High copper concentration reduces biofilm formation in Acidithiobacillus ferrooxidans by decreasing production of extracellular polymeric substances and its adherence to elemental sulfur.

Acidithiobacillus ferrooxidans is an acidophilic bacterium able to grow in environments with high concentrations of metals. It is a chemolithoautotroph able to form biofilms on the surface of solid minerals to obtain its energy. The response of both planktonic and sessile cells of A. ferrooxidans ATCC 23270 grown in elemental sulfur and adapted to high copper concentration was analyzed by quantitative proteomics. It was found that 137 proteins varied their abundance when comparing both lifestyles. Copper effllux proteins, some subunits of the ATP synthase complex, porins, and proteins involved in cell wall modification increased their abundance in copper-adapted sessile lifestyle cells. On the other hand, planktonic copper-adapted cells showed increased levels of proteins such as: cupreredoxins involved in copper cell sequestration, some proteins related to sulfur metabolism, those involved in biosynthesis and transport of lipopolysaccharides, and in assembly of type IV pili. During copper adaptation a decreased formation of biofilms was measured as determined by epifluorescence microscopy. This was apparently due not only to a diminished number of sessile cells but also to their exopolysaccharides production. This is the first study showing that copper, a prevalent metal in biomining environments causes dispersion of A. ferrooxidans biofilms. SIGNIFICANCE: Copper is a metal frequently found in high concentrations at mining environments inhabitated by acidophilic microorganisms. Copper resistance determinants of A. ferrooxidans have been previously studied in planktonic cells. Although biofilms are recurrent in these types of environments, the effect of copper on their formation has not been studied so far. The results obtained indicate that high concentrations of copper reduce the capacity of A. ferrooxidans ATCC 23270 to form biofilms on sulfur. These findings may be relevant to consider for a bacterium widely used in copper bioleaching processes.

A European multicentre evaluation of detection and typing methods for human enteroviruses and parechoviruses using RNA transcripts.

Polymerase chain reaction (PCR) detection has become the gold standard for diagnosis and typing of enterovirus (EV) and human parechovirus (HPeV) infections. Its effectiveness depends critically on using the appropriate sample types and high assay sensitivity as viral loads in cerebrospinal fluid samples from meningitis and sepsis clinical presentation can be extremely low. This study evaluated the sensitivity and specificity of currently used commercial and in-house diagnostic and typing assays. Accurately quantified RNA transcript controls were distributed to 27 diagnostic and 12 reference laboratories in 17 European countries for blinded testing. Transcripts represented the four human EV species (EV-A71, echovirus 30, coxsackie A virus 21, and EV-D68), HPeV3, and specificity controls. Reported results from 48 in-house and 15 commercial assays showed 98% detection frequencies of high copy (1000 RNA copies/5 µL) transcripts. In-house assays showed significantly greater detection frequencies of the low copy (10 copies/5 µL) EV and HPeV transcripts (81% and 86%, respectively) compared with commercial assays (56%, 50%; P = 7 × 10-5 ). EV-specific PCRs showed low cross-reactivity with human rhinovirus C (3 of 42 tests) and infrequent positivity in the negative control (2 of 63 tests). Most or all high copy EV and HPeV controls were successfully typed (88%, 100%) by reference laboratories, but showed reduced effectiveness for low copy controls (41%, 67%). Stabilized RNA transcripts provide an effective, logistically simple and inexpensive reagent for evaluation of diagnostic assay performance. The study provides reassurance of the performance of the many in-house assay formats used across Europe. However, it identified often substantially reduced sensitivities of commercial assays often used as point-of-care tests.

What Is Unfair about Unequal Brute Luck? An Intergenerational Puzzle.

According to Luck egalitarians, fairness requires us to bring it about that nobody is worse off than others where this results from brute bad luck, but not where they choose or deserve to be so. In this paper, I consider one type of brute bad luck that appears paradigmatic of what a Luck Egalitarian ought to be most concerned about, namely that suffered by people who are born to badly off parents and are less well off as a result. However, when we consider what is supposedly unfair about this kind of unequal brute luck, luck egalitarians face a dilemma. According to the standard account of luck egalitarianism, differential brute luck is unfair because of its effects on the distribution of goods. Yet, where some parents are worse off because they have chosen to be imprudent, it may be impossible to neutralize these effects without creating a distribution that seems at least as unfair. This, I argue, is problematic for luck egalitarianism. I, therefore, explore two alternative views that can avoid this problem. On the first of these, proposed by Shlomi Segall, the distributional effects of unequal brute luck are unfair only when they make a situation more unequal, but not when they make it more equal. On the second, it is the unequal brute luck itself, rather than its distributional effects, that is unfair. I conclude with some considerations in favour of this second view, while accepting that both are valid responses to the problem I describe.

Economic evaluation in chronic pain: a systematic review and de novo flexible economic model.

There is unmet need in patients suffering from chronic pain, yet innovation may be impeded by the difficulty of justifying economic value in a field beset by data limitations and methodological variability. A systematic review was conducted to identify and summarise the key areas of variability and limitations in modelling approaches in the economic evaluation of treatments for chronic pain. The results of the literature review were then used to support the development of a fully flexible open-source economic model structure, designed to test structural and data assumptions and act as a reference for future modelling practice. The key model design themes identified from the systematic review included: time horizon; titration and stabilisation; number of treatment lines; choice/ordering of treatment; and the impact of parameter uncertainty (given reliance on expert opinion). Exploratory analyses using the model to compare a hypothetical novel therapy versus morphine as first-line treatments showed cost-effectiveness results to be sensitive to structural and data assumptions. Assumptions about the treatment pathway and choice of time horizon were key model drivers. Our results suggest structural model design and data assumptions may have driven previous cost-effectiveness results and ultimately decisions based on economic value. We therefore conclude that it is vital that future economic models in chronic pain are designed to be fully transparent and hope our open-source code is useful in order to aspire to a common approach to modelling pain that includes robust sensitivity analyses to test structural and parameter uncertainty.

Direct healthcare costs of glaucoma treatment.

AIMS: To report the complete lifetime direct healthcare costs of glaucoma treatment in a database of 1136 patients attending the Glaucoma Clinic at Glasgow Royal Infirmary, Glasgow, UK. METHOD: The database was interrogated to identify all patients who had initiated treatment at the Glaucoma Clinic at Glasgow Royal Infirmary, and who had subsequently died of natural causes. The healthcare resource use based cost assessment was based on two aspects of the direct National Health Service cost: drug costs (prescribed medications) and non-drug costs (inpatient or outpatient/and surgical or procedure costs). RESULTS: 106 patients (53 men, 53 women) were identified for whom there were lifetime treatment data. The mean lifespan of the patients was 80.5 years, and the mean number of years attending the glaucoma clinic was 7.05 years (range 1-22 years). The mean cost of glaucoma treatment over the lifetime of the patients was £3001, with an annual mean cost per patient of £475. Non-drug and drug costs made up 66% and 34% respectively, of the lifetime costs. CONCLUSIONS: This is the only study to directly assess the lifetime treatment costs of glaucoma. Awareness of the costs of glaucoma treatment may be of increased importance in these financially challenging times.

Cost effectiveness of duloxetine in the treatment of fibromyalgia in the United States.

OBJECTIVE: To evaluate the cost effectiveness of duloxetine when considered as an alternative treatment for patients in the United States (US) being treated for fibromyalgia pain. RESEARCH DESIGN AND METHODS: A Markov model was used to evaluate the economic and clinical advantages of duloxetine in controlling fibromyalgia pain symptoms over a 2-year time horizon. A base-case treatment sequence was adopted from clinical guidelines, based on tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, anticonvulsants, and opioids. Treatment response was modeled using changes from baseline in pain severity, and response thresholds: full response (at least a 50% change), response (30-49% change), and no response (less than a 30% change). Clinical efficacy and discontinuation data were taken from placebo- and active-controlled trials identified in a systematic literature review and mixed-treatment comparison. Utility data were based on EQ-5D data. MAIN OUTCOME MEASURES: Additional symptom-control months (SCMs), defined as the amount of time at a response level of 30% or less, and quality-adjusted life-years (QALYs) over a 2-year time horizon. RESULTS: For every 1000 patients, first-line duloxetine resulted in an additional 665 SCMs and 12.3 QALYs, at a cost of $582,911 (equivalent to incremental cost-effectiveness ratios [ICERs] of $877 per SCM and $47,560 per QALY). Second-line duloxetine resulted in an additional 460 SCMs and 8.7 QALYs, at a cost of $143,752 (equivalent to ICERs of $312 per SMC and $16,565 per QALY). LIMITATIONS: Response data for TCAs are limited to 30% improvement levels, reported trials are small, and have low placebo response rates. The model necessarily assumes that response rates are independent of placement in the treatment sequence. CONCLUSIONS: The results suggest that the introduction of duloxetine into the standard treatment sequence for fibromyalgia not only provides additional patient benefits, reflected by time spent in pain control, but also is cost effective when compared with commonly adopted thresholds.

Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision.

SUMMARY: The cost-effectiveness of Fracture Liaison Services (FLSs) for prevention of secondary fracture in osteoporosis patients in the United Kingdom (UK), and the cost associated with their widespread adoption, were evaluated. An estimated 18 fractures were prevented and £21,000 saved per 1,000 patients. Setup across the UK would cost an estimated £9.7 million. INTRODUCTION: Only 11% to 28% of patients with a fragility fracture receive osteoporosis treatment in the UK. FLSs provide an efficient means to identify patients and are endorsed by the Department of Health but have not been widely adopted. The objective of this study was to evaluate the cost-effectiveness of FLSs in the UK and the cost associated with their widespread adoption. METHODS: A cost-effectiveness and budget-impact model was developed, utilising detailed audit data collected by the West Glasgow FLS. RESULTS: For a hypothetical cohort of 1,000 fragility-fracture patients (740 requiring treatment), 686 received treatment in the FLS compared with 193 in usual care. Assessments and osteoporosis treatments cost an additional £83,598 and £206,544, respectively, in the FLS; 18 fractures (including 11 hip fractures) were prevented, giving an overall saving of £21,000. Setup costs for widespread adoption of FLSs across the UK were estimated at £9.7 million. CONCLUSIONS: FLSs are cost-effective for the prevention of further fractures in fragility-fracture patients. The cost of widespread adoption of FLS across the UK is small in comparison with other service provision and would be expected to result in important benefits in fractures avoided and reduced hospital bed occupancy.

Cost effectiveness of duloxetine in the treatment of diabetic peripheral neuropathic pain in the UK.

OBJECTIVE: The objective of this analysis was to evaluate the cost-effectiveness of duloxetine when considered as an additional treatment option for UK-based patients suffering from diabetic peripheral neuropathic pain. RESEARCH DESIGN AND METHODS: A decision-analytic model was used to represent the sequential management of patients with diabetic peripheral neuropathic pain. The standard UK treatment strategy was defined as first-line tricyclic antidepressants (amitriptyline), second-line anticonvulsants (gabapentin) and lastly an opioid-related treatment. The cost-effectiveness of duloxetine was evaluated as an additional first, second, third or fourth-line therapy over a 6-month treatment period for a cohort of 1000 patients. Treatment response was modelled based on changes from baseline pain severity using a standard 11-point pain scale (0-10); full response (>or= 50% change), partial response (30-49%) and no response (< 30%). The model was populated with efficacy and discontinuation data using indirect comparisons of treatment efficacy based on relative effects to a common placebo comparator. RESULTS: The second-line use of duloxetine resulted in cost savings of pound 77,071 for every 1000 treated patients, with an additional 29 patients achieving a full pain response when compared to standard UK treatment. Additional quality-adjusted life years (QALYs) were achieved at 1.88 QALYs per 1000 patients. CONCLUSIONS: This UK-based economic model suggests that second-line use of duloxetine is a beneficial and cost-effective treatment strategy for diabetic peripheral neuropathic pain.

Treatments for spasticity and pain in multiple sclerosis: a systematic review.

OBJECTIVES: To identify the drug treatments currently available for the management of spasticity and pain in multiple sclerosis (MS), and to evaluate their clinical and cost-effectiveness. DATA SOURCES: Electronic bibliographic databases, National Research Register, MRC Clinical Trials Register and the US National Institutes of Health Clinical Trials Register. REVIEW METHODS: Systematic searches identified 15 interventions for the treatment of spasticity and 15 interventions for treatment of pain. The quality and outcomes of the studies were evaluated. Reviews of the treatment of spasticity and pain when due to other aetiologies were also sought. RESULTS: There is limited evidence of the effectiveness of four oral drugs for spasticity: baclofen, dantrolene, diazepam and tizanidine. Tizanidine appears to be no more effective than comparator drugs such as baclofen and has a slightly different side-effects profile. Despite claims that it causes less muscle weakness, there was very little evidence that tizanidine performed any better in this respect than other drugs, although it is more expensive. The findings of this review are consistent with reviews of the same treatments for spasticity derived from other aetiologies. There is good evidence that both botulinum toxin (BT) and intrathecal baclofen are effective in reducing spasticity, and both are associated with functional benefit. However, they are invasive, and substantially more expensive. None of the studies included in the review of pain were designed specifically to evaluate the alleviation of pain in patients with MS and there was no consistency regarding the use of validated outcome measures. It was suggested that, although expensive, the use of intrathecal baclofen may be associated with significant savings in hospitalisation costs in relation to bed-bound patients who are at risk of developing pressure sores, thus enhancing its cost-effectiveness. No studies of cost-effectiveness were identified in the review of pain. There is evidence, albeit limited, of the clinical effectiveness of baclofen, dantrolene, diazepam, tizanidine, intrathecal baclofen and BT and of the potential cost-effectiveness of intrathecal baclofen in the treatment of spasticity in MS. CONCLUSIONS: Many of the interventions identified are not licensed for the alleviation of pain or spasticity in MS and the lack of evidence relating to their effectiveness may also limit their widespread use. Indeed, forthcoming information relating to the use of cannabinoids in MS may result in there being better evidence of the effectiveness of new treatments than of any of the currently used drugs. It may therefore be of value to carry out double-blind randomised controlled trials of interventions used in current practice, where outcomes could include functional benefit and impact on quality of life. Further research into the development and validation of outcomes measures for pain and spasticity may also be useful, as perhaps would cost-utility studies.

Genotyping of measles and mumps virus strains using amplification refractory mutation system analysis combined with enzyme immunoassay: a simple method for outbreak investigations.

A simple method, based on a modification of the amplification refractory mutation system (ARMS), for genotyping outbreak strains of measles and mumps viruses and detecting these in a simple enzyme immunoassay (EIA) is described. Fifty-three measles strains circulating at the time of an outbreak in London in 2000 and 26 strains circulating at the time of a mumps outbreak in Accrington, UK, in 1999 were investigated. All strains were genotyped by direct sequencing. ARMS primers were then designed to amplify the outbreak strain. The ARMS-EIA for measles and mumps detected all 36 measles outbreak strains as genotype D6, and all 15 mumps outbreak strains as genotype F, respectively. The sensitivity and specificity of both the measles D6 and Mumps F genotype ARMS EIA was 100% compared with direct sequencing. The results show that ARMS-EIA can be used as a rapid alternative to genotyping by direct sequence analysis in outbreak situations.

Genetic diversity within populations of cyanobacteria assessed by analysis of single filaments.

We have developed a technique for determining the genetic structure of populations of filamentous cyanobacteria. The sequence diversity at specific gene loci is first characterised in a range of clonal cultures; subsequent analysis involves individual trichomes collected directly from natural populations. This technique has been used to examine the population genetic structure of Nodularia in the Baltic Sea and Planktothrix in Lake Zürich. For Nodularia, studies utilising four polymorphic loci reveal that even though there is a degree of linkage disequilibrium, horizontal transfer of genetic information has been sufficient to generate many of the possible allelic combinations. Analyses reveal both spatial and temporal variation in population genetic structure. Other studies of both Nodularia and Planktothrir have shown a correlation between particular alleles at the gvpC locus and the critical pressure of the gas vesicles that accumulate within the cell. We are now investigating how the natural selection of different gas vesicle phenotypes, imposed by changes in the depth of the upper mixed layer of the water column, affects the relative success of individual cyanobacteria possessing different gvpC alleles.

Characterization of measles virus strains causing SSPE: a study of 11 cases.

Eleven subacute sclerosing panencephalitis (SSPE) cases diagnosed in the UK between 1965 and 2000 were investigated. The entire or partial matrix (M), hemagglutinin (H), and nucleoprotein (N) genes of measles virus (MV) were sequenced following direct RT-PCR amplification from brain tissues. All the M genes showed the characteristic biased hypermutations and a premature termination codon was detected in 5/11 M sequences. Based on the more highly conserved H and N genes observed in persistent MV studies, phylogenetic analysis showed that two of three strains from patients likely to have acquired infection in the 1950s were related to clade C (WHO designation) and one appears to be a novel genotype. Three strains from patients infected in the 1960s and 1970s were clearly related to a MV strain isolated in 1974 belonging to genotype D1. Four strains from patients infected in the 1980s clustered with genotype D7 strains. One sequence from a patient infected in 1990s was identified as genotype D6. No vaccine strains were detected although five of these patients had been previously immunized. The sequence data obtained from these historic strains do not support the view that vaccine strains are associated with SSPE and provide valuable information for further studies of MV epidemiology, evolution, and pathogenesis in SSPE.

Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review.

Spasticity is a common disabling feature of multiple sderosis. A variety of drugs are in regular use as oral treatment induding badofen, dantrolene, tizanidine, and diazepam. Published evidence of effectiveness is limited. Most trials are of small size, of short duration, and have not reported on functional outcomes. Studies have been published which suggest that badofen, tizanidine, and diazepam are all effective in reducing dinical measures of spasticity, but there is little evidence that they lead to an improvement in patient function. There is no evidence to suggest any difference in effectiveness between them. The evidence that dantrolene has any effect on spasticity is of poor quality. Diazepam and dantrolene are associated with more side effects than baclofen and tizanidine. There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value. One randomized controlled trial of threonine does not support its effectiveness.

Expression of lux genes in a clinical isolate of Streptococcus pneumoniae: using bioluminescence to monitor gemifloxacin activity.

A clinical isolate of Streptococcus pneumoniae was transformed with a plasmid containing the lux operon of Photorhabdus luminescens that had been modified to function in gram-positive bacteria. Cells containing this plasmid produced light stably and constitutively, without compromising the growth rate. Light output was correlated with measurements of optical density and viable counts during exponential growth and provided a sensitive, real-time measure of the pharmacodynamics of the fluoroquinolone gemifloxacin.

Office-based arthroscopic synovectomy of the wrist in rheumatoid arthritis.

We present an office-based technique for performing arthroscopic synovectomy of the wrist in patients with rheumatoid arthritis. Intra-articular anesthesia as well as subcutaneous portal anesthesia are used. Standard portals are used in the radial carpal and midcarpal joints. Standard instrumentation is used and the synovectomy is accomplished using a motorized shaver. We performed 30 procedures in 21 patients: 15 complete synovectomies, 3 radioulnar carpal synovectomies because of only limited disease, and 12 limited synovectomies because these patients were participants in a clinical trial and required only limited synovectomy for investigational purposes. There were no complications. Office-based arthroscopic synovectomy of the wrist in patients with refractory rheumatoid arthritis can be performed safety and effectively. This technique is useful in both a clinical as well as a research setting.

Cost-effectiveness of high-dose chemotherapy in first-line treatment of advanced multiple myeloma.

The cost-effectiveness of high-dose chemotherapy in multiple myeloma was considered as part of a UK National Health Service Executive regional evidence-based appraisal process. The use of high-dose chemotherapy supported by autologous stem cell transplantation in patients under 65 years of age was shown to provide a marginal benefit of 0.7 life-years over conventional chemotherapy. This corresponded to an incremental cost 'per life-year gained' figure of approximately pound15 000, based upon initial treatment costs and trial-period data only. The use of high-dose chemotherapy in the first-line treatment of advanced multiple myeloma improves event-free and overall survival and appears to be a cost-effective treatment option.

Triaging patients with serious head injury: results of a simulation evaluating strategies to bypass hospitals without neurosurgical facilities.

OBJECTIVES: to inform the debate on whether seriously head-injured adult patients should be transported directly to the regional neurosurgical unit or indirectly after evaluation and stabilisation at the nearest hospital. DESIGN: a simulation model was constructed to compare triage strategies and to identify those that predicted the maximum survivors. In each strategy, an estimate of the patient's condition in the field was used to determine the receiving hospital. The model used data from previous publications and local ambulance service and hospital databases. In the absence of valid data, expert clinical estimates were made and subjected to sensitivity analyses. SETTING: an area in the North West Midlands of UK, covered by six acute hospitals including one with a regional neurosurgical unit. OUTCOME MEASURE: the number of survivors predicted by each triage strategy. RESULTS: five strategies were identified which consistently predicted the highest number of survivors. Compared with current policy it was predicted that in the North West Midlands, ten lives per year could be saved (6 per million total population per year). The results from sensitivity analyses did not alter these successful policies. CONCLUSION: the successful strategies should be considered as potential improvements to be introduced into clinical practice.

"Norwalk-like viruses". Public health consequences and outbreak management.

"Norwalk-like viruses" (NLVs) cause outbreaks of gastroenteritis and are spread frequently through contaminated food or water. Molecular diagnostics now enables detecting viruses in clinical and environmental specimens, linking of NLV strains causing outbreaks in multiple geographic locations, and tracing them to their sources in contaminated food or water. This report reviews recent advances in NLV detection and provides guidelines and recommendations for investigating NLV-related outbreaks, including specimen collection and disease prevention and control. This report also updates information provided in CDC's previously published, Viral Agents of Gastroenteritis: Public Health Importance and Outbreak Management (MMWR 1990;39 [No. RR-5]: 1-24). These CDC recommendations are intended for public health professionals who investigate outbreaks of acute gastroenteritis but could be useful in academic and research settings as well.