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Many of my colleagues and fellow investigators in the life sciences were surprised in late 2011 to hear about the deliberate laboratory manipulation of highly pathogenic avian influenza viruses for the purpose of creating derivative strains with enhanced capacity for respiratory transmission among mammals— strains with pandemic potential and serious global consequence. More importantly, few were prepared to undertake a reasoned and dispassionate assessment of the risks and benefits of such research and of its publication. This is unfortunate, not only because the resulting paucity of scientific leadership on this topic led to emotional and often unproductive discourse, but because new  instances of concerning research will be increasingly frequent and ever more consequential as the ongoing revolution in the life sciences unfolds.

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Hastings Center Report
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David Relman
David Relman
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Co-sponsored by the Center for South Asia, Stanford University

Human life expectancy improved more in the last 50 years than in the preceding 5000 years. Much of this recent progress arose from declines in childhood mortality, and most of this decline was due to scientific knowledge and technologies (defined widely as drugs, diagnostics, policies, strategies, and epidemiological knowledge). The dominant challenge of the 21st century is to apply scientific knowledge to reduce premature adult mortality, in particular from vascular and neoplastic disease but also from persistent infectious disease such as malaria. Reliable quantification of the causes of death is a key starting point for control of adult diseases, as shown by the early results from India's Million Death Study. Specific global attention is required to tobacco, as on current patterns there will be 1 billion deaths from smoking in the 21st century, as opposed to "only" 100 million deaths from smoking in the 20th century. Scientific research on adult mortality, paired with specific action, might well halve premature adult mortality worldwide in the next few decades.

Professor Prabhat Jha has been a key figure in epidemiology and economics of global health for the past decade. He is the University of Toronto Endowed Professor in Disease Control and Canada Research Chair at the Dalla Lana School of Public Health, and the founding Director of the Centre for Global Health Research at St. Michael's Hospital in Toronto. Professor Jha is a lead investigator of the Million Death Study in India, which quantifies the causes of premature mortality in over 1 million homes from 1997-2014 and which examines the contribution of key risk factors such as tobacco, alcohol, diet and environmental exposures. He is the author of several influential books on tobacco control, including two that helped enable a global treaty on tobacco control, now signed by over 160 countries.

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Prabhat Jha University of Toronto Endowed Professor in Disease Control and Canada Research Chair Speaker the Dalla Lana School of Public Health
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OBJECTIVE: To determine whether children in rural areas have worse health than children in urban areas after liver transplantation (LT). STUDY DESIGN: We used urban influence codes published by the US Department of Agriculture to categorize 3307 pediatric patients undergoing LT in the United Network of Organ Sharing database between 2004 and 2009 as urban or rural. Allograft rejection, patient death, and graft failure were used as primary outcome measures of post-LT health. Pediatric end-stage liver disease/model of end-stage liver disease scores >20 was used to measure worse pre-LT health. RESULTS: In a multivariate analysis, we found greater rates of allograft rejection within 6 months of LT (OR 1.27; 95% CI 1.05-1.53) and a lower occurrence of posttransplantation lymphoproliferative disorder (OR 0.64; 95% CI 0.41-0.99) in patients in rural areas. The difference in allograft rejection was eliminated at 1 year of LT (OR 1.18; 95% CI 0.98-1.42). Rural location did not impact other outcome measures. CONCLUSION: We conclude that rural location makes a negative impact on patient health within the first 6 months of LT by increasing the risk for allograft rejection, although patients in rural areas may have lower rates of developing posttransplantation lymphoproliferative disorder. Long-term adverse health effects were not seen.

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J Pediatr
Authors
KT Park
KT Park
R Bensen
B Lu
P Nanda
C Esquivel
K Cox
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Background: Pediatric liver transplant patients are at increased risk of post transplant lymphoproliferative disease (PTLD) from Epstein Barr virus (EBV) infection or reactivation after transplantation. The goal of this study was to determine the impact of induction and immunosuppression levels on the development of EBV viremia post transplantation. Methods: A retrospective chart review was performed on 104 patients less than 18 years of age who underwent isolated liver transplantation (LT) between 2000-2008 at Lucile Packard Children’s Hospital at Stanford University. Induction regiment, immunosuppression levels, and EBV viremia, as noted by any positive value of EBV polymerase chain reaction testing, was documented for one year post transplantation. Fixed-effects logistic regression models were constructed to determine associations between induction therapy, immunosuppression levels, and EBV viremia. A P-value < 0.05 was considered to be statistically significant. All statistical analyses were performed using STATA 11 (College Station, TX). Results: 56% of patients developed EBV viremia within one year of LT. Patients were more likely develop EBV viremia if they had received either anti-thymocyte globulin [ATG (73%)] or daclizumab (63%) for induction versus neither (39%), though the trend was not statistically significant (ATG: Odds ratio (OR) 0.19; 95% CI 0.024 – 1.58; p = 0.125; daclizumab: OR: 1.07; 95% CI 0.270 – 4.23; p=0.925). Tacrolimus immunosuppression levels were supratherapeutic 37% of the time within the first three months of transplant; however, only supratherapeutic tacrolimus levels between 0-2 weeks after transplant impacted the development of EBV viremia at 2-4 weeks post LT (OR 1.80; 95% CI 1.10-2.94; p=0.02). Only one patient developed PTLD during the study period. Conclusion: The type of induction used in isolated pediatric LT may play a role in the development of EBV viremia, with ATG and daclizumab leading to a higher incidence of EBV viremia, though it was not statistically significant. Supratherapeutic immunosuppression tacrolimus levels 0-2 weeks post LT impacted the development of EBV viremia at 2-4 weeks, but the effect was not seen at other time intervals. The incidence of PTLD in our study was low, suggesting better EBV and immunosuppression monitoring has played an important role in the reduction of complications associated with EBV viremia post pediatric LT.

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Transplantation Proceedings
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BR LuBR Lu
KT Park
KT Park
RB Balise
M Hurwitz
K Cox
WE Berquist
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Context  The effect of global health initiatives on population health is uncertain. Between 2003 and 2008, the US President's Emergency Plan for AIDS Relief (PEPFAR), the largest initiative ever devoted to a single disease, operated intensively in 12 African focus countries. The initiative's effect on all-cause adult mortality is unknown.

Objective  To determine whether PEPFAR was associated with relative changes in adult mortality in the countries and districts where it operated most intensively.

Design, Setting, and Participants  Using person-level data from the Demographic and Health Surveys, we conducted cross-country and within-country analyses of adult mortality (annual probability of death per 1000 adults between 15 and 59 years old) and PEPFAR's activities. Across countries, we compared adult mortality in 9 African focus countries (Ethiopia, Kenya, Mozambique, Namibia, Nigeria, Rwanda, Tanzania, Uganda, and Zambia) with 18 African nonfocus countries from 1998 to 2008. We performed subnational analyses using information on PEPFAR's programmatic intensity in Tanzania and Rwanda. We employed difference-in-difference analyses with fixed effects for countries and years as well as personal and time-varying area characteristics.

Main Outcome Measure  Adult all-cause mortality.

Results  We analyzed information on 1 538 612 adults, including 60 303 deaths, from 41 surveys in 27 countries, 9 of them focus countries. In 2003, age-adjusted adult mortality was 8.3 per 1000 adults in the focus countries (95% CI, 8.0-8.6) and 8.5 per 1000 adults (95% CI, 8.3-8.7) in the nonfocus countries. In 2008, mortality was 4.1 per 1000 (95% CI, 3.6-4.6) in the focus countries and 6.9 per 1000 (95% CI, 6.3-7.5) in the nonfocus countries. The adjusted odds ratio of mortality among adults living in focus countries compared with nonfocus countries between 2004 and 2008 was 0.84 (95% CI, 0.72-0.99; P = .03). Within Tanzania and Rwanda, the adjusted odds ratio of mortality for adults living in districts where PEPFAR operated more intensively was 0.83 (95% CI, 0.72-0.97; P = .02) and 0.75 (95% CI, 0.56-0.99; P = .04), respectively, compared with districts where it operated less intensively.

Conclusions  Between 2004 and 2008, all-cause adult mortality declined more in PEPFAR focus countries relative to nonfocus countries. It was not possible to determine whether PEPFAR was associated with mortality effects separate from reductions in HIV-specific deaths.

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Journal of the American Medical Association
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Eran Bendavid
Eran Bendavid
Charles Holmes
Jay Bhattacharya
Jay Bhattacharya
Grant Miller
Grant Miller
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Currently, more than two-thirds of the population in Africa must leave their home to fetch water for drinking and domestic use. The time burden of water fetching has been suggested to influence the volume of water collected by households as well as time spent on income generating activities and child care. However, little is known about the potential health benefits of reducing water fetching distances. Data from almost 200 000 Demographic and Health Surveys carried out in 26 countries were used to assess the relationship between household walk time to water source and child health outcomes. To estimate the causal effect of decreased water fetching time on health, geographic variation in freshwater availability was employed as an instrumental variable for one-way walk time to water source in a two-stage regression model. Time spent walking to a household’s main water source was found to be a significant determinant of under-five child health. A 15-min decrease in one-way walk time to water source is associated with a 41% average relative reduction in diarrhea prevalence, improved anthropometric indicators of child nutritional status, and a 11% relative reduction in under-five child mortality. These results suggest that reducing the time cost of fetching water should be a priority for water infrastructure investments in Africa.

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Environmental Science and Technology
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Amy Pickering
Jenna Davis
Jenna Davis
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Abstract

The structure of the contact network through which a disease spreads may influence the optimal use of resources for epidemic control. In this work, we explore how to minimize the spread of infection via quarantining with limited resources. In particular, we examine which links should be removed from the contact network, given a constraint on the number of removable links, such that the number of nodes which are no longer at risk for infection is maximized. We show how this problem can be posed as a non-convex quadratically constrained quadratic program (QCQP), and we use this formulation to derive a link removal algorithm. The performance of our QCQP-based algorithm is validated on small Erdo{double acute}s-Renyi and small-world random graphs, and then tested on larger, more realistic networks, including a real-world network of injection drug use. We show that our approach achieves near optimal performance and out-performs other intuitive link removal algorithms, such as removing links in order of edge centrality. © 2011 Elsevier Inc. All rights reserved.

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Mathematical Biosciences
Authors
Eva Enns
Mounzer, J.J.
Margaret Brandeau
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Background and Aims

Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.

Methods

We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).

Results

Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and $6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and $30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.

Conclusions

Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy.

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PLoS One
Authors
Shan Liu
Michaël Schwarzinger
Fabrice Carrat
Jeremy Goldhaber-Fiebert
Jeremy Goldhaber-Fiebert
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