Abdominal aortic calcification, bone mineral density and fractures: a systematic review and meta-analysis protocol

INTRODUCTION: Abdominal aortic calcification (AAC) is associated with low bone mass and increased fracture risk. Two previous meta-analyses have investigated the association between AAC and fracture. However, these meta-analyses only identified articles until December 2016, undertook limited searches and did not explore potential sources of between-study heterogeneity. We aim to undertake a sensitive and comprehensive assessment of the relationship between AAC, bone mineral density (BMD) as well as prevalent and incident fractures. METHODS: We will search MEDLINE, EMBASE, Web of Science core collection and Google Scholar (top 200 articles sorted by relevance) from their inception to 1 June 2018. Reference lists of included studies and previous systematic reviews will be hand searched for additional eligible studies. Retrospective and prospective cohort studies (cross-sectional, case-control and longitudinal) reporting the association between AAC, BMD and fracture at any site will be included. At least two investigators will independently: (A) evaluate study eligibility and extract data, with a third investigator to adjudicate when discrepancies occur, (B) assess study quality by the Newcastle-Ottawa Scale for each cohort/study. The meta-analysis will be reported in adherence to the Meta-analysis of Observational Studies in Epidemiology criteria. AAC will be grouped as either: (1) AAC present or absent, (2) AAC categorised as \u27low\u27 (referent-lowest reported group) versus \u27high\u27 (all other groups) or (3) dose-response when AAC was assessed in ≥3 groups. Where primary event data were reported in individual studies, pooled risk differences and risk ratios with 95% CI will be calculated, from which, a summary estimate will be determined using DerSimonian-Laird random effects models. For the AAC and BMD pooled analyses, estimates will be expressed as standardised mean difference with 95% CI. We will examine the likelihood of publication bias and where possible, investigate potential reasons for between-study heterogeneity using subgroup analyses and meta-regression. ETHICS AND DISSEMINATION: The study will be submitted to a peer- reviewed journal and disseminated via research presentations. PROSPERO REGISTRATION NUMBER: CRD42018088019

Prognostic value of abdominal aortic calcification: A systematic review and meta‐analysis of observational studies

Background The prognostic importance of abdominal aortic calcification (AAC) viewed on noninvasive imaging modalities remains uncertain. Methods and Results We searched electronic databases (MEDLINE and Embase) until March 2018. Multiple reviewers identified prospective studies reporting AAC and incident cardiovascular events or all‐cause mortality. Two independent reviewers assessed eligibility and risk of bias and extracted data. Summary risk ratios (RRs) were estimated using random‐effects models comparing the higher AAC groups combined (any or more advanced AAC) to the lowest reported AAC group. We identified 52 studies (46 cohorts, 36 092 participants); only studies of patients with chronic kidney disease (57%) and the general older‐elderly (median, 68 years; range, 60–80 years) populations (26%) had sufficient data to meta‐analyze. People with any or more advanced AAC had higher risk of cardiovascular events (RR, 1.83; 95% CI, 1.40–2.39), fatal cardiovascular events (RR, 1.85; 95% CI, 1.44–2.39), and all‐cause mortality (RR, 1.98; 95% CI, 1.55–2.53). Patients with chronic kidney disease with any or more advanced AAC had a higher risk of cardiovascular events (RR, 3.47; 95% CI, 2.21–5.45), fatal cardiovascular events (RR, 3.68; 95% CI, 2.32–5.84), and all‐cause mortality (RR, 2.40; 95% CI, 1.95–2.97). Conclusions Higher‐risk populations, such as the elderly and those with chronic kidney disease with AAC have substantially greater risk of future cardiovascular events and poorer prognosis. Providing information on AAC may help clinicians understand and manage patients\u27 cardiovascular risk better

Association between abdominal aortic calcification, bone mineral density and fracture in older women

Although a relationship between vascular disease and osteoporosis has been recognized, its clinical importance for fracture risk evaluation remains uncertain. Abdominal aortic calcification (AAC), a recognized measure of vascular disease detected on single‐energy images performed for vertebral fracture assessment, may also identify increased osteoporosis risk. In a prospective 10‐year study of 1,024 older predominantly Caucasian women (mean age 75.0±2.6 years) from the Perth Longitudinal Study of Aging cohort we evaluated the association between AAC, skeletal structure and fractures. AAC and spine fracture were assessed at the time of hip densitometry and heel quantitative ultrasound. AAC was scored 0 to 24 (AAC24) and categorized into; low AAC (score 0 and 1, n=459), moderate AAC (score 2‐5, n=373) and severe AAC (score \u3e 6, n=192). Prevalent vertebral fractures were calculated using the Genant semi‐quantitative method. AAC24 scores were inversely related to hip bone mineral density (BMD) (rs=‐0.077, p=0.013) and heel broadband ultrasound attenuation (rs=‐0.074, p=0.020) and stiffness index (rs=‐0.073, p=0.022). In cross‐sectional analyses women with moderate to severe AAC were more likely to have prevalent fracture and LSI detected lumbar spine but not thoracic spine fractures (Mantel‐Haentzel test of trend p \u3c 0.05). For 10‐year incident clinical fractures and fracture‐related hospitalizations women with moderate to severe AAC (AAC24 score \u3e1) had increased fracture risk (HR 1.48 [1.15‐1.91], p=0.002; HR 1.46 [1.07‐1.99], p=0.019, respectively) compared to women with low AAC. This relationship remained significant after adjusting for age and hip BMD for clinical fractures (HR 1.40 [1.08‐1.81], p=0.010) but was attenuated for fracture‐related hospitalizations (HR 1.33 [0.98‐1.83], p=0.073). In conclusion, older women with more marked AAC are at higher risk of fracture, not completely captured by bone structural predictors. These findings further support the concept that vascular calcification and bone pathology may share similar mechanisms of causation that remain to be fully elucidated

Giant Molecular Clouds in the Early-type Galaxy NGC 4526

D. Utomo, et al., “Giant Molecular Clouds in the Early-Type Galaxy NGC 4526”, The Astrophysical Journal, Vol. 803(1), April 2015. © 2015. The American Astronomical Society. All rights reserved.We present a high spatial resolution (≈20 pc) of 12CO(2 −1) observations of the lenticular galaxy NGC 4526. We identify 103 resolved giant molecular clouds (GMCs) and measure their properties: size R, velocity dispersion σv, and luminosity L. This is the first GMC catalog of an early-type galaxy. We find that the GMC population in NGC 4526 is gravitationally bound, with a virial parameter α ∼ 1. The mass distribution, dN/dM ∝ M−2.39 ± 0.03, is steeper than that for GMCs in the inner Milky Way, but comparable to that found in some late-type galaxies. We find no size–line width correlation for the NGC 4526 clouds, in contradiction to the expectation from Larson’s relation. In general, the GMCs in NGC 4526 are more luminous, denser, and have a higher velocity dispersion than equal-size GMCs in the Milky Way and other galaxies in the Local Group. These may be due to higher interstellar radiation field than in the Milky Way disk and weaker external pressure than in the Galactic center. In addition, a kinematic measurement of cloud rotation shows that the rotation is driven by the galactic shear. For the vast majority of the clouds, the rotational energy is less than the turbulent and gravitational energy, while the four innermost clouds are unbound and will likely be torn apart by the strong shear at the galactic center. We combine our data with the archival data of other galaxies to show that the surface density Σ of GMCs is not approximately constant, as previously believed, but varies by ∼3 orders of magnitude. We also show that the size and velocity dispersion of the GMC population across galaxies are related to the surface density, as expected from the gravitational and pressure equilibrium, i.e., σv R−1/2 ∝ Σ1/2.Peer reviewe

Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non -diabetic patients with chronic kidney disease (DIAMOND):a randomised, double-blind, crossover trial

Background: SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. Methods: DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18–75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m2, and who were on stable renin–angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. Findings: Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m2 (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730–1560), and mean HbA1c was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI −16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by −6·6 mL/min per 1·73 m2 (–9·0 to −4·2; p<0·0001) at week 6. This reduction was fully reversible within 6 weeks after dapagliflozin discontinuation. Compared with placebo, bodyweight was reduced by 1·5 kg (0·03–3·0; p=0·046) with dapagliflozin; changes in systolic and diastolic blood pressure and concentrations of neurohormonal biomarkers did not differ significantly between dapagliflozin and placebo treatment. The numbers of patients who had one or more adverse events during dapagliflozin treatment (17 [32%] of 53) and during placebo treatment (13 [25%] of 52) were similar. No hypoglycaemic events were reported and no deaths occurred. Interpretation: 6-week treatment with dapagliflozin did not affect proteinuria in patients with chronic kidney disease without diabetes, but did induce an acute and reversible decline in mGFR and a reduction in bodyweight. Long-term clinical trials are underway to determine whether SGLT2 inhibitors can safely reduce the rate of major clinical kidney outcomes in patients with chronic kidney disease with and without diabetes. Funding: AstraZeneca

Effect of real-time computer-aided polyp detection system (ENDO-AID) on adenoma detection in endoscopists-in-training: a randomized trial

Background The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. Methods We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID(OIP-1), Olympus Co., Japan) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years’ experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate-level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. Results 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in CADe than control group (57.5% vs 44.5%, adjusted relative risk 1.41, 95%CI 1.17-1.72, p<0.001). The ADRs for <5mm (40.4% vs 25.0%) and 5-10mm adenomas (36.8% vs 29.2%) were higher in CADe group. The ADRs were higher in CADe group in both right (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in CADe group among beginners (60.0% vs 41.9%) and intermediate-level endoscopists (56.5% vs 45.5%). Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate were higher in CADe group (52.1% vs 35.0%). Conclusions Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov: NCT04838951

Submicron Structures Technology and Research

Contains reports on ten research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)Joint Services Electronics Program (Contract DAAL03-86-K-0002)National Science Foundation (Grant ECS82-05701)National Science Foundation (Grant ECS85-06565)Lawrence Livermore Laboratory (Subcontract 2069209)National Science Foundation (Grant ECS85-03443)U.S. Air Force - Office of Scientific Research (Grant AFOSR-85-0154)National Aeronautics and Space Administration (Grant NGL22-009-638)National Science Foundation (through KMS Fusion, Inc.)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

Haptic spatial configuration learning in deaf and hearing individuals

The present study investigated haptic spatial configuration learning in deaf individuals, hearing sign language interpreters and hearing controls. In three trials, participants had to match ten shapes haptically to the cut-outs in a board as fast as possible. Deaf and hearing sign language users outperformed the hearing controls. A similar difference was observed for a rotated version of the board. The groups did not differ, however, on a free relocation trial. Though a significant sign language experience advantage was observed, comparison to results from a previous study testing the same task in a group of blind individuals showed it to be smaller than the advantage observed for the blind group. These results are discussed in terms of how sign language experience and sensory deprivation benefit haptic spatial configuration processing