Reasons to Accept Vaccine Refusers in Primary Care

Vaccine refusal forces us to confront tensions between many values, including scientific expertise, parental rights, children’s best interests, social responsibility, public trust, and community health. Recent outbreaks of vaccine-preventable and emerging infectious diseases have amplified these issues. The prospect of a coronavirus disease 2019 vaccine signals even more friction on the horizon. In this contentious sociopolitical landscape, it is therefore more important than ever for clinicians to identify ethically justified responses to vaccine refusal

A method for continuous239Pu determinations in Arctic and Antarctic ice cores

Atmospheric nuclear weapons testing (NWT) resulted in the injection of plutonium (Pu) into the atmosphere and subsequent global deposition. We present a new method for continuous semi-quantitative measurement of 239Pu in ice cores, which was used to develop annual records of fallout from NWT in ten ice cores from Greenland and Antarctica. The 239Pu was measured directly using an Inductively Coupled Plasma – Sector Field Mass Spectrometer, thereby reducing analysis time and increasing depth-resolution with respect to previous methods. To validate this method, we compared our one year averaged results to published 239Pu records and other records of NWT. The 239Pu profiles from four Arctic ice cores reflected global trends in NWT and were in agreement with discrete Pu profiles from lower latitude ice cores. The 239Pu measurements in the Antarctic ice cores tracked low latitude NWT, consistent with previously published discrete records from Antarctica. Advantages of the continuous 239Pu measurement method are (1) reduced sample preparation and analysis time; (2) no requirement for additional ice samples for NWT fallout determinations; (3) measurements are exactly co-registered with all other chemical, elemental, isotopic, and gas measurements from the continuous analytical system; and (4) the long half-life means the 239Pu record is stable through time

Utilizing multi-objective decision support tools for protected area selection

Establishing and maintaining protected areas (PAs) is a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting PAs based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences as well as real-time comparison of the outcome. Applying the tool across 1,346 terrestrial PAs, we demonstrate that decision makers frequently face trade-offs among conflicting objectives, e.g., between species protection and ecosystem integrity. Nevertheless, we show that transparent decision support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.publishedVersio

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The Iso2k database: a global compilation of paleo-δ18O and δ2H records to aid understanding of common era climate

Reconstructions of global hydroclimate during the Common Era (CE; the past ~2,000 years) are important for providing context for current and future global environmental change. Stable isotope ratios in water are quantitative indicators of hydroclimate on regional to global scales, and these signals are encoded in a wide range of natural geologic archives. Here we present the Iso2k database, a global compilation of previously published datasets from a variety of natural archives that record the stable oxygen (δ18O) or hydrogen (δ²H) isotopic composition of environmental waters, which reflect hydroclimate changes over the CE. The Iso2k database contains 756 isotope records from the terrestrial and marine realms, including: glacier and ground ice (205); speleothems (68); corals, sclerosponges, and mollusks (145); wood (81); lake sediments and other terrestrial sediments (e.g., loess) (158); and marine sediments (99). Individual datasets have temporal resolutions ranging from sub-annual to centennial, and include chronological data where available. A fundamental feature of the database is its comprehensive metadata, which will assist both experts and non-experts in the interpretation of each record and in data synthesis. Key metadata fields have standardized vocabularies to facilitate comparisons across diverse archives and with climate model simulated fields. This is the first global-scale collection of water isotope proxy records from multiple types of geological and biological archives. It is suitable for evaluating hydroclimate processes through time and space using large-scale synthesis, model-data intercomparison and (paleo)data assimilation. The Iso2k database is available for download at: https://doi.org/10.25921/57j8-vs18 (Konecky and McKay, 2020) and is also accessible via through the NOAA/WDS Paleo Data landing page: https://www.ncdc.noaa.gov/paleo/study/29593

Muscarinic cholinergic regulation of cardiac myocyte I(Ca-L) is absent in mice with targeted disruption of endothelial nitric oxide synthase

Cardiac myocytes have been shown to express constitutively endothelial nitric oxide synthase (eNOS) (nitric oxide synthase 3), the activation of which has been implicated in the regulation of myocyte L-type voltage-sensitive calcium channel current (I(Ca-L)) and myocyte contractile responsiveness to parasympathetic nervous system signaling, although this implication remains controversial. Therefore, we examined the effect of the muscarinic cholinergic agonist carbachol (CCh) on I(Ca-L) and contractile amplitude in isoproterenol (ISO)-prestimulated ventricular myocytes isolated from adult mice, designated eNOS(null) mice, with targeted disruption of the eNOS gene. Although both eNOS(null) and wild-type (WT) ventricular myocytes exhibited similar increases in I(Ca-L) in response to ISO, there was no measurable suppression of I(Ca-L) by CCh in cells from eNOS(null) mice, in contrast to cells from WT mice. These results were reflected in the absence of an effect of CCh on the positive inotropic effect of ISO in eNOS(null) myocytes. Also, unlike myocytes from WT animals, eNOS(null) myocytes failed to exhibit an increase in cGMP content in response to CCh. Nevertheless, the pharmacologic nitric oxide donors 3-morpholino-sydnonimine and S-nitroso-acetyl-cystein increased cGMP generation and suppressed ISO-augmented I(Ca-L) in eNOS(null) cells, suggesting that the signal transduction pathway(s) downstream of eNOS remained intact. Of importance, activation of the acetylcholine-activated K(+) channel by CCh was unaffected in atrial and ventricular eNOS(null) myocytes. These results confirm the obligatory role of eNOS in coupling muscarinic receptor activation to cGMP-dependent control of I(Ca-L) in cardiac myocytes

The Ethics of Creating a Resource Allocation Strategy During the COVID-19 Pandemic

https://deepblue.lib.umich.edu/bitstream/2027.42/155579/1/Laventhal_et_al.pdfDescription of Laventhal_et_al.pdf : Postprin