Health economic evaluation of controlled and maintained physical exercise in the prevention of cardiovascular and other prosperity diseases.

OBJECTIVES: Several studies and reports support the health benefits of frequent physical exercise, on the condition that this exercise is controlled and maintained. Given the scarce resources that can be spent on health and health care, the objective of this study was to evaluate the long-term health and economic outcomes of controlled and maintained physical exercise in a fitness setting. METHODS: A 25-year Markov model with a 12-month cycle-length and states representing diabetes, coronary heart disease, stroke, colon cancer and breast cancer was developed to predict cumulative costs and QALYs (quality adjusted life years) for three defined population cohorts, of different risk levels. Physical exercise was thereby compared with no intervention. Reduced risks associated with physical exercise, cost of diseases and loss of quality of life in case of disease were obtained from published literature. Costs were taken from a societal perspective; Belgium was selected as the setting. One way and probabilistic sensitivity analyses were carried out. RESULTS: For each of the cohorts, physical exercise is predicted to increase the QALYs and to offset a large part of the initial investment. The cost per QALY varies from 2000 to 15,000 Euro per QALY depending on the risk levels, which is better compared with a majority of secondary preventions that are currently publicly financed. CONCLUSION: Controlled and maintained physical exercise is projected to be cost-effective, which is likely to be explained by its simultaneous effect on several diseases and the associated weight loss, which affects quality of life positively.     

Effect of build orientation on the manufacturing process and the properties of stereolithographic dental ceramics for crown frameworks

Statement of problemStereolithography (SLA) ceramic crown frameworks are suitable for clinical use, but the impact of SLA build orientation has not been identified.PurposeThe purpose of this in vitro study was to investigate the effect of 3 build orientations on the physical and mechanical properties and the microstructure of SLA alumina dental ceramics.Material and methodsThe physical and mechanical properties and microstructures of 3 different oriented SLA alumina ceramics (ZX, ZY, and XY) were evaluated by visual observation, hydrostatic weighing (n=10/group), Weibull analyses (n=30/group), scanning electron microscopy, 3-point flexural strength (n=30/group), fracture toughness (indentation, single-edge-V-notched-beam) (n=4/group), and Vickers hardness (n=15/group) testing. The hydrostatic weighing, 3-point flexural strength, fracture toughness, and Vickers hardness testing data were statistically analyzed (α=.05).ResultsThe minimum resting period of slurries between the polymerization of 2 layers was shorter for the ZY- and ZX-oriented specimens and increased with the layer surface. The density and Vickers hardness of the SLA-manufactured specimens were similar for all groups (P>.05). The 95% confidence intervals of the Weibull moduli of the ZX- and ZY-oriented specimens were higher than that of the XY-oriented specimens, with no overlap fraction. The ZY-oriented specimens displayed significantly higher 3-point flexural strength (P<.05) and fracture toughness as evaluated by the single-edge-V-notched-beam method than the ZX-oriented specimens (P<.05). They also displayed significantly higher 3-point flexural strength than the XY-oriented specimens (P<.05). The microstructural analysis showed that the texturing was heterogeneous and that the major axis of the large grains of alumina ran parallel to the orientation of the layers.ConclusionsThe ZY orientation produced a reliable dental ceramic by SLA, with the shortest general manufacturing time and the highest mechanical strength when the layers were perpendicular to the test load surface.     

Synonymous Mutations in RNASEH2A Create Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi–Goutières Syndrome

Aicardi–Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full‐length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.     

Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles.     

A human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo

Endstage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate reinfection of the grafted donor liver by circulating virus is inevitable and liver disease progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients, whereas anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread by way of cell-cell contacts. We generated a human monoclonal antibody against scavenger receptor class B type I (SR-BI), monoclonal antibody (mAb)16-71, which can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 coculture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in "human liver urokinase-type plasminogen activator, severe combined immune deficiency (uPA-SCID) mice" (chimeric mice). A 2-week anti-SR-BI therapy that was initiated 1 day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day postexposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. CONCLUSION: Using in vitro cell culture and human liver-chimeric mouse models, we show that a human mAb targeting the HCV coreceptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following antiviral therapy.     

The additional value of bioelectrical impedance analysis-derived muscle mass as a screening tool in geriatric assessment for fall prevention

Background: The decline in skeletal muscle in old age is a factor in the development of functional limitations. Objective: The objective of this study was to assess if there is a correlation between muscle mass based on bioelectrical impedance analysis (BIA) detection and the fall incidence in nursing home residents and to examine the risk factors for falling in nursing home residents. Methods: This prospective cohort study was part of a longitudinal study on nutritional issues in 52 nursing homes in Antwerp (Belgium) from October 2007 to April 2008. Two hundred and seventy-six people aged 65 years and older were included. Each subject was assessed with BIA, the timed get-up-and-go test, the Katz score, the Mini Nutritional Assessment - Short Form and the 36-Item Short Form Health Survey. The primary outcome parameter was fall incidence during the study. Results: The prevalence of sarcopenia varied from 24.3 to 81.5% depending on which definition was used. No association was found between BIA-derived muscle mass and fall incidence. Logistic regression analysis showed that gait speed (odds ratio 1.029; p = 0.003) and mental health (odds ratio 0.981; p = 0.015) are significantly associated with fall incidence in nursing homes. A receiver operating characteristic curve showed that none of the BIA-derived muscle parameters are good predictors of the risk of falling. Conclusions: This study shows that there is no association between sarcopenia based on BIA and fall incidence and that BIA-derived muscle mass has no additional value in predicting fall incidents compared to the timed get-up-and-go test.     

Escitalopram in major depressive disorder: clinical benefits and cost effectiveness versus citalopram

Objective. Escitalopram is the most selective of the serotonin reuptake inhibitors. Methods. We review all the clinical trials (three pivotal placebo-controlled trials with citalopram as an active reference, one long-term non-inferiority study and one head-to-head superiority study) that include citalopram as an active reference in major depressive disorder (MDD), and studies that evaluate the cost-effectiveness of the two drugs. Results. In two of the pivotal studies and in the long-term study, escitalopram was numerically better than citalopram in reducing Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline, with comparative tolerability. Meta-analyses of these studies showed statistically significant differences in favour of escitalopram in terms of reducing MADRS and increasing response. This effect was particularly apparent in patients with higher baseline MADRS scores. These trends were confirmed in a head-to-head study, which clearly demonstrated the superiority of escitalopram compared with citalopram on primary and secondary endpoints. The difference between treatments was clinically relevant. Cost-effectiveness analyses demonstrated that although escitalopram has a slightly higher unit cost than generic citalopram, expected direct medical and productivity- related costs were lower with escitalopram than citalopram. Conclusion. On the basis of these results, escitalopram was concluded to be more clinically effective and more cost-effective than citalopram for the treatment of MDD, with a similar tolerability profile.     

Selective recovery of zinc from goethite residue in the zinc industry using deep-eutectic solvents

Several deep-eutectic solvents (DESs) were tested for the valorisation of goethite residue produced by the zinc industry. The objective of the work was to selectively recover zinc from the iron-rich matrix using deep-eutectic solvents as lixiviants. The effect of the type of hydrogen bond donor and hydrogen bond acceptor of the deep-eutectic solvent on the leaching efficiency was studied. Levulinic acid–choline chloride (x_ChCl = 0.33) (LevA–ChCl) could selectively leach zinc from the iron-rich matrix, and it was selected as the best-performing system to be used in further study. The leaching process was optimised in terms of temperature, contact time, liquid-to-solid ratio and water content of the deep-eutectic solvent. The role of the choline cation on the leaching process was investigated by considering the leaching properties of a LevA–CaCl₂ mixture. The goethite residue was also leached with pure levulinic acid. The results were compared to a purely hydrometallurgical approach using sulphuric acid leaching. Leaching with LevA–ChCl resulted in higher selectivity compared to the conventional “hot leaching” with 80 g L⁻¹ sulphuric acid. Furthermore, a slightly higher zinc recovery and comparable selectivity for zinc over iron were achieved with LevA–ChCl compared to conventional “neutral leaching” with 10 g L⁻¹ sulphuric acid.

A mixture of levulinic acid and choline chloride can be used to selectively leach zinc from industrial residues with iron-rich matrices.     

The effect of gastric juice on interleukin-8 production by cystic fibrosis primary bronchial epithelial cells

CF patients are often treated with proton pump inhibitors (PPIs) to reduce acidic gastro-esophageal reflux (GER) and bronchial aspiration of duodeno-gastric contents is common in CF. We have previously demonstrated that gastric juice (GJ) from patients “on” PPI can induce interleukin-8 (IL-8) production by bronchial epithelial cells in culture. We hypothesized that such effect would be more pronounced in CF patients known to have high inflammatory susceptibility. We aimed to evaluate the effect of GJ on IL-8 production by primary bronchial epithelial cells (PBEC), derived from a CF patient and a healthy subject.MethodsPBEC obtained from one donor (normal PBEC) and one receptor (CF-PBEC) for lung transplantation were stimulated with GJ from patients “off” and “on” PPI. IL-8 levels were measured in the supernatant.ResultsGJ from patients “on” PPI provoked a significant higher IL-8 production compared to GJ from patients “off” PPI, both in normal PBEC [462 (200–1468) vs. 11 (4–28) pg/ml, p = 0.0001] as in CF-PBEC [1468 (841–2449) vs. 85 (26–131) pg/ml, p < 0.0001]. Exposure of the cells to GJ “off” PPI and “on” PPI provoked significantly higher IL-8 production in the CF-PBEC compared to the normal PBEC [“off” PPI 85 (26–131) vs. 11 (4–28) pg/ml, p = 0.01; “on” PPI 1468 (841–2449) vs. 462 (200–1468) pg/ml, p = 0.01]. Filtration (0.20 μm) of the GJ “on” PPI, to eliminate large particles and bacterial sub-products, resulted in a significant decrease of IL-8 production.ConclusionPatients with CF, treated with PPIs, have GJ with high pH and high endotoxin levels. These patients often have GER and bronchial aspiration. The aspirated material (GJ “on” PPI) has a significantly enhanced inflammatory effect on CF bronchial epithelial cells in culture. As chronic PPI treatment in CF may result in a paradoxically increased inflammatory effect in the airways, alternative anti-reflux therapies should be considered in CF.