Modeling The Zoonotic Transmission Dynamics Of Nipah Virus: Implications For Outbreak Control And Model-Guided Fieldwork

Introduction: Nipah virus is considered a biosafety level-4 pathogen that is endemic to bats of the genus Pteropus. Infection in humans presents clinically as febrile encephalitis with an extremely high case-fatality rate (78.2%). Outbreaks of Nipah virus infection have occurred in Bangladesh and India almost annually since 2001, most recently in January 2013. Methods: To elucidate Nipah virus persistence at the endemic host and human population level we developed a Susceptible-Exposed-Infectious-Recovered dynamic model and parameterized it from published epidemiological case data and serological bats surveys on the Nipah Virus-Bangladesh variant. We conducted a Markov Chain Monte Carlo simulation to estimate the unknown parameters for bat-to-bat, bat-to-human, human-to-human, and corpse-to-human transmission routes. Results: We present the first estimates of the four disease transmission rates and reproductive numbers of Nipah virus in the human and bat population. Our results indicate that at population equilibrium 1.77 bats per day will have an active infection, additionally 93.0% of human infections are the result of zoonotic transmission, but only 5.3% of these primary cases transmit disease to other humans, which may indicate the presence of super-spreaders. Conclusions: This work draws conclusions about enzootic viral maintenance of Nipah in the bat population as well as epizootic outbreaks in human hosts to better inform model- guided fieldwork and public health interventions in Bangladesh

Prenatal stress perturbs fetal iron homeostasis in a sex specific manner

The adverse effects of maternal prenatal stress (PS) on child’s neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.Fil: Zimmermann, Peter. Technische Universitat München; AlemaniaFil: Antonelli, Marta Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Sharma, Ritika. Technische Universitat München; AlemaniaFil: Müller, Alexander. Technische Universitat München; AlemaniaFil: Zelgert, Camilla. Technische Universitat München; AlemaniaFil: Fabre, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Wenzel, Natasha. University of Washington; Estados UnidosFil: Wu, Hau Tieng. University of Duke; Estados UnidosFil: Frasch, Martin Gerbert. University of Washington; Estados UnidosFil: Lobmaier, Silvia M.. Technische Universitat München; Alemani

Effect of developmental stage of HSC and recipient on transplant outcomes

The first hematopoietic stem cells (HSCs) that engraft irradiated adult mice arise in the aorta-gonad-mesonephros (AGM) on embryonic day 11.5 (E11.5). However, at this stage, there is a discrepancy between the apparent frequency of HSCs depicted with imaging and their rarity when measured with limiting dilution transplant. We have attempted to reconcile this difference using neonatal recipients, which are more permissive for embryonic HSC engraftment. We found that embryonic HSCs from E9.5 and E10.5 preferentially engrafted neonates, whereas developmentally mature, definitive HSCs from E14.5 fetal liver or adult bone marrow (BM) more robustly engrafted adults. Neonatal engraftment was enhanced after treating adult BM-derived HSCs with interferon. Adult BM-derived HSCs preferentially homed to the liver in neonatal mice yet showed balanced homing to the liver and spleen in adults. These findings emphasize the functional differences between nascent and mature definitive HSCs

Retrospective Analysis of the 2014-2015 Ebola Epidemic in Liberia.

The 2014-2015 Ebola epidemic has been the most protracted and devastating in the history of the disease. To prevent future outbreaks on this scale, it is imperative to understand the reasons that led to eventual disease control. Here, we evaluated the shifts of Ebola dynamics at national and local scales during the epidemic in Liberia. We used a transmission model calibrated to epidemiological data between June 9 and December 31, 2014, to estimate the extent of community and hospital transmission. We found that despite varied local epidemic patterns, community transmission was reduced by 40-80% in all the counties analyzed. Our model suggests that the tapering of the epidemic was achieved through reductions in community transmission, rather than accumulation of immune individuals through asymptomatic infection and unreported cases. Although the times at which this transmission reduction occurred in the majority of the Liberian counties started before any large expansion in hospital capacity and the distribution of home protection kits, it remains difficult to associate the presence of interventions with reductions in Ebola incidence

Harnessing case isolation and ring vaccination to control Ebola.

As a devastating Ebola outbreak in West Africa continues, non-pharmaceutical control measures including contact tracing, quarantine, and case isolation are being implemented. In addition, public health agencies are scaling up efforts to test and deploy candidate vaccines. Given the experimental nature and limited initial supplies of vaccines, a mass vaccination campaign might not be feasible. However, ring vaccination of likely case contacts could provide an effective alternative in distributing the vaccine. To evaluate ring vaccination as a strategy for eliminating Ebola, we developed a pair approximation model of Ebola transmission, parameterized by confirmed incidence data from June 2014 to January 2015 in Liberia and Sierra Leone. Our results suggest that if a combined intervention of case isolation and ring vaccination had been initiated in the early fall of 2014, up to an additional 126 cases in Liberia and 560 cases in Sierra Leone could have been averted beyond case isolation alone. The marginal benefit of ring vaccination is predicted to be greatest in settings where there are more contacts per individual, greater clustering among individuals, when contact tracing has low efficacy or vaccination confers post-exposure protection. In such settings, ring vaccination can avert up to an additional 8% of Ebola cases. Accordingly, ring vaccination is predicted to offer a moderately beneficial supplement to ongoing non-pharmaceutical Ebola control efforts

Cost-effectiveness of next-generation vaccines: The case of pertussis.

Despite steady vaccination coverage rates, pertussis incidence in the United States has continued to rise. This public health challenge has motivated calls for the development of a new vaccine with greater efficacy and duration of protection. Any next-generation vaccine would likely come at a higher cost, and must provide sufficient health benefits beyond those provided by the current vaccine in order to be deemed cost-effective. Using an age-structured transmission model of pertussis, we quantified the health and economic benefits of a next-generation vaccine that would enhance either the efficacy or duration of protection of the childhood series, the duration of the adult booster, or a combination. We developed a metric, the maximum cost-effective price increase (MCPI), to compare the potential value of such improvements. The MCPI estimates the per-dose price increase that would maintain the cost-effectiveness of pertussis vaccination. We evaluated the MCPI across a range of potential single and combined improvements to the pertussis vaccine. As an upper bound, we found that a next-generation vaccine which could achieve perfect efficacy for the childhood series would permit an MCPI of $18 per dose (95$12-$31). Pertussis vaccine improvements that extend the duration of protection to an average of 75 years would allow for an MCPI of$22 per dose for the childhood series (CI: $10-$33) or $12 for the adult booster (CI:$4-$18). Despite the short duration of the adult booster, improvements to the childhood series could be more valuable than improvements to the adult booster. Combining improvements in both efficacy and duration, a childhood series with perfect efficacy and average duration of 75 years would permit an MCPI of$39 per dose, the highest of any scenario evaluated. Our results highlight the utility of the MCPI metric in evaluating potential vaccines or other interventions when prices are unknown

Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis

Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at embryonic day 9.5, an embryonic stage not previously described to harbor HSCs. Effects on hematopoiesis are mediated in part by a cascade downstream of wall shear stress that involves calcium efflux and stimulation of the prostaglandin E2 (PGE2)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling axis. Blockade of the PGE2-cAMP-PKA pathway in the aorta-gonad-mesonephros (AGM) abolished enhancement in hematopoietic activity. Furthermore, Ncx1 heartbeat mutants, as well as static cultures of AGM, exhibit lower levels of expression of prostaglandin synthases and reduced phosphorylation of the cAMP response element-binding protein (CREB). Similar to flow-exposed cultures, transient treatment of AGM with the synthetic analogue 16,16-dimethyl-PGE2 stimulates more robust engraftment of adult recipients and greater lymphoid reconstitution. These data provide one mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe