Economic Evaluation of Internet-Based Interventions for Harmful Alcohol Use Alongside a Pragmatic Randomized Controlled Trial

Background

Internet interventions with and without therapist support have been found to be effective treatment options for harmful alcohol users. Internet-based therapy (IT) leads to larger and longer-lasting positive effects than Internet-based self-help (IS), but it is also more costly to provide.

Objective

To evaluate the cost effectiveness and cost utility of Internet-based interventions for harmful use of alcohol through the assessment of the incremental cost effectiveness of IT compared with IS.

Methods

This study was performed in a substance abuse treatment center in Amsterdam, the Netherlands. We collected data over the years 2008–2009. A total of 136 participants were included, 70 (51%) were female, and mean age was 41.5 (SD 9.83) years. Reported alcohol consumption and Alcohol Use Disorders Identification Test (AUDIT) scores indicated harmful drinking behavior at baseline. We collected self-reported outcome data prospectively at baseline and 6 months after randomization. Cost data were extracted from the treatment center’s cost records, and sex- and age-specific mean productivity cost data for the Netherlands.

Results

The median incremental cost-effectiveness ratio was estimated at €3683 per additional treatment responder and €14,710 per quality-adjusted life-year (QALY) gained. At a willingness to pay €20,000 for 1 additional QALY, IT had a 60% likelihood of being more cost effective than IS. Sensitivity analyses attested to the robustness of the findings.

Conclusions

IT offers better value for money than IS and might therefore be considered as a treatment option, either as first-line treatment in a matched-care approach or as a second-line treatment in the context of a stepped-care approach.

Trial Registration

Netherlands Trial Register NTR-TC1155; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1155 (Archived by WebCite at http://www.webcitation.org/6AqnV4eTU)     

Diverging associations of an intended early invasive strategy compared with actual revascularization, and outcome in patients with non-ST-segment elevation acute coronary syndrome: the problem of treatment selection bias

AIMS: In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality. We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial. METHODS AND RESULTS: The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year follow-up and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37-0.96] and 0.46 (95% CI 0.31-0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70-1.74) for death and 1.27 (95% CI 0.88-1.85) for death or spontaneous MI. CONCLUSION: The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies.     

Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2)

Background:

Solute carriers (SLCs), in particular organic cation transporters (OCTs), have been implicated in the cellular uptake of platinum-containing anticancer compounds. The activity of these carriers may determine the pharmacokinetics and the severity of side effects, including neuro- and nephrotoxicity of platinum-based chemotherapy. As decreased drug accumulation is a key mechanism of platinum resistance, SLCs may also contribute to the development of resistance. Here, we define the role of hSLC22A2 (OCT2) in the cellular uptake of platinum compounds.

Experimental approach:

Human embryonic kidney (HEK) 293 cells stably expressing the hSLC22A2 gene (HEK293/hSLC22A2) were used in platinum accumulation studies. Following a 2 h exposure to various platinum compounds (100 µM), intracellular platinum levels were determined by flameless atomic absorption spectrometry.

Key results:

HEK293/hSLC22A2 cells, compared with HEK293/Neo control cells, displayed significant increases in oxaliplatin (28.6-fold), Pt[DACH]Cl₂ (20.6-fold), ormaplatin (8.1-fold), tetraplatin (4.5-fold), transplatin (3.7-fold) and cisplatin (1.3-fold), but not carboplatin. SLC22A2-mediated transport could be inhibited by 1-methyl-4-phenylpyridinium. Furthermore, hSLC22A2-mediated oxaliplatin and cisplatin accumulation was time- and concentration-dependent, but non-saturable. Expression of hSLC22A2 in HEK293 cells resulted in enhanced sensitivity to oxaliplatin (12-fold) and cisplatin (1.8-fold). Although, hSLC22A2 mRNA expression was frequently found in ovarian cancer cell lines, its expression in clinical ovarian cancer specimens (n= 80) was low and did not correlate with the treatment outcome of platinum-based regimens.

Conclusions and implications:

The hSLC22A2 drug transporter is a critical determinant in the uptake and cytotoxicity of various platinum compounds, particularly oxaliplatin.     

Continuous versus intermittent exercise effects on urinary excretion of albumin and total protein

Several studies have reported post-exercise increases of urinary concentrations of plasma proteins. However, under normal conditions, through mechanisms of size and electrical charge selection, the kidney restricts the clearance of molecules as large as albumin. Post-exercise increases in albuminuria occur following the physiological stress of intense exercise, most likely as a result of the exercise induced blood acidity changes which lead to a change in the arrangement of the albumin molecule, and subsequently the filtration characteristics of the glomerular capillary wall. The purpose of the present study was therefore to determine the extent to which different types of exercise could induce a transient condition of post-exercise increases in the urinary output of total protein and albumin. All 14 males, who agreed to participate in the study, performed a continuous and an intermittent cycling protocol on a stationary bicycle ergometer. The results showed that: a) intermittent exercise had a greater influence than continuous exercise on the total output of urine albumin, and of urine total protein; b) concentrations of blood pH and blood lactate, were associated with changes in the clearance of urine albumin and urine total protein. Post-exercise proteinuria response seems to be transient and therefore renal trauma is not suspected at the early stages of observation. Furthermore, these results indicate that the kidney undergoes distinct physiological adjustments during exercise, and that these adjustments are relative to the intensity of the exercise stress.     

Antimicrobial activities of pomegranate rind extracts: enhancement by addition of metal salts and vitamin C

Background

Uncomplicated chronic rachialgia is a highly prevalent complaint, and one for which therapeutic results are contradictory. The aim of the present study is to evaluate the effectiveness and safety of treatment with auriculopressure, in the primary healthcare sector, carried out by trained healthcare professionals via a 30-hour course.

Methods/Design

The design consists of a multi-centre randomized controlled trial, with placebo, with two parallel groups, and including an economic evaluation. Patients with chronic uncomplicated rachialgia, whose GP is considering referral for auriculopressure sensory stimulation, are eligible for inclusion. Sampling will be by consecutive selection, and randomised allocation to one of the two study arms will be determined using a centralised method, following a 1:1 plan (true auriculopressure; placebo auriculopressure). The implants (true and placebo) will be replaced once weekly, and the treatment will have a duration of 8 weeks. The primary outcome measure will be the change in pain intensity, measured on a visual analogue scale (VAS) of 100 mm, at 9 weeks after beginning the treatment. A follow up study will be performed at 6 months after beginning treatment. An assessment will also be made of the changes measured in the Spanish version of the McGill Pain Questionnaire, of the changes in the Lattinen test, and of the changes in quality of life (SF-12). Also planned is an analysis of cost-effectiveness and also, if necessary, a cost-benefit analysis.

Discussion

This study will contribute to developing evidence on the use of auriculotherapy using Semen vaccariae [wang bu liu xing] for the treatment of uncomplicated chronic rachialgia.

Trial registration

Current Controlled Trials ISRCTN01897462.     

Hutchinson-Gilford progeria syndrome: oral and craniofacial phenotypes

Objective:  Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene ( LMNA ) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include 'bird-like' facies, alopecia, craniofacial disproportion, and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS.
Methods:  Fifteen patients with confirmed p.G608G LMNA mutation (1–17 years, seven males, eight females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones, and dentition were identified.
Results:  Radiographic findings included hypodontia ( n  = 7), dysmorphic teeth ( n  = 5), steep mandibular angles ( n  = 11), and thin basal bone ( n  = 11). Soft tissue findings included ogival palatal arch ( n  = 8), median sagittal palatal fissure ( n  = 7), and ankyloglossia ( n  = 7). Calculated dental ages (9 months to 11 years 2 months) were significantly lower than chronological ages (1 year 6 months to 17 years 8 months) ( P  = 0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms.
Conclusion:  Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS.     

The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate

BACKGROUND AND PURPOSE

BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P₁ and S1P₅ receptors. S1P₁ receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data.

EXPERIMENTAL APPROACH

BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects.

KEY RESULTS

BAF312 effectively suppressed EAE in rats by internalizing S1P₁ receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4⁺ T cells, T_naïve, T_{central memory} and B cells within 4–6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P₃ receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia.

CONCLUSION AND IMPLICATIONS

This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.