Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2018
Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua.
Dengue virus (DENV) is the most prevalent human vector-borne viral disease. The force of infection (FoI), the rate at which susceptible individuals are infected in a population, is an important metric for infectious disease modeling. Understanding how and why the FoI of DENV changes over time is critical for developing immunization and vector control policies. ⋯ We show that the initial high FoI can be explained by the introduction of DENV-3 in 1994-1998, and that the overall gradual decline in the FoI can be attributed to demographic shifts. Changes in immunity and demographics strongly impacted DENV transmission in Nicaragua. Population-level measures of transmission intensity are dynamic and thus challenging to use to guide vaccine implementation locally and globally.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2018
Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy.
In gene therapy for Duchenne muscular dystrophy there are two potential immunological obstacles. An individual with Duchenne muscular dystrophy has a genetic mutation in dystrophin, and therefore the wild-type protein is "foreign," and thus potentially immunogenic. The adeno-associated virus serotype-6 (AAV6) vector for delivery of dystrophin is a viral-derived vector with its own inherent immunogenicity. ⋯ Treatment with the engineered DNA construct encoding microdystrophin markedly reduced antibody responses to dystrophin and to AAV6. Muscle force in the treated mice was also improved compared with control mice. These data highlight the potential benefits of administration of an engineered DNA plasmid encoding the delivered protein to overcome critical barriers in gene therapy to achieve optimal functional gene expression.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2018
The impact of exposure to air pollution on cognitive performance.
This paper examines the effect of both cumulative and transitory exposures to air pollution for the same individuals over time on cognitive performance by matching a nationally representative longitudinal survey and air quality data in China according to the exact time and geographic locations of the cognitive tests. We find that long-term exposure to air pollution impedes cognitive performance in verbal and math tests. We provide evidence that the effect of air pollution on verbal tests becomes more pronounced as people age, especially for men and the less educated. The damage on the aging brain by air pollution likely imposes substantial health and economic costs, considering that cognitive functioning is critical for the elderly for both running daily errands and making high-stake decisions.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2018
Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption.
Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in breast cancer brain metastases at cellular resolution: doxorubicin, a nontargeted chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy, we demonstrate significant increases in the extravasation of both agents (sevenfold and twofold for doxorubicin and T-DM1, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 µm and 42 ± 7 vs. 12 ± 4 µm for doxorubicin and T-DM1, respectively) after the application of FUS compared with control (non-FUS). ⋯ Quantification with PBPK modeling reveals an increase in transmembrane transport by more than two orders of magnitude. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel wall pores with a narrow range of sizes (diameter, 10-50 nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of strategies to treat brain metastases.
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2018
Multicenter StudyPatient-physician gender concordance and increased mortality among female heart attack patients.
Very interesting study covering 20 years of Floridian ED patient admissions for myocardial infarct, looking specifically at the influence of gender-discordance between patient and doctor.
The headline finding was that female heart-attack patients experienced lower survival when treated by a male physician than when by a female physician. Baseline mortality across all patients was 11.9%, with a 1.5% absolute survival decrease when compared to male patients treated by female physicians.
Although on the surface this absolute effect size could be misinterpreted as small, it represents a 12% relative risk difference – quite meaningful when we are considering mortality from the leading cause of death in the U.S.
Could the researchers suggest a reason?
The authors identified two interesting points:
- Female patients treated in EDs with a higher percentage or a higher number of female physicians were more likely to survive. Although true of both care from a female or male physician, the beneficial survival effect of a greater female physician presence, was more marked when treated by a male doctor.
- Female patients treated by male physicians were also more likely to survive when the male physician had previously seen more female patients (0.02% increased survival for each female patient seen in the last quarter!).
summary"These results suggest a reason why gender inequality in heart attack mortality persists: Most physicians are male, and male physicians appear to have trouble treating female patients." – Greenwood, 2018