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Cornell M.,Center for Infectious Disease | Johnson L.F.,Center for Infectious Disease | Schomaker M.,Center for Infectious Disease | Tanser F.,University of Cape Town | And 11 more authors.
The Lancet HIV | Year: 2015

Background As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the eff ect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the eff ect of age on mortality of patients on ART in South Africa and whether this eff ect is mediated by baseline immunological status. Methods In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the fi rst time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDSSouthern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. Findings Between Jan 1, 2004, and Dec 31, 2013, 84 078 eligible adults started ART. Of these, we followed up 83 566 patients for 174 640 patient-years. 8% (1817 of 23 258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2·52 (95% CI 2·01-3·17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per μL, the adjusted mortality hazard ratio was 2·52 (2·04-3·11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per μL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44 909 patients still alive and in care were aged 50 years or older. Interpretation Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. Funding National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis.


Sotgiu G.,University of Sassari | Centis R.,Care and Research Institute | D'Ambrosio L.,Care and Research Institute | Alffenaar J.-W.C.,University of Groningen | And 17 more authors.
European Respiratory Journal | Year: 2012

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Metaanalysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid. Copyright©ERS 2012.


Schecter G.F.,Center for Infectious Disease | Scott C.,Center for Infectious Disease | Scott C.,Centers for Disease Control and Prevention | True L.,Center for Infectious Disease | And 3 more authors.
Clinical Infectious Diseases | Year: 2010

Background. Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDRTB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. Methods. Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. Results. During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. Conclusions. Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB. © 2009 by the Infectious Diseases Society of America. All rights reserved.


News Article | December 20, 2016
Site: www.eurekalert.org

LA JOLLA, CA--Aedes aegypti mosquitoes harboring parasitic Zika virus (ZIKV) are the primary transmitters of virus to humans, potentially causing catastrophic congenital microcephaly in babies born to women bitten by infected mosquitoes. But confirmation earlier this year by the Centers for Disease Control and Prevention (CDC) that ZIKV can also be sexually transmitted raised new alarm that virus could be passed between sexual partners in venues far from mosquito habitats. Now La Jolla Institute for Allergy & Immunology (LJI) investigator Sujan Shresta, Ph.D., employs two different mouse models to confirm that live ZIKV placed directly in the vagina infects the mouse's reproductive tract, replicates, moves into the bloodstream, and causes clinical signs of disease. Intriguingly, that study published in the December 20, 2016 issue of Cell Reports, also reports that the stage of the reproductive cycle during which a female mouse is exposed to virus determines vulnerability to infection. If applicable to humans, this discovery has public health implications for virus transmission to a population of great concern, women of child-bearing age. "Currently, almost all of our efforts in terms of Zika prevention focus on mosquito control," says Shresta, an associate professor in LJI's Center for Infectious Disease. "Our new work begs clinicians to also address whether sexual transmission of the virus constitutes a small or large proportion of cases." Investigators knew that virus hides in semen of men who contract ZIKV from mosquitoes and that virus is transmitted vaginally in rodent models. But the biological questions--what cells are infected, how stable the virus is in bodily fluids--were unanswered. Shresta's group began to explore them by placing live ZIKV in the vaginas of female mice that had been genetically engineered to be immunocompromised. But before the procedure, they treated mice with hormones to create two groups that differed with regard to where they were in their menstrual cycle. Dramatic differences emerged post-infection: mice infected in the diestrus or in between phase became progressively sick, lost weight, and died in 2-3 weeks, as one might predict in these mice. Remarkably, the same strain of immunocompromised AG129 mice infected in estrus phase showed no sign of disease. William Weihao Tang, the study's first author, calls this one the paper's most intriguing findings. "The strain of mice we used, called AG129, were originally engineered to be extremely vulnerable to infection," he says. "But even these mice, when infected in estrus phase, appeared completely resistant to virus. That surprised us." Shresta says that a caveat is that responses in mouse strains like AG129, which were purposely engineered to serve as a "lethal" model of infection, must be tested in mice with greater immune function. "For science to be relevant to humans, we always confirm results in the most 'immunocompetent' mouse that better reflects a normal human immune system." To do that, her team repeated experiments in an entirely different type of engineered mouse, one only moderately susceptible to infection, which scientists call a "non-lethal" model. When infected in diestrus phase, those mice lost weight and exhibited clinical signs of disease but, unlike their AG129 counterparts, eventually recovered. However, just like the AG129 mice, when infected in estrus phase "non-lethal" mice showed no sign of Zika-like disease. This trend was reflected in other experimental outcomes. For example, in both lethal and non-lethal strains, viral RNA, which serves as direct evidence of virus, persisted in the vaginal canal sometimes as long as 10 days post-infection in diestrus. By contrast, viral RNA disappeared three days after infection in estrus phase. Virus persistence in vaginal fluids may account for why diestrus-infected mice become sick, regardless of mouse strain, yet the molecular or cellular basis for susceptibility remains unclear. Mice analyzed in the study were experimentally synchronized or "staged" at one of two reproductive phases by hormonal injection, which may provide a clue. "Hormones changed the mouse female reproductive tract in ways that either enhanced or protected against sexual transmission," says Tang, although he and Shresta caution it is much too early to generalize mouse findings to humans. But if similar mechanisms prove relevant to human transmission, they are cause for concern, largely because most Zika-infected men or women show few or no symptoms. Thus they could unwittingly engage in sexual activity resulting in adult disease or even in utero transfer of virus to an unborn child. Recent CDC "case counts" suggest that thus far that few Zika cases in the US were likely transmitted sexually. But these numbers are estimates, and sexual transmission of ZIKV is taken extremely seriously in other regions, such as South America. In fact, one mathematical modeling study of Baranquilla, Colombia, estimated that as many as 47% of Zika cases reported there emerged from sexual contact. "In humans sexual transmission may be a bigger deal than has been thought," says Shresta, emphasizing that currently we know very little about this mode of Zika transmission. "We know that in males virus can remain in semen for possibly months, while a man shows no symptoms. During that time he could unknowingly pass it to a sexual partner." The next step for the Shresta lab is to take advantage of these two mouse models to define immune signals that make mice susceptible to or protected from ZIKV infection. "We are ultimately interested in drugs or vaccines to prevent the disease," says Shresta, who has also used immunodeficient mice as models to study dengue virus infection. "Being able to test interventions in two animal models, one that succumbs to infection and another that recovers, is a plus. Developing vaccines requires access to models representing all scenarios." Other contributors include Matthew Perry Young, Anila Mamidi, Jose Angel Regla-Nava, PhD, and Kenneth Kim, DVM, all from LJI. The study was funded by NIAID/NIH grant 1R01 AI116813 and by institutional support from the La Jolla Institute for Allergy and Immunology. La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.


News Article | December 23, 2016
Site: www.eurekalert.org

A newly discovered virus infecting the fungus that causes white-nose syndrome in bats could help scientists and wildlife agencies track the spread of the disease that is decimating bat populations in the United States, a new study suggests. Regional variations in this virus could provide clues that would help researchers better understand the epidemiology of white-nose syndrome, according to Marilyn Roossinck, professor of plant pathology and environmental microbiology, College of Agricultural Sciences, Penn State. White-nose syndrome is a particularly lethal wildlife disease, killing an estimated 6 million bats in North America since it was identified in 2006. The disease, caused by the fungus Pseudogymnoascus destructans, first was found in New York and now has spread to 29 states and four Canadian provinces. Although several species of bats have been affected, some of the most prevalent species in the Northeast -- such as little brown bats -- have suffered estimated mortality as high as 99 percent. These losses have serious ecological implications. For instance, bats have a voracious appetite for insects and are credited with helping to control populations of mosquitoes and some agricultural pests. The researchers examined 62 isolates of the fungus, including 35 from the United States, 10 from Canada and 17 from Europe, with the virus infection found only in North American samples. P. destructans is clonal, meaning it is essentially identical everywhere it has been found in North America, making it difficult to determine how it is moving, said Roossinck, who also is affiliated with Penn State's Center for Infectious Disease Dynamics. "But the virus it harbors has quite a bit of variation," she said. "For example, in all the fungal isolates from Pennsylvania we analyzed, the viruses are similar. But those viruses differ from the ones we found in isolates from Canada, New York and so forth." Roossinck explained that fungal viruses are not readily transmitted among fungi, so the variation in the viral genome probably is occurring as the virus evolves within each fungal isolate, providing a marker. "So we believe the differences in the viruses reflect the movement of the fungus, and this viral variability should enable us to get a better handle on how the disease is spreading," she said. The virus is not thought to cause disease, but researchers don't yet know whether it influences the virulence of the fungus, Roossinck noted. "It's very difficult to study virulence in terms of infection in the bats in part because there are almost no bats left to study, and we don't have an experimental system that works." The researchers, who reported their results today (Dec 23) online in PLOS Pathogens, were able to eliminate the virus from one fungal isolate, which provided a virus-free isolate that they could compare to wild isolates that harbor the virus to look for biochemical changes. "Although we didn't look directly at the role of the virus in white-nose syndrome, there is evidence of a close biological relationship between the fungus and the virus," Roossinck said. "We found that the virus-free isolate makes many fewer spores than an isolate with the virus, suggesting that the virus may be beneficial to the fungus in reproduction. "We don't know whether the fungus spreads through spores or through direct contact between bats," she said. "But if it spreads via spores, the virus actually could be enhancing the spread of white-nose syndrome as a result of this increased spore production." Roossinck said the study has important implications in the search for ways to save the bats of North America. "There's a lot we don't know about white-nose syndrome, and before we can develop control strategies, we have to better understand the biology of the system. We now have a tool that can be used in broader studies to examine the epidemiology of the disease." Other Penn State researchers on this project were Vaskar Thapa, postdoctoral fellow in plant pathology and environmental microbiology, and Susan Hafenstein, assistant professor of medicine. Other researchers were Gregory G. Turner, Pennsylvania Game Commission; Barrie E. Overton, biology professor, Lock Haven University of Pennsylvania, and Karen J. Vanderwolf, formerly at New Brunswick Museum, Saint John, Canada, and now at University of Wisconsin, Madison. The Pennsylvania Game Commission, the Huck Institutes of the Life Sciences and the College of Agricultural Sciences, Penn State supported this research.


Gershon A.A.,Columbia University | Gershon M.D.,Columbia University | Breuer J.,Center for Infectious Disease | Levin M.J.,University of Colorado at Denver | And 2 more authors.
Journal of Clinical Virology | Year: 2010

SUMMARY: The primary varicella zoster virus (VZV) infection results in chickenpox (varicella), which is transmitted via the airborne route. VZV is highly infectious, but in the USA the incidence of varicella has been reduced by 76-87% as a result of the varicella vaccine. The virus establishes latency in the dorsal root ganglia during varicella and, when reactivated, travels along the sensory nerve axons to cause shingles (herpes zoster [HZ]). There are over 1 million cases of HZ in the USA each year, with an estimated lifetime attack rate of 30%. The incidence of HZ, which causes significant morbidity, increases with age and reaches approximately 10 cases per 1,000 patient-years by age 80. Cell-mediated immunity (CMI) is known to decline with age as part of immunosenescence, and decreased CMI is associated with reactivation of VZV. This article provides an overview of our emerging understanding of the epidemiology and pathogenesis of varicella and HZ, in addition to exploring the current theories on latency and reactivation. Understanding the risk factors for developing HZ and the complications associated with infection, particularly in older people, is important for prompt diagnosis and management of HZ in primary care, and they are therefore also reviewed. © 2010 Elsevier B.V. All rights reserved.


Price C.L.,Imperial College London | Hassi H.O.S.A.,Imperial College London | English N.R.,Imperial College London | Blakemore A.I.F.,Imperial College London | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2010

Increased methylglyoxal (MG) concentrations and formation of advanced glycation end-products (AGEs) are major pathways of glycaemic damage in diabetes, leading to vascular and neuronal complications. Diabetes patients also suffer increased susceptibility to many common infections, the underlying causes of which remain elusive. We hypothesized that immune glycation damage may account for this increased susceptibility. We previously showed that the reaction mixture (RM) for MG glycation of peptide blocks up regulation of CD83 in myeloid cells and inhibits primary stimulation of T cells. Here, we continue to investigate immune glycation damage, assessing surface and intracellular cytokine protein expression by flow cytometry, T-cell proliferation using a carboxyfluorescein succinimidyl ester assay, and mRNA levels by RT-PCR. We show that the immunomodulatory component of this RM was MG itself, with MG alone causing equivalent block of CD83 and loss of primary stimulation. Block of CD83 expression could be reversed by MG scavenger N-acetyl cysteine. Further, MG within RM inhibited stimulated production of interleukin (IL)-10 protein from myeloid cells plus interferon (IFN)-γ and tumour necrosis factor (TNF)-α from T cells. Loss of IL-10 and IFN-γ was confirmed by RT-PCR analysis of mRNA, while TNF-α message was raised. Loss of TNF-α protein was also shown by ELISA of culture supernatants. In addition, MG reduced major histocompatibility complex (MHC) class I expression on the surface of myeloid cells and increased their propensity to apoptose. We conclude that MG is a potent suppressor of myeloid and T-cell immune function and may be a major player in diabetes-associated susceptibility to infection. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Halpin H.A.,University of California at Berkeley | Milstein A.,Stanford University | Shortell S.M.,University of California at Berkeley | Vanneman M.,University of California at Berkeley | Rosenberg J.,Center for Infectious Disease
Health Affairs | Year: 2011

One way to motivate hospitals to improve patient safety is to publicly report their rates of hospital-acquired infections, as California is starting to do this year. We conducted a baseline study of California's acute care hospitals just before mandatory reporting of hospital-acquired infection rates to the state began, in 2008. We found variability in many areas: For example, 70.1 percent of hospitals said that they were fully implementing evidence-based guidelines to fight infection by methicillin-resistant Staphylococcus aureus, but 22.8 percent of hospitals had not adopted any. Our analysis showed that rural hospitals, many of which lack resources to implement needed procedures, faced the greatest challenges in reporting and improving infection rates. Our findings should be of interest to Medicare policy makers who will implement the hospital-acquired infection performance measures in the Affordable Care Act, and to leaders in the thirty-eight states that have enacted legislation requiring reports of hospital-acquired infection rates. California's baseline data also present a unique opportunity to assess the impact of mandatory and public reporting laws. © 2011 by Project HOPE - The People-to-People Health Foundation, Inc.


Regional variations in this virus could provide clues that would help researchers better understand the epidemiology of white-nose syndrome, according to Marilyn Roossinck, professor of plant pathology and environmental microbiology, College of Agricultural Sciences, Penn State. White-nose syndrome is a particularly lethal wildlife disease, killing an estimated 6 million bats in North America since it was identified in 2006. The disease, caused by the fungus Pseudogymnoascus destructans, first was found in New York and now has spread to 29 states and four Canadian provinces. Although several species of bats have been affected, some of the most prevalent species in the Northeast—such as little brown bats—have suffered estimated mortality as high as 99 percent. These losses have serious ecological implications. For instance, bats have a voracious appetite for insects and are credited with helping to control populations of mosquitoes and some agricultural pests. The researchers examined 62 isolates of the fungus, including 35 from the United States, 10 from Canada and 17 from Europe, with the virus infection found only in North American samples. P. destructans is clonal, meaning it is essentially identical everywhere it has been found in North America, making it difficult to determine how it is moving, said Roossinck, who also is affiliated with Penn State's Center for Infectious Disease Dynamics. "But the virus it harbors has quite a bit of variation," she said. "For example, in all the fungal isolates from Pennsylvania we analyzed, the viruses are similar. But those viruses differ from the ones we found in isolates from Canada, New York and so forth." Roossinck explained that fungal viruses are not readily transmitted among fungi, so the variation in the viral genome probably is occurring as the virus evolves within each fungal isolate, providing a marker. "So we believe the differences in the viruses reflect the movement of the fungus, and this viral variability should enable us to get a better handle on how the disease is spreading," she said. The virus is not thought to cause disease, but researchers don't yet know whether it influences the virulence of the fungus, Roossinck noted. "It's very difficult to study virulence in terms of infection in the bats in part because there are almost no bats left to study, and we don't have an experimental system that works." The researchers, who reported their results today (Dec 23) online in PLOS Pathogens, were able to eliminate the virus from one fungal isolate, which provided a virus-free isolate that they could compare to wild isolates that harbor the virus to look for biochemical changes. "Although we didn't look directly at the role of the virus in white-nose syndrome, there is evidence of a close biological relationship between the fungus and the virus," Roossinck said. "We found that the virus-free isolate makes many fewer spores than an isolate with the virus, suggesting that the virus may be beneficial to the fungus in reproduction. "We don't know whether the fungus spreads through spores or through direct contact between bats," she said. "But if it spreads via spores, the virus actually could be enhancing the spread of white-nose syndrome as a result of this increased spore production." Roossinck said the study has important implications in the search for ways to save the bats of North America. "There's a lot we don't know about white-nose syndrome, and before we can develop control strategies, we have to better understand the biology of the system. We now have a tool that can be used in broader studies to examine the epidemiology of the disease." Explore further: Some bats develop resistance to devastating fungal disease


Burghardt N.O.,Center for Infectious Disease | Chow J.M.,Center for Infectious Disease | Steiner A.,Center for Infectious Disease | Bauer H.M.,Center for Infectious Disease
Sexually Transmitted Diseases | Year: 2016

Background Juvenile detention facilities house adolescents at high risk for sexually transmitted diseases. Collaboration between health departments and juvenile detention authorities can provide routine, cost-efficient chlamydia screening and treatment to females with limited access to care. We describe trends in screening, positivity, treatment, and associated costs in a well-established juvenile detention chlamydia screening program. Methods In the California Chlamydia Screening Project, juvenile detention facilities in 12 counties collected quarterly aggregate data on female census and line-listed chlamydia test results and treatment data from fiscal year (FY) 2003-2004 to FY 2013-2014. Trends in the proportion of females screened, positivity, and treatment by age, race/ethnicity, and facility volume were evaluated by Cochran-Armitage test. The median cost of the program per chlamydia positive identified was compared by facility in FY 2013-2014. Results Data from 59,518 test records among juvenile females indicated high screening rates (75.1%-79.4%). Chlamydia positivity, although consistently high, decreased from 14.8% in 2003-2004 to 11.5% in 2013-2014 (P < 0.001). Documented treatment decreased (88.8% in 2005-2006 to 79.0% in 2013-2014, P < 0.001); of those treated, treatment within 7 days increased (80.1% in 2005-2006 to 88.8% in 2013-2014, P < 0.001). The median cost per chlamydia positive identified was $708 (interquartile range, $669-$894) and was lowest for facilities with high chlamydia positivity. Conclusions The California Chlamydia Screening Project demonstrated consistently high rates of chlamydia screening and positivity among adolescent females while keeping costs low for high-volume facilities. Further improvement in timely treatment rates remains a challenge for extending the impact of screening in this high-risk population. © 2015 Lippincott Williams & Wilkins.

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