Septins are known to play key roles in supporting cytoskeletal stability, vesicular transport, endo-/exocytosis, stabilizing cellular membranes and forming diffusion barriers. Their function in ...mammalian cells is poorly investigated. The osteoclast offers an interesting tool to investigate septins because all cellular activities septins were reported to be involved in are critical for osteoclasts. However, the existence of septins in osteoclasts has not even been reported. Here we show that the SEPT9 gene and Septin 9 (SEPT9) protein are expressed and synthesized during differentiation of human osteoclasts. Pharmacological stabilization of septin filaments dose dependently inhibits bone resorption of human osteoclasts in vitro suggesting a role for septins in bone resorption. Attesting to this, conditional deletion of Sept9 in mice leads to elevated levels of trabecular bone and diminished femoral growth in vivo. Finally, systematic interrogation of the spatial organization of SEPT9 by confocal microscopy reveals that SEPT9 is closely associated to the structures known to be critical for osteoclast activity. We propose that septins in general and SEPT9 in particular play a previously unappreciated role in osteoclastic bone resorption.
In this paper, we report the first measurement of the parity-violating elastic electron scattering asymmetry on 27Al. The 27Al elastic asymmetry is $A_{\text{PV}}$ = 2.16 ± 0.11(stat) ± 0.16(syst) ...ppm, and was measured at $\langle Q^2\rangle$ = 0.02357 ± 0.00010 GeV$^2$, $\angleθ_{\text{lab}}$ = 7.61° ± 0.02°, and $\langle E_{\text{lab}}$ = 1.157 GeV with the Qweak apparatus at Jefferson Lab. Predictions using a simple Born approximation as well as more sophisticated distorted-wave calculations are in good agreement with this result. From this asymmetry the 27Al neutron radius $R_n$ = 2.89 ± 0.12 fm was determined using a many-models correlation technique. The corresponding neutron skin thickness $R_n – R_p$ = –0.04 ± 0.12 fm is small, as expected for a light nucleus with a neutron excess of only 1. This result thus serves as a successful benchmark for electroweak determinations of neutron radii on heavier nuclei. A tree-level approach was used to extract the 27Al weak radius $R_w$ = 3.00 ± 0.15 fm, and the weak skin thickness $R_{\text{wk}} – R_{\text{ch}}$ = –0.04 ± 0.15 fm. The weak form factor at this $Q^2$ is $F_{\text{wk}}$ = 0.39 ± 0.04.
Neodymium (Nd) isotopes extracted from authigenic sediment phases are increasingly used as a proxy for past variations in water mass provenance. To better constrain the controls of water mass ...provenance and nonconservative effects on the archived Nd isotope signal, we present a new depth transect of Nd isotope reconstructions from the Blake Bahama Outer Ridge along the North American continental margin covering the past 30 ka. We investigated five sediment cores that lie directly within the main flow path of the Deep Western Boundary Current, a major advection route of North Atlantic Deep Water. We found offsets between core tops and seawater Nd isotopic compositions that are observed elsewhere in the Northwest Atlantic. A possible explanation for this is the earlier suggested redistribution of sediment by nepheloid layers at intermediate as well as abyssal depths, transporting material downslope and along the continental margin. These processes potentially contributed to Nd isotope excursions recorded in Northwest Atlantic sediment cores during the Bølling‐Allerød and early Holocene. An Atlantic‐wide comparison of Nd isotope records shows that the early Holocene excursions had an additional contribution from conservative advection of unradiogenic dissolved Nd. Nevertheless, the trends of the Nd isotope records are in general agreement with previous reconstructions of water mass provenance from the entire Atlantic and also reveal millennial‐scale changes during the last deglaciation in temporal high resolution, which have rarely been reported before. Further, the new records confirm that during cold periods the Northwest Atlantic was bathed by an increased contribution of southern sourced water.
Plain Language Summary
The Atlantic Meridional Overturning Circulation is of great importance for the climate system since it distributes heat to the northern high latitudes, where the only deep water of the Northern Hemisphere is formed. Here, we investigate how this North Atlantic Deep Water propagated southward in response to deglacial climatic trends during the transition from the last ice age to modern day. However, we found differences between the archived modern signal and modern seawater measurements that might hinder the interpretation of past water mass provenance. We attribute this effect to influences from suspended material altering the local bottom waters. This process was likely most prominent during the invigoration of northern deep water formation during the Bølling‐Allerød and early Holocene but less pronounced to absent during cold time periods. Nevertheless, the findings of this study confirm that North Atlantic Deep Water was partly replaced in the deep Northwest Atlantic basin by southern sourced water during cold intervals.
Key Points
Sedimentary archives indicate alteration of local bottom water Nd isotope signatures in the Northwest Atlantic by nepheloid layers
New high‐resolution Nd isotope depth transect from the Blake Bahama Outer Ridge constrains deglacial millennial‐scale water mass changes
An increased contribution of southern sourced water is confirmed for all cold periods of the past 30 ka
Mesh-motion (r-refinement) grid adaptivity schemes are attractive due to their potential to minimize the numerical error for a prescribed number of degrees of freedom. However, a key roadblock to a ...widespread deployment of this class of techniques has been the formulation of robust, reliable mesh-motion governing principles, which (1) guarantee a solution in multiple dimensions (2D and 3D), (2) avoid grid tangling (or folding of the mesh, whereby edges of a grid cell cross somewhere in the domain), and (3) can be solved effectively and efficiently. In this study, we formulate such a mesh-motion governing principle, based on volume equidistribution via Monge–Kantorovich optimization (MK). In earlier publications
1,2, the advantages of this approach with regard to these points have been demonstrated for the time-independent case. In this study, we demonstrate that Monge–Kantorovich equidistribution can in fact be used effectively in a time-stepping context, and delivers an elegant solution to the otherwise pervasive problem of grid tangling in mesh-motion approaches, without resorting to
ad hoc time-dependent terms (as in moving-mesh PDEs, or MMPDEs
3,4). We explore two distinct r-refinement implementations of MK: the direct method, where the current mesh relates to an initial, unchanging mesh, and the sequential method, where the current mesh is related to the previous one in time. We demonstrate that the direct approach is superior with regard to mesh distortion and robustness. The properties of the approach are illustrated with a hyperbolic PDE, the advection of a passive scalar, in 2D and 3D. Velocity flow fields with and without flow shear are considered. Three-dimensional grid, time-step, and nonlinear tolerance convergence studies are presented which demonstrate the optimality of the approach.
To design a segmented inversion-recovery turbo fast low-angle shot (turboFLASH) magnetic resonance (MR) imaging pulse sequence for the visualization of myocardial infarction, compare this technique ...with other MR imaging approaches in a canine model of ischemic injury, and evaluate its utility in patients with coronary artery disease.
Six dogs and 18 patients were examined. In dogs, infarction was produced and images were acquired by using 10 different pulse sequences. In patients, the segmented turboFLASH technique was used to acquire contrast material-enhanced images 19 days +/- 7 (SD) after myocardial infarction.
Myocardial regions of increased signal intensity were observed in all animals and patients at imaging. With the postcontrast segmented turboFLASH sequence, the signal intensity of the infarcted myocardium was 1,080% +/- 214 higher than that of the normal myocardium in dogs-nearly twice that of the next best sequence tested and approximately 10-fold greater than that in previous reports. All 18 patients with myocardial infarction demonstrated high signal intensity at imaging. On average, the signal intensity of the high-signal-intensity regions in patients was 485% +/- 43 higher than that of the normal myocardium.
The segmented inversion-recovery turboFLASH sequence produced the greatest differences in regional myocardial signal intensity in animals. Application of this technique in patients with infarction substantially improved differentiation between injured and normal regions.
We report measurements of the parity-conserving beam-normal single-spin elastic scattering asymmetries Bn on 12C and 27Al, obtained with an electron beam polarized transverse to its momentum ...direction. These measurements add an additional kinematic point to a series of previous measurements of Bn on 12C and provide a first measurement on 27Al. The experiment utilized the Qweak apparatus at Jefferson Lab with a beam energy of 1.158 GeV. The average lab scattering angle for both targets was 7.7°, and the average Q2 for both targets was 0.02437 GeV2 (Q = 0.1561 GeV). The asymmetries are Bn = -10.68 ± 0.90 (stat) ± 0.57 (syst) ppm 12C and Bn = -12.16 ± 0.58 (stat) ± 0.62 (syst) ppm for 27Al. The results are consistent with theoretical predictions, and are compared to existing data. When scaled by Z/A, the Q dependence of all the far-forward angle (θ < 10°) data from 1H to 27Al can be described by the same slope out to Q ≈ 0.35 GeV. Larger-angle data from other experiments in the same Q range are consistent with a slope about twice as steep.
Tuberculosis remains a leading infectious cause of death in resource-limited settings. Effective treatment is the cornerstone of tuberculosis control, reducing mortality, recurrence and transmission. ...Supporting treatment adherence through facility-based observations of medication taking can be costly to providers and patients. Digital adherence technologies (DATs) may facilitate treatment monitoring and differentiated care. The ASCENT-Ethiopia study is a three-arm cluster randomised trial assessing two DATs with differentiated care for supporting tuberculosis treatment adherence in Ethiopia. This study is part of the ASCENT consortium, assessing DATs in South Africa, the Philippines, Ukraine, Tanzania and Ethiopia. The aim of this study is to determine the costs, cost-effectiveness and equity impact of implementing DATs in Ethiopia.
A total of 78 health facilities have been randomised (1:1:1) into one of two intervention arms or a standard-of-care arm. Approximately 50 participants from each health facility will be enrolled on the trial. Participants in facilities randomised to the intervention arms are offered a DAT linked to the ASCENT adherence platform for daily adherence monitoring and differentiated response for those who have missed doses. Participants at standard-of-care facilities receive routine care. Treatment outcomes and resource utilisation will be measured for each participant. The primary effectiveness outcome is a composite index of unfavourable end-of-treatment outcomes (lost to follow-up, death or treatment failure) or treatment recurrence within 6 months of end-of-treatment. For the cost-effectiveness analysis, end-of-treatment outcomes will be used to estimate disability-adjusted life years (DALYs) averted. Provider and patient cost data will be collected from a subsample of 5 health facilities per study arm, 10 participants per facility (n = 150). We will conduct a societal cost-effectiveness analysis using Bayesian hierarchical models that account for the individual-level correlation between costs and outcomes as well as intra-cluster correlation. An equity impact analysis will be conducted to summarise equity efficiency trade-offs.
Trial enrolment is ongoing. This paper follows the published trial protocol and describes the protocol and analysis plan for the health economics work package of the ASCENT-Ethiopia trial. This analysis will generate economic evidence to inform the implementation of DATs in Ethiopia and globally.
Pan African Clinical Trial Registry (PACTR) PACTR202008776694999. Registered on 11 August 2020, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 .
•Machine learning without sharing patient data, quickly and at scale.•Connecting 8 oncology institutes from 5 countries.•Survival prediction modelling on 20 000+ patient cases.•A study completed in ...4 months.
Access to healthcare data is indispensable for scientific progress and innovation. Sharing healthcare data is time-consuming and notoriously difficult due to privacy and regulatory concerns. The Personal Health Train (PHT) provides a privacy-by-design infrastructure connecting FAIR (Findable, Accessible, Interoperable, Reusable) data sources and allows distributed data analysis and machine learning. Patient data never leaves a healthcare institute.
Lung cancer patient-specific databases (tumor staging and post-treatment survival information) of oncology departments were translated according to a FAIR data model and stored locally in a graph database. Software was installed locally to enable deployment of distributed machine learning algorithms via a central server. Algorithms (MATLAB, code and documentation publicly available) are patient privacy-preserving as only summary statistics and regression coefficients are exchanged with the central server. A logistic regression model to predict post-treatment two-year survival was trained and evaluated by receiver operating characteristic curves (ROC), root mean square prediction error (RMSE) and calibration plots.
In 4 months, we connected databases with 23 203 patient cases across 8 healthcare institutes in 5 countries (Amsterdam, Cardiff, Maastricht, Manchester, Nijmegen, Rome, Rotterdam, Shanghai) using the PHT. Summary statistics were computed across databases. A distributed logistic regression model predicting post-treatment two-year survival was trained on 14 810 patients treated between 1978 and 2011 and validated on 8 393 patients treated between 2012 and 2015.
The PHT infrastructure demonstrably overcomes patient privacy barriers to healthcare data sharing and enables fast data analyses across multiple institutes from different countries with different regulatory regimens. This infrastructure promotes global evidence-based medicine while prioritizing patient privacy.
Objective
The aim of this study was to investigate the association of obesity with in‐hospital coronavirus disease 2019 (COVID‐19) outcomes in different ethnic groups.
Methods
Patients admitted to ...hospital with COVID‐19 in the United Kingdom through the Clinical Characterisation Protocol UK (CCP‐UK) developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) were included from February 6 to October 12, 2020. Ethnicity was classified as White, South Asian, Black, and other minority ethnic groups. Outcomes were admission to critical care, mechanical ventilation, and in‐hospital mortality, adjusted for age, sex, and chronic diseases.
Results
Of the participants included, 54,254 (age = 76 years; 45.0% women) were White, 3,728 (57 years; 41.1% women) were South Asian, 2,523 (58 years; 44.9% women) were Black, and 5,427 (61 years; 40.8% women) were other ethnicities. Obesity was associated with all outcomes in all ethnic groups, with associations strongest for black ethnicities. When stratified by ethnicity and obesity status, the odds ratios for admission to critical care, mechanical ventilation, and mortality in black ethnicities with obesity were 3.91 (3.13‐4.88), 5.03 (3.94‐6.63), and 1.93 (1.49‐2.51), respectively, compared with White ethnicities without obesity.
Conclusions
Obesity was associated with an elevated risk of in‐hospital COVID‐19 outcomes in all ethnic groups, with associations strongest in Black ethnicities.
Summary
The influence of age and sex steroids on bone density and geometry of the radius was examined in two European Caucasian populations. Age-related change in bone density and geometry was ...observed. In older men, bioavailable oestradiol may play a role in the maintenance of cortical and trabecular bone mineral density (BMD).
Introduction
To examine the effect of age and sex steroids on bone density and geometry of the radius in two European Caucasian populations.
Methods
European Caucasian men aged 40–79 years were recruited from population registers in two centres: Manchester (UK) and Leuven (Belgium), for participation in the European Male Ageing Study. Total testosterone (T) and oestradiol (E
2
) were measured by mass spectrometry and the free and bioavailable fractions calculated. Peripheral quantitative computed tomography was used to scan the radius at distal (4%) and midshaft (50%) sites.
Results
Three hundred thirty-nine men from Manchester and 389 from Leuven, mean ages 60.2 and 60.0 years, respectively, participated. At the 50% radius site, there was a significant decrease with age in cortical BMD, bone mineral content (BMC), cortical thickness, and muscle area, whilst medullary area increased. At the 4% radius site, trabecular and total volumetric BMD declined with age. Increasing bioavailable E
2
(bioE
2
) was associated with increased cortical BMD (50% radius site) and trabecular BMD (4% radius site) in Leuven, but not Manchester, men. This effect was predominantly in those aged 60 years and over. In older Leuven men, bioavailable testosterone (Bio T) was linked with increased cortical BMC, muscle area and SSI (50% radius site) and total area (4% radius site).
Conclusions
There is age-related change in bone density and geometry at the midshaft radius in middle-aged and elderly European men. In older men bioE
2
may maintain cortical and trabecular BMD. BioT may influence bone health through associations with muscle mass and bone area.
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