensions of culture, independent of socioeconomic and demographic factors, and their relationships with health. STUDY DESIGN: A survey research design with correlational analyses was used. METHODS: A survey packet including the Community Culture Survey - Revised (CCS-R), demographic, health, and other individual-level measures was administered through convenience sampling across the United States (US) and to a sample in Thailand from 2016 to 2018. US county-level variables were obtained from zip codes. RESULTS: 1930 participants from 49 US states (n = 1592) and Thailand (n = 338) completed all CCS-R items, from which 12 subscales were derived: Social Support & Connectedness, Responsibility for Self & Others, Family Ties & Duties, Social Distress, Urban Diversity, Discontinuity, Church-Engaged, External Resource-Seeking, Locally Owned Business-Active, Power Deference, Next Generation Focus, and Self-Reliance. Neighborhood culture subscale scores varied more by geography than by participants demographics. All subscales predicted one or more health indicator, and some of these relationships were significant after adjusting for participant age and county-level socioeconomic variables. Most of the significant differences on subscales by race/ethnicity were no longer significant after adjusting for participants age and county-level socioeconomic variables. Most rural/urban and regional differences in culture within the US persisted after these adjustments. Based on correlational analyses, Social Support & Connectedness and Responsibility for Self & Others were the best predictors of participants overall health and quality of life, and Responsibility for Self & Others was the best predictor (inversely) of the CDCs measures of social vulnerability. CONCLUSIONS: Neighborhood culture is measurable, multi-dimensional, distinct from race/ethnicity, and related to health even after controlling for age and socioeconomic factors. The CCS-R is useful for advancing research and practice addressing the complex interactions between individuals, their neighborhood communities, and health outcomes

Comment on 'Does replacing coal with wood lower CO2 emissions? Dynamic lifecycle analysis of wood bioenergy'

An analysis by Sterman et al (2018 Environ. Res. Lett. 13 015007) suggests that use of wood for bioenergy production results in a worse climate outcome than from using coal. However, many of the assumptions on which their primary wood bioenergy scenario is based are not realistic and therefore are not informative. Assumptions of uncharacteristically long rotations for southern pine plantations, no utilization of wood for longer-duration products, and a single harvest over 100 years understate the carbon performance of current forest management practices. We provide references that support realistic modeling of forest carbon dynamics that are reflective of current practice and therefore more informative