Comparison of EQ-5D-3L with QLU-C10D in Metastatic Melanoma Using Cost-Utility Analysis.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) prefers the use of the generic EQ-5D instrument to estimate quality-adjusted life years (QALYs), and recommends that condition-specific instruments only be used when EQ-5D data are not available or not appropriate. OBJECTIVE: This study aimed to compare the utility gain and cost-effectiveness results of using the generic EQ-5D-3L instrument to the condition-specific Quality-of-Life Utility Measure-Core 10 dimensions (QLU-C10D) by applying both sets of values in a published cost-utility analysis (CUA) of immunotherapy for metastatic melanoma. METHODS: Quality-of-life data were drawn from a clinical study in which both QLQ-C30 and EQ-5D-3L tools were used. The potential influence of the two instruments on cost-effectiveness was assessed using a three-state Markov model. Descriptive statistics and standard health economic outputs were compared between analyses that applied the two different utility measures. RESULTS: Mean baseline utility values as measured by the QLU-C10D (mean = 0.744, SD = 0.219) were not statistically different (p > 0.05) compared to values derived from EQ-5D-3L (mean = 0.735, SD = 0.239). The two instruments were correlated (Pearson's correlation = 0.74); however, concordance was low (Lin's concordance correlation coefficient < 0.90) at baseline. The model predicted slightly higher QALYs gained when using EQ-5D-3L over QLU-C10D-derived utilities (1.87 vs 1.74, respectively). This resulted in an incremental cost-effectiveness ratio of US$30.5K when using EQ-5D-3L utilities, compared to US$32.7K when using QLU-C10D utilities. Cost-effectiveness acceptability curves based on the two sets of utilities were almost indistinguishable. CONCLUSION: This study supports the use of the generic EQ-5D instrument in immunotherapy treated metastatic melanoma, and found no additional benefit for using the disease-specific QLU-C10D when using Australian weights.

The Antarctic psychrophiles Chlamydomonas spp. UWO241 and ICE-MDV exhibit differential restructuring of photosystem I in response to iron.

Chlamydomonas sp. UWO241 is a psychrophilic alga isolated from the deep photic zone of a perennially ice-covered Antarctic lake (east lobe Lake Bonney, ELB). Past studies have shown that C. sp. UWO241 exhibits constitutive downregulation of photosystem I (PSI) and high rates of PSI-associated cyclic electron flow (CEF). Iron levels in ELB are in the nanomolar range leading us to hypothesize that the unusual PSI phenotype of C. sp. UWO241 could be a response to chronic Fe-deficiency. We studied the impact of Fe availability in C. sp. UWO241, a mesophile, C. reinhardtii SAG11-32c, as well as a psychrophile isolated from the shallow photic zone of ELB, Chlamydomonas sp. ICE-MDV. Under Fe-deficiency, PsaA abundance and levels of photooxidizable P700 (ΔA820/A820) were reduced in both psychrophiles relative to the mesophile. Upon increasing Fe, C. sp. ICE-MDV and C. reinhardtii exhibited restoration of PSI function, while C. sp. UWO241 exhibited only moderate changes in PSI activity and lacked almost all LHCI proteins. Relative to Fe-excess conditions (200 µM Fe2+), C. sp. UWO241 grown in 18 µM Fe2+ exhibited downregulation of light harvesting and photosystem core proteins, as well as upregulation of a bestrophin-like anion channel protein and two CEF-associated proteins (NdsS, PGL1). Key enzymes of starch synthesis and shikimate biosynthesis were also upregulated. We conclude that in response to variable Fe availability, the psychrophile C. sp. UWO241 exhibits physiological plasticity which includes restructuring of the photochemical apparatus, increased PSI-associated CEF, and shifts in downstream carbon metabolism toward storage carbon and secondary stress metabolites.

A real world example of coverage with evidence development in Australia - ipilimumab for the treatment of metastatic melanoma.

BACKGROUND: Australian Government subsidisation of ipilimumab for the treatment of patients with metastatic melanoma was conditional on the sponsor entering a 'managed entry scheme' to assess the 2-year overall survival rate in metastatic melanoma patients who received ipilimumab in the first year of Pharmaceutical Benefits Scheme listing. METHODS: All unresectable stage IIIc / IV metastatic melanoma patients treated with at least one dose of ipilimumab therapy in Australia from the PBS listing date to a time point 12 months later (i.e. from 1-Aug-2013 to 31-Jul-2014) were invited to participate. Overall survival at 2 years post treatment initiation was measured, with Cox regression analysis used to examine the relationship between survival and patient baseline characteristics. RESULTS: The evaluable population (910 patients) was on average 63.3 years old, male (70.1%) and treated in a public hospital (64.4%) in an urban area (76.5%). The majority of patients were treatment naïve (63.3%), did not have brain metastases (71.1%), and were classified as ECOG performance status 0 or 1 (90.4%). The 2 year overall survival rate was conservatively calculated to be at least 23.9% and potentially as high as 34.2%. A significant difference in overall survival at 2 years was demonstrated across the categories of ECOG performance status (p < 0.0001), M-status (p = 0.0005) and treatment status (p = 0.0114). No statistical difference in survival rate was observed when examining brain metastases vs no brain metastases (p = 0.2622), treatment at private vs public hospitals (p = 0.7601) nor treatment in the urban vs rural setting (p = 0.5048). CONCLUSIONS: The 2 year overall survival rate for all patients receiving PBS subsidised ipilimumab in Australia from the first year Pharmaceutical Benefits Scheme cohort is estimated to be between 23.9% and 34.2%, which is higher than the 23.5% observed in the key ipilimumab registrational trial. Results and learnings from the ipilimumab 'managed entry scheme' illustrate that early access with the promise of future evidence to confirm a medicine's cost-effectiveness can work, but needs to be carefully considered, constructed and managed.

From Regulatory Approval to Subsidized Patient Access in the Asia-Pacific Region: A Comparison of Systems Across Australia, China, Japan, Korea, New Zealand, Taiwan, and Thailand.

OBJECTIVES: To compare processes and timings of regulatory and subsidized access systems for medicines across seven jurisdictions within the Asia-Pacific region. METHODS: A questionnaire was developed focusing on regulatory and health technology assessment-based subsidized access processes and timings in each of the seven surveyant's jurisdictions. RESULTS: Australia and Thailand are the only two jurisdictions that formally allow the subsidized access evaluation process to be conducted in parallel with the regulatory evaluation process. Australian, Japanese, Korean, New Zealand, and Taiwanese systems afford broad coverage, whereas Chinese and Thai systems provide limited coverage for medicines under patent. Subsidized access systems for all jurisdictions except Thailand have an associated patient co-payment for each medicine/prescription. The biggest disparity across the study group relates to time from regulatory submission to subsidized access of patented medicines-ranging from just over 1 year (Japan) to a minimum of 5 years (China). CONCLUSIONS: There is consistency across the seven jurisdictions studied in relation to regulatory and subsidized patient access processes-that is, regulatory approval is required before subsidized access review; subsidized access coverage is broad; and the cost of medicine subsidization is offset, in part, by patient co-payments. Although local differences will always exist in relation to budget and pricing negotiation, there may be efficiencies that can be applied across systems to improve time to subsidized access. Closer understanding of regulatory and subsidized access systems can lead to best-practice sharing and, ultimately, timely access and better health outcomes for patients.

Feature Extraction for BCIs Based on Electromagnetic Source Localization and Multiclass Filter Bank Common Spatial Patterns.

Brain-Computer Interfaces (BCIs) provide means for communication and control without muscular movement and, therefore, can offer significant clinical benefits. Electrical brain activity recorded by electroencephalography (EEG) can be interpreted into software commands by various classification algorithms according to the descriptive features of the signal. In this paper we propose a novel EEG BCI feature extraction method employing EEG source reconstruction and Filter Bank Common Spatial Patterns (FBCSP) based on Joint Approximate Diagonalization (JAD). The proposed method is evaluated by the commonly used reference EEG dataset yielding an average classification accuracy of 77.1 ± 10.1 %. It is shown that FBCSP feature extraction applied to reconstructed source components outperforms conventional CSP and FBCSP feature extraction methods applied to signals in the sensor domain.

Angiotensin-converting enzyme inhibitors in the perioperative period.

Angiotensin-converting enzyme (ACE) inhibitors inhibit the enzyme that cleaves angiotensin I to form angiotensin II. They are potent vasodilators as they decrease concentrations of angiotensin II and noradrenaline and increase concentrations of bradykinin and nitric oxide. They reduce secretion of aldosterone and antidiuretic hormone, thus reducing salt and water reabsorption by the kidney (Groban and Butterworth, 2006).

Using gas chromatography with ion mobility spectrometry to resolve explosive compounds in the presence of interferents.

Ion mobility spectrometry (IMS) is a valued field detection technology because of its speed and high sensitivity, but IMS cannot easily resolve analytes of interest within mixtures. Coupling gas chromatography (GC) to IMS adds a separation capability to resolve complex matrices. A GC-IONSCAN® operated in IMS and GC/ IMS modes was evaluated with combinations of five explosives and four interferents. In 100 explosive/interferent combinations, IMS yielded 21 false positives while GC/ IMS substantially reduced the occurrence of false positives to one. In addition, the results indicate that through redesign or modification of the preconcentrator there would be significant advantages to using GC/ IMS, such as enhancement of the linear dynamic range (LDR) in some situations. By balancing sensitivity with LDR, GC/ IMS could prove to be a very advantageous tool when addressing real world complex mixture situations.

Comparison of BOLD and direct-MR neuronal detection (DND) in the human visual cortex at 3T.

Direct-MR neuronal detection (DND) of transient magnetic fields has recently been investigated as a novel imaging alternative to the conventional BOLD functional MRI (fMRI) technique. However, there remain controversial issues and debate surrounding this methodology, and this study attempts clarification by comparing BOLD responses in the human visual system with those of DND. BOLD relies on indirectly measuring blood oxygenation and flow changes as a result of neuronal activity, whereas the putative DND method is based on the hypothesis that the components of the in vivo neuronal magnetic fields, which lie parallel to the B(0) field, can potentially modulate the MR signal, thus providing a means of direct detection of nerve impulses. Block paradigms of checkerboard patterns were used for visual stimulation in both DND and BOLD experiments, allowing detection based on different frequency responses. This study shows colocalization of some voxels with slow BOLD responses and putative fast DND responses using General Linear Model (GLM) analysis. Frequency spectra for the activated voxel cluster are also shown for both stimulated and control data. The mean percentage signal change for the DND responses is 0.2%, corresponding to a predicted neuronal field of 0.14 nT.

Cost-effectiveness analysis of entecavir versus lamivudine in the first-line treatment of Australian patients with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) virus infection is a major global healthcare problem. The recent introduction of entecavir in Australia for the treatment of CHB patients in the naive treatment setting has triggered significant optimism with regards to improved clinical outcomes for CHB patients. OBJECTIVE: To estimate, from an Australian healthcare perspective, the cost effectiveness of entecavir 0.5 mg/day versus lamivudine 100 mg/day in the treatment of CHB patients naive to nucleos(t)ide therapy. METHODS: A cost-utility analysis to project the clinical and economic outcomes associated with CHB disease and treatment was conducted by developing two decision-tree models specific to hepatitis B e antigen-positive (HBeAg+ve) and HBeAg-ve CHB patient subsets. This analysis was constructed using the Australian payer perspective of direct costs and outcomes, with indirect medical costs and lost productivity not being included. The study population comprised a hypothetical cohort of 1000 antiviral treatment-naive CHB patients who received either entecavir 0.5 mg/day or lamivudine 100 mg/day at model entry. The population of patients used in this analysis was representative of those patients likely to receive initial antiviral therapy in clinical practice in Australia. The long-term cost effectiveness of entecavir compared with lamivudine in the first-line treatment of CHB patients was expressed as an incremental cost per life-year gained (LYG) or QALY gained. RESULTS: Results revealed that the availability of entecavir 0.5 mg/day as part of the Australian hepatologist's treatment armamentarium should result in significantly lower future rates of compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) events (i.e. 54 fewer cases of CC, seven fewer cases of DC, and 20 fewer cases of HCC over the model's timeframe for HBeAg+ve CHB patients, and 69 fewer cases of CC, eight fewer cases of DC and 25 fewer cases of HCC over the model's timeframe for HBeAg-ve CHB patients). Compared with lamivudine 100 mg/day, entecavir 0.5 mg/day generated an estimated incremental cost per LYG of Australian dollars ($A, year 2006 values) 5046 and an estimated incremental cost per QALY of $A5952 in the HBeAg+ve CHB patient population, an estimated incremental cost per LYG of $A7063 and an estimated incremental cost per QALY of $A8003 in the HBeAg-ve CHB patient population, and an overall estimated incremental cost per LYG of $A5853 and an estimated incremental cost per QALY of $A6772 in the general CHB population. CONCLUSION: The availability of entecavir in Australian clinical practice should make long-term suppression of hepatitis B virus replication increasingly attainable, resulting in fewer CHB sequelae, at an acceptable financial cost.

Investigation of axonal magnetic fields in the human corpus callosum using visual stimulation based on MR signal modulation.

PURPOSE: To investigate the possibility of detecting visually-evoked axonal currents in the splenium of the human corpus callosum using a 3.0T MRI system. MATERIALS AND METHODS: Axonal currents produce weak and transient magnetic fields, and the components of these that lie parallel to the B(0) field of the MRI system can potentially modulate the MR signal, which can be detected as an integrated effect over time. A fast gradient-echo echo-planar imaging (GE-EPI) sequence with short TR and intermediate TE was employed in an attempt to detect such axonal currents using light-emitting diode (LED) visual stimulation paradigms. RESULTS: The mean magnitude signal change, expressed relative to the fully relaxed equilibrium signal calculated from the measured value using the known T1 of white matter, was 0.014 +/- 0.004% at TE = 30 msec. This corresponded to a mean axonal field of 0.11 +/- 0.03 nT, according to the hypothesis that the axonal currents create a Lorentzian field distribution within an imaging voxel. CONCLUSION: Measured frequency spectra and statistical mapping using the general linear model (GLM) showed evidence of the stimulus localized within the splenium of the corpus callosum, which was not thought to be due to motion artifacts or physiological responses.

The effect of GSM and TETRA mobile handset signals on blood pressure, catechol levels and heart rate variability.

An acute rise in blood pressure has been reported in normal volunteers during exposure to signals from a mobile phone handset. To investigate this finding further we carried out a double blind study in 120 healthy volunteers (43 men, 77 women) in whom we measured mean arterial pressure (MAP) during each of six exposure sessions. At each session subjects were exposed to one of six different radio frequency signals simulating both GSM and TETRA handsets in different transmission modes. Blood catechols before and after exposure, heart rate variability during exposure, and post exposure 24 h ambulatory blood pressure were also studied. Despite having the power to detect changes in MAP of less than 1 mmHg none of our measurements showed any effect which we could attribute to radio frequency exposure. We found a single statistically significant decrease of 0.7 mmHg (95% CI 0.3-1.2 mmHg, P = .04) with exposure to GSM handsets in sham mode. This may be due to a slight increase in operating temperature of the handsets when in this mode. Hence our results have not confirmed the original findings of an acute rise in blood pressure due to exposure to mobile phone handset signals. In light of this negative finding from a large study, coupled with two smaller GSM studies which have also proved negative, we are of the view that further studies of acute changes in blood pressure due to GSM and TETRA handsets are not required.

Cadherin-2 participates in the morphogenesis of the zebrafish inner ear.

Molecular mechanisms that control inner ear morphogenesis from the placode to the three-dimensional functional organ are not well understood. We hypothesize that cell-cell adhesion, mediated by cadherin molecules, contributes significantly to various stages of inner ear formation. Cadherin-2 (Cdh2) function during otic vesicle morphogenesis was investigated by examining morpholino antisense oligonucleotide knockdown and glass onion (glo) (Cdh2 mutant) zebrafish embryos. Placode formation, vesicle cavitation and specification occurred normally, but morphogenesis of the otic vesicle was affected by Cdh2 deficiency: semicircular canals were reduced or absent. Phalloidin staining of the hair cell stereocillia demonstrated that cadherin-2 (cdh2) loss-of-function did not affect hair cell number, but acetylated tubulin labeling showed that hair cell kinocilia were shorter and irregularly shaped. Statoacoustic ganglion size was significantly reduced, which suggested that neuron differentiation or maturation was affected. Furthermore, cdh2 loss-of-function did not cause a general developmental delay, since differentiation of other tissues, including eye, proceeded normally. These findings demonstrate that Cdh2 selectively affects epithelial morphogenetic cell movements, particularly semicircular canal formation, during normal ear mophogenesis.

Investigation of MR signal modulation due to magnetic fields from neuronal currents in the adult human optic nerve and visual cortex.

Neuronal currents produce weak transient magnetic fields, and the hypothesis being investigated here is that the components of these parallel to the B0 field can potentially modulate the MR signal, thus providing a means of direct detection of nerve impulses. A theory for the phase and amplitude changes of the MR signal over time due to an external magnetic field has been developed to predict this modulation. Experimentally, a fast gradient-echo EPI sequence (TR = 158 ms, TE = 32.4 ms) was employed in an attempt to directly detect these neuronal currents in the adult human optic nerve and visual cortex using a 280-mm quadrature head coil at 1.5 T. A symmetrical intravoxel field distribution, which can be plausibly hypothesized for the axonal fields in the optic nerve and visual cortex, would result in phase cancellation within a voxel, and hence, only amplitude changes would be expected. On the other hand, an asymmetrical intravoxel field distribution would produce both phase and amplitude changes. The in vivo magnitude image data sets show a significant nerve firing detection rate of 56%, with zero detection using the phase image data sets. The percentage magnitude signal changes relative to the fully relaxed equilibrium signal fall within a predicted RMS field range of 1.2-2.1 nT in the optic nerve and 0.4-0.6 nT in the visual cortex, according to the hypothesis that the axonal fields create a symmetrical Lorentzian field distribution within the voxel.

Investigating direct detection of axon firing in the adult human optic nerve using MRI.

The aim of this study was to directly detect spectral components of the magnetic fields of ionic currents caused by firing of the axons in the optic nerve in response to visual strobe stimulation. The magnetic field parallel to the main B0 field can potentially alter the local phase and magnitude of the MR signal which can cause signal loss due to intravoxel dephasing. Measured frequency spectra showed evidence of the strobe stimulus localized to regions containing the optic nerve, not thought to be due to motion artifacts, in 30 out of 52 experiments in 5 adult human subjects. The effect was (0.15 +/- 0.05)% of the mean magnitude equilibrium signal from the voxel in the frequency range 0.7-3.3 Hz, corresponding to an estimated field of (1.2 +/- 0.4) nT, at an echo time of TE = 32.4 ms using a 1.5 T MRI scanner. Only 1 of 12 phase image experiments showed effects. These findings provide preliminary evidence for direct detection of axonal firing in the optic nerve.

Effect of 900 MHz electromagnetic fields on nonthermal induction of heat-shock proteins in human leukocytes.

Despite many studies, the evidence as to whether radiofrequency fields are detrimental to health remains controversial, and the debate continues. Cells respond to some abnormal physiological conditions by producing cytoprotective heat-shock (or stress) proteins. The aim of this study was to determine whether exposure to mobile phone-type radiation causes a nonthermal stress response in human leukocytes. Human peripheral blood was sham-exposed or exposed to 900 MHz fields (continuous-wave or GSM-modulated signal) at three average specific absorption rates (0.4, 2.0 and 3.6 W/kg) for different durations (20 min, 1 h and 4 h) in a calibrated TEM cell placed in an incubator to give well-controlled atmospheric conditions at 37 degrees C and 95% air/5% CO(2). Positive (heat-stressed at 42 degrees C) and negative (kept at 37 degrees C) control groups were incubated simultaneously in the same incubator. Heat caused an increase in the number of cells expressing stress proteins (HSP70, HSP27), measured using flow cytometry, and this increase was dependent on time. However, no statistically significant difference was detected in the number of cells expressing stress proteins after RF-field exposure. These results suggest that mobile phone-type radiation is not a stressor of normal human lymphocytes and monocytes, in contrast to mild heating.

Mapping of periodic waveforms using the ghost reconstructed alternating current estimation (GRACE) magnetic resonance imaging technique.

A new method of estimating alternating currents using ghost images created when the magnetic field from a fluctuating current modulates the phase of the magnetic resonance (MR) signal between successive phase-encode views is described. The method, known as ghost reconstructed alternating current estimation (GRACE), may be useful for directly mapping fields, and hence current impulses produced by neuronal firing events when synchronized periodic modulation can be induced. Images were acquired on a 1.5 T MR system with small oil capsule phantoms and a single wire with an applied alternating current, placed perpendicular to the main field direction. Computer simulations of these experiments yielded ghost images that agreed with experimental results. A simulated ghost image resulting from an evoked neuronal waveform is also discussed. Weak magnetic fields were detected from both sinusoidal and square wave modulations.