Practice variation in opioid prescribing for non-cancer pain in Dutch primary care: A retrospective database study.

BACKGROUND: Prescription opioid use has increased steadily in many Western countries over the past two decades, most notably in the US, Canada, and most European countries, including the Netherlands. Especially the increasing use of prescription opioids for chronic non-cancer pain has raised concerns. Most opioids in the Netherlands are prescribed in general practices. However, little is known about variation in opioid prescribing between general practices. To better understand this, we investigated practice variation in opioid prescribing for non-cancer pain between Dutch general practices. METHODS: Data from 2017-2019 of approximately 10% of all Dutch general practices was used. Each year included approximately 1000000 patients distributed over approximately 380 practices. The primary outcome was the proportion of patients with chronic (>90 days) high-dose (≥90 oral morphine equivalents) opioid prescriptions. The secondary outcome was the proportion of patients with chronic (<90 oral morphine equivalents) opioid prescriptions. Practice variation was expressed as the ratio of the 95th/5th percentiles and the ratio of mean top 10/bottom 10. Funnel plots were used to identify outliers. Potential factors associated with unwarranted variation were investigated by comparing outliers on practice size, patient neighbourhood socioeconomic status, and urbanicity. RESULTS: Results were similar across all years. The magnitude of variation for chronic high-dose opioid prescriptions in 2019 was 7.51-fold (95%/5% ratio), and 15.1-fold (top 10/bottom 10 ratio). The percentage of outliers in the funnel plots varied between 13.8% and 21.7%. Practices with high chronic high-dose opioid prescription proportions were larger, and had more patients from lower income and densely populated areas. CONCLUSIONS: There might be unwarranted practice variation in chronic high-dose opioid prescriptions in primary care, pointing at possible inappropriate use of opioids. This appears to be related to socioeconomic status, urbanicity, and practice size. Further investigation of the factors driving practice variation can provide target points for quality improvement and reduce inappropriate care and unwarranted variation.

The societal burden of HIV/AIDS in Northern Italy: an analysis of costs and quality of life.

This study aims to measure the direct and indirect costs of HIV/AIDS care and quality of life (QoL) of HIV-infected patients in Northern Italy. We conducted a prospective cohort study over 12 months, enrolling a sample of 121 patients with HIV infection from two cities in Northern Italy. Patients were surveyed at baseline and were followed-up at 6 and 12 months. To assess the relationship between costs and stage of disease, patients were categorized into three groups at baseline: "No HAART" (asymptomatic and never before on highly active antiretroviral therapy (HAART)), "Stable HAART" (HAART with mild HIV infection and no prior opportunistic infections) and "HAART failure" (primary HAART regimen was altered because of severe side effects or immunological failure). Direct medical costs were based on utilization of (day) hospital admissions, diagnostic procedures, laboratory tests, clinic visits, consultations and antiretroviral drug use. Indirect costs included production losses due to absence from work, reduced productivity at work and reduced unpaid labour participation. QoL was assessed by visual analogue scale. Parametric regression was used to estimate the expected value and the standard deviation of annual costs per patient. The expected value of total annual costs was 1818 euros and 9820 euros and 12,332 euros, for groups "No HAART", "Stable HAART" and "HAART failure" respectively. We estimated annual expected earnings as 14,994 euros and 10,811 euros and 9820 euros for the same respective groups. The expected value of QoL on a scale of 0-1 in these same patient groups was 0.80, 0.78 and 0.64. We conclude that indirect costs contribute substantially to total costs and are comparable in magnitude to the direct costs excluding antiretroviral drugs. The costs of inpatient care in our cohort were almost negligible compared to total costs. Despite being in treatment, many patients were still gainfully employed and generated substantial expected annual earnings.

QTc prolongation during erythromycin used as prokinetic agent in ICU patients.

BACKGROUND: High-dose erythromycin used as antibiotic prolongs QTc interval. Low-dose erythromycin is frequently used as a prokinetic agent, especially in patients in the intensive care unit (ICU). It is unknown whether low-dose erythromycin affects cardiac repolarisation and puts patients at risk for torsades de pointes. METHODS: In this prospective study, we included ICU patients treated with erythromycin as prokinetic in a dose of 200 mg twice a day. An ECG was performed before, 15 min and 24 hours after the start of erythromycin. Cardiac repolarisation was assessed by rate-corrected analysis of the QT interval (QTc) on the ECG by two independent investigators. Starting or stopping other possibly QTc prolonging drugs during the study period was an exclusion criterion. Wilcoxon signed-rank test and Friedman's test were used for statistical analysis to assess prolongation of QTc. Primary outcome was defined by the prolongation of QTc after 15 min and 24 hours. RESULTS: 51 patients were eligible for this study. In these patients, QTc increased significantly from 430 ms at baseline to 439 ms (p=0.03) after 15 min and 444 ms (p=0.01) after 24 hours. After 15 min and 24 hours, the upper limit of 95% CI for prolongation of QTc was well above 10 ms. No QTc-related arrhythmias were seen. CONCLUSIONS: During treatment with erythromycin in a dose of 200 mg twice a day. QTc prolonged mildly but significantly. Sequential ECG registration should be performed when low-dose erythromycin is prescribed, especially in the presence of other risk factor for QTc prolongation.

[Proton pump inhibitors: not as safe as they seem]. / Protonpompremmers: niet zo veilig als ze lijken.

- Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. However, some patients use them without a good indication.- Although PPIs are generally safe, there is an increasing number of signals of potentially serious side effects.- This article gives an overview of the incidence and prevalence of the following side effects: gastroenteritis, respiratory tract infections, hypomagnesaemia, renal function disorders, vitamin B12 and iron deficiency, dementia, osteoporosis and fractures.- It is important to prescribe a PPI only when there is a good indication for use. Patients with chronic PPI use should be checked periodically to see whether there is still an indication.- If any of the listed side effects should occur, it is advisable to consider PPI as a possible cause.

Discounting health effects in pharmacoeconomic evaluations: current controversies.

Currently, much debate still surrounds the discounting of health effects. Most general consensus statements have argued for the same discount rate for health and money; however, this practice has been questioned by several authors. The choice of discount rate can have varying effects on interventions, depending on the disease area. In this paper, we review two major current controversies around discounting: the use of similar or differential discount rates for health and money; and the validity of the underlying discounting model (time preference, constant discounting and the use of aggregated utilities for health effects). Various arguments justify a different rate of discounting for health effects than for money. Empirical evidence questions the validity of the constant discounting model, pointing out that time preference is not constant and should not be applied as such. Also, the validity of the aggregated utility model for health might be questioned, implying that a life cannot simply be cut into life years as single entities that are discounted back to the net present value. Such debates have led to varying methodologies being employed in economic evaluations, causing difficulties in their interpretation. Although there is sufficient evidence to question the use of similar discount rates for health and money, currently there is not enough information on the nature of the different processes that constitute discounting to reach a solid conclusion on the use of a different method. The lack of consensus on one of the most important topics in pharmacoeconomics makes the case for a more restricted use of cost-effectiveness or cost-utility ratios than as the most important singular outcome of pharmacoeconomic studies. Instead, results should be presented in a non-aggregated manner that enables policy makers to value health gains according to timing and to which subpopulation they are accrued in.

Cost-effectiveness of HIV screening of patients attending clinics for sexually transmitted diseases in Amsterdam.

OBJECTIVE: To estimate the cost-effectiveness of universal HIV screening of patients attending a clinic for sexually transmitted diseases (STD) in Amsterdam. DESIGN: Cost effectiveness analysis. METHODS: A Bernoulli model for the secondary transmission of HIV was linked with epidemiological data on infection with HIV and other STD in patients attending a STD clinic in Amsterdam from 1991 to 1997. This gave estimates of the number of secondary HIV infections caused by attenders of the STD clinic. Combined with data on the health and monetary benefits of averting HIV infection and costs of HIV screening, we assessed the cost-effectiveness of HIV-screening of attenders of the STD clinic. RESULTS: Increased risk for HIV infection was found in STD clinic attendees infected with other STD. (odds ratio, 2.07). The risk differed for specific STD: the highest odds ratios were found for syphilis and gonorrhoea. Screening of all attendees was estimated at net costs of 82,552 Euro per secondary infection averted. The cost-effectiveness ranges between 680 Euro and 9335 Euro per life-year gained, depending on the value of key parameters used in the model. CONCLUSION: Compared to other interventions in infectious diseases control in the Netherlands, screening of STD clinic attendees for HIV has an acceptable cost-effectiveness.

The uptake and expression of the factor VIII and reporter genes by vascular cells.

The conditions and efficacy of transfection of vascular cells in primary culture using DEAE-dextran, calcium phosphate and lipofectin have been investigated using chloramphenicol acetyltransferase and luciferase as reporter genes. Subsequently factor VIII was expressed in endothelial and smooth muscle cells. Both reporter genes could be expressed after transfection of umbilical vein endothelial cells, umbilical artery smooth muscle cells and fibroblasts. The expression of both reporter genes in endothelial and smooth muscle cells was highest using lipofectin. After transfection of smooth muscle cells with both full-length and mutant factor VIII genes, factor VIII activity and antigen were secreted into the culture medium, the secretion remaining stable to serial cell passage. The secretion of factor VIII from transfected smooth muscle cells was confirmed by the immunoprecipitation of [35S]methionine labelled protein. Endothelial cells also were successfully transfected with the mutant factor VIII gene.

A voice-enabled, structured medical reporting system.

Kurzweil Applied Intelligence received a research grant from the National Institute of Standards and Technology (NIST) Advanced Technology Program to develop a prototype voice-enabled, structured medical reporting system. In typical usage, the physician dictates to the system, which then uses automatic speech recognition and medical knowledge bases to produce a structured report. This report can then be formatted and viewed on a computer screen, stored in databases of patient information, transmitted to other systems, used to support outcome studies, or viewed on a Web browser. The output reports are structured according to two standard, platform-independent formats: SGML and CORBA. These formats represent the data in a way that can be read by both computers and humans, and efficiently communicated to a wide range of databases and communications protocols.

The economics of HIV vaccines: projecting the impact of HIV vaccination of infants in sub-Saharan Africa.

OBJECTIVES: (i) To project vaccine parameters, economic consequences and market size associated with HIV-1 vaccination of infants in sub-Saharan Africa through the Expanded Program on Immunisation (EPI); and (ii) to assess threshold values for price and effectiveness. STUDY DESIGN AND METHODS: Cost-effectiveness analysis using a decision-analysis model linking epidemiological data with economic information. Epidemiological data on the burden of disease of HIV were obtained from the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS. The decision analysis model was constructed using estimates of lifetime chances of HIV infection. To assess threshold values for price and effectiveness, a maximum value for cost effectiveness in developing countries of $US100 was used in the base case. One-way and multivariate sensitivity analysis was performed on relevant parameters, assessing the impact of these parameters on the results of our analysis. In the base case, health benefits and consequences were discounted at a rate of 3%. STUDY PERSPECTIVE: Societal. RESULTS: According to our model, introduction of an HIV-1 vaccine in the EPI would result in the vaccination of 8717112 infants in sub-Saharan Africa per year. This corresponds to the prevention of 1839355 cases of HIV per year, gaining 16461800 disability-adjusted life years (DALYs). The cost-effectiveness ratio of the intervention would be $US3.4 per DALY gained (1998 values) at a vaccine price in the base case of $US5. At the same price the estimated size of the market would be approximately $US44536111 per year. CONCLUSION: If technological and financial problems associated with the development of an HIV vaccine can be solved, HIV vaccination in Africa could be both cost effective and potentially profitable.

Economic evaluation of influenza vaccination. Assessment for The Netherlands.

OBJECTIVE: The objective of this study was to determine the costs associated with influenza and the cost effectiveness (net costs per life-year gained) of influenza vaccination in The Netherlands. DESIGN AND SETTING: The economic evaluation comprised a cost-of-illness assessment and a cost-effectiveness analysis, both of which were conducted from the healthcare perspective in The Netherlands. The modelling framework for the economic evaluation linked epidemiological aspects of influenza (e.g. incidence, mortality, years of life lost) to vaccination coverage and healthcare resource use. Healthcare resource use was specified for hospitalisations, general practitioner visits and drugs. INTERVENTION: The intervention assessed in the cost-effectiveness analysis was influenza vaccination. MAIN OUTCOME MEASURES AND RESULTS: The costs of influenza were estimated to be 31 million euros (EUR) for the influenza season 1995/96 in The Netherlands (EUR1 approximately $US1.1). For the extended programme in 1997/98, i.e. all elderly people, the cost-effectiveness ratio was estimated at EUR1820 per life-year gained. Sub-group analysis demonstrated that the programme had a more favourable cost effectiveness among the chronically ill elderly population (cost saving) than among the rest of the elderly population (EUR6900 per life-year gained). CONCLUSION: Influenza vaccination has a cost-effectiveness ratio that is better than or comparable to that of other implemented Dutch programmes in the prevention of infectious diseases.

Traffic accident reduction by monitoring driver behaviour with in-car data recorders.

People who are aware of being observed tend to modify their behaviour. This phenomenon could potentially be used to encourage individuals to behave more safely when driving if there were means of providing feedback to the drivers about their behaviour on the road. So-called 'vehicle data recorders' offer such a means of providing behavioural feedback by confronting drivers with their recorded driving actions. A field trial of a 'matched experimental/control group design with intervention' was planned with the objective of investigating whether this feedback mechanism would reduce the number of road traffic accidents in everyday driving conditions. In the study, seven experimental vehicle fleets were involved, which varied widely in terms of the kind of transport sector concerned, the type of vehicles used, and the traffic circumstances in which the vehicles are operated. Each fleet was matched with at least one control vehicle fleet, taking into account those relevant traffic safety characteristics. In total, accident and exposure data were collected for 840 vehicles of which 270 equipped with a recorder. During an observation period representing a total of about 3,100 vehicle years, these vehicles were involved in 1,836 road accidents. Analysis of the effects of the use of data recorders in these fleets resulted in an average estimated accident reduction of some 20%. The analysis shows that the actual savings vary depending on the transport sector involved and on the prior level of the fleet's safety record. Further studies are needed to identify the more promising application of such a use of traffic data recorders as a means of reducing road accidents.

Calcium channel blockers in the management of preterm labor and hypertension in pregnancy.

Calcium channel blockers (CCBs) have the ability to inhibit contractility in smooth muscle cells. CCBs have an already established role in the treatment of non-pregnant hypertension and angina pectoris. Some epidemiological studies found an association between the use of CCBs and an increase in cardiovascular mortality, malignancy, and gastrointestinal bleeding. More recent studies with many more patients and a longer follow-up did not find these associations. In obstetrics CCBs have become increasingly popular for the management of preterm labor and pregnancy-induced hypertensive disorders. Meta-analysis shows that use of nifedipine in comparison with betamimetics is associated with a more frequent successful prolongation of pregnancy in case of preterm labor, resulting in significantly fewer admissions of newborns to the neonatal intensive care unit (NICU), and is associated with a lower incidence of respiratory distress syndrome. No adverse fetal side effects in humans have been reported with the use of nifedipine for obstetric indications. Nifedipine is an effective and safe drug to use when tocolytic therapy is indicated for preterm labor. In preeclampsia nifedipine effectively lowers blood pressure and can be a good alternative for (di) hydralazine.

Using cluster random assignment to measure program impacts. Statistical implications for the evaluation of education programs.

This article explores the possibility of randomly assigning groups (or clusters) of individuals to a program or a control group to estimate the impacts of programs designed to affect whole groups. This cluster assignment approach maintains the primary strength of random assignment--the provision of unbiased impact estimates--but has less statistical power than random assignment of individuals, which usually is not possible for programs focused on whole groups. To explore the statistical implications of cluster assignment, the authors (a) outline the issues involved, (b) present an analytic framework for studying these issues, and (c) apply this framework to assess the potential for using the approach to evaluate education programs targeted on whole schools. The findings suggest that cluster assignment of schools holds some promise for estimating the impacts of education programs when it is possible to control for the average performance of past student cohorts or the past performance of individual students.

The use of health economics to guide drug development decisions: Determining optimal values for an RSV-vaccine in a model-based scenario-analytic approach.

Health-economic modelling is useful for assessing the clinical requirements and impact of new vaccines. In this study, we estimate the impact of potential vaccination for respiratory syncytial virus (RSV) of infants in the Netherlands. A decision analysis model was employed using seasonal data from a cohort of children (1996-1997 through 1999-2000) to assess hospitalisation, costs and impact of vaccination. Yearly, an estimated 3670 infants are hospitalised with RSV-infection in the Netherlands, vaccination protecting infants from 3 months of life onwards could prevent approximately 1000-3000 hospitalisations, depending on the effectiveness of the potential vaccine. Additionally, vaccination could prevent a major share of RSV-related costs. Comparison of the calculated break-even prices with the average price of recently introduced vaccines indicates that pricing for a potential RSV-vaccine most likely allows for only a single dose vaccination or several doses at a relatively low price per dose in order to achieve cost savings. However, if evidence on relevant RSV-related mortality would become available, higher pricing would be justified, while still remaining below accepted thresholds for cost-effectiveness.

Enhanced decision support for policy makers using a web interface to health-economic models--illustrated with a cost-effectiveness analysis of nation-wide infant vaccination with the 7-valent pneumococcal conjugate vaccine in the Netherlands.

We have developed a web-based user-interface (web interface) to enhance the usefulness of health-economic evaluations to support decision making (http://pcv.healtheconomics.nl). It allows the user to interact with a health-economic model to evaluate predefined and customized scenarios and perform sensitivity analysis. To explore its usefulness, it was applied to an evaluation of cost-effectiveness of nation-wide infant vaccination with the 7-valent pneumococcal conjugate vaccine (PCV7), that was used to support a policy decision on the inclusion of PCV7 in the national vaccination program (NVP) of the Netherlands. We used a decision-tree analytic model to project the impact of infant vaccination with four doses of PCV7 on an annual cohort of infants born in the Netherlands. The base-case analysis includes the beneficial effects on unvaccinated individuals (herd protection). Additional scenarios varying the number of doses, discount rate for effects and the number of serotypes in the vaccine were evaluated and can be analysed on the web. Our model projects a base-case incremental cost-effectiveness ratio (iCER) of euro14,000 (95% uncertainty interval (UI): 9,800-20,200) per quality adjusted life year (QALY) or euro15,600 (95% UI: 11,100-23,900) per life year gained (LYG).

Distribution of motor unit potential velocities in short static and prolonged dynamic contractions at low forces: use of the within-subject's skewness and standard deviation variables.

Behaviour of motor unit potential (MUP) velocities in relation to (low) force and duration was investigated in biceps brachii muscle using a surface electrode array. Short static tests of 3.8 s (41 subjects) and prolonged dynamic tests (prolonged tests) of 4 min (30 subjects) were performed as position tasks, applying forces up to 20% of maximal voluntary contraction (MVC). Four variables, derived from the inter-peak latency technique, were used to describe changes in the surface electromyography signal: the mean muscle fibre conduction velocity (CV), the proportion between slow and fast MUPs expressed as the within-subject skewness of MUP velocities, the within-subject standard deviation of MUP velocities [SD-peak velocity (PV)], and the amount of MUPs per second (peak frequency=PF). In short static tests and the initial phase of prolonged tests, larger forces induced an increase of the CV and PF, accompanied with the shift of MUP velocities towards higher values, whereas the SD-PV did not change. During the first 1.5-2 min of the prolonged lower force levels tests (unloaded, and loaded 5 and 10% MVC) the CV and SD-PV slightly decreased and the MUP velocities shifted towards lower values; then the three variables stabilized. The PF values did not change in these tests. However, during the prolonged higher force (20% MVC) test, the CV decreased and MUP velocities shifted towards lower values without stabilization, while the SD-PV broadened and the PF decreased progressively. It is argued that these combined results reflect changes in both neural regulatory strategies and muscle membrane state.

Pharmacoeconomic evaluation of intensified antiretroviral treatment strategies in HIV/AIDS.

There have been great technological advances in the use of antiretroviral therapies to slow down disease progression in HIV/AIDS. Combinations of therapeutics and the use of several diagnostic methods have resulted in both declines in mortality and the occurrence of opportunistic infections. The higher costs of these therapeutics have prompted questions about the economic aspects of treatment with antiretrovirals. In this review, we provide an overview of the research that has been published on this topic and list the important outcomes and methodological issues associated with the different therapies.

Cutaneous responses to smallpox revaccination with calf lymph and the effect of fluorocarbon purification of the vaccine.

For several years the routine smallpox revaccination procedures at a central inoculation unit were arranged to assess the relation between vaccine titre (pock count) and success. Calf lymph batches were applied, diluted and undiluted, over a log titre range of 7.0-9.8. The dose-effect relationship did not appear to fit a linear equation on a log-probit scale, except in the lower part of the titre range. Plotted on this scale, the take rates of nearly all vaccine specimens of the required strength (> 10(8) PFU/ml) were lower than anticipated by linear extrapolation from low titres. Differences between batches were noted. These findings relate to pulp processing without purification. Fluorocarbon extraction of the calf skin harvest resulted in a 4-fold increase of vaccine volume with commensurate virus dilution; it also gave clearly higher take rates than parallel nonpurified vaccine specimens, whether at original strength or at 4-fold dilution.

Health economics of a hexavalent meningococcal outer-membrane vesicle vaccine in children: potential impact of introduction in the Dutch vaccination program.

The cost-effectiveness of universal vaccination of infants with a new hexavalent meningococcal B outer-membrane vesicle vaccine is projected for The Netherlands by applying decision analysis. The societal perspective is taken and direct and productivity costs (friction costs method) are considered. Future costs and effects are discounted at 4% (base year 1998). In this simulation model, vaccination would prevent 19 deaths and eight cases with severe long-term sequelae per year, rendering 526 additional quality adjusted life years (QALYs) per year. Yearly costs of acute phase of illness due to meningococcal infections in children are estimated at 1,426,634, while the future costs due to sequelae are estimated at 3,801,121 per year. Of all these costs, the vaccination program could prevent 3,334,052 per year. The program costs of meningococcal vaccination are estimated at 11,601,356, resulting in a cost-effectiveness ratio (CER) of 15,721 per QALY. These results are sensitive to the vaccine dose price (conservatively estimated at 10), efficacy, and coverage of meningococcal sero-subtypes.