Osteogenic preconditioning in perfusion bioreactors improves vascularization and bone formation by human bone marrow aspirates.

Cell-derived extracellular matrix (ECM) provides a niche to promote osteogenic differentiation, cell adhesion, survival, and trophic factor secretion. To determine whether osteogenic preconditioning would improve the bone-forming potential of unfractionated bone marrow aspirate (BMA), we perfused cells on ECM-coated scaffolds to generate naïve and preconditioned constructs, respectively. The composition of cells selected from BMA was distinct on each scaffold. Naïve constructs exhibited robust proangiogenic potential in vitro, while preconditioned scaffolds contained more mesenchymal stem/stromal cells (MSCs) and endothelial cells (ECs) and exhibited an osteogenic phenotype. Upon implantation into an orthotopic calvarial defect, BMA-derived ECs were present in vessels in preconditioned implants, resulting in robust perfusion and greater vessel density over the first 14 days compared to naïve implants. After 10 weeks, human ECs and differentiated MSCs were detected in de novo tissues derived from naïve and preconditioned scaffolds. These results demonstrate that bioreactor-based preconditioning augments the bone-forming potential of BMA

Computational Modeling of Silicate Glasses: A Quantitative Structure-Property Relationship Perspective

This article reviews the present state of Quantitative Structure-Property Relationships (QSPR) in glass design and gives an outlook into future developments. First an overview is given of the statistical methodology, with particular emphasis to the integration of QSPR with molecular dynamics simulations to derive informative structural descriptors. Then, the potentiality of this approach as a tool for interpretative and predictive purposes is highlighted by a number of recent inspiring applications

Referral Criteria for Specialist Palliative Care for Patients With Dementia

Importance: Patients with dementia have considerable supportive care needs. Specialist palliative care may be beneficial, but it is unclear which patients are most appropriate for referral and when they should be referred.Objective: To identify a set of consensus referral criteria for specialist palliative care for patients with dementia. Design, Setting, and Participants: In this survey study using 3 rounds of Delphi surveys, an international, multidisciplinary panel of clinicians from 5 continents with expertise in the integration of dementia and palliative care were asked to rate 83 putative referral criteria (generated from a previous systematic review and steering committee discussion). Specialist palliative care was defined as an interdisciplinary team consisting of practitioners with advanced knowledge and skills in palliative medicine offering consultative services for specialist-level palliative care in (nonhospice) inpatient, outpatient, community, and home-based settings. Main Outcomes and Measures: Consensus was defined a priori as at least 70% agreement among experts. A criterion was coded as major if the experts advocated that meeting 1 criterion alone was satisfactory to justify a referral. Data were summarized using descriptive statistics. Results: Of the 63 invited and eligible panelists, the response rate was 58 (92.1%) in round 1, 58 (92.1%) in round 2, and 60 (95.2%) in round 3. Of the 58 panelists who provided demographic data in round 1, most were aged 40 to 49 years (28 of 58 [48.3%]), and 29 panelists (50%) each were men and women. Panelists achieved consensus on 15 major and 42 minor criteria for specialist palliative care referral. The 15 major criteria were grouped under 5 categories, including dementia type (eg, rapidly progressive dementia), symptom distress (eg, severe physical symptoms), psychosocial factors or decision-making (eg, request for hastened death, assisted suicide, or euthanasia), comorbidities or complications (eg, ≥2 episodes of aspiration pneumonia in the past 12 months); and hospital use (eg, ≥2 hospitalizations within the past 3 months). Conclusions and Relevance: In this Delphi survey study, international experts reached consensus on a range of criteria for referral to specialist palliative care. With testing and validation, these criteria may be used to standardize specialist palliative care access for patients with dementia across various care settings.</p

Loss of the Auxiliary α 2δ1 Voltage-Sensitive Calcium Channel Subunit Impairs Bone Formation and Anabolic Responses to Mechanical Loading

Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation

Role of carbon cycle observations and knowledge in carbon management

Author Posting. © Annual Reviews, 2003. This article is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Environment and Resources 28 (2003): 521-558, doi:10.1146/annurev.energy.28.011503.163443.Agriculture and industrial development have led to inadvertent changes in the natural carbon cycle. As a consequence, concentrations of carbon dioxide and other greenhouse gases have increased in the atmosphere and may lead to changes in climate. The current challenge facing society is to develop options for future management of the carbon cycle. A variety of approaches has been suggested: direct reduction of emissions, deliberate manipulation of the natural carbon cycle to enhance sequestration, and capture and isolation of carbon from fossil fuel use. Policy development to date has laid out some of the general principles to which carbon management should adhere. These are summarized as: how much carbon is stored, by what means, and for how long. To successfully manage carbon for climate purposes requires increased understanding of carbon cycle dynamics and improvement in the scientific capabilities available for measurement as well as for policy needs. The specific needs for scientific information to underpin carbon cycle management decisions are not yet broadly known. A stronger dialogue between decision makers and scientists must be developed to foster improved application of scientific knowledge to decisions. This review focuses on the current knowledge of the carbon cycle, carbon measurement capabilities (with an emphasis on the continental scale) and the relevance of carbon cycle science to carbon sequestration goals.The National Center for Atmospheric Research is supported by the National Science Foundation

Subclinical Atherosclerosis and Cardiovascular Events Among Patients With Colorectal Cancer

Background: Prior studies have documented that patients with colorectal cancer (CRC) are at an increased risk of cardiovascular disease (CVD). Objectives: To examine coronary artery calcium (CAC) as a marker of subclinical atherosclerosis and its association with major adverse cardiovascular events (MACE) in patients with CRC across the cancer treatment trajectory. Methods: Adults with newly diagnosed CRC were enrolled in the prospective ColoCare study from 2017 to 2024. CAC was measured from routine diagnostic computed tomography (CT) and positron emission tomography‐CT scans at CRC diagnosis until 5 years post‐diagnosis. Atherosclerosis was defined as the presence of CAC. We used multivariable‐adjusted Fine and Gray models to assess the association between CAC and MACE risk, accounting for competing risks. Results: Among 300 CRC patients, the most common CVD risk factors at cancer diagnosis were hypertension (37%), hyperlipidemia (24%), and diabetes (14%). During follow‐up (median = 5.3 years), 75 (25%) individuals experienced MACE: stroke (3%), new/worsening HF (9%), HF exacerbation requiring hospitalization (2%), coronary revascularization (3%), and death (19%). Among individuals with imaging at baseline (n = 101), 37 (36.6%) had CAC, and statins were not prescribed in 11 (55.0%) patients with moderate/high CAC. For those with serial imaging (n = 61), 31.1% showed worsening CAC and 3% developed new CAC. Baseline CAC conferred a higher risk of MACE (HR = 4.79; 95% CI: 1.05–21.75, p = 0.04) after accounting for cancer‐related deaths as a competing risk. Conclusions: Subclinical atherosclerosis and MACE are common among patients with CRC. Integrating CAC from routine cancer imaging can identify patients who may benefit from cardio‐preventive treatment