Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Reinforcement learning in dendritic structures

The discovery of binary dendritic events such as local NMDA spikes in dendritic subbranches led to the suggestion that dendritic trees could be computationally equivalent to a 2-layer network of point neurons, with a single output unit represented by the soma, and input units represented by the dendritic branches. Although this interpretation endows a neuron with a high computational power, it is functionally not clear why nature would have preferred the dendritic solution with a single but complex neuron, as opposed to the network solution with many but simple units. We show that the dendritic solution has a distinguished advantage over the network solution when considering different learning tasks. Its key property is that the dendritic branches receive an immediate feedback from the somatic output spike, while in the corresponding network architecture the feedback would require additional backpropagating connections to the input units. Assuming a reinforcement learning scenario we formally derive a learning rule for the synaptic contacts on the individual dendritic trees which depends on the presynaptic activity, the local NMDA spikes, the somatic action potential, and a delayed reinforcement signal. We test the model for two scenarios: the learning of binary classifications and of precise spike timings. We show that the immediate feedback represented by the backpropagating action potential supplies the individual dendritic branches with enough information to efficiently adapt their synapses and to speed up the learning process.

Reinforcement learning in dendritic structures

The discovery of binary dendritic events such as local NMDA spikes in dendritic subbranches led to the suggestion that dendritic trees could be computationally equivalent to a 2-layer network of point neurons, with a single output unit represented by the soma, and input units represented by the dendritic branches. Although this interpretation endows a neuron with a high computational power, it is functionally not clear why nature would have preferred the dendritic solution with a single but complex neuron, as opposed to the network solution with many but simple units. We show that the dendritic solution has a distinguished advantage over the network solution when considering different learning tasks. Its key property is that the dendritic branches receive an immediate feedback from the somatic output spike, while in the corresponding network architecture the feedback would require additional backpropagating connections to the input units. Assuming a reinforcement learning scenario we formally derive a learning rule for the synaptic contacts on the individual dendritic trees which depends on the presynaptic activity, the local NMDA spikes, the somatic action potential, and a delayed reinforcement signal. We test the model for two scenarios: the learning of binary classifications and of precise spike timings. We show that the immediate feedback represented by the backpropagating action potential supplies the individual dendritic branches with enough information to efficiently adapt their synapses and to speed up the learning process.

Closed-loop control of mean arterial blood pressure during surgery with alfentanil: clinical evaluation of a novel model-based predictive controller

BACKGROUND: In contrast to hypnosis, there is no surrogate parameter for analgesia in anesthetized patients. Opioids are titrated to suppress blood pressure response to noxious stimulation. The authors evaluated a novel model predictive controller for closed-loop administration of alfentanil using mean arterial blood pressure and predicted plasma alfentanil concentration (Cp Alf) as input parameters. METHODS: The authors studied 13 healthy patients scheduled to undergo minor lumbar and cervical spine surgery. After induction with propofol, alfentanil, and mivacurium and tracheal intubation, isoflurane was titrated to maintain the Bispectral Index at 55 (+/- 5), and the alfentanil administration was switched from manual to closed-loop control. The controller adjusted the alfentanil infusion rate to maintain the mean arterial blood pressure near the set-point (70 mmHg) while minimizing the Cp Alf toward the set-point plasma alfentanil concentration (Cp Alfref) (100 ng/ml). RESULTS: Two patients were excluded because of loss of arterial pressure signal and protocol violation. The alfentanil infusion was closed-loop controlled for a mean (SD) of 98.9 (1.5)% of presurgery time and 95.5 (4.3)% of surgery time. The mean (SD) end-tidal isoflurane concentrations were 0.78 (0.1) and 0.86 (0.1) vol%, the Cp Alf values were 122 (35) and 181 (58) ng/ml, and the Bispectral Index values were 51 (9) and 52 (4) before surgery and during surgery, respectively. The mean (SD) absolute deviations of mean arterial blood pressure were 7.6 (2.6) and 10.0 (4.2) mmHg (P = 0.262), and the median performance error, median absolute performance error, and wobble were 4.2 (6.2) and 8.8 (9.4)% (P = 0.002), 7.9 (3.8) and 11.8 (6.3)% (P = 0.129), and 14.5 (8.4) and 5.7 (1.2)% (P = 0.002) before surgery and during surgery, respectively. A post hoc simulation showed that the Cp Alfref decreased the predicted Cp Alf compared with mean arterial blood pressure alone. CONCLUSION: The authors' controller has a similar set-point precision as previous hypnotic controllers and provides adequate alfentanil dosing during surgery. It may help to standardize opioid dosing in research and may be a further step toward a multiple input-multiple output controller.

Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. CONCLUSION: We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.

Fine structure of hippocampal mossy fiber synapses following rapid high-pressure freezing

Synapses of hippocampal neurons play important roles in learning and memory processes and are involved in aberrant hippocampal function in temporal lobe epilepsy. Major neuronal types in the hippocampus as well as their input and output synapses are well known, but it has remained an open question to what extent conventional electron microscopy (EM) has provided us with the real appearance of synaptic fine structure under in vivo conditions. There is reason to assume that conventional aldehyde fixation and dehydration lead to protein denaturation and tissue shrinkage, likely associated with the occurrence of artifacts. However, realistic fine-structural data of synapses are required for our understanding of the transmission process and for its simulation. Here, we used high-pressure freezing and cryosubstitution of hippocampal tissue that was not subjected to aldehyde fixation and dehydration in ethanol to monitor the fine structure of an identified synapse in the hippocampal CA3 region, that is, the synapse between granule cell axons, the mossy fibers, and the proximal dendrites of CA3 pyramidal neurons. Our results showed that high-pressure freezing nicely preserved ultrastructural detail of this particular synapse and allowed us to study rapid structural changes associated with synaptic plasticity.

The World Trade Organization’s Legitimacy Crisis: What Does The Beast Look Like?

The concept of legitimacy has many facets. The article reviews from a politics and law perspective the diagnosis of an ``institution in crisis''. This article is divided into three sections. It starts with a cautionary note on existing fallacies about assessing multilateral intergovernmental institutions and discusses competing schools of thought that approach the World Trade Organization (WTO) with varying perceptions of democracy and legitimacy. Section II takes up the actual debate on redesigning the WTO and directs attention to the question of balancing input and output legitimacy. Section III sketches potential avenues of research that have been neglected in the past.

Business and Public–Private Partnerships for Sustainability: Beyond Corporate Social Responsibility?

This article analyses public–private partnerships (PPPs) in the field of sustainable development from an international relations perspective with insights from the business and ethics literature. We argue that the role of business in these types of arrangements has not been sufficiently explored. After presenting three ways of approaching PPPs to stress the many facets of partnerships across the public–private divide, we discuss the emergence of these novel forms of governance from a demand side and contrast such a functionalist reading with the supply side. Then we look at the micro-economic incentives for corporations to engage in such endeavours. We develop arguments derived from the dominant literature to provide an analytical framework for explaining business participation. Finally, we discuss the role of PPPs in light of input and output legitimacy. We conclude by alluding to the emergence of an expectation-capacity gap and normative issues related to the global PPP architecture.

Minimum carbon payment along an aridity gradient for dryland afforestation in non annex I countries with stochastic weather and prices

Recent findings demonstrate that trees in deserts are efficient carbon sinks. It remains however unknown whether the Clean Development Mechanism will accelerate the planting of trees in Non Annex I dryland countries. We estimated the price of carbon at which a farmer would be indifferent between his customary activity and the planting of trees to trade carbon credits, along an aridity gradient. Carbon yields were simulated by means of the CO2FIX v3.1 model for Pinus halepensis with its respective yield classes along the gradient (Arid – 100mm to Dry Sub Humid conditions – 900mm). Wheat and pasture yields were predicted on somewhat similar nitrogen-based quadratic models, using 30 years of weather data to simulate moisture stress. Stochastic production, input and output prices were afterwards simulated on a Monte Carlo matrix. Results show that, despite the high levels of carbon uptake, carbon trading by afforesting is unprofitable anywhere along the gradient. Indeed, the price of carbon would have to raise unrealistically high, and the certification costs would have to drop significantly, to make the Clean Development Mechanism worthwhile for non annex I dryland countries farmers. From a government agency's point of view the Clean Development Mechanism is attractive. However, such agencies will find it difficult to demonstrate “additionality”, even if the rule may be somewhat flexible. Based on these findings, we will further discuss why the Clean Development Mechanism, a supposedly pro-poor instrument, fails to assist farmers in Non Annex I dryland countries living at minimum subsistence level.

Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls

In multiple sclerosis (MS), fatigue is a common and often disabling symptom. It has multiple causes with central motor fatigue playing an important role.

Validation of prognostic factors and survival of patients with multiple myeloma in a real-life autologous stem cell transplantation setting: a Swiss single centre experience

High-dose chemotherapy with subsequent autologous stem cell transplantation (ASCT) is an important treatment option in younger patients with multiple myeloma (MM). We analysed the outcome of patients treated at our institution outside the clinical trials framework and tried to identify risk factors prognostic for survival.

First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies

Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide.

Comparison of online single-breath vs. online multiple-breath exhaled nitric oxide in school-age children

Standards for online multiple-breath (mb) exhaled nitric oxide (eNO) measurements and studies comparing them with online single-breath (sb) eNO measurements are lacking, although eNOmb requires less cooperation in children at school age or younger.