HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015

BACKGROUND: In January 2015, a total of 11 new diagnoses of human immunodeficiency virus (HIV) infection were reported in a small community in Indiana. We investigated the extent and cause of the outbreak and implemented control measures. METHODS: We identified an outbreak-related case as laboratory-confirmed HIV infection newly diagnosed after October 1, 2014, in a person who either resided in Scott County, Indiana, or was named by another case patient as a syringe-sharing or sexual partner. HIV polymerase (pol) sequences from case patients were phylogenetically analyzed, and potential risk factors associated with HIV infection were ascertained. RESULTS: From November 18, 2014, to November 1, 2015, HIV infection was diagnosed in 181 case patients. Most of these patients (87.8%) reported having injected the extended-release formulation of the prescription opioid oxymorphone, and 92.3% were coinfected with hepatitis C virus. Among 159 case patients who had an HIV type 1 pol gene sequence, 157 (98.7%) had sequences that were highly related, as determined by phylogenetic analyses. Contact tracing investigations led to the identification of 536 persons who were named as contacts of case patients; 468 of these contacts (87.3%) were located, assessed for risk, tested for HIV, and, if infected, linked to care. The number of times a contact was named as a syringe-sharing partner by a case patient was significantly associated with the risk of HIV infection (adjusted risk ratio for each time named, 1.9; P<0.001). In response to this outbreak, a public health emergency was declared on March 26, 2015, and a syringe-service program in Indiana was established for the first time. CONCLUSIONS: Injection-drug use of extended-release oxymorphone within a network of persons who inject drugs in Indiana led to the introduction and rapid transmission of HIV. (Funded by the state government of Indiana and others.)

SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen Aspergillus fumigatus

Sterol regulatory element binding proteins (SREBPs) are a class of basic helix-loop-helix transcription factors that regulate diverse cellular responses in eukaryotes. Adding to the recognized importance of SREBPs in human health, SREBPs in the human fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus are required for fungal virulence and susceptibility to triazole antifungal drugs. To date, the exact mechanism(s) behind the role of SREBP in these observed phenotypes is not clear. Here, we report that A. fumigatus SREBP, SrbA, mediates regulation of iron acquisition in response to hypoxia and low iron conditions. To further define SrbA's role in iron acquisition in relation to previously studied fungal regulators of iron metabolism, SreA and HapX, a series of mutants were generated in the ΔsrbA background. These data suggest that SrbA is activated independently of SreA and HapX in response to iron limitation, but that HapX mRNA induction is partially dependent on SrbA. Intriguingly, exogenous addition of high iron or genetic deletion of sreA in the ΔsrbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of ΔsrbA. Thus, we conclude that the fungal SREBP, SrbA, is critical for coordinating genes involved in iron acquisition and ergosterol biosynthesis under hypoxia and low iron conditions found at sites of human fungal infections. These results support a role for SREBP–mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

SREBP-Dependent Triazole Susceptibility in Aspergillus fumigatus Is Mediated through Direct Transcriptional Regulation of erg11A (cyp51A)

As triazole antifungal drug resistance during invasive Aspergillus fumigatus infection has become more prevalent, the need to understand mechanisms of resistance in A. fumigatus has increased. The presence of two erg11 (cyp51) genes in Aspergillus spp. is hypothesized to account for the inherent resistance of this mold to the triazole fluconazole (FLC). Recently, an A. fumigatus null mutant of a transcriptional regulator in the sterol regulatory element binding protein (SREBP) family, the ΔsrbA strain, was found to have increased susceptibility to FLC and voriconazole (VCZ). In this study, we examined the mechanism engendering the observed increase in A. fumigatus triazole susceptibility in the absence of SrbA. We observed a significant reduction in the erg11A transcript in the ΔsrbA strain in response to FLC and VCZ. Transcript levels of erg11B were also reduced but not to the extent of erg11A. Interestingly, erg11A transcript levels increased upon extended VCZ, but not FLC, exposure. Construction of an erg11A conditional expression strain in the ΔsrbA strain was able to restore erg11A transcript levels and, consequently, wild-type MICs to the triazole FLC. The VCZ MIC was also partially restored upon increased erg11A transcript levels; however, total ergosterol levels remained significantly reduced compared to those of the wild type. Induction of the erg11A conditional strain did not restore the hypoxia growth defect of the ΔsrbA strain. Taken together, our results demonstrate a critical role for SrbA-mediated regulation of ergosterol biosynthesis and triazole drug interactions in A. fumigatus that may have clinical importance

Hypoxia enhances innate immune activation to Aspergillus fumigatus through cell wall modulation

International audienceInfection by the human fungal pathogen Aspergillus fumigatus induces hypoxic microenvironments within the lung that can alter the course of fungal pathogenesis. How hypoxic microenvironments shape the composition and immune activating potential of the fungal cell wall remains undefined. Herein we demonstrate that hypoxic conditions increase the hyphal cell wall thickness and alter its composition particularly by augmenting total and surface-exposed β-glucan content. In addition, hypoxia-induced cell wall alterations increase macrophage and neutrophil responsiveness and antifungal activity as judged by inflammatory cytokine production and ability to induce hyphal damage. We observe that these effects are largely dependent on the mammalian β-glucan receptor dectin-1. In a corticosteroid model of invasive pulmonary aspergillosis, A. fumigatus β-glucan exposure correlates with the presence of hypoxia in situ. Our data suggest that hypoxia-induced fungal cell wall changes influence the activation of innate effector cells at sites of hyphal tissue invasion, which has potential implications for therapeutic outcomes of invasive pulmonary aspergillosis

Bone Marrow Transplantation as a Therapy for Autosomal Dominant Osteopetrosis Type 2 in Mice

Autosomal dominant osteopetrosis type II (ADO2) is a heritable bone disease of impaired osteoclastic bone resorption caused by missense mutations in the chloride channel 7 (CLCN7) gene. Clinical features of ADO2 include fractures, osteomyelitis of jaw, vision loss, and in severe cases, bone marrow failure. Currently, there is no effective therapy for ADO2, and patients usually receive symptomatic treatments. Theoretically, bone marrow transplantation (BMT), which is commonly used in recessive osteopetrosis, could be used to treat ADO2, although the frequency of complications related to BMT is quite high. We created an ADO2 knock-in (p.G213R mutation) mouse model on the 129 genetic background, and their phenotypes mimic the human disease of ADO2. To test whether BMT could restore osteoclast function and rescue the bone phenotypes in ADO2 mice, we transplanted bone marrow cells from 6-8 weeks old male WT donor mice into recipient female ADO2 mice. Also, to determine whether age at the time of transplant may play a role in transplant success, we performed BMT in young (12-week-old) and old (9-month-old) ADO2 mice. Our data indicate that ADO2 mice transplanted with WT marrow achieved more than 90% engraftment up to 6 months post-transplantation at both young and old ages. The in-vivo DXA data revealed that young ADO2 mice transplanted with WT marrow had significantly lower whole body and spine areal bone mineral density (aBMD) at month 6 post-transplantation compared to the ADO2 control mice. The old ADO2 mice also displayed significantly lower whole body, femur and spine aBMD at months 4 and 5 post-transplantation compared to the age-matched control mice. The in-vivo micro-CT data showed that ADO2 experimental mice transplanted with WT marrow had significantly lower BV/TV at months 2 and 4 post-transplantation compared to the ADO2 control mice at young age. In contrast, ADO2 control and experimental mice displayed similar BV/TV values for all post-transplantation time points at old age. In addition, serum CTX was significantly higher at month 2 post-transplantation in both young and old ADO2 experimental mice compared to the ADO2 control mice. Serum P1NP levels in young ADO2 experimental mice were significantly higher at baseline and month 2 post-transplantation compared to the ADO2 control mice. These data suggest that BMT may provide, at least, some beneficial effect at both young and adult ages

ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence.

The Aspergillus fumigatus sterol regulatory element binding protein (SREBP) SrbA belongs to the basic Helix-Loop-Helix (bHLH) family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA). How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. To further understand the role of SrbA in fungal infection site pathobiology, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) was used to identify genes under direct SrbA transcriptional regulation in hypoxia. These results confirmed the direct regulation of ergosterol biosynthesis and iron uptake by SrbA in hypoxia and revealed new roles for SrbA in nitrate assimilation and heme biosynthesis. Moreover, functional characterization of an SrbA target gene with sequence similarity to SrbA identified a new transcriptional regulator of the fungal hypoxia response and virulence, SrbB. SrbB co-regulates genes involved in heme biosynthesis and demethylation of C4-sterols with SrbA in hypoxic conditions. However, SrbB also has regulatory functions independent of SrbA including regulation of carbohydrate metabolism. Loss of SrbB markedly attenuates A. fumigatus virulence, and loss of both SREBPs further reduces in vivo fungal growth. These data suggest that both A. fumigatus SREBPs are critical for hypoxia adaptation and virulence and reveal new insights into SREBPs' complex role in infection site adaptation and fungal virulence

A large HCV transmission network enabled a fast-growing HIV outbreak in rural Indiana, 2015Research in context

Background: A high prevalence (92.3%) of hepatitis C virus (HCV) co-infection among HIV patients identified during a large HIV outbreak associated with injection of oxymorphone in Indiana prompted genetic analysis of HCV strains. Methods: Molecular epidemiological analysis of HCV-positive samples included genotyping, sampling intra-host HVR1 variants by next-generation sequencing (NGS) and constructing transmission networks using Global Hepatitis Outbreak and Surveillance Technology (GHOST). Findings: Results from the 492 samples indicate predominance of HCV genotypes 1a (72.2%) and 3a (20.4%), and existence of 2 major endemic NS5B clusters involving 49.8% of the sequenced strains. Among 76 HIV co-infected patients, 60.5% segregated into 2 endemic clusters. NGS analyses of 281 cases identified 826,917 unique HVR1 sequences and 51 cases of mixed subtype/genotype infections. GHOST mapped 23 transmission clusters. One large cluster (n = 130) included 50 cases infected with ≥2 subtypes/genotypes and 43 cases co-infected with HIV. Rapid strain replacement and superinfection with different strains were found among 7 of 12 cases who were followed up. Interpretation: GHOST enabled mapping of HCV transmission networks among persons who inject drugs (PWID). Findings of numerous transmission clusters, mixed-genotype infections and rapid succession of infections with different HCV strains indicate a high rate of HCV spread. Co-localization of HIV co-infected patients in the major HCV clusters suggests that HIV dissemination was enabled by existing HCV transmission networks that likely perpetuated HCV in the community for years. Identification of transmission networks is an important step to guiding efficient public health interventions for preventing and interrupting HCV and HIV transmission among PWID. Fund: US Centers for Disease Control and Prevention, and US state and local public health departments