Howard Markel

SUCCESSFUL TREATMENT OF HOMOZYGOUS PROTEIN C DEFICIENCY BY HEPATIC TRANSPLANTATION

A child with homozygous protein C deficiency was treated at age 20 months by orthotopic hepatic transplantation. Postoperatively there was complete reconstitution of protein C activity and resolution of the thrombotic condition.

The Foreignness of Germs: The Persistent Association of Immigrants and Disease in American Society

During the 20th century the United States witnessed social, political, and economic transformations as well as advancements in medical diagnosis and care. Despite changes in demography, the meaning of citizenship, and the ability to treat and cure acute and chronic diseases, foreigners were consistently associated with germs and contagion. This article explores why, at critical junctures in American history, immigrants have been stigmatized as the etiology of a variety of physical and societal ills. The article analyzes three periods from 1880 to the present and suggests that now, as germs progressively and, often, indiscriminately cross national, social, and economic boundaries through multiple vectors, the mistakes of the past must not be repeated. Protecting the public health in the current era of globalization requires an ecumenical, pragmatic, and historically informed approach to understanding the links between immigration and disease.

Research findings from nonpharmaceutical intervention studies for pandemic influenza and current gaps in the research.

In June 2006, the Centers for Disease Control and Prevention released a request for applications to identify, improve, and evaluate the effectiveness of nonpharmaceutical interventions (NPIs)-strategies other than vaccines and antiviral medications-to mitigate the spread of pandemic influenza within communities and across international borders (RFA-CI06-010). These studies have provided major contributions to seasonal and pandemic influenza knowledge. Nonetheless, key concerns were identified related to the acceptability and protective efficacy of NPIs. Large-scale intervention studies conducted over multiple influenza epidemics, as well as smaller studies in controlled laboratory settings, are needed to address the gaps in the research on transmission and mitigation of influenza in the community setting. The current novel influenza A (H1N1) pandemic underscores the importance of influenza research.

Reconstruction of the 1918 Influenza Virus: Unexpected Rewards from the Past

ABSTRACT The influenza pandemic of 1918–1919 killed approximately 50 million people. The unusually severe morbidity and mortality associated with the pandemic spurred physicians and scientists to isolate the etiologic agent, but the virus was not isolated in 1918. In 1996, it became possible to recover and sequence highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims. These viral RNA sequences eventually permitted reconstruction of the complete 1918 virus, which has yielded, almost a century after the deaths of its victims, novel insights into influenza virus biology and pathogenesis and has provided important information about how to prevent and control future pandemics.

Nonpharmaceutical Influenza Mitigation Strategies, US Communities, 1918-1920 Pandemic

We studied nonpharmaceutical interventions used to mitigate the second, and most deadly, wave of the 1918–1920 influenza pandemic in the United States. We conclude that several small communities implemented potentially successful attempts at preventing the introduction of influenza.

Ontology-based combinatorial comparative analysis of adverse events associated with killed and live influenza vaccines.

Vaccine adverse events (VAEs) are adverse bodily changes occurring after vaccination. Understanding the adverse event (AE) profiles is a crucial step to identify serious AEs. Two different types of seasonal influenza vaccines have been used on the market: trivalent (killed) inactivated influenza vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV). Different adverse event profiles induced by these two groups of seasonal influenza vaccines were studied based on the data drawn from the CDC Vaccine Adverse Event Report System (VAERS). Extracted from VAERS were 37,621 AE reports for four TIVs (Afluria, Fluarix, Fluvirin, and Fluzone) and 3,707 AE reports for the only LAIV (FluMist). The AE report data were analyzed by a novel combinatorial, ontology-based detection of AE method (CODAE). CODAE detects AEs using Proportional Reporting Ratio (PRR), Chi-square significance test, and base level filtration, and groups identified AEs by ontology-based hierarchical classification. In total, 48 TIV-enriched and 68 LAIV-enriched AEs were identified (PRR>2, Chi-square score >4, and the number of cases >0.2% of total reports). These AE terms were classified using the Ontology of Adverse Events (OAE), MedDRA, and SNOMED-CT. The OAE method provided better classification results than the two other methods. Thirteen out of 48 TIV-enriched AEs were related to neurological and muscular processing such as paralysis, movement disorders, and muscular weakness. In contrast, 15 out of 68 LAIV-enriched AEs were associated with inflammatory response and respiratory system disorders. There were evidences of two severe adverse events (Guillain-Barre Syndrome and paralysis) present in TIV. Although these severe adverse events were at low incidence rate, they were found to be more significantly enriched in TIV-vaccinated patients than LAIV-vaccinated patients. Therefore, our novel combinatorial bioinformatics analysis discovered that LAIV had lower chance of inducing these two severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines.

Donabedian’s Lasting Framework for Health Care Quality

In a landmark article published 50 years ago, Avedis Donabedian proposed using the triad of structure, process, and outcome to evaluate the quality of health care. That triad, along with his eventual seven pillars of quality, continues to inform efforts to improve care.

What Mexico Taught the World About Pandemic Influenza Preparedness and Community Mitigation Strategies

ON APRIL 24, 2009, FOR THE FIRST TIME IN MEXIcan history, President Felipe Calderon invoked the emergency health powers outlined in Mexico’s Constitution and General Health Law. The catalyst for this dramatic action was the appearance of a novel strain of influenza A(H1N1) of unclear severity. Harkening back to measures that originated in the late 14th century, when bubonic plague stalked much of Europe and Asia prompting ports and nation-states to order mass quarantines, Mexico instituted a broad-based and exacting menu of community mitigation strategies, or nonpharmaceutical interventions (NPIs), including school closure, public gathering bans, isolation, quarantine, and social distancing. Beginning on the morning of April 24, all schools were closed in Mexico City, the world’s third largest metropolis (population 20 million), which encompasses the federal district and state of Mexico. By April 27, authorities cast the net wider and all Mexicans awoke to shuttered schools, emptied restaurants, a steady stream of personal hygiene messages, and sporting events closed to spectators but broadcast on national television. For the next 2 weeks, Mexico came to a virtual standstill. The foundation of Mexico’s response is an increasing body of historical, epidemiological, and modeling data demonstrating statistically significant associations between the early, layered, and sustained implementation of NPIs and a reduction in peak mortality rate, the time to reach peak mortality, and the cumulative mortality burden from influenza. As Ignacio Villasenor Ruiz, MD of Mexico City’s health department told us in a recent interview, “[We] had to recognize that influenza transmission could not be stopped, but we could do two things” using community mitigation strategies, “first, slow the transmission rate and second, lower mortality.” The prevailing perception among international health experts is that Mexico responded swiftly, transparently, and efficaciously to mitigate the spread of influenza. However, these actions carried high social, political, and economic costs. The critical question to ask, as nations and communities consider applying such disruptive measures this coming fall, is what successes, problems, and lessons for the future can be gleaned from what many Mexicans consider a watershed in public health. To capture a historical snapshot of these events, we traveled to Mexico in early July 2009 and interviewed dozens of Mexican citizens and public officials. The following is a precis of our impressions.

Patents, profits, and the American people--the Bayh-Dole Act of 1980.

The Bayh–Dole Act of 1980 permitted scientists, universities, and businesses to patent and profit from discoveries made through federally funded research. A review of the laws history supports the idea that such policies merit frequent reappraisal and reform.

LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents

Two adolescents with a long history of abuse of lysergic acid diethylamide (LSD) and symptoms consistent with major depressive disorder, on initiation of antidepressant therapy with selective serotonin reuptake inhibitor agents, had the new onset or worsening of LSD flashback syndrome. The similarity in neuroreceptor physiology for both LSD and serotonin suggests that the LSD flashback syndrome may be induced by these drugs in patients with a history of LSD abuse.