Twenty years of global surveillance of antituberculosis-drug resistance

Antimicrobial resistance represents a major threat to global health and security. In 2014, the World Health Assembly called on all nations and the international community to take every necessary measure to control it, including surveillance of its emergence and spread.1 The development of drug resistance in Mycobacterium tuberculosis was first documented in the late 1940s, soon after antibiotic therapy was introduced for tuberculosis treatment.2 It quickly became obvious that combination chemotherapy could prevent the emergence of drug resistance3 and that patients infected with drug-resistant strains were less likely to be cured.4 Nevertheless, it was only in the early 1990s that drugresistant tuberculosis began to receive global attention as a public health threat. This coincided with the detection of outbreaks of multidrugresistant (MDR) tuberculosis (defined as resistance to at least rifampin and isoniazid) that were associated with high mortality among patients coinfected with the human immunodeficiency virus (HIV).5-8 The urgent need for a global mechanism to monitor the emergence and spread of resistance to antituberculosis drugs became clear. In 1994, the Global Tuberculosis Program of the World Health Organization (WHO), with the support of the International Union against Tuberculosis and Lung Disease (the Union), established the Global Project on Anti-Tuberculosis Drug Resistance Surveillance (hereafter referred to as \u201cthe project\u201d) to measure the magnitude of drug resistance and to monitor trends. This project remains the oldest and largest initiative on the surveillance of antimicrobial resistance in the world.9 In this article, we describe the history of global surveillance of drug resistance in tuberculosis and discuss methods for surveillance, the quality of available data, the key achievements and findings to date, the main challenges that remain, and future directions

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

The orphaning experience: descriptions from Ugandan youth who have lost parents to HIV/AIDS

The HIV/AIDS epidemic has continued to pose significant challenges to countries in Sub-Saharan Africa. Millions of African children and youth have lost parents to HIV/AIDS leaving a generation of orphans to be cared for within extended family systems and communities. The experiences of youth who have lost parents to the HIV/AIDS epidemic provide an important ingress into this complex, evolving, multi-dimensional phenomenon. A fundamental qualitative descriptive study was conducted to develop a culturally relevant and comprehensive description of the experiences of orphanhood from the perspectives of Ugandan youth. A purposeful sample of 13 youth who had lost one or both parents to HIV/AIDS and who were affiliated with a non-governmental organization providing support to orphans were interviewed. Youth orphaned by HIV/AIDS described the experience of orphanhood beginning with parental illness, not death. Several losses were associated with the death of a parent including lost social capitol, educational opportunities and monetary assets. Unique findings revealed that youth experienced culturally specific stigma and conflict which was distinctly related to their HIV/AIDS orphan status. Exploitation within extended cultural family systems was also reported. Results from this study suggest that there is a pressing need to identify and provide culturally appropriate services for these Ugandan youth prior to and after the loss of a parent(s)

The Contribution of Coevolving Residues to the Stability of KDO8P Synthase

The evolutionary tree of 3-deoxy-D-manno-octulosonate 8-phosphate (KDO8P) synthase (KDO8PS), a bacterial enzyme that catalyzes a key step in the biosynthesis of bacterial endotoxin, is evenly divided between metal and non-metal forms, both having similar structures, but diverging in various degrees in amino acid sequence. Mutagenesis, crystallographic and computational studies have established that only a few residues determine whether or not KDO8PS requires a metal for function. The remaining divergence in the amino acid sequence of KDO8PSs is apparently unrelated to the underlying catalytic mechanism.The multiple alignment of all known KDO8PS sequences reveals that several residue pairs coevolved, an indication of their possible linkage to a structural constraint. In this study we investigated by computational means the contribution of coevolving residues to the stability of KDO8PS. We found that about 1/4 of all strongly coevolving pairs probably originated from cycles of mutation (decreasing stability) and suppression (restoring it), while the remaining pairs are best explained by a succession of neutral or nearly neutral covarions.Both sequence conservation and coevolution are involved in the preservation of the core structure of KDO8PS, but the contribution of coevolving residues is, in proportion, smaller. This is because small stability gains or losses associated with selection of certain residues in some regions of the stability landscape of KDO8PS are easily offset by a large number of possible changes in other regions. While this effect increases the tolerance of KDO8PS to deleterious mutations, it also decreases the probability that specific pairs of residues could have a strong contribution to the thermodynamic stability of the protein

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses