Treatment costs and priority setting in health care: A qualitative study

Background

The aim of this study is to investigate whether the public believes high cost patients should be a lower priority for public health care than low cost patients, other things being equal, in order to maximise health gains from the health budget. Semi-structured group discussions were used to help participants reflect critically upon their own views and gain exposure to alternative views, and in this way elicit underlying values rather than unreflective preferences. Participants were given two main tasks: first, to select from among three general principles for setting health care priorities the one that comes closest to their own views; second, to allocate a limited hospital budget between two groups of imaginary patients. Forty-one people, varying in age, occupation, income and education level, participated in a total of six group discussions with each group comprising between six and eight people.

Results

After discussion and deliberation, 30 participants rejected the most cost-effective principle for setting priorities, citing reasons such as 'moral values' and 'a personal belief that we shouldn't discriminate'. Only three participants chose to allocate the entire hospital budget to the low cost patients. Reasons for allocating some money to inefficient (high cost) patients included 'fairness' and the desire to give all patients a 'chance'.

Conclusion

Participants rejected a single-minded focus on efficiency – maximising health gains – when setting priorities in health care. There was a concern to avoid strategies that deny patients all hope of treatment, and a willingness to sacrifice health gains for a 'fair' public health system.

     

Inter-hemispheric inhibition is impaired in mirror dystonia

Surround inhibition, a neural mechanism relevant for skilled motor behavior, has been shown to be deficient in the affected primary motor cortex (M1) in patients with focal hand dystonia (FHD). Even in unilateral FHD, however, electrophysiological and neuroimaging studies have provided evidence for bilateral M1 abnormalities. Clinically, the presence of mirror dystonia, dystonic posturing when the opposite hand is moved, also suggests abnormal interhemispheric interaction. To assess whether a loss of inter-hemispheric inhibition (IHI) may contribute to the reduced surround inhibition, IHI towards the affected or dominant M1 was examined in 13 patients with FHD (seven patients with and six patients without mirror dystonia, all affected on the right hand) and 12 right-handed, age-matched healthy controls (CON group). IHI was tested at rest and during three different phases of a right index finger movement in a synergistic, as well as in a neighboring, relaxed muscle. There was a trend for a selective loss of IHI between the homologous surrounding muscles in the phase 50 ms before electromyogram onset in patients with FHD. Post hoc analysis revealed that this effect was due to a loss of IHI in the patients with FHD with mirror dystonia, while patients without mirror dystonia did not show any difference in IHI modulation compared with healthy controls. We conclude that mirror dystonia may be due to impaired IHI towards neighboring muscles before movement onset. However, IHI does not seem to play a major role in the general pathophysiology of FHD.     

Connections of the marmoset rostrotemporal auditory area: express pathways for analysis of affective content in hearing

The current hierarchical model of primate auditory cortical processing proposes a core of 'primary-like' areas, which is surrounded by secondary (belt) and tertiary (parabelt) regions. The rostrotemporal auditory cortical area (RT) remains the least well characterized of the three proposed core areas, and its functional organization has only recently come under scrutiny. Here we used injections of anterograde and retrograde tracers in the common marmoset ( Callithrix jacchus ) to examine the connectivity of RT and its adjacent areas. As expected from the current model, RT exhibited dense core-like reciprocal connectivity with the ventral division of the medial geniculate body, the rostral core area and the auditory belt, but had weaker connections with the parabelt. However, RT also projected to the ipsilateral rostromedial prefrontal cortex (area 10), the dorsal temporal pole and the ventral caudate nucleus, as well as bilaterally to the lateral nucleus of the amygdala. Thus, RT has connectivity with limbic structures previously believed to connect only with higher-order auditory association cortices, and is probably functionally distinct from the other core areas. While this view is consistent with a proposed role of RT in temporal integration, our results also indicate that RT could provide an anatomical 'shortcut' for processing affective content in auditory information.     

Imaging seizure activity: a combined EEG/EMG-fMRI study in reading epilepsy

Purpose:   To characterize the spatial relationship between activations related to language-induced seizure activity, language processing, and motor control in patients with reading epilepsy.
Methods:   We recorded and simultaneously monitored several physiological parameters [voice-recording, electromyography (EMG), electrocardiography (ECG), electroencephalography (EEG)] during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in nine patients with reading epilepsy. Individually tailored language paradigms were used to induce and record habitual seizures inside the MRI scanner. Voxel-based morphometry (VBM) was used for structural brain analysis. Reading-induced seizures occurred in six out of nine patients.
Results:   One patient experienced abundant orofacial reflex myocloni during silent reading in association with bilateral frontal or generalized epileptiform discharges. In a further five patients, symptoms were only elicited while reading aloud with self-indicated events. Consistent activation patterns in response to reading-induced myoclonic seizures were observed within left motor and premotor areas in five of these six patients, in the left striatum (n = 4), in mesiotemporal/limbic areas (n = 4), in Brodmann area 47 (n = 3), and thalamus (n = 2). These BOLD activations were overlapping or adjacent to areas physiologically activated during language and facial motor tasks. No subtle structural abnormalities common to all patients were identified using VBM, but one patient had a left temporal ischemic lesion.
Discussion:   Based on the findings, we hypothesize that reflex seizures occur in reading epilepsy when a critical mass of neurons are activated through a provoking stimulus within corticoreticular and corticocortical circuitry subserving normal functions.     

Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma

Tanespimycin (17‐allylamino‐17‐demethoxygeldanamycin, 17‐AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open‐label multicentre study, we compared 1·3 mg/m² bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m² in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource‐based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.     

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor,induces pleiotropic anti‐myeloma activity in vitro and in vivo

This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G₀‐G₁ cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome.