Finite element modelling of healthy and osteoporotic bone

On a macro-structural level, the bones of the human skeleton is comprised mainly of trabecular (spongy) and cortical bone (dense). Trabecular bone typically occurs at the end points of long bones and has a structure described as a network of plates and rods. Cortical bone forms the hard outer shell and comprised mainly of osteons called Haversian systems. Bone is a composite material consisting mainly of an organic collagenous matrix ad carbonated apatite crystals. The structure of bone material is hierarchically organised and the inhomogeneous nature of bone material results in anisotropic mechanical properties. Bone adapts to its loading history and undergoes hypertrophy as result of increased loading and atrophy when loading is significantly reduced or completely removed. Osteoporosis is a disease of the bone which is characterised by loss of bone material and hence weakening of the bone. As a result of this, osteoporotic bone is more likely to fracture as a result of everyday loading. In this study three-dimensional finite element models of the shaft of the tibia were developed using the ABAQUS (Simula) finite element modelling programme. Models were developed to represent three symptoms of osteoporosis - bone thinning, low density and increased porosity. The models were subjected to compressive and torsional loading, and the stress distribution in response to these loads was analysed to gain an understanding of what areas of the tibia are at greatest risk of fracture and under what loading conditions. A risk of fracture for each of the elements was calculated and the maximum risk of fracture in each model gave an indication of fracture likelihood. This study found that osteoporotic bone showed increased stress and risk of fracture in both compression and torsion. However, torsion of bone with increased porosity was the only combination that produced results that indicate the occurrence of fracture. The aim is for the bone models developed in this study to be used clinically to reduce fracture occurrence in patients with osteoporotic bone loss.On a macro-structural level, the bones of the human skeleton is comprised mainly of trabecular (spongy) and cortical bone (dense). Trabecular bone typically occurs at the end points of long bones and has a structure described as a network of plates and rods. Cortical bone forms the hard outer shell and comprised mainly of osteons called Haversian systems. Bone is a composite material consisting mainly of an organic collagenous matrix ad carbonated apatite crystals. The structure of bone material is hierarchically organised and the inhomogeneous nature of bone material results in anisotropic mechanical properties. Bone adapts to its loading history and undergoes hypertrophy as result of increased loading and atrophy when loading is significantly reduced or completely removed. Osteoporosis is a disease of the bone which is characterised by loss of bone material and hence weakening of the bone. As a result of this, osteoporotic bone is more likely to fracture as a result of everyday loading. In this study three-dimensional finite element models of the shaft of the tibia were developed using the ABAQUS (Simula) finite element modelling programme. Models were developed to represent three symptoms of osteoporosis - bone thinning, low density and increased porosity. The models were subjected to compressive and torsional loading, and the stress distribution in response to these loads was analysed to gain an understanding of what areas of the tibia are at greatest risk of fracture and under what loading conditions. A risk of fracture for each of the elements was calculated and the maximum risk of fracture in each model gave an indication of fracture likelihood. This study found that osteoporotic bone showed increased stress and risk of fracture in both compression and torsion. However, torsion of bone with increased porosity was the only combination that produced results that indicate the occurrence of fracture. The aim is for the bone models developed in this study to be used clinically to reduce fracture occurrence in patients with osteoporotic bone loss

Moral injury and psychological wellbeing in UK healthcare staff

BACKGROUND: Potentially morally injurious events (PMIEs) can negatively impact mental health. The COVID-19 pandemic may have placed healthcare staff at risk of moral injury. AIM: To examine the impact of PMIE on healthcare staff wellbeing. METHODS: Twelve thousand nine hundred and sixty-five healthcare staff (clinical and non-clinical) were recruited from 18 NHS-England trusts into a survey of PMIE exposure and wellbeing. RESULTS: PMIEs were significantly associated with adverse mental health symptoms across healthcare staff. Specific work factors were significantly associated with experiences of moral injury, including being redeployed, lack of PPE, and having a colleague die of COVID-19. Nurses who reported symptoms of mental disorders were more likely to report all forms of PMIEs than those without symptoms (AOR 2.7; 95% CI 2.2, 3.3). Doctors who reported symptoms were only more likely to report betrayal events, such as breach of trust by colleagues (AOR 2.7, 95% CI 1.5, 4.9). CONCLUSION: A considerable proportion of NHS healthcare staff in both clinical and non-clinical roles report exposure to PMIEs during the COVID-19 pandemic. Prospective research is needed to identify the direction of causation between moral injury and mental disorder as well as continuing to monitor the longer term outcomes of exposure to PMIEs

Suppression of Epithelial to Mesenchymal Transitioning (EMT) Enhances Ex Vivo Reprogramming of Human Exocrine Pancreatic Tissue towards Functional Insulin Producing β-Like Cells

Because of the lack of tissue available for islet transplantation, new sources of β-cells have been sought for the treatment of type 1 diabetes. The aim of this study was to determine whether the human exocrine-enriched fraction from the islet isolation procedure could be reprogrammed to provide additional islet tissue for transplantation. The exocrine-enriched cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these mesenchymal cells arose, in part, through a process of epithelial-to-mesenchymal transitioning (EMT). A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA, and Pax4 generated a population of cells that were enriched in glucagon-secreting α-like cells. Transdifferentiation or reprogramming toward insulin-secreting β-cells was enhanced, however, when using unpassaged cells in combination with inhibition of EMT by inclusion of Rho-associated kinase (ROCK) and transforming growth factor-β1 inhibitors. Resultant cells were able to secrete insulin in response to glucose and on transplantation were able to normalize blood glucose levels in streptozotocin diabetic NOD/SCID mice. In conclusion, reprogramming of human exocrine-enriched tissue can be best achieved using fresh material under conditions whereby EMT is inhibited, rather than allowing the culture to expand as a mesenchymal monolayer

Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats

Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission

Effect of angiotensin II and small GTPase Ras signaling pathway inhibition on early renal changes in a murine model of obstructive nephropathy

This is an open access article distributed under the Creative Commons Attribution License.Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.This study was supported by grants from Ministerio de Economía y Competitividad (Grant SAF2010-15881 and Red de Investigacion Cooperativa en Enfermedades Renales REDINREN RD12/0021/0032), Junta de Castilla y León (Grant SA 001/C05 and Excellence Group GR100), and REDINREN which is an initiative of the Instituto de Salud Carlos III of Spain supported by FEDER funds. When performing the present study, Ana B. Rodríguez-Pena was a fellow of the Fundacion Renal “Iñigo Ávarez de Toledo” and Neil G. Docherty was a fellow ofThe Marie Curie Programme, EU.Peer Reviewe

A Comparison of Total Food Intake at a Personalised Buffet in People with Obesity, before and 24 Months after Roux-en-Y-Gastric Bypass Surgery

Long-term reductions in the quantity of food consumed, and a shift in intake away from energy dense foods have both been implicated in the potent bariatric effects of Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised that relative to pre-operative assessment, a stereotypical shift to lower intake would be observed at a personalised ad libitum buffet meal 24 months after RYGB, driven in part by decreased selection of high energy density items. At pre-operative baseline, participants (n = 14) rated their preference for 72 individual food items, each of these mapping to one of six categories encompassing high and low-fat choices in combination with sugar, complex carbohydrate or and protein. An 18-item buffet meal was created for each participant based on expressed preferences. Overall energy intake was reduced on average by 60% at the 24-month buffet meal. Reductions in intake were seen across all six food categories. Decreases in the overall intake of all individual macronutrient groups were marked and were generally proportional to reductions in total caloric intake. Patterns of preference and intake, both at baseline and at follow-up appear more idiosyncratic than has been previously suggested by verbal reporting. The data emphasise the consistency with which reductions in ad libitum food intake occur as a sequel of RYGB, this being maintained in the setting of a self-selected ad libitum buffet meal. Exploratory analysis of the data also supports prior reports of a possible relative increase in the proportional intake of protein after RYGB

Generation of Functional Beta-Like Cells from Human Exocrine Pancreas

<div><p>Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin⁺ cells. The resultant β-like cells expressed insulin protein levels at ~15–30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.</p></div

A Scalable Home Care System Infrastructure Supporting Domiciliary Care

Technology-mediated home care is attractive for older people living at home and also for their carers. It provides the information necessary to give confidence and assurance to everyone interested in the wellbeing of the older person. From a care delivery perspective, however, widespread deployment of home care technologies presents system developers with a set of challenges. These challenges arise from the issues associated with scaling from individual installations to providing a community-wide service, particularly when each installation is to be fitted to the particular but changing needs of the residents, their in-home carers and the larger healthcare community. This paper presents a home care software architecture and services that seek to address these challenges. The approach aims to generate the information needed in a timely and appropriate form to inform older residents and their carers about changing life style that may indicate a loss of well-being. It unites sensor-based services, home care policy management, resource discovery, multimodal interaction and dynamic configuration services. In this way, the approach offers the integration of a variety of home care services with adaptation to the context of use