Estimating the probability of demonstrating vaccine efficacy in the declining Ebola epidemic: a Bayesian modelling approach.

OBJECTIVES: We investigate the chance of demonstrating Ebola vaccine efficacy in an individually randomised controlled trial implemented in the declining epidemic of Forécariah prefecture, Guinea. METHODS: We extend a previously published dynamic transmission model to include a simulated individually randomised controlled trial of 100,000 participants. Using Bayesian methods, we fit the model to Ebola case incidence before a trial and forecast the expected dynamics until disease elimination. We simulate trials under these forecasts and test potential start dates and rollout schemes to assess power to detect efficacy, and bias in vaccine efficacy estimates that may be introduced. RESULTS: Under realistic assumptions, we found that a trial of 100,000 participants starting after 1 August had less than 5% chance of having enough cases to detect vaccine efficacy. In particular, gradual recruitment precludes detection of vaccine efficacy because the epidemic is likely to go extinct before enough participants are recruited. Exclusion of early cases in either arm of the trial creates bias in vaccine efficacy estimates. CONCLUSIONS: The very low Ebola virus disease incidence in Forécariah prefecture means any individually randomised controlled trial implemented there is unlikely to be successful, unless there is a substantial increase in the number of cases

Duration of Ebola virus RNA persistence in semen of survivors: population-level estimates and projections.

Ebola virus can persist in semen after recovery, potentially for months, which may impact the duration of enhanced surveillance required after interruption of transmission. We combined recent data on viral RNA persistence with weekly disease incidence to estimate the current number of semen-positive men in affected West African countries. We find the number is low, and since few reported sexual transmission events have occurred, the future risk is also likely low, although sexual health promotion remains critical

Myocarditis in Paediatrics

La miocarditis es una enfermedad inflamatoria del músculo cardiaco no asociada a anormalidades valvulares y en ausencia de enfermedad isquémica. Su prevalencia e incidencia se desconocen, ya que se presenta de manera subaguda o con síntomas iniciales inespecíficos. Su fisiopatología consta de tres fases: aguda (< 3 días---da˜no miocárdico mediado por acción directa del virus), subaguda (4-14 días---el da˜no miocárdico resulta de una disregulación de la respuesta autoinmune del huésped) y crónica (> 15 días---aclaramiento viral insuficiente y perpetuación del proceso inflamatorio, que conduce a remodelamiento cardiaco y falla cardiaca). Como agente etiológico más frecuente se describe el Parvovirus B19 y el herpes virus humano 6. Entre las manifestaciones clínicas: dolor torácico, arritmias, en lactantes (letargo, taquipnea, dificultad respiratoria leve, etc.), puede iniciar con pródromo viral, disfunción ventricular o muerte súbita. Tiene cuatro posibles presentaciones clínicas: asintomático, miocarditis aguda, fulminante o miocardiopatía crónica dilatada. El electrocardiograma detecta anormalidades entre el 93 al 100%; la resonancia magnética nuclear cardiovascular con gadolinio es de mayor uso, principalmente en la biopsia endomiocárdica. El tratamiento se basa en la monitorización hemodinámica del paciente, la evaluación de la necesidad de diuréticos, inhibidores de la enzima convertidora de angiotensina, betabloqueadores no selectivos, soporte inotrópico, antiarrítmicos o, en casos severos, el requerimiento de soporte mecánico cardiovascular.Myocarditis is an inflammatory disease of the heart muscle unrelated to valvularabnormalities and ischaemic disease. The prevalence and incidence are unknown since it is pre-sented sub-acutely or with non-specific initial symptoms. Its pathophysiology consists of threephases: acute 15 days - insufficient viral clearance and perpetuation of the inflammatory process,which leads to cardiac remodelling and heart failure). Parvovirus B19 and human herpesvirus 6have been described as the most common aetiological agents. The clinical signs include, chestpain, arrhythmias, and in infants (lethargy, tachypnoea, mild shortness of breath, etc.) It canstart with a viral prodrome, ventricular dysfunction, or sudden death. There are four possibi-lities of clinical presentation: asymptomatic, acute myocarditis, fulminant or dilated chroniccardiomyopathy. The electrocardiogram detects between 93%-100% of abnormalities. Cardiovas-cular nuclear magnetic resonance with gadolinium is the most used, mainly in endomyocardialbiopsy. Treatment is based on the haemodynamic monitoring of the patient, the evaluation ofthe need for diuretics, angiotensin converting enzyme inhibitors, non-selective beta-blockers,inotropic support, anti-arrhythmic drugs or, in severe cases, and the need for mechanical cardio-vascular support. The use of immunoglobulin has been evaluated, and there is controversy overthe use of immunosuppressives and antivirals. The prognosis is variable and depends on factorsinherent to the environment and the host. An updated review of the literature is presented

Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I

Insulin-like growth factor binding proteins (IGFBPs) have been shown to serve as carrier proteins for the insulin-like growth factors (IGFs) and to modulate their biologic effects. Since extracellular matrix (ECM) has been shown to be a reservoir for IGF-I and IGF-II, we examined the ECM of cultured human fetal fibroblasts and found that IGFBP-5 was incorporated intact into ECM, while mostly inert proteolytic fragments were found in the medium. In contrast, two other forms of IGFBP that are secreted by these cells were either present in ECM in minimal amounts (IGFBP-3) or not detected (IGFBP-4). Likewise, when purified IGFBPs were incubated with ECM, IGFBP-5 bound preferentially. IGFBP-5 was found to bind to types III and IV collagen, laminin, and fibronectin. Increasing salt concentrations inhibited the binding of IGFBP-5 to ECM and accelerated the release of IGFBP-5 from ECM, suggesting an ionic basis for this interaction. ECM-associated IGFBP-5 had a sevenfold decrease in affinity for IGF-I compared to IGFBP-5 in solution. Furthermore, when IGFBP-5 was present in cell culture substrata, it potentiated the growth stimulatory effects of IGF- I on fibroblasts. When IGFBP-5 was present only in the medium, it was degraded to a 22-kD fragment and had no effect on IGF-I-stimulated growth. We conclude that IGFBP-5 is present in fibroblast ECM, where it is protected from degradation and can potentiate the biologic actions of IGF-I. These findings provide a molecular explanation for the association of the IGF's with the extracellular matrix, and suggest that the binding of the IGF's to matrix, via IGFBP-5, may be important in mediating the cellular growth response to these growth factors

Using Web Search Query Data to Monitor Dengue Epidemics: A New Model for Neglected Tropical Disease Surveillance

A variety of obstacles, including bureaucracy and lack of resources, delay detection and reporting of dengue and exist in many countries where the disease is a major public health threat. Surveillance efforts have turned to modern data sources such as Internet usage data. People often seek health-related information online and it has been found that the frequency of, for example, influenza-related web searches as a whole rises as the number of people sick with influenza rises. Tools have been developed to help track influenza epidemics by finding patterns in certain web search activity. However, few have evaluated whether this approach would also be effective for other diseases, especially those that affect many people, that have severe consequences, or for which there is no vaccine. In this study, we found that aggregated, anonymized Google search query data were also capable of tracking dengue activity in Bolivia, Brazil, India, Indonesia and Singapore. Whereas traditional dengue data from official sources are often not available until after a long delay, web search query data is available for analysis within a day. Therefore, because it could potentially provide earlier warnings, these data represent a valuable complement to traditional dengue surveillance

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

<p>Abstract</p> <p>Background</p> <p>CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.</p> <p>Methods</p> <p>Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4⁺/CD8⁺cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis.</p> <p>Results</p> <p>Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8⁺cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup.</p> <p>Conclusion</p> <p>Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood.</p> <p>Clinical trial registration number</p> <p>NCT00086489</p

Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing.</p> <p>Methods</p> <p>The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity.</p> <p>Results</p> <p>Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by <it>in vitro </it>immune monitoring assays.</p> <p>Conclusions</p> <p>The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma.</p> <p>Clinical trial registration</p> <p>NCT00107159.</p

Measurements of elliptic and triangular flow in high-multiplicity 3^{3}He++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

We present the first measurement of elliptic ($v_2$) and triangular ($v_3$) flow in high-multiplicity $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in $^{3}$He$+$Au and in $p$$+$$p$ collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the $^{3}$He$+$Au system. The collective behavior is quantified in terms of elliptic $v_2$ and triangular $v_3$ anisotropy coefficients measured with respect to their corresponding event planes. The $v_2$ values are comparable to those previously measured in $d$$+$Au collisions at the same nucleon-nucleon center-of-mass energy. Comparison with various theoretical predictions are made, including to models where the hot spots created by the impact of the three $^{3}$He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.Comment: 630 authors, 9 pages, 4 figures, 2 tables. v2 is the version accepted for publication by Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm