Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation

BACKGROUND: In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease (CVD) events. People with HIV have elevated levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer; HIV-induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD. Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. METHODS AND RESULTS: Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD. Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios (ORs) (fatal versus nonfatal CVD) (95% confidence intervals [CIs]) associated with a doubling of IL-6, D-dimer, hsCRP, and a 1-unit increase in an IL-6 and D-dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD, 23 died during follow-up. Hazard ratios (95% CI) for all-cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL-6, D-dimer, hsCRP, and the IL-6 and D-dimer score. CONCLUSIONS: Higher IL-6 and D-dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrial.gov Unique identifier: SMART: NCT00027352, ESPRIT: NCT00004978, SILCAAT: NCT00013611

Relação entre o número de espécies e o número de táxones de alto nível para a fauna de artrópodes dos Açores

Nesta contribuição pretendemos avaliar a aplicação dos modelos RESTAN, "Relação entre o número de Espécies e o número de Táxones de Alto Nível", à fauna de artrópodes de vários habitats das ilhas dos Açores. Utilizámos várias bases de dados recentemente obtidas baseadas em amostragens estandardizadas de artrópodes epígeos do solo em florestas de áreas protegidas, artrópodes fitófagos e predadores de pastagens semeadas e semi-naturais e artrópodes da copa da árvore endémica Juniperus brevifolia. Os modelos RESTAN são aplicados não só usando dados puramente taxonómicos, mas igualmente agrupando os taxa em termos de estratégias ecológicas (e.g. herbívoros, predadores) e de colonização das ilhas (e.g. endémicos). Deste modo pensamos poder avaliar a aplicabilidade destes modelos em estudos de estrutura de comunidades e de conservação. Para os Açores, a aplicação dos modelos RESTAN constitui uma forma muito prática e eficaz de obter estimativas de diversidade. De facto, em todas as matrizes de dados analisadas a riqueza de espécies pode ser estimada eficazmente usando apenas a riqueza em géneros, sendo a relação linear. Ao nível da família, os modelos estimadores possuem um menor poder explicativo e são melhor explicados por uma função exponencial. O escalonamento de Reservas Florestais Naturais dos Açores em termos de biodiversidade de artrópodes endémicos pode ser efectuado usando informação taxonómica ao nível do género. A aplicação de métodos de estimativa rápida de biodiversidade fica assim facilitada, podendo usar-se parataxonomistas bem treinados para o processo de triagem do grande número de amostras geralmente necessárias em estudos ecológicos. Discute-se igualmente a aplicabilidade dos modelos RESTAN a dados de diversidade alfa, beta e gama.ABSTRACT: In this contribution we examine the predictive power of numbers of higher taxa (orders, families and genera) as surrogates of species richness ("RESTAN" models – models based on linear relationship between species and higher taxa numbers) for the Azorean arthropod fauna. Recently, two large entomological and ecological studies were performed in the Azores, using standardized sampling protocols to estimate the diversity of arthropods in grassland and native forests. We use datasets available from those studies to address a few technical questions: A. what is the impact of using several measures of diversity (alpha, gamma and beta species diversity; Shannon-Wiener index of diversity; Evenness) based on numbers of families and genera for canopy arthropods? For instance, could be predicted that values of beta-diversity decrease with the use of higher-taxa estimates. All the measures of diversity could be used, being the genera the best predictor; B. how well behave the RESTAN models for functional groups of species like grass-feeding and web-building spiders in grasslands? The predictive power of higher-taxa is low using web-building spiders, due to few families being envolved and some genera having many species locally represented; C. assuming at least one sample with no species then there will be also no highertaxa in that sample. Consequently, the curve of the relationship between highertaxa richness and species richness should be anchored to the origin (y= bx). What is the predictive value of this model in comparison with the linear (y =a + bx), log-log (log y = a + b log x) and exponential (y = A • e b x) models? The best fit was obtained with the linear model for the genus-species relationship, but the variables are not normally distributed and the log-log model should be preferable. For the family-species relationship the exponential model is the best. The linear model anchored to the origin (y =bx) has some statistical pitfalls and was of less predictive value; D. in conservation studies what is the predictive value of higher-taxa in ranking protected areas? We found that the numbers of arthropod genera could successfully rank the Natural Forest Reserves as well as numbers of species (using endemic species dataset). We found that in the Azores the predictions of species richness using higher-taxa are quite reasonable, mainly because of low levels of diversity. Therefore, costeffective studies could use only genera, since the species richness of arthropods could be predicted reasonably closely from their genus-level richness. Family and order-level data were less informative for all datasets. We suggest that in the Azores as a consequence of the low levels of species diversification with a great proportion of monospecific genera, the use of parataxonomists trained in genus-level identification could be appropriate for sorting large numbers of ecological samples

Factors associated with D-dimer levels in HIV-infected individuals.

BACKGROUND: Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood. METHODS: In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol. RESULTS: Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels. CONCLUSIONS: D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels

The effect of interrupted/deferred antiretroviral therapy on disease risk: a SMART & START combined analysis

Background: Pooled data from SMART and START were used to compare deferred/intermittent versus immediate/continuous antiretroviral therapy (ART) on disease risk. Methods: Endpoints assessed were AIDS, serious non-AIDS (SNA), cardiovascular disease (CVD), cancer, and death. Pooled (stratified by study) hazard ratios (HRs) from Cox models were obtained for deferred/intermittent ART vs immediate/continuous ART; analyses were conducted to assess consistency of HRs across baseline-defined subgroups. Results: Among 10156 participants, there were 124 AIDS, 247 SNA, 117 cancers, 103 CVD and 120 deaths. Interventions in each trial led to similar differences in CD4 count and viral suppression Pooled HRs (95% CI) of deferred/intermittent ART vs immediate/continuous ART were for AIDS 3.63 (2.37, 5.56); SNA 1.62 (1.25-2.09); CVD 1.59 (1.07-2.37); cancer 1.93 (1.32-2.83); and death 1.80 (1.24-2.61). Underlying risk was greater in SMART than START. Given the similar HRs for each study, absolute risk differences between treatment groups were greater in SMART than START. Pooled HRs were similar across subgroups. Conclusions: Treatment group differences in CD4 count and viral suppression were similar in SMART and START. Likely as a consequence, relative differences in risk of AIDS and SNA between immediate/continuous ART and deferred/intermittent ART were similar

Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral Treated People With Human Immunodeficiency Virus (HIV)

Background: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. Methods: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. Results: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/μL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. Conclusions: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM

Ranking protected areas in the Azores using standardised sampling of soil epigean arthropods

Copyright © Springer 2005.Nineteen areas in seven of the nine Azorean islands were evaluated for species diversity and rarity based on soil epigean arthropods. Fifteen out of the 19 study areas are managed as Natural Forest Reserves and the remaining four were included due to their importance as indigenous forest cover. Four of the 19 areas are not included in the European Conservation network, NATURA 2000. Two sampling replicates were run per study area, and a total of 191 species were collected; 43 of those species (23%) are endemic to the archipelago and 12 have yet to be described. To produce an unbiased multiple-criteria index (importance value for conservation, IV-C) incorporating diversity and rarity based indices, an iterative partial multiple regression analysis was performed. In addition, an irreplaceability index and the complementarity method (using both optimisation and heuristic methods) were used for priority-reserves analyses. It was concluded that at least one well-managed reserve per island is absolutely necessary to have a good fraction of the endemic arthropods preserved. We found that for presence/absence data the suboptimal complementarity algorithm provides solutions as good as the optimal algorithm. For abundance data, optimal solutions indicate that most reserves are needed if we want that at least 50% of endemic arthropod populations are represented in a minimum set of reserves. Consistently, two of the four areas not included in the NATURA 2000 framework were considered of high priority, indicating that vascular plants and bird species used to determine NATURA 2000 sites are not good surrogates of arthropod diversity in the Azores. The most irreplaceable reserves are those located in older islands, which indicates that geological history plays an important role in explaining faunal diversity of arthropods in the Azores. Based both on the uniqueness of species composition and high species richness, conservation efforts should be focused on the unmanaged Pico Alto region in the archipelago’s oldest island, Santa Maria

Classification of death causes after transplantation (CLASS):Evaluation of methodology and initial results

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry

Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation

Background-In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease (CVD) events. People with HIV have elevated levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer; HIV-induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD. Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. Methods and Results-Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD. Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios (ORs) (fatal versus nonfatal CVD) (95% confidence intervals [CIs]) associated with a doubling of IL-6, D-dimer, hsCRP, and a 1-unit increase in an IL-6 and D-dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD, 23 died during follow-up. Hazard ratios (95% CI) for all-cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL-6, D-dimer, hsCRP, and the IL-6 and D-dimer score. Conclusions-Higher IL-6 and D-dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD even