Use of Cannabis as a Harm Reduction Strategy Among People Who Use Drugs: A Cohort Study.

Introduction: While substance use contributes to a substantial burden of disease, access to evidence-based harm reduction interventions remains limited or inaccessible. Preliminary research suggests that some individuals use cannabis to reduce the harms associated with their use of other substances, including opioids and stimulants. This study examines factors associated with the self-reported use of cannabis for harm reduction among people who use drugs (PWUD). Methods: We drew data from three prospective, community-recruited cohorts of PWUD in Vancouver, Canada, between June 2016 and May 2018. Multivariable generalized linear mixed-effects modeling was used to examine factors associated with the primary outcome of use of cannabis for harm reduction, defined as self-reported use of cannabis to substitute for other substances, treat withdrawal, or come down off other drugs. Results: One thousand nine hundred thirty-six participants contributed 5706 observations. In adjusted analyses, daily methamphetamine use (adjusted odds ratio [AOR]=1.43, 95% confidence interval [CI]: 1.09-1.89), experiencing barriers to accessing addiction treatment (AOR=1.92, 95% CI: 1.21-3.03), and enrollment in addiction treatment modalities other than opioid agonist therapy (AOR=1.64, 95% CI: 1.17-2.29) were positively associated with using cannabis for harm reduction. Older age was negatively associated (AOR=0.97, 95% CI: 0.95-0.98). Among 1281 (66.2%) participants who use cannabis, daily cannabis use and obtaining cannabis from unregulated dispensaries were also independent correlates of using cannabis for harm reduction. Discussion and Conclusions: Individuals who were more likely to use cannabis for harm reduction reported difficulty accessing addiction treatment or used substances, such as methamphetamines, where effective treatments are limited. These findings highlight the need to better understand the potential harm-reducing impacts of cannabis among PWUD in these scenarios

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care

A Tale of 3 Dwarfs: No Extreme Cluster Formation in Extreme Star-Forming Galaxies

Nearly all current simulations predict that outcomes of the star formation process, such as the fraction of stars that form in bound clusters (Gamma), depend on the intensity of star formation activity (SigmaSFR) in the host galaxy. The exact shape and strength of the predicted correlations, however, vary from simulation to simulation. Observational results also remain unclear at this time, because most works have mixed estimates made from very young clusters for galaxies with higher SigmaSFR with those from older clusters for galaxies with lower SigmaSFR. The three blue compact dwarf (BCD) galaxies ESO185-IG13, ESO338-IG04, and Haro11 have played a central role on the observational side because they have some of the highest known SigmaSFR and published values of Gamma. We present new estimates of Gamma for these BCDs in three age intervals (1-10 Myr, 10-100 Myr, 100-400 Myr), based on age-dating which includes Halpha photometry to better discriminate between clusters younger and older than ~10 Myr. We find significantly lower values for Gamma (1-10 Myr) than published previously. The likely reason for the discrepancy is that previous estimates appear to be based on age-reddening results that underestimated ages and overestimated reddening for many clusters, artificially boosting Gamma (1-10 Myr). We also find that fewer stars remain in clusters over time, with ~15-39% in 1-10 Myr, ~5-7% in 10-100 Myr, and ~1-2% in 100-400 Myr clusters. We find no evidence that Gamma increases with SigmaSFR. These results imply that cluster formation efficiency does not vary with star formation intensity in the host galaxy. If confirmed, our results will help guide future assumptions in galaxy-scale simulations of cluster formation and evolution.Comment: Accepted for publication in Ap

Maltreatment or violence-related injury in children and adolescents admitted to the NHS:Comparison of trends in England and Scotland between 2005 and 2011

Legislation to safeguard children from maltreatment by carers or violence by others was advanced in England and Scotland around 2004-2005 and resulted in different policies and services. We examined whether subsequent trends in injury admissions to hospital related to maltreatment or violence varied between the two countries

Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases

Arp 220: A Post-starburst Galaxy with Little Current Star Formation outside of Its Nuclear Disks

The ultraluminous infrared galaxy Arp 220 is a late-stage merger with several tidal structures in the outskirts and two very compact, dusty nuclei that show evidence for extreme star formation and host at least one active galactic nucleus (AGN). New and archival high-resolution images taken by the Hubble Space Telescope provide a state-of-the-art view of the structures, dust, and stellar clusters in Arp 220. These images cover the near-ultraviolet, optical, and near-infrared in both broad- and narrowband filters. We find that ∼90% of the H α emission arises from a shock-ionized bubble emanating from the AGN in the western nucleus, while the nuclear disks dominate the Pa β emission. Four very young (∼3–6 Myr) but lower-mass (≲10 ^4 M _⊙ ) clusters are detected in H α within a few arcseconds of the nuclei, but they produce less than 1% of the line emission. We see little evidence for a population of massive clusters younger than 100 Myr anywhere in Arp 220, unlike previous reports in the literature. From the masses and ages of the detected clusters, we find that star formation took place more or less continuously starting approximately a few gigayears ago with a moderate rate between ≈3 and 12 M _⊙ yr ^−1 . Approximately 100 Myr ago, star formation shut off suddenly everywhere (possibly due to a merging event), except in the nuclear disks. A very recent flicker of weak star formation produced the four young, low-mass clusters, while the rest of the galaxy appears to have remained in a post-starburst state. Cluster ages indicate that the tidal structures on the west side of the galaxy are older than those on the east side, but all appear to predate the shutoff of star formation. Arp 220 has many of the characteristics expected of a “shocked post-starburst galaxy,” since most of the system has been in a post-starburst state for the past ∼100 Myr and the detected H α emission arises from shocked rather than photoionized gas

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders