Early characterization of the severity and transmissibility of pandemic influenza using clinical episode data from multiple populations

The potential rapid availability of large-scale clinical episode data during the next influenza pandemic suggests an opportunity for increasing the speed with which novel respiratory pathogens can be characterized. Key intervention decisions will be determined by both the transmissibility of the novel strain (measured by the basic reproductive number R0) and its individual-level severity. The 2009 pandemic illustrated that estimating individual-level severity, as described by the proportion pC of infections that result in clinical cases, can remain uncertain for a prolonged period of time. Here, we use 50 distinct US military populations during 2009 as a retrospective cohort to test the hypothesis that real-time encounter data combined with disease dynamic models can be used to bridge this uncertainty gap. Effectively, we estimated the total number of infections in multiple early-affected communities using the model and divided that number by the known number of clinical cases. Joint estimates of severity and transmissibility clustered within a relatively small region of parameter space, with 40 of the 50 populations bounded by: pC, 0.0133-0.150 and R0, 1.09-2.16. These fits were obtained despite widely varying incidence profiles: some with spring waves, some with fall waves and some with both. To illustrate the benefit of specific pairing of rapidly available data and infectious disease models, we simulated a future moderate pandemic strain with pC approximately ×10 that of 2009; the results demonstrating that even before the peak had passed in the first affected population, R0 and pC could be well estimated. This study provides a clear reference in this two-dimensional space against which future novel respiratory pathogens can be rapidly assessed and compared with previous pandemics

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies

Sommerfeld Enhancement from Multiple Mediators

We study the Sommerfeld enhancement experienced by a scattering object that couples to a tower of mediators. This can occur in, e.g., models of secluded dark matter when the mediator scale is generated naturally by hidden-sector confinement. Specializing to the case of a confining CFT, we show that off-resonant values of the enhancement can be increased by ~ 20% for cases of interest when (i) the (strongly-coupled) CFT admits a weakly-coupled dual description and (ii) the conformal symmetry holds up to the Planck scale. Larger enhancements are possible for lower UV scales due to an increase in the coupling strength of the tower.Comment: 17p, 2 figures; v2 JHEP version (inconsequential typo fixed, references added

The Worldvolume Action of Kink Solitons in AdS Spacetime

A formalism is presented for computing the higher-order corrections to the worldvolume action of co-dimension one solitons. By modifying its potential, an explicit "kink" solution of a real scalar field in AdS spacetime is found. The formalism is then applied to explicitly compute the kink worldvolume action to quadratic order in two expansion parameters--associated with the hypersurface fluctuation length and the radius of AdS spacetime respectively. Two alternative methods are given for doing this. The results are expressed in terms of the trace of the extrinsic curvature and the intrinsic scalar curvature. In addition to conformal Galileon interactions, we find a non-Galileon term which is never sub-dominant. This method can be extended to any conformally flat bulk spacetime.Comment: 32 pages, 3 figures, typos corrected and additional comments adde

Atypical disengagement from faces and its modulation by the control of eye fixation in children with Autism Spectrum Disorder

By using the gap overlap task, we investigated disengagement from faces and objects in children (9–17 years old) with and without autism spectrum disorder (ASD) and its neurophysiological correlates. In typically developing (TD) children, faces elicited larger gap effect, an index of attentional engagement, and larger saccade-related event-related potentials (ERPs), compared to objects. In children with ASD, by contrast, neither gap effect nor ERPs differ between faces and objects. Follow-up experiments demonstrated that instructed fixation on the eyes induces larger gap effect for faces in children with ASD, whereas instructed fixation on the mouth can disrupt larger gap effect in TD children. These results suggest a critical role of eye fixation on attentional engagement to faces in both groups

Reasons for and consequences of missed appointments in general practice in the UK: questionnaire survey and prospective review of medical records

Background Missed appointments are a common occurrence in primary care in the UK, yet little is known about the reasons for them, or the consequences of missing an appointment. This paper aims to determine the reasons for missed appointments and whether patients who miss an appointment subsequently consult their general practitioner (GP). Secondary aims are to compare psychological morbidity, and the previous appointments with GPs between subjects and a comparison group. Methods Postal questionnaire survey and prospective medical notes review of adult patients missing an appointment and the comparison group who attended appointments over a three week period in seven general practices in West Yorkshire. Results Of the 386 who missed appointments 122 (32%) responded. Of the 386 in the comparison group 223 (58%) responded, resulting in 23 case-control matched pairs with complete data collection. Over 40% of individuals who missed an appointment and participated said that they forgot the appointment and a quarter said that they tried very hard to cancel the appointment or that it was at an inconvenient time. A fifth reported family commitments or being too ill to attend. Over 90% of the patients who missed an appointment subsequently consulted within three months and of these nearly 60% consulted for the stated problem that was going to be presented in the missed consultation. The odds of missing an appointment decreased with increasing age and were greater among those who had missed at least one appointment in the previous 12 months. However, estimates for comparisons between those who missed appointments and the comparison group were imprecise due to the low response rate. Conclusion Patients who miss appointments tend to cite practice factors and their own forgetfulness as the main reasons for doing so, and most attend within three months of a missed appointment. This study highlights a number of implications for future research. More work needs to be done to engage people who miss appointments into research in a meaningful way

Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel

Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats

Peer reviewedPublisher PD

Effects of temperature on thick branes and the fermion (quasi-)localization

Following Campos's work [Phys. Rev. Lett. 88, 141602 (2002)], we investigate the effects of temperature on flat, de Sitter (dS), and anti-de Following Campos's work [Phys. Rev. Lett. \textbf{88}, 141602 (2002)], we investigate the effects of temperature on flat, de Sitter (dS), and anti-de Sitter (AdS) thick branes in five-dimensional (5D) warped spacetime, and on the fermion (quasi-)localization. First, in the case of flat brane, when the critical temperature reaches, the solution of the background scalar field and the warp factor is not unique. So the thickness of the flat thick brane is uncertain at the critical value of the temperature parameter, which is found to be lower than the one in flat 5D spacetime. The mass spectra of the fermion Kaluza-Klein (KK) modes are continuous, and there is a series of fermion resonances. The number and lifetime of the resonances are finite and increase with the temperature parameter, but the mass of the resonances decreases with the temperature parameter. Second, in the case of dS brane, we do not find such a critical value of the temperature parameter. The mass spectra of the fermion KK modes are also continuous, and there is a series of fermion resonances. The effects of temperature on resonance number, lifetime, and mass are the same with the case of flat brane. Last, in the case of AdS brane, {the critical value of the temperature parameter can less or greater than the one in the flat 5D spacetime.} The spectra of fermion KK modes are discrete, and the mass of fermion KK modes does not decrease monotonically with increasing temperature parameter.Comment: 24 pages, 15 figures, published versio

Sperm design and variation in the New World blackbirds (Icteridae)

Post-copulatory sexual selection (PCSS) is thought to be one of the evolutionary forces responsible for the rapid and divergent evolution of sperm design. However, whereas in some taxa particular sperm traits are positively associated with PCSS, in other taxa, these relationships are negative, and the causes of these different patterns across taxa are poorly understood. In a comparative study using New World blackbirds (Icteridae), we tested whether sperm design was influenced by the level of PCSS and found significant positive associations with the level of PCSS for all sperm components but head length. Additionally, whereas the absolute length of sperm components increased, their variation declined with the intensity of PCSS, indicating stabilizing selection around an optimal sperm design. Given the diversity of, and strong selection on, sperm design, it seems likely that sperm phenotype may influence sperm velocity within species. However, in contrast to other recent studies of passerine birds, but consistent with several other studies, we found no significant link between sperm design and velocity, using four different species that vary both in sperm design and PCSS. Potential reasons for this discrepancy between studies are discussed