Reassessing the value of short-term mortality in sepsis: comparing conventional approaches to modeling

OBJECTIVE: Clinical trials of therapies for sepsis have been mostly unsuccessful in impacting mortality. This may be partly due to the use of insensitive mortality end points. We explored whether modeling survival was more sensitive than traditional end points in detecting mortality differences in cohorts of patients with sepsis. DESIGN: Patients were stratified into seven a priori defined paired subgroups that reflected high and low mortality risk according to known clinical risk factors. We fitted an exponential survival model to the high- and low-risk cohort of each subgroup, providing estimates of the rate of dying, long-term survival, and excess day 1 mortality. Mortality in the high- and low-risk cohorts in each subgroup was compared using model parameters, fixed-point mortality, and Kaplan-Meier survival analysis. SETTING: Eight intensive care units within a university teaching institution. PATIENTS: One hundred thirty patients with severe sepsis or suspected Gram-negative bacteremia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall mortality of the cohort was 58.5% at 28 days. The survival of the entire cohort was well described by an exponential model (r2 =.99). Modeling identified differences in high- and low-risk cohorts in five of the seven paired subgroups, while conventional end-points only detected differences in 2. CONCLUSIONS: Modeling survival was more sensitive than conventional end-points in identifying survival differences between high- and low-risk subgroups. We encourage further evaluation of modeling in the search for more sensitive mortality end points.     

Apparent frequency-dependent effect of clonidine on cardiac sympathetic transmission: the role of neuronal uptake

Decreases in spontaneous atrial period (tachycardia) were measured in atropinized guinea-pig isolated right atria in response to intramural sympathetic nerve stimulation. Electrical field pulses were applied only during the atrial refractory period to avoid arrhythmias. Responses to one to six field pulses delivered in a single refractory period were substantially reduced by clonidine (1-1000 nM), providing no evidence that the blocking action of this drug is frequency-dependent. Stimulus-response lines to one, two or four field pulses delivered as one field pulse per refractory period (1/1) were displaced to the right by clonidine (0.1 microM) such that 8, 16 and 32 field pulses were required to obtain responses equivalent to control. Stimulus-response lines to lower frequencies of field stimulation (one field pulse every 4 or 8 refractory periods) were lower in slope and displaced further by clonidine, whereas lines from stimuli at higher frequencies (2/1 and 4/1) were steeper and less displaced by clonidine. These findings confirmed an "apparent" frequency-dependent blocking action of clonidine. However, substantial blockade of neuronal uptake by desipramine (0.1 microM) raised the slope and decreased the shift of the stimulus-response lines to the lower frequencies of field stimulation compared with 2/1 or 4/1. Clonidine (0.1 microM) had no effect on the responses to exogenous norepinephrine. We suggest that clonidine reduces the amount of norepinephrine released per field pulse independently of the frequency of stimulation. The decrease in tissue response may appear to be frequency-dependent under some circumstances due to the effects of uptake and removal processes.     

Hodgkin's disease: a population-adjusted clinical epidemiology study (PACE) of management at presentation. Northern Region Lymphoma Group

Between January 1991 and December 1993, all newly-diagnosed patients with Hodgkin's disease in the Northern Health Region (population 3.08 million) were entered into a prospective population-based (PACE) study to assess the accuracy of staging at diagnosis, and to evaluate treatment and outcome. On histological review, 202 patients were confirmed to have Hodgkin's disease, an incidence of 2.2 per 100,000 per annum. Radiological review revealed that only 12% of patients were staged to recognized guidelines. In early-stage disease, treatment outcome was comparable to published results in Stage IA disease, but disappointing for Stage IIA. This was partly due to inadequate or inaccurate staging. In-built audit in the process was followed by the introduction and implementation of improved guidelines. Of younger patients (15-55 years) with 'poor-risk disease', 75% of the eligible population were entered into the appropriate randomized controlled trial. This intensive treatment has led to improved survival in this group over that which might be expected on four-drug therapy. The results of the randomized trial are not discussed as it is currently ongoing. This combined research/audit programme has resulted in greater standardization of care across a whole region, and confirms that the PACE (population-adjusted clinical epidemiology) approach facilitates the flow of information from research into practice and vice versa.      

Hospital costs in patients receiving prolonged mechanical ventilation: does age have an impact?

BACKGROUND: The aging of the population is one of the causes of the increase in healthcare costs in the past few decades. It is controversial whether chronological age alone should be used in making healthcare decisions. OBJECTIVE: To determine the association between age and hospital costs in patients receiving mechanical ventilation (MV). DESIGN: Prospective, observational study. SETTING: Intensive care units at a teaching hospital. PATIENTS: A total of 813 adults who received prolonged (> or =48 hrs) mechanical ventilation. INTERVENTION: None. MEASUREMENTS: Severity of illness, comorbidities, length of stay, hospital costs, and mortality. We evaluated the independent association of age with hospital costs using linear regression. RESULTS: Mean (+/-sd) age of patients was 60.4 +/- 18.8 yrs. Median Acute Physiology Chronic Health Evaluation III score and probability of hospital death at intensive care unit admission were 64 and 0.31, respectively. Hospital mortality was 36%. Median total hospital costs and daily costs were $ 56,056 and $2,655 US dollars, respectively. Older age was associated with lower total hospital costs after controlling for sex, intensive care unit type, severity of illness, length of stay, insurance type, resuscitation status, and survival. Hospital costs were significantly less in older patients in all cost departments examined, except for respiratory care and intensive care unit room costs. CONCLUSIONS: Daily and total hospital costs were lower in older patients. Decreased hospital resource use in older patients may be related to a preference for less aggressive care by older patients and their families or by healthcare providers.     

Assessing the impact of training on mental health nurses' therapeutic attitudes and knowledge about co-morbidity: a randomised controlled trial

BACKGROUND: Substance misuse can trigger or be causally associated with mental health problems. Therapeutic attitude is important in predicting effective engagement with people with alcohol and drug problems but health professionals' attitudes towards this client group are often negative. Education regarding substance misuse has often been neglected and nurses may lack knowledge to provide appropriate care. OBJECTIVES: To test the impact of training for staff who work with people who have co-existing mental health and substance use problems. DESIGN: A randomised controlled trial. SETTING: An NHS Primary Care Division in the West of Scotland. PARTICIPANTS: Forty-nine mental health nurses. METHODS: Intervention. A four-day training programme. Measurements: (a) therapeutic attitudes measured by the co-morbidity problems perceptions questionnaire; (b) knowledge of alcohol, drugs and co-morbidity measured by a structured questionnaire. RESULTS: Significant effects for group (F=30.42, p<0.001) were found in therapeutic attitude scores and also over time (F=10.66, p<0.001). A significant interaction was also found (p<0.001). Post-hoc testing revealed that the mean pre-training attitude score was significantly different from post-training (p=0.001; 95% CI 5.53, 25.38) and from six-months follow-up (p<0.001; 95% CI 11.26, 32.49) but that post-training and follow-up mean scores were not significantly different (p=0.358; 95% CI -4.71, 17.55). For knowledge, a significant group effect was found (F=10.32, p=0.002), and also a significant time effect (F=3.35, p=0.039) but no significant interaction effect was present (p=0.169). The post-hoc testing revealed that only a pre-training to six-month follow-up time effect was statistically significant (p=0.005; 95% CI 1.37, 9.29). CONCLUSIONS: The training programme was effective in improving the therapeutic attitudes of participants to working with clients who have co-existing mental health and substance use problems, both immediately after the training was delivered, and at six-months follow-up. It was also effective in improving participants' overall knowledge of alcohol, drugs and co-morbidity.     

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.