Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein

Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcRI and FcRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection

Estimating the number needed to treat from continuous outcomes in randomised controlled trials: methodological challenges and worked example using data from the UK Back Pain Exercise and Manipulation (BEAM) trial

Background Reporting numbers needed to treat (NNT) improves interpretability of trial results. It is unusual that continuous outcomes are converted to numbers of individual responders to treatment (i.e., those who reach a particular threshold of change); and deteriorations prevented are only rarely considered. We consider how numbers needed to treat can be derived from continuous outcomes; illustrated with a worked example showing the methods and challenges. Methods We used data from the UK BEAM trial (n = 1, 334) of physical treatments for back pain; originally reported as showing, at best, small to moderate benefits. Participants were randomised to receive 'best care' in general practice, the comparator treatment, or one of three manual and/or exercise treatments: 'best care' plus manipulation, exercise, or manipulation followed by exercise. We used established consensus thresholds for improvement in Roland-Morris disability questionnaire scores at three and twelve months to derive NNTs for improvements and for benefits (improvements gained+deteriorations prevented). Results At three months, NNT estimates ranged from 5.1 (95% CI 3.4 to 10.7) to 9.0 (5.0 to 45.5) for exercise, 5.0 (3.4 to 9.8) to 5.4 (3.8 to 9.9) for manipulation, and 3.3 (2.5 to 4.9) to 4.8 (3.5 to 7.8) for manipulation followed by exercise. Corresponding between-group mean differences in the Roland-Morris disability questionnaire were 1.6 (0.8 to 2.3), 1.4 (0.6 to 2.1), and 1.9 (1.2 to 2.6) points. Conclusion In contrast to small mean differences originally reported, NNTs were small and could be attractive to clinicians, patients, and purchasers. NNTs can aid the interpretation of results of trials using continuous outcomes. Where possible, these should be reported alongside mean differences. Challenges remain in calculating NNTs for some continuous outcomes

Calculating confidence intervals for impact numbers

BACKGROUND: Standard effect measures such as risk difference and attributable risk are frequently used in epidemiological studies and public health research to describe the effect of exposures. Recently, so-called impact numbers have been proposed, which express the population impact of exposures in form of specific person or case numbers. To describe estimation uncertainty, it is necessary to calculate confidence intervals for these new effect measures. In this paper, we present methods to calculate confidence intervals for the new impact numbers in the situation of cohort studies. METHODS: Beside the exposure impact number (EIN), which is equivalent to the well-known number needed to treat (NNT), two other impact numbers are considered: the case impact number (CIN) and the exposed cases impact number (ECIN), which describe the number of cases (CIN) and the number of exposed cases (ECIN) with an outcome among whom one case is attributable to the exposure. The CIN and ECIN represent reciprocals of the population attributable risk (PAR) and the attributable fraction among the exposed (AF(e)), respectively. Thus, confidence intervals for these impact numbers can be calculated by inverting and exchanging the confidence limits of the PAR and AF(e). EXAMPLES: We considered a British and a Japanese cohort study that investigated the association between smoking and death from coronary heart disease (CHD) and between smoking and stroke, respectively. We used the reported death and disease rates and calculated impact numbers with corresponding 95% confidence intervals. In the British study, the CIN was 6.46, i.e. on average, of any 6 to 7 persons who died of CHD, one case was attributable to smoking with corresponding 95% confidence interval of [3.84, 20.36]. For the exposed cases, the results of ECIN = 2.64 with 95% confidence interval [1.76, 5.29] were obtained. In the Japanese study, the CIN was 6.67, i.e. on average, of the 6 to 7 persons who had a stroke, one case was attributable to smoking with corresponding 95% confidence interval of [3.80, 27.27]. For the exposed cases, the results of ECIN = 4.89 with 95% confidence interval of [2.86, 16.67] were obtained. CONCLUSION: The consideration of impact numbers in epidemiological analyses provides additional information and helps the interpretation of study results, e.g. in public health research. In practical applications, it is necessary to describe estimation uncertainty. We have shown that the calculation of confidence intervals for the new impact numbers is possible by means of known methods for attributable risk measures. Therefore, estimated impact numbers should always be complemented by appropriate confidence intervals

A Small Conductance Calcium-Activated K⁺ Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying

In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al

Radar interferometry based settlement monitoring in tunnelling: visualisation and accuracy analyses

Background The accurate, efficient and economical monitoring of settlements caused by tunnel boring machines, especially in regions of particular interest such as critical inner city areas, has become an important aspect of the tunnelling operation. Besides conventional terrestrial based methods to capture settlements, satellite based techniques that can accurately determine displacements remotely, are increasingly being used to augment standard terrestrial measurements. However, not much attention has been paid to analyse the accuracy of satellite based measurement data. In addition, there is also a lack of studies on how to visualise the resulting huge amount of data in the context of both the tunnel advancement and the existing building infrastructure. Methods This paper introduces the basics of settlement monitoring using radar interferometry methods, in particular showing the results obtained by processing radar images from the TerraSAR-X satellite to monitor a downtown construction site in Düsseldorf, Germany, where a new underground line (“Wehrhahn-Linie”) is being built. By comparing terrestrial measurements with remote satellite based settlement data in temporal and spatial corridors, the accuracy of the radar interferometry method is shown. Moreover, a 4D visualisation concept is presented that correlates satellite and terrestrial based settlement data correlated with above-ground buildings and boring machine performance parameters within a Virtual Reality (VR) environment. Results By comparing up to 23,000 pairs of satellite and terrestrial based settlement data points of a real tunnelling project an accuracy of about ±1.5 mm in the measurement of deformation using the method of radar interferometry in urban areas can be stated. In addition, providing a visual analysis of data sources within a VR environment, the accuracy of terrestrial and satellite-based measurements can be visualised in different time steps. Sources of error that affect the degree of accuracy, such as atmospheric conditions, systematic errors in the evaluation of radar images and local events in the spatial corridor, can be quantified. In addition, the 4D visualisation can help reveal direct interdependencies between settlement data and boring machine performance data. Conclusions The Persistent Scatterer Interferometry (PSI) based on high resolution radar images of the TerraSAR-X satellite, in combination with conventional ground-based terrestrial measurements, provides a new settlement monitoring approach in tunnelling. For example, due to minimized surveying works and disruptions of construction activities on site and due to the large settlement area coming with a high magnitude of settlement data points, this combined monitoring approach is very practical and economical. Moreover, by visualizing the settlement data properly, the risk of damage of surface structures can be analysed and understood more precisely, which increases the safety of underground works

Activation in a Frontoparietal Cortical Network Underlies Individual Differences in the Performance of an Embedded Figures Task

The Embedded Figures Test (EFT) requires observers to search for a simple geometric shape hidden inside a more complex figure. Surprisingly, performance in the EFT is negatively correlated with susceptibility to illusions of spatial orientation, such as the Roelofs effect. Using fMRI, we previously demonstrated that regions in parietal cortex are involved in the contextual processing associated with the Roelofs task. In the present study, we found that similar parietal regions (superior parietal cortex and precuneus) were more active during the EFT than during a simple matching task. Importantly, these parietal activations overlapped with regions found to be involved during contextual processing in the Roelofs illusion. Additional parietal and frontal areas, in the right hemisphere, showed strong correlations between brain activity and behavioral performance during the search task. We propose that the posterior parietal regions are necessary for processing contextual information across many different, but related visuospatial tasks, with additional parietal and frontal regions serving to coordinate this processing in participants proficient in the task

Graphene plasmonics

Two rich and vibrant fields of investigation, graphene physics and plasmonics, strongly overlap. Not only does graphene possess intrinsic plasmons that are tunable and adjustable, but a combination of graphene with noble-metal nanostructures promises a variety of exciting applications for conventional plasmonics. The versatility of graphene means that graphene-based plasmonics may enable the manufacture of novel optical devices working in different frequency ranges, from terahertz to the visible, with extremely high speed, low driving voltage, low power consumption and compact sizes. Here we review the field emerging at the intersection of graphene physics and plasmonics.Comment: Review article; 12 pages, 6 figures, 99 references (final version available only at publisher's web site

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure

More than a century of bathymetric observations and present-day shallow sediment characterization in Belfast Bay, Maine, USA: implications for pockmark field longevity

This paper is not subject to U.S. copyright. The definitive version was published in Geo-Marine Letters 31 (2011): 237-248, doi:10.1007/s00367-011-0228-0.Mechanisms and timescales responsible for pockmark formation and maintenance remain uncertain, especially in areas lacking extensive thermogenic fluid deposits (e.g., previously glaciated estuaries). This study characterizes seafloor activity in the Belfast Bay, Maine nearshore pockmark field using (1) three swath bathymetry datasets collected between 1999 and 2008, complemented by analyses of shallow box-core samples for radionuclide activity and undrained shear strength, and (2) historical bathymetric data (report and smooth sheets from 1872, 1947, 1948). In addition, because repeat swath bathymetry surveys are an emerging data source, we present a selected literature review of recent studies using such datasets for seafloor change analysis. This study is the first to apply the method to a pockmark field, and characterizes macro-scale (>5 m) evolution of tens of square kilometers of highly irregular seafloor. Presence/absence analysis yielded no change in pockmark frequency or distribution over a 9-year period (1999–2008). In that time pockmarks did not detectably enlarge, truncate, elongate, or combine. Historical data indicate that pockmark chains already existed in the 19th century. Despite the lack of macroscopic changes in the field, near-bed undrained shear-strength values of less than 7 kPa and scattered downcore 137Cs signatures indicate a highly disturbed setting. Integrating these findings with independent geophysical and geochemical observations made in the pockmark field, it can be concluded that (1) large-scale sediment resuspension and dispersion related to pockmark formation and failure do not occur frequently within this field, and (2) pockmarks can persevere in a dynamic estuarine setting that exhibits minimal modern fluid venting. Although pockmarks are conventionally thought to be long-lived features maintained by a combination of fluid venting and minimal sediment accumulation, this suggests that other mechanisms may be equally active in maintaining such irregular seafloor morphology. One such mechanism could be upwelling within pockmarks induced by near-bed currents.Graduate support for Brothers came from a Maine Economic Improvement Fund Dissertation Fellowship

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m(2 )of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects