Comparative analysis of progenitor cells isolated from the iris, pars plana, and ciliary body of the adult porcine eye

Photoreceptor loss causes irreversible blindness in many retinal diseases. The identification of suitable donor cell populations is of considerable interest because of their potential use to replace the photoreceptors lost in disease. Stem or progenitor cells that give rise to neurons and glia have been identified in several regions of the brain, including the embryonic retina and the ciliary epithelium of the adult eye, raising the possibility of autologous transplantation. However, there has been little systematic investigation into precisely which regions of the large mammalian adult eye give rise to such cells. Here, we show for the first time using the porcine eye the presence of progenitor cells in additional regions of the adult eye, including the pars plana and iris, regions that, in the human, are readily accessible during routine eye surgery. When cultured in the presence of growth factors, these cells proliferate to form neurospheres comprised of cells expressing retinal progenitor markers. Using an adherent monolayer culture system, these cells could be readily expanded to increase their number more than 1 million-fold and maintain a progenitor phenotype. When grown on the substrate laminin in the presence of serum, cells derived from both spheres and monolayer cultures differentiated into neurons and glia. These results suggest that a population of cells derived from the adult iris, pars plana, and ciliary body of a large mammalian species, the pig, has progenitor properties and neurogenic potential, thereby providing novel sources of donor cells for transplantation studies. Disclosure of potential conflicts of interest is found at the end of this article.     

Estimating the public health impact of disbanding a government alcohol monopoly: application of new methods to the case of Sweden

Background

Government alcohol monopolies were created in North America and Scandinavia to limit health and social problems. The Swedish monopoly, Systembolaget, reports to a health ministry and controls the sale of all alcoholic beverages with >?3.5% alcohol/volume for off-premise consumption, within a public health mandate. Elsewhere, alcohol monopolies are being dismantled with evidence of increased consumption and harms. We describe innovative modelling techniques to estimate health outcomes in scenarios involving Systembolaget being replaced by 1) privately owned liquor stores, or 2) alcohol sales in grocery stores. The methods employed can be applied in other jurisdictions and for other policy changes.

Methods

Impacts of the privatisation scenarios on pricing, outlet density, trading hours, advertising and marketing were estimated based on Swedish expert opinion and published evidence. Systematic reviews were conducted to estimate impacts on alcohol consumption in each scenario. Two methods were applied to estimate harm impacts: (i) alcohol attributable morbidity and mortality were estimated utilising the International Model of Alcohol Harms and Policies (InterMAHP); (ii) ARIMA methods to estimate the relationship between per capita alcohol consumption and specific types of alcohol-related mortality and crime.

Results

Replacing government stores with private liquor stores (Scenario 1) led to a 20.0% (95% CI, 15.3–24.7) increase in per capita consumption. Replacement with grocery stores (Scenario 2) led to a 31.2% (25.1–37.3%) increase. With InterMAHP there were 763 or?+?47% (35–59%) and 1234 or?+?76% (60–92%) more deaths per year, for Scenarios 1 and 2 respectively. With ARIMA, there were 850 (334–1444) more deaths per year in Scenario 1 and 1418 more in Scenario 2 (543–2505). InterMAHP also estimated 10,859 or?+?29% (22–34%) and 16,118 or?+?42% (35–49%) additional hospital stays per year respectively.

Conclusions

There would be substantial adverse consequences for public health and safety were Systembolaget to be privatised. We demonstrate a new combined approach for estimating the impact of alcohol policies on consumption and, using two alternative methods, alcohol-attributable harm. This approach could be readily adapted to other policies and settings. We note the limitation that some significant sources of uncertainty in the estimates of harm impacts were not modelled.

     

An evaluation of the performance of cast gold bonded restorations in clinical practice, a retrospective study

OBJECTIVES: To evaluate the performance of cast gold bonded restorations in clinical practice. MATERIALS AND METHODS: The records of all patients treated with cast gold bonded restorations between 1997 and 2004 of The Dental Hospital of Newcastle upon Tyne were reviewed. The following data were recorded: sex of patient, location of teeth (anterior or posterior), position of teeth (upper or lower) and type of cement (glass ionomer, zinc phosphate or resin cement). The survival time was calculated for each restoration; and the reason for failure (either debond or change of treatment plan) identified for each case. The restorations were stratified according to the age of the patient into 10-year age bands and survival analysis was used to identify variables associated with increased risk of failure. RESULTS: Restorations luted with resin cement showed the highest rate of survival after 7 years of follow-up. The alternative lutes had significantly worse survival (p<0.05). Restorations on anterior teeth had poorer survival than on posterior teeth but there were no differences between those placed in the mandible and the maxilla. CONCLUSIONS: Within the limitations of this study resin cements are most appropriate for this type of restoration with 80% survival at 7 years. Restorations placed on posterior teeth survived better.     

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis

OBJECTIVE: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). DESIGN: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. SETTING: A total of 164 medical centers in 11 countries. PATIENTS: A total of 1,690 patients with severe sepsis. MEASUREMENTS AND MAIN RESULTS: We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a > or = 20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. CONCLUSIONS: The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.     

Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis

OBJECTIVE: To assess the cost-effectiveness of drotrecogin alfa (activated) therapy, which was recently shown to reduce mortality in severe sepsis. DESIGN: Estimates of effectiveness and resource use were based on data collected prospectively as part of a multicenter international trial. Estimates of hospital costs were based on a subset of the patients treated in the United States (33% of all enrolled patients). Lifetime projections were modeled from published sources and tested in sensitivity analyses. Analyses were conducted from the United States societal perspective, limited to healthcare costs, and using a 3% annual discount rate. SETTING: A total of 164 medical institutions in 11 countries. PATIENTS: Adults > or = 18 yrs of age with severe sepsis INTERVENTIONS: Eligible patients were randomly assigned to receive a 96-hr intravenous infusion of drotrecogin alfa (activated) at 24 microg/kg/hr (n = 850) or placebo (n = 840). MEASUREMENTS AND MAIN RESULTS: Base Case: incremental short-term (days 1-28) healthcare costs per day-28 survivor; Panel on Cost-Effectiveness in Health and Medicine Reference Case: incremental lifetime healthcare costs per quality-adjusted life-year. Over the first 28 days (short-term Base Case), drotrecogin alfa (activated) increased the costs of care by $9,800 and survival by 0.061 lives saved per treated patient. Thus, drotrecogin alfa (activated) cost $160,000 per life saved (with 84.7% probability that ratio is <$250,000 per life saved). Projected to lifetime (lifetime Reference Case), drotrecogin alfa (activated) increased the costs of care by $16,000 and quality-adjusted survival by 0.33 quality-adjusted life-years per treated patient. Thus, drotrecogin alfa (activated) cost $48,800 per quality-adjusted life-year (with 82% probability that ratio is <$100,000 per quality-adjusted life-year). Estimates were generally robust to sensitivity analyses, although cost-effectiveness deteriorated to >$100,000 per quality-adjusted life-year if survivors lived <4.6 yrs on average. Drotrecogin alfa (activated) cost $27,400 per quality-adjusted life-year when limited to patients with an Acute Physiology and Chronic Health Evaluation II score > or = 25 and was cost-ineffective when limited to patients with a score <25. CONCLUSIONS: Drotrecogin alfa has a cost-effectiveness profile similar to that of many well-accepted healthcare strategies and below commonly quoted thresholds.     

Scapulothoracic fusion for painful winging of the scapula in nondystrophic patients

A modified technique of scapulothoracic fusion was used in 6 patients who did not have muscular dystrophy and who were later evaluated clinically. The cause of the painful winging of the scapula was traumatic disruption of the trapezius and the accessory nerve in 3 patients, injury to the brachial plexus in 2, and Sprengel's deformity in 1. To obtain fusion, double wires were passed around each of 4 ribs. A Rush pin was then contoured to fit the curvature of the scapula, and the wires were passed through the scapula and tied over the Rush pin with bone graft. The mean age of the patients was 30 years (range, 22-39 years), with a mean follow-up of 49 months. The mean increase in elevation was 18 degrees with significant pain relief. The medium-term results showed that this operation was successful in achieving stability of the scapula while improving pain and function in patients without facioscapulohumeral dystrophy.     

Adapting low back pain guidelines within a multidisciplinary context: a process evaluation

Rationale, aims and objectives The Alberta Ambassador Program (AAP) adapted seven clinical practice guidelines on low back pain (LBP) into a single guideline spanning the continuum of care from prevention and diagnosis through to treatment. The Ambassador adaptation process was evaluated to

• 1 Identify the major challenges encountered and successful strategies utilized;
• 2 Assess strengths and weaknesses by benchmarking it with the ADAPTE framework; and
• 3 Identify opportunities for improvement.

Method External consultants reviewed the Ambassador and ADAPTE materials and conducted semi‐structured telephone interviews with 29 participants from the AAP committees. All participants were asked about the major challenges encountered and potential areas for improvement. Results The response rate was 83% (29/35). There was strong consensus that the Ambassador guideline adaptation process was sound and rigorous all respondents indicated willingness to participate in further iterations of the Program. Key elements of success were identified. The main steps and sequence of the process were closely aligned with the ADAPTE framework, although the AAP incorporated additional enhancements which augmented the process. The main divergences between the two frameworks centred on the organizational structure and the methods used to overcome methodological difficulties. Conclusion The AAP successfully utilized existing stakeholder interest to create an overarching guideline for managing LBP across multiple primary care disciplines. The study highlighted the strengths and weaknesses of the Program, and identified practical strategies for improvement. Evaluating guideline adaptation processes is pivotal to ensuring that they continue to be an efficient, rigorous and practicable option for producing contextualized, clinically relevant guidelines.