Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Binding asymmetry and conformational studies of the AtGSDA dimer.

Guanosine deaminase (GSDA) is an important deaminase that converts guanosine to xanthosine, a key intermediate in nitrogen recycling in plants. We previously solved complex structures of Arabidopsis thaliana GSDA bound by various ligands and examined its catalytic mechanism. Here, we report cocrystal structures of AtGSDA bound by inactive guanosine derivatives, which bind relatively weakly to the enzyme and mostly have poor binding geometries. The two protomers display unequal binding performances, and molecular dynamics simulation identified diverse conformations during the enzyme-ligand interactions. Moreover, intersubunit, tripartite salt bridges show conformational differences between the two protomers, possibly acting as "gating" systems for substrate binding and product release. Our structural and biochemical studies provide a comprehensive understanding of the enzymatic behavior of this intriguing enzyme.

Plasma Biomarkers of Alzheimer Disease in Women With and Without HIV.

Importance: Blood-based biomarkers associated with increased risk of Alzheimer disease (AD) are understudied in people living with and without HIV, particularly women. Objective: To determine whether baseline or 1-year changes in plasma amyloid-ß40 (Aß40), Aß42, ratio of Aß42 to Aß40, total tau (t-tau), phosphorylated tau 231 (p-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NFL) are associated with neuropsychological performance (NP) among women living with HIV (WLWH) and women living without HIV (WLWOH). Design, Setting, and Participants: This longitudinal, prospective, cohort study with 1-year repeated clinical measures (NP only measured once) and biospecimen collection occurred between 2017 and 2019. Participants were women aged 40 years or older from 10 clinical research sites in cities across the US that were part of the Women's Interagency HIV Study. Data analysis was conducted from April to December 2022. Exposure: Laboratory-confirmed HIV status and AD biomarkers. Main Outcomes and Measures: Sociodemographically adjusted NP T-scores (attention and working memory, executive function, processing speed, memory, learning, verbal fluency, motor function, and global performance) were the primary outcomes. Baseline and 1-year fasting plasma Aß40, Aß42, t-tau, p-tau231, GFAP, and NFL levels were measured and analyzed using multivariable linear regression. Results: The study consisted of 307 participants (294 aged ≥50 years [96%]; 164 African American or Black women [53%]; 214 women with a high school education or higher [70%]; 238 women who were current or former smokers [78%]; and 236 women [77%] who were overweight or obese [body mass index >25]) including 209 WLWH and 98 WLWOH. Compared with WLWOH at baseline, WLWH performed worse on learning (mean [SD] T-score 47.8 [11.3] vs 51.4 [10.5]), memory (mean [SD] T-score 48.3 [11.6] vs 52.4 [10.2]), verbal fluency (mean [SD] T-score 48.3 [9.8] vs 50.7 [8.5]), and global (mean [SD] T-score 49.2 [6.8] vs 51.1 [5.9]) NP assessments. Baseline median Aß40, GFAP, and NFL levels were higher among WLWH vs WLWOH. There were no differences in 1-year biomarker change by HIV serostatus. Lower learning, memory, and motor NP were associated with 1-year Aß40 increase; lower learning and motor with Aß42 increase; lower motor with p-tau231 increase; and lower processing speed, verbal fluency and motor with NFL increase in the entire sample. Among WLWH, a 1-year increase in Aß40 from baseline to follow-up was associated with worse learning, memory, and global NP; a 1-year increase in t-tau with worse executive function; and a 1-year increase in NFL with worse processing speed. Among WLWOH, a 1-year increase in Aß40 and Aß42 were associated with poorer memory performance and NFL was associated with poorer motor performance. Conclusions and Relevance: These findings suggest that increases in certain plasma AD biomarkers are associated with NP in WLWH and WLWOH and may be associated with later onset of AD, and measuring these biomarkers could be a pivotal advancement in monitoring aging brain health and development of AD among women with and without HIV.

Spatial heterogeneity and scenario simulation of carbon budget on provincial scale in China.

BACKGROUND: Conducting an extensive study on the spatial heterogeneity of the overall carbon budget and its influencing factors and the decoupling status of carbon emissions from economic development, by undertaking simulation projections under different carbon emission scenarios is crucial for China to achieve its targets to peak carbon emissions by 2030 and to achieve carbon neutrality by 2060. There are large disparities in carbon emissions from energy consumption, the extent of land used for carbon absorption, and the status of decoupling of emissions from economic development, among various regions of China. RESULTS: Based on night light data and land use data, we investigated carbon budget through model estimation, decoupling analysis, and scenario simulation. The results show that the carbon deficit had a continuous upward trend from 2000 to 2018, and there was a significant positive spatial correlation. The overall status of decoupling first improved and then deteriorated. Altogether, energy consumption intensity, population density of built-up land, and built-up land area influenced the decoupling of carbon emissions from economic development. There are significant scenarios of carbon emissions from energy consumption for the study area during the forecast period, only in the low-carbon scenario will the study area reach the expected carbon emissions peak ahead of schedule in 2027; the peak carbon emissions will be 6479.27 million tons. CONCLUSIONS: China's provincial-scale carbon emissions show a positive correlation with economic development within the study period. It is necessary to optimize the economic structure, transforming the economic development mode, and formulating policies to control the expansion of built-up land. Efforts must be made to improve technology and promote industrial restructuring, to effectively reduce energy consumption intensity.

Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection.

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

Cumulative exposure to viremia: Methods for the implementation of standardized variables in longitudinal HIV studies.

Measures of viremic exposure over time, including HIV viral copy-years or durable viremic suppression, may be more relevant measures of viral load exposure for comorbid outcomes and mortality than single time point viral load measures. However, there are many subjective decisions that go into creating a cumulative variable such as HIV viral copy-years, including the appropriate anchoring point to begin accumulating exposure, the handling of viral load levels below an assay's lower limit of detection (LLD), the handling of gaps in the viral load trajectory, and when to apply the log10 transformation (before or after the accumulation calculation). Different decisions produce different values for HIV viral copy-years, and such differences could impact inferences in subsequent analyses of relationships with outcomes. In this paper, we develop several HIV viral copy-years variables that are standardized across:•Anchoring point•Handling of viral loads measured below the LLD and missing viral load measures•Application of the log10 transformation. These standardized variables may be consistently used in analyses of longitudinal cohort data. We also define a supplementary dichotomous HIV viral load exposure variable that may be used in tandem, or alternatively to, the HIV viral copy-years variables.

Soil Erosion Characteristics and Scenario Analysis in the Yellow River Basin Based on PLUS and RUSLE Models.

Soil erosion is an important global environmental issue that severely affects regional ecological environment and socio-economic development. The Yellow River (YR) is China's second largest river and the fifth largest one worldwide. Its watershed is key to China's economic growth and environmental security. In this study, six impact factors, including rainfall erosivity (R), soil erosivity (K), slope length (L), slope steepness (S), cover management (C), and protective measures (P), were used. Based on the revised universal soil loss equation (RUSLE) model, and combined with a geographic information system (GIS), the temporal and spatial distribution of soil erosion (SE) in the YR from 2000 to 2020 was estimated. The patch-generating land use simulation (PLUS) model was used to simulate the land-use and land-cover change (LUCC) under two scenarios (natural development and ecological protection) in 2040; the RUSLE factor P was found to be associated with LUCC in 2040, and soil erosion in the Yellow River Basin (YRB) in 2040 under the two scenarios were predicted and evaluated. This method has great advantages in land-use simulation, but soil erosion is greatly affected by rainfall and slope, and it only focuses on the link between land-usage alteration and SE. Therefore, this method has certain limitations in assessing soil erosion by simulating and predicting land-use change. We found that there is generally slight soil erosivity in the YRB, with the most serious soil erosion occurring in 2000. Areas with serious SE are predominantly situated in the upper reaches (URs), followed by the middle reaches (MRs), and soil erosion is less severe in the lower reaches. Soil erosion in the YRB decreased 11.92% from 2000 to 2020; thus, soil erosion has gradually reduced in this area over time. Based on the GIS statistics, land-use change strongly influences SE, while an increase in woodland area has an important positive effect in reducing soil erosion. By predicting land-use changes in 2040, compared to the natural development scenario, woodland and grassland under the ecological protection scenario can be increased by 1978 km2 and 2407 km2, respectively. Soil erosion can be decreased by 6.24%, indicating the implementation of woodland and grassland protection will help reduce soil erosion. Policies such as forest protection and grassland restoration should be further developed and implemented on the MRs and URs of the YR. Our research results possess important trend-setting significance for soil erosion control protocols and ecological environmental protection in other large river basins worldwide.

Substrate Specificity of GSDA Revealed by Cocrystal Structures and Binding Studies.

In plants, guanosine deaminase (GSDA) catalyzes the deamination of guanosine for nitrogen recycling and re-utilization. We previously solved crystal structures of GSDA from Arabidopsis thaliana (AtGSDA) and identified several novel substrates for this enzyme, but the structural basis of the enzyme activation/inhibition is poorly understood. Here, we continued to solve 8 medium-to-high resolution (1.85-2.60 Å) cocrystal structures, which involved AtGSDA and its variants bound by a few ligands, and investigated their binding modes through structural studies and thermal shift analysis. Besides the lack of a 2-amino group of these guanosine derivatives, we discovered that AtGSDA's inactivity was due to the its inability to seclude its active site. Furthermore, the C-termini of the enzyme displayed conformational diversities under certain circumstances. The lack of functional amino groups or poor interactions/geometries of the ligands at the active sites to meet the precise binding and activation requirements for deamination both contributed to AtGSDA's inactivity toward the ligands. Altogether, our combined structural and biochemical studies provide insight into GSDA.

Statins Utilization in Adults With HIV: The Treatment Gap and Predictors of Statin Initiation.

BACKGROUND: We characterized trends in statin eligibility and subsequent statin initiation among people with HIV (PWH) from 2001 to 2017 and identified predictors of statin initiation between 2014 and 2017. SETTING: PWH participating in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) enrolled in 12 US cohorts collecting data on statin eligibility criteria/prescriptions from 2001 to 2017. METHODS: We determined the annual proportion eligible for statins, initiating statins, and median waiting time (from statin eligibility to initiation). Eligibility was defined using ATP III guidelines (2001-2013) and ACC/AHA guidelines (2014-2017). We assessed initiation predictors in 2014-2017 among statin-eligible PWH using Poisson regression, estimating adjusted prevalence ratios (aPRs) with 95% confidence intervals (95% CIs). RESULTS: Among 16,409 PWH, 7386 (45%) met statin eligibility criteria per guidelines (2001-2017). From 2001 to 2013, statin eligibility ranged from 22% to 25%. Initiation increased from 13% to 45%. In 2014, 51% were statin-eligible, among whom 25% initiated statins, which increased to 32% by 2017. Median waiting time to initiation among those we observed declined over time. Per 10-year increase in age, initiation increased 46% (aPR 1.46, 95% CI: 1.29 to 1.67). Per 1-year increase in calendar year from 2014 to 2017, there was a 41% increase in the likelihood of statin initiation (aPR 1.41, 95% CI: 1.25 to 1.58). CONCLUSIONS: There is a substantial statin treatment gap, amplified by the 2013 ACC/AHA guidelines. Measures are warranted to clarify reasons we observe this gap, and if necessary, increase statin use consistent with guidelines including efforts to help providers identify appropriate candidates.

Diffusions in Aqueous Solutions with Multivalent Cations and Especially in Cationic First Hydration Shell.

Compared with univalent cationic diffusion, little is known about the diffusion behavior of multivalent cations let alone the diffusion of water in their first hydration shell. Here, we show that all published translational diffusion coefficients of multivalent cations and water measured at room temperature exhibit the same concentration dependence when plotted as a function of the mass fraction of free water or of hydrated solute. This behavior is held until only hydration and confined water remain in solutions, wherein their concentration dependences become cationic charge number-dependent. We also found that the iceberg model can well describe the diffusions of multivalent cations with decreasing water content until only hydration water is present. However, 1H-pulsed-field-gradient nuclear magnetic resonance measurements confirmed that 1H in the first hydration shell diffuses faster than Al3+ at room temperature and they have the same diffusion coefficient only with decreasing the temperature down to about 243 K. Therefore, iceberg model only equivalently describes the effect of strong ion-water interaction on multivalent cationic diffusion. These results will also help us reconceive our current understanding of the pathway for hydration water affecting the diffusion behavior of solutes with relatively weak solute-water interactions.

Prediction of the potential geographical distribution of Betula platyphylla Suk. in China under climate change scenarios.

Climate is a dominant factor affecting the potential geographical distribution of species. Understanding the impact of climate change on the potential geographic distribution of species, which is of great significance to the exploitation, utilization, and protection of resources, as well as ecologically sustainable development. Betula platyphylla Suk. is one of the most widely distributed temperate deciduous tree species in East Asia and has important economic and ecological value. Based on 231 species distribution data points of Betula platyphylla Suk. in China and 37 bioclimatic, soil, and topography variables (with correlation coefficients < 0.75), the potential geographical distribution pattern of Betula platyphylla Suk. under Representative Concentration Pathway (RCP) climate change scenarios at present and in the 2050s and 2070s was predicted using the MaxEnt model. We analyzed the main environmental variables affecting the distribution and change of suitable areas and compared the scope and change of suitable areas under different climate scenarios. This study found: (1) At present, the main suitable area for Betula platyphylla Suk. extends from northeastern to southwestern China, with the periphery area showing fragmented distribution. (2) Annual precipitation, precipitation of the warmest quarter, mean temperature of the warmest quarter, annual mean temperature, and precipitation of the driest month are the dominant environmental variables that affect the potential geographical distribution of Betula platyphylla Suk. (3) The suitable area for Betula platyphylla Suk. is expected to expand under global warming scenarios. In recent years, due to the impact of diseases and insect infestation, and environmental damage, the natural Betula platyphylla Suk. forest in China has gradually narrowed. This study accurately predicted the potential geographical distribution of Betula platyphylla Suk. under current and future climate change scenarios, which can provide the scientific basis for the cultivation, management, and sustainable utilization of Betula platyphylla Suk. resources.

Projecting the age-distribution of men who have sex with men receiving HIV treatment in the United States.

BACKGROUND: The age-distribution of men who have sex with men (MSM) continues to change in the 'Treat-All' era as effective test-and-treat programs target key-populations. However, the nature of these changes and potential racial heterogeneities remain uncertain. METHODS: The PEARL model is an agent-based simulation of MSM in HIV care in the US, calibrated to data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). RESULTS: PEARL projects a gradual decrease in median age of MSM at ART initiation from 36 to 31 years during 2010-2030, accompanied by changes in mortality among Black, White, and Hispanic MSM on ART by -8.4%, 42.4% and -19.6%. The median age of all MSM on ART is projected to increase from 45 to 47 years from 2010-2030, with the proportion of ART-users age ≥60y increasing from 6.7% to 28.0%. Almost half (49.7%) of White MSM ART-users are projected to age ≥60y by 2030, compared to 19.5% of Black and 17.2% of Hispanic MSM. CONCLUSIONS: The overall age of US MSM in HIV care is expected to increase over the next decade, and differentially by race/ethnicity. As this population age, HIV programs should expand care for age-related causes of morbidity and mortality.

The shifting age distribution of people with HIV using antiretroviral therapy in the United States.

OBJECTIVE: To project the future age distribution of people with HIV using antiretroviral therapy (ART) in the United States, under expected trends in HIV diagnosis and survival (baseline scenario) and achieving the ending the HIV epidemic (EHE) goals of a 75% reduction in HIV diagnoses from 2020 to 2025 and sustaining levels to 2030 (EHE75% scenario). DESIGN: An agent-based simulation model with mathematical functions estimated from North American AIDS Cohort Collaboration on Research and Design data and parameters from the US Centers for Disease Control and Prevention's annual HIV surveillance reports. METHODS: The PEARL (ProjEcting Age, MultimoRbidity, and PoLypharmacy in adults with HIV) model simulated individuals in 15 subgroups of sex-and-HIV acquisition risk and race/ethnicity. Simulation outcomes from the baseline scenario are compared with outcomes from the EHE75% scenario. RESULTS: Under the baseline scenario, PEARL projects a substantial increase in number of ART-users over time, reaching a population of 909 638 [95% uncertainty range (UR): 878 449-946 513] by 2030. The overall median age increased from 50 years in 2020 to 52 years in 2030, with 23% of ART-users age ≥65 years in 2030. Under the EHE75% scenario, the projected number of ART-users was 718 348 [703 044-737 817] (median age = 56 years) in 2030, with a 70% relative reduction in ART-users <30 years and a 4% relative reduction in ART-users age ≥65 years compared to baseline, and persistent heterogeneities in projected numbers by sex-and-HIV acquisition risk group and race/ethnicity. CONCLUSIONS: It is critical to prepare healthcare systems to meet the impending demand of the US population aging with HIV.

New State-Diagram of Aqueous Solutions Unveiling Ionic Hydration, Antiplasticization, and Structural Heterogeneities in LiTFSI-H2O.

Here, we report a new state-diagram for aqueous solutions based on concentration-dependent glass-transition temperatures of concentrated and ice freeze-concentrated solutions. Different from the equilibrium phase diagram, this new state-diagram can provide comprehensive information about the hydration numbers of solutes, nonequilibrium vitrification/cold-crystallization, and vitrification/devitrification processes of aqueous solutions in three distinct concentration zones separated by two critical water-content points of only functions of the hydration number. Based on this new state-diagram, we observe the comparable hydration ability of LiTFSI to LiCl and an atypical concentration-dependent cold-crystallization behavior of the LiTFSI-H2O system. These results unveil the negligible hydration ability of TFSI- in a water-rich solution, characterize the antiplasticizing effect of water induced by the strengthened Li+-TFSI--H2O interaction when only hydration water and confined water are present, and confirm the increasing fraction of water-rich domains with the decrease in water content when the cation and anion become incompletely hydrated on average. These results highlight the novel water-content-mediated interactions among the anion, cation, and H2O for LiTFSI-H2O.

The C-terminal loop of Arabidopsis thaliana guanosine deaminase is essential to catalysis.

Guanosine deaminase (GSDA) in plants specifically deaminates (de)guanosine to produce xanthosine with high specificity, which is further converted to xanthine, a key intermediate in purine metabolism and nitrogen recycling. We solved GSDA's structures from Arabidopsis thaliana in the free and ligand-bound forms at high resolutions. Unlike GDA, the enzyme employs a single-proton shuttle mechanism for catalysis and both the substrate and enzyme undergo structural rearrangements. The last fragment of the enzyme loops back and seals the active site, and the substrate rotates during the reaction, both essential to deamination. We further identified more substrates that could be employed by the enzyme and compare it with other deaminases to reveal the recognition differences of specific substrates. Our studies provide insight into this important enzyme involved in purine metabolism and will potentially aid in the development of deaminase-based gene-editing tools.

The Crystal Structure of the Spodoptera litura Chemosensory Protein CSP8.

Spodoptera litura F. is a generalist herbivore and one of the most important economic pests feeding on about 300 host plants in many Asian countries. Specific insect behaviors can be stimulated after recognizing chemicals in the external environment through conserved chemosensory proteins (CSPs) in chemoreceptive organs, which are critical components of the olfactory systems. To explore its structural basis for ligand-recognizing capability, we solved the 2.3 Å crystal structure of the apoprotein of S. litura CSP8 (SlCSP8). The SlCSP8 protein displays a conserved spherical shape with a negatively charged surface. Our binding assays showed that SlCSP8 bound several candidate ligands with differential affinities, with rhodojaponin III being the most tightly bound ligand. Our crystallographic and biochemical studies provide important insight into the molecular recognition mechanism of the sensory protein SlCSP8 and the CSP family in general, and they suggest that CSP8 is critical for insects to identify rhodojaponin III, which may aid in the CSP-based rational drug design in the future.

Life-Expectancy Disparities Among Adults With HIV in the United States and Canada: The Impact of a Reduction in Drug- and Alcohol-Related Deaths Using the Lives Saved Simulation Model.

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities.

Mind the gap: observation windows to define periods of event ascertainment as a quality control method for longitudinal electronic health record data.

PURPOSE: Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We estimated "observation windows" (OWs), defined as periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrated the impact of OWs on estimating the rates of type II diabetes mellitus (diabetes) from HIV clinical cohorts. METHODS: Data contributed by 16 HIV clinical cohorts to the NA-ACCORD were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included (1) gathering cohort-level data; (2) visualizing and summarizing gaps in observations; (3) systematically establishing start and stop dates during which the assumption of complete ascertainment of diabetes events was reasonable; and (4) visualizing the diabetes OWs relative to the cohort open and close dates to identify immortal person-time. We estimated diabetes occurrence event rates and 95% confidence intervals in the most recent decade that data were available (January 1, 2007, to December 31, 2016). RESULTS: The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 [1.29, 1.35] per 100 person-years with the use of diabetes OWs. CONCLUSIONS: As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete.

Recent Abacavir Use Increases Risk of Type 1 and Type 2 Myocardial Infarctions Among Adults With HIV.

BACKGROUND: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV. METHODS: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence. RESULTS: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome. CONCLUSIONS: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared With the General Population.

BACKGROUND: Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort. METHODS: We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC. RESULTS: Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/µL: ref; 350-499 cells/µL: aIRR = 1.32 (0.98 to 1.77); 200-349 cells/µL: aIRR = 1.37 (1.01 to 1.86); 100-199 cells/µL: aIRR = 1.60 (1.09 to 2.34); <100 cells/µL: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded. CONCLUSIONS: The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.