Lipid lowering and Alzheimer's disease risk: a Mendelian randomization study

Objective: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets isassociated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to correspondingtherapeutics.Methods: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets ofseveral approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target forPCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encodingthe target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C)using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates forregional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls).Results: Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classeswould affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase ADrisk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug tar-get = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, thedegree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.Interpretation: We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for ADprevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9inhibitors may be warranted

Multivariate decoding of brain images using ordinal regression.

Neuroimaging data are increasingly being used to predict potential outcomes or groupings, such as clinical severity, drug dose response, and transitional illness states. In these examples, the variable (target) we want to predict is ordinal in nature. Conventional classification schemes assume that the targets are nominal and hence ignore their ranked nature, whereas parametric and/or non-parametric regression models enforce a metric notion of distance between classes. Here, we propose a novel, alternative multivariate approach that overcomes these limitations - whole brain probabilistic ordinal regression using a Gaussian process framework. We applied this technique to two data sets of pharmacological neuroimaging data from healthy volunteers. The first study was designed to investigate the effect of ketamine on brain activity and its subsequent modulation with two compounds - lamotrigine and risperidone. The second study investigates the effect of scopolamine on cerebral blood flow and its modulation using donepezil. We compared ordinal regression to multi-class classification schemes and metric regression. Considering the modulation of ketamine with lamotrigine, we found that ordinal regression significantly outperformed multi-class classification and metric regression in terms of accuracy and mean absolute error. However, for risperidone ordinal regression significantly outperformed metric regression but performed similarly to multi-class classification both in terms of accuracy and mean absolute error. For the scopolamine data set, ordinal regression was found to outperform both multi-class and metric regression techniques considering the regional cerebral blood flow in the anterior cingulate cortex. Ordinal regression was thus the only method that performed well in all cases. Our results indicate the potential of an ordinal regression approach for neuroimaging data while providing a fully probabilistic framework with elegant approaches for model selection

A dusty pinwheel nebula around the massive star WR 104

Wolf-Rayet (WR) stars are luminous massive blue stars thought to be immediate precursors to the supernova terminating their brief lives. The existence of dust shells around such stars has been enigmatic since their discovery some 30 years ago; the intense radiation field from the star should be inimical to dust survival. Although dust-creation models, including those involving interacting stellar winds from a companion star, have been put forward, high-resolution observations are required to understand this phenomena. Here we present resolved images of the dust outflow around Wolf-Rayet WR 104, obtained with novel imaging techniques, revealing detail on scales corresponding to about 40 AU at the star. Our maps show that the dust forms a spatially confined stream following precisely a linear (or Archimedian) spiral trajectory. Images taken at two separate epochs show a clear rotation with a period of 220 +/- 30 days. Taken together, these findings prove that a binary star is responsible for the creation of the circumstellar dust, while the spiral plume makes WR 104 the prototype of a new class of circumstellar nebulae unique to interacting wind systems.Comment: 7 pages, 2 figures, Appearing in Nature (1999 April 08

Mental health and unemployment: A systematic review and meta-analysis of interventions to improve depression and anxiety outcomes

Background: Unemployment is associated with substantially greater depression and anxiety, constituting a considerable public health concern. The current review provides the most comprehensive synthesis to date, and first meta-analysis, of controlled intervention trials aimed at improving depression and anxiety outcomes during unemployment. Methods: Searches were conducted within PsycInfo, Cochrane Central, PubMed and Embase from their inception to September 2022. Included studies conducted controlled trials of interventions focused on improving mental health within unemployed samples, and reported on validated measures of depression, anxiety, or distress (mixed depression and anxiety). Narrative syntheses and random effects meta-analyses were conducted among prevention- and treatment-level interventions for each outcome. Results: A total of 39 articles reporting on 33 studies were included for review (sample sizes ranging from 21 to 1801). Both prevention and treatment interventions tended to be effective overall, with treatment interventions producing larger effect sizes than prevention interventions. The clearest evidence for particular intervention approaches emerged for prevention-level Cognitive Therapy/CBT, followed by prevention-level work-related interventions, although neither produced entirely consistent effects. Limitations: Risk of bias was generally high across studies. Low numbers of studies within subgroups precluded any comparisons between long-term and short-term unemployment, limited comparisons among treatment studies, and reduced the power of meta-analyses. Conclusions: Both prevention- and treatment-level mental health-focused interventions have merit for reducing symptoms of anxiety and depression among those experiencing unemployment. Cognitive Therapy/CBT and work-related interventions hold the most robust evidence base, which can inform both prevention and treatment strategies implemented by clinicians, employment services providers, and governments

Bus accident severity and passenger injury: evidence from Denmark

Purpose Bus safety is a concern not only in developing countries, but also in the U.S. and Europe. In Denmark, disentangling risk factors that are positively or negatively related to bus accident severity and injury occurrence to bus passengers can contribute to promote safety as an essential principle of sustainable transit and advance the vision “every accident is one too many”. Methods Bus accident data were retrieved from the national accident database for the period 2002–2011. A generalized ordered logit model allows analyzing bus accident severity and a logistic regression enables examining occurrence of injury to bus passengers. Results Bus accident severity is positively related to (i) the involvement of vulnerable road users, (ii) high speed limits, (iii) night hours, (iv) elderly drivers of the third party involved, and (v) bus drivers and other drivers crossing in yellow or red light. Occurrence of injury to bus passengers is positively related to (i) the involvement of heavy vehicles, (ii) crossing intersections in yellow or red light, (iii) open areas, (iv) high speed limits, and (v) slippery road surface. Conclusions The findings of the current study provide a comprehensive picture of the bus safety situation in Denmark and suggest the necessity of further research into bus drivers’ attitudes and perceptions of risks and road users’ perceptions of bus operations. Moreover, these findings suggest the need for further training into bus drivers’ hazard recognition skills and infrastructural solutions to forgive possible driving errors

Structure of a seeded palladium nanoparticle and its dynamics during the hydride phase transformation

Palladium absorbs large volumetric quantities of hydrogen at room temperature and ambient pressure, making the palladium hydride system a promising candidate for hydrogen storage. Here, we use Bragg coherent diffraction imaging to map the strain associated with defects in three dimensions before and during the hydride phase transformation of an individual octahedral palladium nanoparticle, synthesized using a seed-mediated approach. The displacement distribution imaging unveils the location of the seed nanoparticle in the final nanocrystal. By comparing our experimental results with a finite-element model, we verify that the seed nanoparticle causes a characteristic displacement distribution of the larger nanocrystal. During the hydrogen exposure, the hydride phase is predominantly formed on one tip of the octahedra, where there is a high number of lower coordinated Pd atoms. Our experimental and theoretical results provide an unambiguous method for future structure optimization of seed-mediated nanoparticle growth and in the design of palladium-based hydrogen storage systems

Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability

Objective: Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability. Design: Multicentre, single-blind, randomised controlled trial. Setting: Recruitment through neurodisability teams; treatment by parents. Participants: Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). Exclusion criteria: medication contraindicated; in a trial that could affect drooling or management. Intervention: Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks. Primary and secondary outcomes: Primary outcome: Drooling Impact Scale (DIS) score at week-4. Secondary outcomes: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children’s perception about treatment. Results: Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95). Conclusions: Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation