Bone health, cardiovascular disease, and imaging outcomes in UK Biobank: a causal analysis

This study examined the association of estimated heel bone mineral density (eBMD, derived from quantitative ultrasound) with: (1) prevalent and incident cardiovascular diseases (CVDs: ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), non-ischemic cardiomyopathy (NICM), arrhythmia), (2) mortality (all-cause, CVD, IHD), and (3) cardiovascular magnetic resonance (CMR) measures of left ventricular and atrial structure and function and aortic distensibility, in the UK Biobank. Clinical outcomes were ascertained using health record linkage over 12.3 yr of prospective follow-up. Two-sample Mendelian randomization (MR) was conducted to assess causal associations between BMD and CMR metrics using genetic instrumental variables identified from published genome-wide association studies. The analysis included 485 257 participants (55% women, mean age 56.5 ± 8.1 yr). Higher heel eBMD was associated with lower odds of all prevalent CVDs considered. The greatest magnitude of effect was seen in association with HF and NICM, where 1-SD increase in eBMD was associated with 15% lower odds of HF and 16% lower odds of NICM. Association between eBMD and incident IHD and MI was non-significant; the strongest relationship was with incident HF (SHR: 0.90 [95% CI, 0.89-0.92]). Higher eBMD was associated with a decreased risk in all-cause, CVD, and IHD mortality, in the fully adjusted model. Higher eBMD was associated with greater aortic distensibility; associations with other CMR metrics were null. Higher heel eBMD is linked to reduced risk of a range of prevalent and incident CVD and mortality outcomes. Although observational analyses suggest associations between higher eBMD and greater aortic compliance, MR analysis did not support a causal relationship between genetically predicted BMD and CMR phenotypes. These findings support the notion that bone-cardiovascular associations reflect shared risk factors/mechanisms rather than direct causal pathways

FINAL REPORT DM1200 TESTS WITH AZ 101 HLW SIMULANTS VSL-03R3800-4 REV 0 2/17/04

This report documents melter and off-gas performance results obtained on the DM 1200 HLW Pilot Melter during processing of simulated HLW AZ-101 feed. The principal objectives of the DM1200 melter testing were to determine the achievable glass production rates for simulated HLW AZ-101 feed; determine the effect of bubbling rate and feed solids content on production rate; characterize melter off-gas emissions; characterize the performance of the prototypical off-gas system components as well as their integrated performance; characterize the feed, glass product, and off-gas effluents; and to perform pre- and post-test inspections of system components. The test objectives (including test success criteria), along with how they were met, are outlined in a table

FINAL REPORT INTEGRATED DM1200 MELTER TESTING OF BUBBLER CONFIGURATIONS USING HLW AZ-101 SIMULANTS VSL-04R4800-4 REV 0 10/5/04

This report documents melter and off-gas performance results obtained on the DM1200 HLW Pilot Melter during processing of AZ-101 HLW simulants. The tests reported herein are a subset of six tests from a larger series of tests described in the Test Plan for the work; results from the other tests have been reported separately. The solids contents of the melter feeds were based on the WTP baseline value for the solids content of the feeds from pretreatment which changed during these tests from 20% to 15% undissolved solids resulting in tests conducted at two feed solids contents. Based on the results of earlier tests with single outlet 'J' bubblers, initial tests were performed with a total bubbling rate of 651 pm. The first set of tests (Tests 1A-1E) addressed the effects of skewing this total air flow rate back and forth between the two installed bubblers in comparison to a fixed equal division of flow between them. The second set of tests (2A-2D) addressed the effects of bubbler depth. Subsequently, as the location, type and number of bubbling outlets were varied, the optimum bubbling rate for each was determined. A third (3A-3C) and fourth (8A-8C) set of tests evaluated the effects of alternative bubbler designs with two gas outlets per bubbler instead of one by placing four bubblers in positions simulating multiple-outlet bubblers. Data from the simulated multiple outlet bubblers were used to design bubblers with two outlets for an additional set of tests (9A-9C). Test 9 was also used to determine the effect of small sugar additions to the feed on ruthenium volatility. Another set of tests (10A-10D) evaluated the effects on production rate of spiking the feed with chloride and sulfate. Variables held constant to the extent possible included melt temperature, plenum temperature, cold cap coverage, the waste simulant composition, and the target glass composition. The feed rate was increased to the point that a constant, essentially complete, cold cap was achieved, which was used as an indicator of a maximized feed rate for each test. The first day of each test was used to build the cold cap and decrease the plenum temperature. The remainder of each test was split into two- to six-day segments, each with a different bubbling rate, bubbler orientation, or feed concentration of chloride and sulfur

Consequences and Utility of the Zinc-Dependent Metalloprotease Activity of Anthrax Lethal Toxin

Anthrax is caused by the gram-positive bacterium Bacillus anthracis. The pathogenesis of this disease is dependent on the presence of two binary toxins, edema toxin (EdTx) and lethal toxin (LeTx). LeTx, the major virulence factor contributing to anthrax, contains the effector moiety lethal factor (LF), a zinc-dependent metalloprotease specific for targeting mitogen-activated protein kinase kinases. This review will focus on the protease-specific activity and function of LF, and will include a discussion on the implications and consequences of this activity, both in terms of anthrax disease, and how this activity can be exploited to gain insight into other pathologic conditions

Crowding: risk factor or protective factor for lower respiratory disease in young children?

BACKGROUND: To study the effects of household crowding upon the respiratory health of young children living in the city of São Paulo, Brazil. METHODS: Case-control study with children aged from 2 to 59 months living within the boundaries of the city of São Paulo. Cases were children recruited from 5 public hospitals in central São Paulo with an acute episode of lower respiratory disease. Children were classified into the following diagnostic categories: acute bronchitis, acute bronchiolitis, pneumonia, asthma, post-bronchiolitis wheezing and wheezing of uncertain aetiology. One control, crudely matched to each case with regard to age (<2, 2 years old or more), was selected among healthy children living in the neighborhood of the case. All buildings were surveyed for the presence of environmental contaminants, type of construction and building material. Plans of all homes, including measurements of floor area, height of walls, windows and solar orientation, was performed. Data were analysed using conditional logistic regression. RESULTS: A total of 313 pairs of children were studied. Over 70% of the cases had a primary or an associated diagnosis of a wheezing illness. Compared with controls, cases tended to live in smaller houses with less adequate sewage disposal. Cases and controls were similar with respect to the number of people and the number of children under five living in the household, as well the number of people sharing the child's bedroom. After controlling for potential confounders, no evidence of an association between number of persons sharing the child's bedroom and lower respiratory disease was identified when all cases were compared with their controls. However, when two categories of cases were distinguished (infections, asthma) and each category compared separately with their controls, crowding appeared to be associated with a 60% reduction in the incidence of asthma but with 2 1/2-fold increase in the incidence of lower respiratory tract infections (p = 0.001). CONCLUSION: Our findings suggest that household crowding places young children at risk of acute lower respiratory infection but may protect against asthma. This result is consistent with the hygiene hypothesis

Consensus paper:Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research. The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson\u2019s disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum. The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial

Background: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH).   Methods: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks’ gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records.   Results: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode.   Conclusions: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD

Associations Between Late Pregnancy Dietary Inflammatory Index (DII) and Offspring Bone Mass: A Meta-Analysis of the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC).

Systemic inflammation is associated with reduced bone mineral density and may be influenced by pro-inflammatory diets. We undertook an observational analysis of associations between late pregnancy energy-adjusted dietary inflammatory index (E-DII) scores and offspring bone outcomes in childhood. E-DII scores (higher scores indicating pro-inflammatory diets) were derived from food frequency questionnaires in late pregnancy in two prospective mother-offspring cohorts: the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). The mean (SD) offspring age at dual-energy X-ray absorptiometry (DXA) scanning was 9.2 (0.2) years. Linear regression was used to assess associations between E-DII and bone outcomes, adjusting for offspring sex and age at DXA and maternal age at childbirth, educational level, pre-pregnancy body mass index (BMI), parity, physical activity level, and smoking in pregnancy. Associations were synthesized using fixed-effect meta-analysis. Beta coefficients represent the association per unit E-DII increment. In fully adjusted models (total n = 5910) late pregnancy E-DII was negatively associated with offspring whole body minus head bone area (BA: β = -3.68 [95% confidence interval -6.09, -1.27] cm2 /unit), bone mineral content (BMC: β = -4.16 [95% CI -6.70, -1.62] g/unit), and areal bone mineral density (aBMD: β = -0.0012 [95% CI -0.0020, -0.0004] g.cm-2 /unit), but there was only a weak association with BMC adjusted for BA (β = -0.48 [95% CI -1.11, 0.15] g/unit) at 9 years. Adjustment for child height partly or, for weight, fully attenuated the associations. Higher late pregnancy E-DII scores (representing a more pro-inflammatory diet) are negatively associated with offspring bone measures, supporting the importance of maternal and childhood diet on longitudinal offspring bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Perturbation of Mouse Retinal Vascular Morphogenesis by Anthrax Lethal Toxin

Lethal factor, the enzymatic moiety of anthrax lethal toxin (LeTx) is a protease that inactivates mitogen activated protein kinase kinases (MEK or MKK). In vitro and in vivo studies demonstrate LeTx targets endothelial cells. However, the effects of LeTx on endothelial cells are incompletely characterized. To gain insight into this process we used a developmental model of vascularization in the murine retina. We hypothesized that application of LeTx would disrupt normal retinal vascularization, specifically during the angiogenic phase of vascular development. By immunoblotting and immunofluorescence microscopy we observed that MAPK activation occurs in a spatially and temporally regulated manner during retinal vascular development. Intravitreal administration of LeTx caused an early delay (4 d post injection) in retinal vascular development that was marked by reduced penetration of vessels into distal regions of the retina as well as failure of sprouting vessels to form the deep and intermediate plexuses within the inner retina. In contrast, later stages (8 d post injection) were characterized by the formation of abnormal vascular tufts that co-stained with phosphorylated MAPK in the outer retinal region. We also observed a significant increase in the levels of secreted VEGF in the vitreous 4 d and 8 d after LeTx injection. In contrast, the levels of over 50 cytokines other cytokines, including bFGF, EGF, MCP-1, and MMP-9, remained unchanged. Finally, co-injection of VEGF-neutralizing antibodies significantly decreased LeTx-induced neovascular growth. Our studies not only reveal that MAPK signaling plays a key role in retinal angiogenesis but also that perturbation of MAPK signaling by LeTx can profoundly alter vascular morphogenesis

Oral abstracts of the 21st International AIDS Conference 18-22 July 2016, Durban, South Africa

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n=122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression.Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed.Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants.Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches