Pharmaco-epistemology for the prescribing geriatrician

Clinicians are becoming more reliant on their interpretation of clinical trial information to guide prescribing rather than their clinical skills. Thus to improve prescribing, it is increasingly important for clinicians to have an appreciation of epistemology (the science of knowledge and its interpretation) and the broader social context of knowledge. The insights of epistemologists can be useful in understanding the different ways in which clinical trials data are interpreted

The Effects of Old Age on Hepatic Stellate Cells

Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24–27 mths) and mice (2-3 mths versus 20–22 mths). Desmin-positive HSC doubled in old age in both mice and rats. Alpha-smooth muscle actin- (αSMA-) positive cells did not increase significantly and remained only a small percentage of desmin-positive cells. Electron microscopy revealed that old age is associated with HSC that have a substantial increase in the number of lipid droplets which are larger in diameter. There was also a marked increase of HSC that protruded into the sinusoidal lumen in old mice. In conclusion, old age is associated with hyperplasia of HSC that are not activated and are engorged with lipid droplets

Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project

Background: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. Methods: the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. Results: overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. Conclusion: frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive intervention

Interventions based on early intensive applied behaviour analysis for autistic children : A systematic review and cost-effectiveness analysis

BACKGROUND: Early intensive applied behaviour analysis-based interventions are intensive interventions for autistic children that are often delivered on a one-to-one basis for 20-50 hours per week. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of early intensive applied behaviour analysis-based interventions for autistic children, based on current evidence. METHODS: A systematic review and individual participant data meta-analysis were conducted to evaluate the clinical effectiveness of an early intensive applied behaviour analysis-based intervention for autistic children. An economic analysis included a review of existing analyses and the development of a new model. RESULTS: Twenty studies were included in the clinical review. Individual participant data were retrieved from 15 of these studies. Results favoured the interventions when assessing adaptive behaviour after 2 years compared with treatment as usual/eclectic interventions (mean difference 7.00, 95% confidence interval 1.95 to 12.06). In analyses of cognitive ability (intelligence quotient), results favoured the interventions by approximately 10 points after 1 year (mean difference 9.16, 95% confidence interval 4.38 to 13.93) and 2 years (mean difference 14.13, 95% confidence interval 9.16 to 19.10). Evidence for other outcomes was limited and meta-analyses were generally inconclusive. There was no evidence that the effect of the interventions varied with characteristics of the children, but data were limited. Adopting a £30,000 per quality-adjusted life-year threshold, the results of the cost-effectiveness analysis indicate that early intensive applied behaviour analysis-based interventions would need to generate larger benefits or cost savings to be cost-effective. Adopting a public sector perspective and making pessimistic assumptions about long-term effects, the incremental cost-effectiveness ratio for early intensive applied behaviour analysis-based therapy compared with treatment as usual is £189,122 per quality-adjusted life-year. When optimistic assumptions are made, the incremental cost-effectiveness ratio is £46,768 per quality-adjusted life-year. Scenario analyses indicated that these interventions can potentially be cost-effective if long-term improvements persist into adulthood, or if they have significant impact on educational placement. Care should be taken when interpreting these scenarios owing to the limited data. LIMITATIONS: All included studies were at risk of bias, there was substantial heterogeneity and effects varied considerably across studies. The effect of intervention on autism symptom severity, language development and school placement remains uncertain because of the limited data. The long-term effects are unclear owing to a lack of follow-up data. CONCLUSIONS: This review found limited evidence that early intensive applied behaviour analysis-based interventions may improve cognitive ability and adaptive behaviour, but the long-term impact of the interventions remains unknown. The economic analysis is constrained by the limited effectiveness evidence, but suggests that these interventions are unlikely to be cost-effective unless clear long-term benefits, or a substantial change in which schools children attend, can be identified. FUTURE WORK: Further studies into the effectiveness of early intensive applied behaviour analysis-based interventions may be warranted if they include well-defined, alternative interventions as comparators and collect relevant outcomes. Consideration should be given to future studies that not only address whether or not early intensive applied behaviour analysis-based interventions are clinically effective, but also aim to identify which components of early intensive applied behaviour analysis-based interventions might drive effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017068303. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 35. See the NIHR Journals Library website for further project information

Ischemia/reperfusion injury in the aged liver: The importance of the sinusoidal endothelium in developing therapeutic strategies for the elderly.

The liver endothelium plays a key role in the progression and resolution of liver diseases in young and adult individuals. However, its role in older people remains unknown. We have herein evaluated the importance of the sinusoidal endothelium in the pathophysiology of acute liver injury, and investigated the applicability of simvastatin, in aged animals.18 months old male Wistar rats underwent 60 min of partial warm ischemia followed by 2h of reperfusion (WIR). A group of aged rats received simvastatin for 3 days before WIR. Endothelial phenotype, parenchymal injury, oxidative and nitrosative stress, and fenestrae dynamics were analysed. The effects of WIR and simvastatin were investigated in primary LSEC from aged animals.The results of this study demonstrated that WIR significantly damages the liver endothelium and its effects are markedly worse in old animals. WIR-aged livers exhibited reduced vasodilation and sinusoidal capillarization, associated with liver damage and cellular stress. Simvastatin prevented the detrimental effects of WIR in aged livers.In conclusion, the liver sinusoidal endothelium of old animals is highly vulnerable to acute insult, thus targeted protection is especially relevant in preventing liver damage. Simvastatin represents a useful therapeutic strategy in aging

Muslime in Europa zwischen Globalisierung und Lokalisierung. Gesellschaftspolitische und theologische Perspektiven im Anschluss an Enes Karic und Tariq Ramadan

). Culture media was collected from hyperoxic conditions (open bars) or normoxic conditions (filled bars) at 24 hours intervals. Final concentrations were estimated from individual standard curves. Generation of endogenous HOwas monitored in separate experiments at the indicated time-points in LSEC cultures by HO-mediated oxidation of DCFH-DA into DFC during 6 h (b). Values are total fluorescence emitted at 545 nm.<p><b>Copyright information:</b></p><p>Taken from "The influence of oxygen tension on the structure and function of isolated liver sinusoidal endothelial cells"</p><p>http://www.comparative-hepatology.com/content/7/1/4</p><p>Comparative Hepatology 2008;7():4-4.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2408922.</p><p></p

Quantum Dot Nanomedicine Formulations Dramatically Improve Pharmacological Properties and Alter Uptake Pathways of Metformin and Nicotinamide Mononucleotide in Aging Mice

Orally administered Ag2S quantum dots (QDs) rapidly cross the small intestine and are taken up by the liver. Metformin and nicotinamide mononucleotide (NMN) target metabolic and aging processes within the liver. This study examined the pharmacology and toxicology of QD-based nanomedicines as carriers of metformin and NMN in young and old mice, determining if their therapeutic potency and reduced effects associated with aging could be improved. Pharmacokinetic studies demonstrated that QD-conjugated metformin and NMN have greater bioavailability, with selective accumulation in the liver following oral administration compared to unconjugated formulations. Pharmacodynamic data showed that the QD-conjugated medicines had increased physiological, metabolic, and cellular potency compared to unconjugated formulations (25× metformin; 100× NMN) and highlighted a shift in the peak induction of, and greater metabolic response to, glucose tolerance testing. Two weeks of treatment with low-dose QD-NMN (0.8 mg/kg/day) improved glucose tolerance tests in young (3 months) mice, whereas old (18 and 24 months) mice demonstrated improved fasting and fed insulin levels and insulin resistance. High-dose unconjugated NMN (80 mg/kg/day) demonstrated improvements in young mice but not in old mice. After 100 days of QD (320 μg/kg/day) treatment, there was no evidence of cellular necrosis, fibrosis, inflammation, or accumulation. Ag2S QD nanomedicines improved the pharmacokinetic and pharmacodynamic properties of metformin and NMN by increasing their therapeutic potency, bypassing classical cellular uptake pathways, and demonstrated efficacy when drug alone was ineffective in aging mice