The need for cost-effectiveness analyses of antimicrobial stewardship programmes: A structured review

The cost effectiveness of antimicrobial stewardship (AMS) programmes was reviewed in hospital settings of Organisation for Economic Co-operation and Development (OECD) countries, and limited to adult patient populations. In each of the 36 studies, the type of AMS strategy and the clinical and cost outcomes were evaluated. The main AMS strategy implemented was prospective audit with intervention and feedback (PAIF), followed by the use of rapid technology, including rapid polymerase chain reaction (PCR)-based methods and matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology, for the treatment of bloodstream infections. All but one of the 36 studies reported that AMS resulted in a reduction in pharmacy expenditure. Among 27 studies measuring changes to health outcomes, either no change was reported post-AMS, or the additional benefits achieved from these outcomes were not quantified. Only two studies performed a full economic evaluation: one on a PAIF-based AMS intervention; and the other on use of rapid technology for the selection of appropriate treatment for serious Staphylococcus aureus infections. Both studies found the interventions to be cost effective. AMS programmes achieved a reduction in pharmacy expenditure, but there was a lack of consistency in the reported cost outcomes making it difficult to compare between interventions. A failure to capture complete costs in terms of resource use makes it difficult to determine the true cost of these interventions. There is an urgent need for full economic evaluations that compare relative changes both in clinical and cost outcomes to enable identification of the most cost-effective AMS strategies in hospitals.

The clinical effectiveness and cost-effectiveness of exercise referral schemes: A systematic review and economic evaluation

- Background Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. - Objective To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. - Data sources MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. - Methods Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. - Results Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. - Limitations We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. - Conclusions There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. - Funding The National Institute for Health Research Health Technology Assessment programme.

Study of sleep and evaluation of sumatriptan and rizatriptan in the acute treatment of migraine in children and adolescents

Migraine is a common disease in children and adolescents, affecting roughly 10% of school-aged children. Recent studies have revealed an increasing incidence of childhood migraine, but migraine remains an underrecognized and undertreated condition in the pediatric population. Migraine attacks are painful and disabling and can affect a child´s life in many ways. Effective drug treatment is usually needed. The new migraine drugs, triptans, were introduced at the beginning of the 1990s and have since been shown to be very effective in the treatment of migraine attacks in adults. Although they are widely used in adults, the acute treatment of migraine in children and adolescents is still based on paracetamol and nonsteroidal anti-inflammatory drugs. Some children can control their attacks satisfactorily with simple analgesics, but at least one-third need more powerful treatments. When this thesis work commenced, hardly any information existed on the efficacy and safety of triptans in children. The study aim of the thesis was to identify more efficient treatments of migraine for children and adolescents by investigating the efficacy of sumatriptan nasal spray and oral rizatriptan compared with placebo in them. Sleep has an impact on migraine in many aspects. Despite the clinical relevance and common manifestation of sleep in the context of migraine in children, very little research data on the true frequency of sleep exist. As sleeping is so often related to childhood migraine, it can be a confounding factor in clinical drug trials of migraine treatments in children and adolescents. How the results of a sleeping child should be analyzed is under continual debate. The aim of the thesis was also to clarify this as well as to evaluate the frequency of sleeping during migraine attacks in children and factors affecting frequency. Both nasal sumatriptan and oral rizatriptan were effective (superior to placebo), and well tolerated in treatment of migraine attacks in children and adolescents aged 8-17 and 6-17 years, respectively. No serous adverse effects were observed. The results of this work suggest that nasal sumatriptan 20 mg and rizatriptan 10 mg can be effectively and safely used to treat migraine attacks in adolescents aged over 12 years if more effective drugs than NSAIDs are needed. No difference was observed in efficacy or safety of nasal sumatriptan and rizatriptan between children aged younger than 12 years and older children, but because the treated number of patients under 12 years is still small, more studies are needed before sumatriptan or rizatriptan can be recommended for use in this population. Sleeping during migraine attacks was very common, and most children at least occasionally slept during an attack. Falling asleep was especially common in children under eight years of age and during the first hour after the onset of attack. Children who were able to sleep soon after attack onset were more likely pain-free at two hours. Sleeping probably both improves recovery from a migraine attack and is a sign of headache relief. Falling asleep should be classified as a sign of headache relief in clinical drug trials when studying migraine treatments in children and adolescents.

A Critical Evaluation of the MARS Treatment in Finland

The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal albumin dialysis device which is used in the treatment of liver failure patients. This treatment was first utilized in Finland in 2001, and since then, over 200 patients have been treated. The aim of this thesis was to evaluate the impact of the MARS treatment on patient outcome, the clinical and biochemical variables, as well as on the psychological and economic aspects of the treatment in Finland. This thesis encompasses 195 MARS-treated patients (including patients with acute liver failure (ALF), acute-on-chronic liver failure (AOCLF) and graft failure), and a historical control group of 46 ALF patients who did not undergo MARS. All patients received a similar standard medical therapy at the same intensive care unit. The baseline data (demographics, laboratory and clinical variables) and MARS treatment-related and health-related quality-of-life data were recorded before and after treatment. The direct medical costs were determined for a period of 3.5 years.Additionally, the outcome of patients (survival, native liver recovery and need for liver transplantation) and survival predicting factors were investigated. In the outcome analysis, for the MARS-treated ALF patients, their 6-month survival (75% vs. 61%, P=0.07) and their native liver recovery rate (49% vs. 17%, P<0.001) were higher, and their need for transplantations was lower (29% vs. 57%, P= 0.001) than for the historical controls. However, the etiological distribution of the ALF patients referred to our unit has changed considerably over the past decade and the percentage of patients with a more favorable prognosis has increased. The etiology of liver failure was the most important predictor of the outcome. Other survival predicting factors in ALF included hepatic encephalopathy, the coagulation factors and the liver enzyme levels prior to MARS treatment. In terms of prognosis, the MARS treatment of the cirrhotic AOCLF patient seems meaningful only when the patient is eligible for transplantation. The MARS treatment appears to halt the progression of encephalopathy and reduce the blood concentration of neuroactive amino acids, albumin-bound and water-soluble toxins. In general, the effects of the MARS treatment seem to stabilize the patients, thus allowing additional time either for the native liver to recover, or for the patients to endure the prolonged waiting for transplantation. Furthermore, for the ALF patients, the MARS treatment appeared to be less costly and more cost-efficient than the standard medical therapy alone. In conclusion, the MARS treatment appears to have a beneficial effect on the patient outcome in ALF and in those AOCLF patients who can be bridged to transplantation.

Guided respiration mindfulness therapy: Development and evaluation of a brief therapist training program

The present paper describes the development and evaluation of a standardized multi-component therapist training program in guided respiration mindfulness therapy (GRMT). GMRT is a manual-based, experimental clinical intervention involving concentrated focus on sustained self-regulation of breathing, application of mindfulness to emergent somatic experience and relaxation. Therapists (n = 61) new to the approach attended a 2-day experiential workshop and were evaluated pre-post workshop for change in intervention knowledge, as well as change in mindfulness. These trainees also participated in post-workshop focus group sessions to explore perception of the intervention. A subset of 40 therapists participated in a second training component, and 14 of these were rated for competent delivery of the intervention during participation in a clinical trial. During training, therapists personally received the treatment giving the opportunity to assess treatment session (n = 283) impact on sense of wellbeing. Results indicated a brief focused training program can equip therapists with basic knowledge and skills required to deliver the standardized manual-based treatment. Qualitative analysis of focus group sessions showed that therapists endorsed the intervention for clinical use and found it personally beneficial. This research provides a foundation for further evaluation of clinical effectiveness of the intervention.

Oncolytic Adenoviruses with Radiation Therapy for Treatment of Prostate Cancer

Prostate cancer is the most common cancer in males. Although many patients with localized disease can be cured with surgery and radiotherapy, advanced disease and especially castration resistant metastatic disease remains incurable, with a median life expectancy of less than 18 months. Oncolytic adenoviruses (Ads) are a new promising treatment against cancer due to their innate capacity to kill cancer cells. Viral replication in tumor cells leads to oncolysis and production of a multiplicity of new virions that are capable of further destroying cancerous tissue. Oncolytic Ads can be modified for tumor targeted infection and replication and be armed with therapeutic transgenes to maximize the oncolytic effect. Worldwide, clinical trials with oncolytic Ads have demonstrated good safety while the antitumor efficacy remains to be improved. Importantly, the best responses have been reported when oncolytic adenoviruses have been combined with standard cancer treatments, such as chemotherapy and radiation. Further, a challenge in many virotherapy approaches has been the monitoring of virus replication in vivo. Reporter genes have been extensively used as transgenes to evaluate the biodistribution of the virus and activity of specific promoters. However, these techniques are often limited to preclinical evaluation and not amenable to human use. The aim of the thesis was to find and develop new oncolytic Ads with maximum efficacy against metastatic, castration resistant prostate cancer and study them in vitro and in vivo combined to different forms of radiation therapy. Using combination therapy, we were aiming for better antitumor efficacy with reduced side effects. Capsid modified Ads for enhanced transduction were studied. Serotype 3 targeted chimera, Ad5/3, was found to have enhanced infectivity for prostate cancer and was used for developing new viruses for the study. Correlation between Ad-encoded marker peptide secretion and simultaneous viral replication was evaluated and the effects of radiotherapy on viral replication were studied in detail. We found that the repair of double strand breaks caused by ionizing radiation was inhibited by adenoviral proteins and led to autophagic cell death. Both subcutaneous models and intrapulmonary tumor models mimicking metastatic, aggressive disease were used in vivo. Virus efficacy was evaluated by intratumoral injections. Also, intravenous administration was evaluated to study the effectiveness in metastatic disease. Oncolytic adenovirus treatment led to significant tumor growth control and increased the survival rate of the mice. These results were further improved when oncolytic Ads were combined with radiation therapy. Oncolytic Ads expressing human sodium/iodide transporter (hNIS) as a transgene were evaluated for their oncolytic potency and for the functionality of hNIS in vitro and in vivo. Monitoring of viral replication was also assessed using different imaging modalities relative to clinical use. SPECT imaging of tumor-bearing mice was evaluated and combined with simultaneous CT-scanning to obtain important anatomical information on biodistribution, also in a three-dimensional form. It was shown that hNIS-expressing adenoviruses could harbour a bi-functional transgene allowing for localization and imaging of viral replication. Targeted radiotherapy was applied by systemic radioiodide administration and resulted in iodide accumulation into Ad-infected tumor. The combination treatment showed significantly enhanced antitumor efficacy in mice bearing prostate cancer tumors. In summary, the results presented above aim to provide new treatment modalities for castration resistant prostate cancer. Molecular insights were provided for better understanding of the benefits of combined radiation therapy and oncolytic adenoviruses, which will hopefully facilitate the translation of the approach into clinical use for humans.

PERFECT Stroke : PERFormance, Effectiveness, and Costs of treatment episodes in Stroke

Stroke is a major cause of death and disability, incurs significant costs to healthcare systems, and inflicts severe burden to the whole society. Stroke care in Finland has been described in several population-based studies between 1967 and 1998, but not since. In the PERFECT Stroke study presented here, a system for monitoring the Performance, Effectiveness, and Costs of Treatment episodes in Stroke was developed in Finland. Existing nationwide administrative registries were linked at individual patient level with personal identification numbers to depict whole episodes of care, from acute stroke, through rehabilitation, until the patients went home, were admitted to permanent institutional care, or died. For comparisons in time and between providers, patient case-mix was adjusted for. The PERFECT Stroke database includes 104 899 first-ever stroke patients over the years 1999 to 2008, of whom 79% had ischemic stroke (IS), 14% intracerebral hemorrhage (ICH), and 7% subarachnoid hemorrhage (SAH). A 18% decrease in the age and sex adjusted incidence of stroke was observed over the study period, 1.8% improvement annually. All-cause 1-year case-fatality rate improved from 28.6% to 24.6%, or 0.5% annually. The expected median lifetime after stroke increased by 2 years for IS patients, to 7 years and 7 months, and by 1 year for ICH patients, to 4 years 5 months. No change could be seen in median SAH patient survival, >10 years. Stroke prevalence was 82 000, 1.5% of total population of Finland, in 2008. Modern stroke center care was shown to be associated with a decrease in both death and risk of institutional care of stroke patients. Number needed to treat to prevent these poor outcomes at one year from stroke was 32 (95% confidence intervals 26 to 42). Despite improvements over the study period, more than a third of Finnish stroke patients did not have access to stroke center care. The mean first-year healthcare cost of a stroke patient was ~20 000 , and among survivors ~10 000 annually thereafter. Only part of this cost was incurred by stroke, as the same patients cost ~5000 over the year prior to stroke. Total lifetime costs after first-ever stroke were ~85 000 . A total of 1.1 Billion , 7% of all healthcare expenditure, is used in the treatment of stroke patients annually. Despite a rapidly aging population, the number of new stroke patients is decreasing, and the patients are more likely to survive. This is explained in part by stroke center care, which is effective, and should be made available for all stroke patients. It is possible, in a suitable setting with high-quality administrative registries and a common identifier, to avoid the huge workload and associated costs of setting up a conventional stroke registry, and still acquire a fairly comprehensive dataset on stroke care and outcome.

The effectiveness of infrainguinal percutaneous transluminal angioplasty in the treatment of critical limb ischaemia

Critical chronic lower limb ischaemia (CLI) is the most severe form of peripheral arterial disease. Even though the treatment of CLI has evolved during the last decade, CLI is still associated with considerable morbidity, mortality and a decreased quality of life, in addition to a large financial impact on society. ---- Bypass surgery has traditionally been considered the approach of choice to treat CLI patients in order to avoid amputation. However, there are increasing data on the efficacy of endovascular revascularization procedures, such as percutaneous transluminal angioplasty (PTA), to achieve good leg salvage rates as well. Data gathered on all the 2,054 CLI patients revascularized at the Helsinki University Central Hospital between 2000 and 2007 were retrospectively analyzed. This patient cohort was used to compare the results of infrainguinal PTA and bypass surgery as well as to investigate predictors of failure after PTA. This study showed that infrainguinal PTA and bypass surgery yielded rather similar results in terms of survival, amputation-free survival and freedom from any re-intervention. When the femoropoliteal segment was treated, leg salvage was significantly better in the bypass surgery group, whereas no significant difference was observed between the two treatment methods when the revascularization extended to the infrapopliteal segment. PTA resulted in a significantly lower freedom from surgical re-interventions when compared to surgical revascularization. In this study the most important predictors of poor outcome after PTA for CLI were cardiac morbidity, nonambulatory status upon hospital arrival, and gangrene as a manifestation of CLI. Thus, when feasible, PTA seems to be a valid alternative for bypass surgery in the treatment of CLI provided that active redo-surgery is utilized. The optimal revascularization strategy should always be sought for each CLI patient individually considering the clinical state of the leg, the occlusive lesions to be treated, co-morbidities, life-expectancy, and the availability of a suitable vein for bypass.

Performance evaluation of nonthermal plasma reactors for NO oxidation in diesel engine exhaust gas treatment

The discharge plasma-chemical hybrid process for NOinfinity removal from the flue gas emissions is an extremely effective and economical approach in comparison with the conventional selective catalytic reduction system. In this paper we bring out a relative comparison of several discharge plasma reactors from the point of NO removal efficiency. The reactors were either energized by ac or by repetitive pulses. Ferroelectric pellets were used to study the effect of pellet assisted discharges on gas cleaning. Diesel engine exhaust, at different loads; is used to approximately simulate the flue gas composition. Investigations were carried out at room temperature with respect to the variation of reaction products against the discharge power. Main emphasis is laid on the oxidation of NO to NO2, without reducing NOx concentration (i.e., minimum reaction byproducts), with least power consumption. The produced NO2 will be totally converted to N-2 and Na-2 SO4 using Na-2 SO3. The ac packed-bed reactor and pelletless pulsed corona reactor showed better performance, with minimum reaction products for a given power, when the NO concentration was low (similar to 100 ppm). When the engine load exceeds 50% (NO > 300 ppm) there was not much decrease in NO reduction and more or less all the reactors performed equally. The total operating cost of the plasma-chemical hybrid system becomes $4010/ton of NO, which is 1/3-1/5 of the conventional selective catalytic process.

Performance evaluation of nonthermal plasma reactors for NO oxidation in diesel engine exhaust gas treatment

The discharge plasma-chemical hybrid process for NO/sub x/ removal from the due gas emissions is an extremely effective and economical approach in comparison with the conventional selective catalytic reduction system. In this paper we bring out a relative comparison of several discharge plasma reactors from the point of NO removal efficiency. The reactors were either energized by AC or by repetitive pulses. Ferroelectric pellets were used to study the effect of pellet assisted discharges on gas cleaning. Diesel engine exhaust, at different loads, is used to approximately simulate the due gas composition. Investigations were carried out at room temperature with respect to the variation of reaction products against the discharge power. Main emphasis is laid on the oxidation of NO to NO/sub 2/, without reducing NOx concentration (i.e., minimum reaction byproducts), with least power consumption. The produced NO/sub 2/ will be totally converted to N/sub 2/ and Na/sub 2/SO/sub 4/ using Na/sub 2/SO/sub 3/. The AC packed bed reactor and pelletless pulsed corona reactor showed better performance, with minimum reaction products for a given power, when the NO concentration was low (/spl sim/100 ppm). At high engine loads (NO>300 ppm) there was not much decrease in NO/sub x/ reduction and more or less all the reactors performed equally. The paper discusses these observations in detail.

An Evaluation of the Effectiveness of a Charged Bilayered Conducting Fine Mesh as a Dust Filter

Aim: To develop a mesh meant to be mounted on a windowpane that will act as a barrier for dust, while allowing wind to pass freely. Materials and Methods: Two small metal meshes separated at 1 cm, connected to an electrostatic generator and holding opposite charges are used. A videographic analysis has been performed. Results: The charged bilayered mesh was able to prevent a large portion of dust from passing through. Conclusion: The device is a simple, economical, and reliable way of reducing the entry of dust into a room, easing the need for periodic cleaning, and thus creating a healthier environment for the inhabitants of the building. It also has potential space applications.

Evaluation of the Effectiveness of Representative Methods for Determining Young's Modulus and Hardness from Instrumented Indentation Data

The effectiveness of Oliver & Pharr's (O&P's) method, Cheng & Cheng's (C&C's) method, and a new method developed by our group for estimating Young's modulus and hardness based on instrumented indentation was evaluated for the case of yield stress to reduced Young's modulus ratio (sigma(y)/E-r) >= 4.55 x 10(-4) and hardening coefficient (n) <= 0.45. Dimensional theorem and finite element simulations were applied to produce reference results for this purpose. Both O&P's and C&C's methods overestimated the Young's modulus under some conditions, whereas the error can be controlled within +/- 16% if the formulation was modified with appropriate correction functions. Similar modification was not introduced to our method for determining Young's modulus, while the maximum error of results was around +/- 13%. The errors of hardness values obtained from all the three methods could be even larger and were irreducible with any correction scheme. It is therefore suggested that when hardness values of different materials are concerned, relative comparison of the data obtained from a single standard measurement technique would be more practically useful. It is noted that the ranges of error derived from the analysis could be different if different ranges of material parameters sigma(y)/E-r and n are considered.

Agricultural Best Management Practices and Treatment Wetlands in the Gabilan Watershed: Project Asessment and Evaluation Plan

Several local groups have come together for this project to addresses water quality concerns in the Gabilan Watershed – also known as the Reclamation Ditch Watershed (Fig. 1.1). These are Moss Landing Marine Laboratories (MLML), the Resource Conservation District of Monterey County (RCDMC), Central Coast Watershed Studies (CCoWS), Return of the Natives (RON), Community Alliance with Family Farmers (CAFF), and Coastal Conservation and Research (CC&R). The primary goal is to reduce non-point source pollution – particularly suspended sediment, nutrients, and pesticides – and thereby improve near-shore coastal waters of Moss Landing Harbor and the Monterey Bay. (Document contains 33 pages)