Deep space experiment to measure GG

Responding to calls from the National Science Foundation (NSF) for new proposals to measure the gravitational constant $G$, we offer an interesting experiment in deep space employing the classic gravity train mechanism. Our setup requires three bodies: a larger layered solid sphere with a cylindrical hole through its center, a much smaller retroreflector which will undergo harmonic motion within the hole and a host spacecraft with laser ranging capabilities to measure round trip light-times to the retroreflector but ultimately separated a significant distance away from the sphere-retroreflector apparatus. Measurements of the period of oscillation of the retroreflector in terms of host spacecraft clock time using existing technology could give determinations of $G$ nearly three orders of magnitude more accurate than current measurements here on Earth. However, significant engineering advances in the release mechanism of the apparatus from the host spacecraft will likely be necessary. Issues with regard to the stability of the system are briefly addressed.Comment: 13 pp, 3 figs, accepted CQ

Advances in the therapy of Alzheimer's disease: Targeting amyloid beta and tau and perspectives for the future

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

A New Panel-Estimated GFR, Including beta(2)-Microglobulin and beta-Trace Protein and Not Including Race, Developed in a Diverse Population

RATIONALE AND OBJECTIVE: GFR estimation based on creatinine and cystatin C (eGFR(cr-cys)) is more accurate than eGFR based on either creatinine or cystatin C alone (eGFR(cr) or eGFR(cys)), but the inclusion of creatinine in eGFR(cr-cys) requires specification of a person’s race. Beta-2-microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in pooled population of seven studies with 5017 participants with and without chronic kidney disease. External validation in a pooled population of seven other studies with 2245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (three-marker panel) or creatinine and cystatin C (four-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of Cr-EDTA RESULTS: Mean measured GFR was 58.1 and 83.2 ml/min/1.73m(2) and the proportion of blacks was 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared to equations without age and sex, but addition of race did not further improve the performance. In validation, the four-marker panels were more accurate than the three-marker panels (p<0.001). The three-marker panel without race was more accurate than eGFR(cys) [1- P(30) of 15.6 vs 17.4% (p=0.014)], and the four-marker panel without race was as accurate as eGFR(cr-cys) [1- P(30) of 8.6 vs 9.4% (p=0.17)]. Results were generally consistent across subgroups. LIMITATIONS: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. CONCLUSIONS: The four-marker panel eGFR is as accurate as eGFR(cr-cys), without requiring specification of race. A more accurate race-free eGFR could be an important advance

Accessibility audit of the Midwest Chapter of the Medical Library Association

Background: In 2023, JJ Pionke became President of the Midwest Chapter of the Medical Library Association (MWCMLA). He determined that for his presidential year, he would form a task force to determine the accessibility levels of the chapter and remediate accessibility issues as appropriate. Case Presentation: To accomplish the accessibility audit of the MWCMLA, Pionke formed an Accessibility Task Force that was time limited to one year. Task force meetings were held once a month to keep people accountable and to share out progress and requests for assistance. The task force was broken up into four teams: annual meeting, policy, social media, and website. Task force members could be on more than one team. The goals of each team were generally the same: what are other organizations doing, what do we have already if anything, and develop best practices/policy/etc. as needed. Conclusions: The teams fulfilled their mandate by creating best practices/guidelines/policies documents.  Some accessibility remediation was needed for the chapter website. The task force’s findings and materials were shared out among the MWCMLA as well as passed on to the presidents of the other chapters, many of whom had expressed interest in the results

Group Process and Organizational Environment: Student Organizations in the University

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68768/2/10.1177_089976407400300305.pd

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage