An evaluation of air quality impact prediction performance undertaken as part of environmental impact assessment (EIA) in India.

Effective implementation of the Environmental Impact Assessment (EIA) is recognised as a global issue, in particular the impact prediction stage, which is the 'core' of EIA. Consisting of four stages: impact identification, impact assessment, significance evaluation, and mitigation measures on the possible environmental repercussions of project developmental activities, the efficacy of impact prediction can define the quality of the EIA process, which will better align environmental decision-making to sustainable development. The weakness of impact prediction in EIA demands more study to enhance practice. Although this is widely explored in the context of developed countries such as the UK, it is particularly concerning in India. A specialised review package built from several sources is utilised to assess the efficacy of air quality impact prediction, based on Lee & Colley (1991). 20 EIA reports of Category A (mega-scale projects causing significant environmental impacts) are reviewed. This study's evaluation indicates that significance evaluation and mitigation actions are the weakest phases and a major concern while assessing air quality studies conducted as a part of EIA. Recommendations to improve the process include prioritising the cumulative impact assessment within the regulatory framework, enhancing capacity building, embedding public participation and instilling accountability among stakeholders, which can be adopted globally. Additional recommendations specifically for India are revising the National Ambient Air Quality Standards (NAAQS), restructuring the EIA review mechanism by EAC and improving mitigation measures by adopting GIS and remote sensing technologies.

Integrated evidence-based extent of occurrence for North American bison (Bison bison) since 1500 CE and before.

Following the near extinction of bison (Bison bison) from its historic range across North America in the late 19th century, novel bison conservation efforts in the early 20th century catalyzed a popular widespread conservation movement to protect and restore bison among other species and places. Since Allen's initial delineation (1876) of the historic distribution of North American bison, subsequent attempts have been hampered by knowledge gaps about bison distribution and abundance prior to and following colonial arrival and settlement. For the first time, we applied a multidisciplinary approach to assemble a comprehensive, integrated geographic database and meta-analysis of bison occurrence over the last 200,000 years, with particular emphasis on the 450 years before present. We combined paleontology, archaeology, and historical ecology data for our database, which totaled 6438 observations. We derived the observations from existing online databases, published literature, and first-hand exploration journal entries. To illustrate the conservative maximum historical extent of occurrence of bison, we created a concave hull using observations occurring over the last 450 years (n = 3379 observations), which is the broadly accepted historical benchmark at 1500 CE covering 59% of the North American continent. Although this distribution represents a historic extent of occurrence-merely delineating the maximum margins of the near-continental distribution-it does not replace a density-based approach reconstructing potential historical range distributions, which identifies core and marginal ranges. However, we envision the observations contained in this database will contribute to further research in the increasingly evidence-based disciplines of bison ecology, evolution, rewilding, management, and conservation. There are no copyright or proprietary restrictions on these data, and this data paper should be cited when the data are reused.

A comparison of Mini-FLOTAC and McMaster techniques, overdispersion and prevalence of parasites in naturally infected North American bison (Bison bison) in the USA.

Several quantitative diagnostic techniques are available to estimate gastrointestinal parasite counts in the feces of ruminants. Comparing egg and oocyst magnitudes in naturally infected samples has been a recommended approach to rank fecal techniques. In this study, we compared the Mini-FLOTAC (sensitivity of 5 eggs per gram (EPG)/oocysts per gram (OPG)) and different averaged replicates of the modified McMaster techniques (sensitivity of 33.33 EPG/OPG) in 387 fecal samples from 10 herds of naturally infected North American bison in the Central Great Plains region of the USA. Both techniques were performed with fecal slurries homogenized in a fill-FLOTAC device. In the study population, prevalence of strongyle eggs, Eimeria spp. oocysts, Moniezia spp. eggs and Trichuris spp. eggs was 81.4%, 73.9%, 7.5%, and 3.1%, respectively. Counts of strongyle eggs and Eimeria spp. oocysts obtained from 1 to 3 averaged technical replicates of the modified McMaster technique were compared to a single replicate of the Mini-FLOTAC. Correlation between the two techniques increased with an increase in the number of averaged technical replicates of the modified McMaster technique used to calculate EGP/OPG. The correlation for Moniezia spp. EPG when averaged triplicates of the modified McMaster technique were compared to a single replicate of the Mini-FLOTAC count was high; however, the correlation for Trichuris spp. eggs was low. Additionally, we used averaged counts from both techniques to show the overdispersion of parasites in bison herds.

Attenuated HIV-1 Nef But Not Vpu Function in a Cohort of Rwandan Long-Term Survivors.

HIV-1 accessory proteins Nef and Vpu enhance viral pathogenesis through partially overlapping immune evasion activities. Attenuated Nef or Vpu functions have been reported in individuals who display slower disease progression, but few studies have assessed the relative impact of these proteins in non-B HIV-1 subtypes or examined paired proteins from the same individuals. Here, we examined the sequence and function of matched Nef and Vpu clones isolated from 29 long-term survivors (LTS) from Rwanda living with HIV-1 subtype A and compared our results to those of 104 Nef and 62 Vpu clones isolated from individuals living with chronic untreated HIV-1 subtype A from the same geographic area. Nef and vpu coding regions were amplified from plasma HIV RNA and cloned. The function of one intact, phylogenetically-validated Nef and Vpu clone per individual was then quantified by flow cytometry following transient expression in an immortalized CD4+ T-cell line. We measured the ability of each Nef clone to downregulate CD4 and HLA class I, and of each Vpu clone to downregulate CD4 and Tetherin, from the cell surface. Results were normalized to reference clones (Nef-SF2 and Vpu-NL4.3). We observed that Nef-mediated CD4 and HLA downregulation functions were lower in LTS compared to the control cohort (Mann-Whitney p=0.03 and p<0.0001, respectively). Moreover, we found a positive correlation between Nef-mediated CD4 downregulation function and plasma viral load in LTS and controls (Spearman ρ= 0.59, p=0.03 and ρ=0.30, p=0.005, respectively). In contrast, Vpu-mediated functions were similar between groups and did not correlate with clinical markers. Further analyses identified polymorphisms at Nef codon 184 and Vpu codons 60-62 that were associated with function, which were confirmed through mutagenesis. Overall, our results support attenuated function of Nef, but not Vpu, as a contributor to slower disease progression in this cohort of long-term survivors with HIV-1 subtype A.

Survey of Nursing Faculty Preparation for Guiding DNP Quality Improvement Projects.

BACKGROUND: Quality improvement (QI) projects comprise the majority of University of Maryland School of Nursing (UMSON) Doctor of Nursing Practice (DNP) projects. METHODS: An online survey was completed by 51% (n = 38) of faculty, who teach or mentor DNP students, and was analyzed using quantitative and descriptive methods. RESULTS: Faculty were somewhat or not familiar with developing a QI charter 68.4%, human error theory and error proofing 63.2%, driver diagrams 60.5%, characteristics of high-reliability organizations 60.5%, and Standards for Quality Improvement Reporting Excellence (SQUIRE) guidelines 55.3%. The faculty were most interested in learning more about (n = 97 responses) were human error theory and error proofing (28.9%), SQUIRE guidelines (26.3%), statistical process control (21.1%), and implementation strategies and tactics (21.1%). The most commonly identified challenges included identifying QI projects (24%), project time constraints (16%), keeping up-to-date on QI concepts, methods, and tools (12%), and balancing professional workload (10%). CONCLUSIONS: Gaps in self-reported QI knowledge indicate there is a need for further development of DNP and PhD prepared faculty at the UMSON.

Practice and Quality Improvement Leaders Survey of Expectations of DNP Graduates' Quality Improvement Expertise.

BACKGROUND: Input from practice leaders will improve how doctor of nursing practice (DNP) education is meeting the needs of the employer and improving patient outcomes. PURPOSE: This article describes the expectations practice leaders have of new DNP graduates' ability to contribute to quality improvement (QI) efforts within health care organizations. METHODS: A survey of practice leaders and QI experts investigated the importance and use of QI knowledge and skills. Practice leaders were also asked about the expectations of DNP graduates at the time of hire. RESULTS: The results of this study support the need for nurses pursuing a DNP in advanced nursing practice to have education and training beyond their area of specialization, specifically in QI methods and tools. CONCLUSIONS: Faculty need to provide DNP students education that includes concepts in QI and leadership to meet the expectations of future employers and the needs of a complex and changing health care system.

Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5.

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.

An ecological framework for contextualizing carnivore-livestock conflict.

Carnivore predation on livestock is a complex management and policy challenge, yet it is also intrinsically an ecological interaction between predators and prey. Human-wildlife interactions occur in socioecological systems in which human and environmental processes are closely linked. However, underlying human-wildlife conflict and key to unpacking its complexity are concrete and identifiable ecological mechanisms that lead to predation events. To better understand how ecological theory accords with interactions between wild predators and domestic prey, we developed a framework to describe ecological drivers of predation on livestock. We based this framework on foundational ecological theory and current research on interactions between predators and domestic prey. We used this framework to examine ecological mechanisms (e.g., density-mediated effects, behaviorally mediated effects, and optimal foraging theory) through which specific management interventions operate, and we analyzed the ecological determinants of failure and success of management interventions in 3 case studies: snow leopards (Panthera uncia), wolves (Canis lupus), and cougars (Puma concolor). The varied, context-dependent successes and failures of the management interventions in these case studies demonstrated the utility of using an ecological framework to ground research and management of carnivore-livestock conflict. Mitigation of human-wildlife conflict appears to require an understanding of how fundamental ecological theories work within domestic predator-prey systems.

Un Marco de Trabajo Ecológico para Contextualizar el Conflicto Carnívoro - Ganado Resumen La depredación del ganado por carnívoros es un reto complejo para el manejo y las políticas, a pesar de que es intrínsecamente una interacción ecológica entre depredadores y presas. Las interacciones entre humanos y la fauna ocurren en sistemas socio-ecológicos en los que los humanos y los procesos ambientales están conectados estrechamente. Sin embargo, el conflicto humano - fauna subyacente y la clave para desenredar su complejidad son mecanismos ecológicos complejos e identificables que resultan en eventos de depredación. Para tener un mejor entendimiento sobre cómo la teoría ecológica armoniza con las interacciones entre los depredadores silvestres y la presa doméstica, desarrollamos un marco de trabajo para describir las causantes ecológicas de la depredación del ganado. Basamos este marco de trabajo en las principales teorías ecológicas y las investigaciones actuales sobre las interacciones entre los depredadores y las presas domésticas. Usamos este marco de trabajo para examinar los mecanismos ecológicos (es decir, los efectos mediados por la densidad, los efectos mediados por el comportamiento, y la teoría del forrajeo óptimo) mediante los cuales operan ciertas intervenciones específicas de manejo y analizamos las determinantes ecológicas del fracaso y el éxito de las intervenciones de manejo en tres estudios de caso: el leopardo de las nieves (Panthera uncia), el lobo (Canis lupus), y el puma (Puma concolor). Los éxitos y fracasos variados y dependientes del contexto que sufrieron las intervenciones de manejo en estos estudios de caso demostraron la utilidad del uso de un marco de trabajo ecológico para aterrizar la investigación y el manejo del conflicto carnívoro - ganado. La mitigación del conflicto humano - fauna parece requerir de un entendimiento sobre cómo funcionan las teorías ecológicas fundamentales dentro del sistema doméstico depredador - presa.

Differential Vpu-Mediated CD4 and Tetherin Downregulation Functions among Major HIV-1 Group M Subtypes.

Downregulation of BST-2/tetherin and CD4 by HIV-1 viral protein U (Vpu) promotes viral egress and allows infected cells to evade host immunity. Little is known however about the natural variability in these Vpu functions among the genetically diverse viral subtypes that contribute to the HIV-1 pandemic. We collected Vpu isolates from 332 treatment-naive individuals living with chronic HIV-1 infection in Uganda, Rwanda, South Africa, and Canada. Together, these Vpu isolates represent four major HIV-1 group M subtypes (A [n = 63], B [n = 84], C [n = 94], and D [n = 59]) plus intersubtype recombinants and uncommon strains (n = 32). The ability of each Vpu clone to downregulate endogenous CD4 and tetherin was quantified using flow cytometry following transfection into an immortalized T-cell line and compared to that of a reference Vpu clone derived from HIV-1 subtype B NL4.3. Overall, the median CD4 downregulation function of natural Vpu isolates was similar to that of NL4.3 (1.01 [interquartile range {IQR}, 0.86 to 1.18]), while the median tetherin downregulation function was moderately lower than that of NL4.3 (0.90 [0.79 to 0.97]). Both Vpu functions varied significantly among HIV-1 subtypes (Kruskal-Wallis P < 0.0001). Specifically, subtype C clones exhibited the lowest CD4 and tetherin downregulation activities, while subtype D and B clones were most functional for both activities. We also identified Vpu polymorphisms associated with CD4 or tetherin downregulation function and validated six of these using site-directed mutagenesis. Our results highlight the marked extent to which Vpu function varies among global HIV-1 strains, raising the possibility that natural variation in this accessory protein may contribute to viral pathogenesis and/or spread.IMPORTANCE The HIV-1 accessory protein Vpu enhances viral spread by downregulating CD4 and BST-2/tetherin on the surface of infected cells. Natural variability in these Vpu functions may contribute to HIV-1 pathogenesis, but this has not been investigated among the diverse viral subtypes that contribute to the HIV-1 pandemic. In this study, we found that Vpu function differs significantly among HIV-1 subtypes A, B, C, and D. On average, subtype C clones displayed the lowest ability to downregulate both CD4 and tetherin, while subtype B and D clones were more functional. We also identified Vpu polymorphisms that associate with functional differences among HIV-1 isolates and subtypes. Our study suggests that genetic diversity in Vpu may play an important role in the differential pathogenesis and/or spread of HIV-1.

Decadal heat and drought drive body size of North American bison (Bison bison) along the Great Plains.

Large grazers are visible and valuable indicators of the effects of projected changes in temperature and drought on grasslands. The grasslands of the Great Plains have supported the greatest number of bison (Bison bison; Linnaeus, 1758) since prehistoric times. We tested the hypothesis that body mass (BM, kg) and asymptotic body mass (ABM, kg) of Bison decline with rising temperature and increasing drought over both temporal and spatial scales along the Great Plains. Temporally, we modeled the relationship of annual measures of BM and height (H, m) of 5,781 Bison at Wind Cave National Park (WICA) from 1966 to 2015. We used Gompertz equations of BM against age to estimate ABM in decadal cohorts; both females and males decreased from the 1960s to the 2010s. Male ABM was variable but consistently larger (699 vs. 441 kg) than female ABM. We used local mean decadal temperature (MDT) and local mean decadal Palmer Drought Severity Index (dPDSI) to model the effects of climate on ABM. Drought decreased ABM temporally (-16 kg/local dPDSI) at WICA. Spatially, we used photogrammetry to measure body height (HE ) of 773 Bison to estimate BME in 19 herds from Saskatchewan to Texas, including WICA. Drought also decreased ABM spatially (-16 kg/local dPDSI) along the Great Plains. Temperature decreased ABM both temporally at WICA (-115 kg/°C local MDT) and spatially (-1 kg/°C local MDT) along the Great Plains. Our data indicate that temperature and drought drive Bison ABM presumably by affecting seasonal mass gain. Bison body size is likely to decline over the next five decades throughout the Great Plains due to projected increases in temperatures and both the frequency and intensity of drought.

Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity.

The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol, and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies.IMPORTANCE The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.

CYP2B6 Genetic Polymorphisms, Depression, and Viral Suppression in Adults Living with HIV Initiating Efavirenz-Containing Antiretroviral Therapy Regimens in Uganda: Pooled Analysis of Two Prospective Studies.

Single-nucleotide polymorphisms (SNPs) in CYP2B6 have been shown to predict variation in plasma efavirenz concentrations, but associations between these SNPs and efavirenz-mediated depression and viral suppression are less well described. We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419) in Ugandan persons living with HIV. To define exposure, we used previously published pharmacokinetic modeling data to categorize participants as normal, intermediate, and poor efavirenz metabolizers. Our outcomes were probable depression in the first 2 years after antiretroviral therapy (ART) initiation (mean score of >1.75 on the Hopkins Symptom Depression Checklist) and viral suppression 6 months after ART initiation. We fit generalized estimating equation and modified Poisson regression models adjusted for demographic, clinical, and psychosocial characteristics with or without individuals with depression at the time of ART initiation. Among 242 participants, there were no differences in the pre-ART depression or viral load by efavirenz metabolism strata (p > .05). Participants were classified as normal (32%), intermediate (50%), and poor (18%) metabolizers. Seven percent (56/242) of follow-up visits met criteria for depression. Eighty-five percent (167/202) of participants who completed a 6-month visit achieved viral suppression. CYP2B6 metabolizer strata did not have a statistically significant association with either depression [adjusted risk ratio (aRR) comparing intermediate or poor vs. normal, 1.46; 95% confidence interval (CI), 0.72-2.95] or 6-month viral suppression (aRR, 1.01; 95% CI, 0.88-1.15). However, in analyses restricted to participants without pre-ART depression, poorer CYP2B6 metabolism was associated with increased odds of depression (adjusted odds ratio, 4.11; 95% CI, 1.04-16.20). Efavirenz-metabolizing allele patterns are strongly associated with risk of incident depression. Future work should elucidate further region-specific gene-environment interactions and whether alternate polymorphisms may be associated with efavirenz metabolism.

Bison body size and climate change.

The relationship between body size and temperature of mammals is poorly resolved, especially for large keystone species such as bison (Bison bison). Bison are well represented in the fossil record across North America, which provides an opportunity to relate body size to climate within a species. We measured the length of a leg bone (calcaneal tuber, DstL) in 849 specimens from 60 localities that were dated by stratigraphy and 14C decay. We estimated body mass (M) as M = (DstL/11.49)3. Average annual temperature was estimated from δ18O values in the ice cores from Greenland. Calcaneal tuber length of Bison declined over the last 40,000 years, that is, average body mass was 37% larger (910 ± 50 kg) than today (665 ± 21 kg). Average annual temperature has warmed by 6°C since the Last Glacial Maximum (~24-18 kya) and is predicted to further increase by 4°C by the end of the 21st century. If body size continues to linearly respond to global temperature, Bison body mass will likely decline by an additional 46%, to 357 ± 54 kg, with an increase of 4°C globally. The rate of mass loss is 41 ± 10 kg per°C increase in global temperature. Changes in body size of Bison may be a result of migration, disease, or human harvest but those effects are likely to be local and short-term and not likely to persist over the long time scale of the fossil record. The strong correspondence between body size of bison and air temperature is more likely the result of persistent effects on the ability to grow and the consequences of sustaining a large body mass in a warming environment. Continuing rises in global temperature will likely depress body sizes of bison, and perhaps other large grazers, without human intervention.

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers.

The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5+ CD4+ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5+ CD4+ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5+ CD4+ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5+ CD4+ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5+ CD4+ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

Fatal disseminated cowpox virus infection in an adolescent renal transplant recipient.

BACKGROUND: A 17-year-old boy on long-term immunosuppression following renal transplantation for chronic kidney disease (CKD), the result of dysplastic kidneys, initially presented with a swelling in his neck while attending hospital for an unrelated problem. A clinical diagnosis of tonsillitis was made, and he was treated with broad-spectrum antibiotics. Over a few days, his condition deteriorated, and he developed multiple vesicopustular skin lesions and required an emergency tonsillectomy due to respiratory distress. CASE DIAGNOSIS/TREATMENT: Histological investigation of the skin and tonsillar tissue suggested a viral aetiology, and subsequent electron microscopy and polymerase chain reaction (PCR) tissue examination proved disseminated cowpox infection. The family cat, which was reported as having self-resolving sores on its skin, was likely the source of the infection. The child failed to respond to antiviral treatment and succumbed to multiorgan failure within a month of admission. CONCLUSIONS: We report this case of fatal disseminated cowpox infection to highlight an increasing risk of this illness in the post-transplant population and to detail some unusual features not previously described, such as tonsillar involvement, disseminated skin lesions and multiorgan failure.

Illustration of a measure to combine viral suppression and viral rebound in studies of HIV therapy.

Viral load is an important tool for assessing antiretroviral treatment efficacy. However, the most common viral load end point, virologic failure, may be flawed. We illustrate an alternative end point that estimates the average time patients spent suppressed before rebound in the AIDS Clinical Trials Group A5095 trial. Patients averaged 644 days suppressed in the 3-drug arm and 686 days suppressed in the 4-drug arm, for a difference of 42 days in favor of the 4-drug regimen (95% confidence interval: -11 to 96). These results agree with results using virologic failure as the end point but better emphasize the separate suppression and rebound processes.

Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada.

BACKGROUND: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000-2007 in the U.S. and Canada. METHODS: Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables. RESULTS: The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000-2002 to 2006-2007. Men and women had comparable life expectancies in all periods except the last (2006-2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm(3). CONCLUSIONS: A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.

Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes.

BACKGROUND: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef's most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. RESULTS: Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function. CONCLUSIONS: Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation.