CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.

Author instructions in biomedical journals infrequently address systematic review reporting and methodology: a cross-sectional study.

OBJECTIVES: We aimed to analyze how instructions for authors in journals indexed in MEDLINE address systematic review (SR) reporting and methodology. STUDY DESIGN AND SETTING: We analyzed instructions for authors in 20% of MEDLINE-indexed journals listed in the online catalog of the National Library of Medicine on July 27, 2021. We extracted data only from the instructions published in English. We extracted data on the existence of instructions for reporting and methodology of SRs. RESULTS: Instructions from 1,237 journals mentioned SRs in 45% (n = 560) of the cases. Systematic review (SR) registration was mentioned in 104/1,237 (8%) of instructions. Guidelines for reporting SR protocols were found in 155/1,237 (13%) of instructions. Guidelines for reporting SRs were explicitly mentioned in 461/1,237 (37%), whereas the EQUATOR (Enhancing the Quality and Transparency of Health Research) network was referred to in 474/1,237 (38%) of instructions. Less than 2% (n = 20) of instructions mentioned risk of bias and meta-analyses; less than 1% mentioned certainty of evidence assessment, methodological expectations, updating of SRs, overviews of SRs, or scoping reviews. CONCLUSION: Journals indexed in MEDLINE rarely provide instructions for authors regarding SR reporting and methodology. Such instructions could potentially raise authors' awareness and improve how SRs are prepared and reported.

Addressing Challenges When Applying GRADE to Public Health Guidelines: A Scoping Review Protocol and Pilot Analysis.

This is a protocol for a scoping review that aims to determine how guideline authors using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach have addressed previously identified challenges related to public health. The Joanna Briggs Institute (JBI) methodology for scoping reviews will be followed. We will search and screen titles of guidelines for all languages published in 2013-2021 in: the GIN library, BIGG database, Epistemonikos GRADE guidelines repository, GRADEpro Database, MAGICapp, NICE and WHO websites. Two reviewers will independently screen full texts of the documents identified. The following information will be extracted: methods used for identifying different stakeholders and incorporating their perspectives; methods for identification and prioritization of non-health outcomes; methods for determining thresholds for decision-making; methods for incorporating and grading evidence from non-randomized studies; methods for addressing concerns with conditional recommendations in public health; methods for reaching consensus; additional methodological concerns; and any modifications made to GRADE. A combination of directed content analysis and descriptive statistics will be used for data analysis, and the findings presented narratively in a tabular and graphical form. In this protocol, we present the pilot results from 13 identified eligible guidelines issued between January and August 2021. We will publish the full review results when they become available.