Vision Problems As a Contributor to Lower Engagement in Care Among Aging Men Living with HIV.

PURPOSE: To investigate vision impairment as a barrier to engagement in medical care among aging persons living with HIV (PLWH) who experience multimorbidity and complex care needs. SETTING: Multicenter AIDS Cohort Study (MACS), a prospective observational cohort of aging PLWH men. METHODS: We examined relationships of self-reported vision difficulty with indicators of care engagement: 1) adherence to HIV antiretroviral therapy (ART; defined as taking ≥95% of medications); 2) self-reported avoidance of medical care; 3) self-reported tendency to ask a doctor questions about care (>2 questions at a medical visit), as well as with quality of life. A modified version of the National Eye Institute Vision Function Questionnaire was administered at three semi-annual visits (from October 2017 to March 2019) to assess difficulty performing vision-dependent tasks. RESULTS: We included 1063 PLWH (median age 57 years, 31% Black). Data on care engagement outcomes were analyzed using repeated measures logistic regression with generalized estimating equations adjusted for race, and at visit values for age, education level, depressive symptoms, alcohol use, and smoking status. Compared to no vision difficulty, those reporting moderate to extreme vision difficulty on at least one task had 2.2 times higher odds (95% CI: 1.4, 3.4) of having less than optimal ART adherence, 1.9 times higher odds (95% CI: 1.1, 3.4) of avoiding necessary medical care and median quality of life scores 8 points lower. CONCLUSION: These findings suggest vision impairment decreases medical care engagement including HIV care and quality of life among aging PLWH.

Effectiveness of mRNA Booster Vaccine Against Coronavirus Disease 2019 Infection and Severe Outcomes Among Persons With and Without Immune Dysfunction: A Retrospective Cohort Study of National Electronic Medical Record Data in the United States.

Background: Real-world evidence of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) booster effectiveness among patients with immune dysfunction are limited. Methods: We included data from patients in the United States National COVID Cohort Collaborative (N3C) who completed ≥2 doses of mRNA vaccination between 10 December 2020 and 27 May 2022. Immune dysfunction conditions included human immunodeficiency virus infection, solid organ or bone marrow transplant, autoimmune diseases, and cancer. We defined incident COVID-19 BTI as positive results from laboratory tests or diagnostic codes 14 days after at least 2 doses of mRNA vaccination; and severe COVID-19 BTI as hospitalization, invasive cardiopulmonary support, and/or death. We used propensity scores to match boosted versus nonboosted patients and evaluated hazards of incident and severe COVID-19 BTI using Cox regression after matching. Results: Among patients without immune dysfunction, the relative effectiveness of booster (3 doses) after 6 months from the primary (2 doses) vaccination against BTI ranged from 69% to 81% during the Delta-predominant period and from 33% to 39% during the Omicron-predominant period. Relative effectiveness against BTI was lower among patients with immune dysfunction but remained statistically significant in both periods. Boosted patients had lower risk of COVID-19-related hospitalization (hazard ratios [HR] ranged from 0.5 [95% confidence interval {CI}, .48-.53] to 0.63 [95% CI, .56-.70]), invasive cardiopulmonary support, or death (HRs ranged from 0.46 [95% CI, .41-.52] to 0.63 [95% CI, .50-.79]) during both periods. Conclusions: Booster vaccines remain effective against severe COVID-19 BTI throughout the Delta- and Omicron-predominant periods, regardless of patients' immune status.

COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial.

IMPORTANCE: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

Comparison of postoperative mobilization measurements by activPAL versus Johns Hopkins Highest Level of Mobility scale after major abdominal surgery.

BACKGROUND: The Johns Hopkins Highest Level of Mobility scale is a validated tool for assessing patient mobility in the hospital. It has excellent inter-rater and test-retest reliabilities, but it is unknown how accurately Johns Hopkins Highest Level of Mobility documentation reflects the patients' mobility performance in the immediate postoperative period compared to objective measures such as accelerometers. METHODS: In this single-center observational study, consented adults undergoing open abdominal surgery wore a research-grade accelerometer, activPAL, starting immediately postoperatively until hospital discharge or up to 7 days. We collected the Johns Hopkins Highest Level of Mobility scores documented by hospital staff via retrospective chart review and evaluated their accuracy in describing the type, frequency, and volume of postoperative out-of-bed mobilization using the activPAL as the criterion. RESULTS: We analyzed data from 56 participants. The activPAL showed that participants spent 97.7% of their time lying in bed or sitting in a chair. Meanwhile, the Johns Hopkins Highest Level of Mobility documentation of preambulatory activities (scores 1-5) was rare. The activPAL detected 4 times more out-of-bed mobilization than routine Johns Hopkins Highest Level of Mobility documentation. Whereas the frequency of activPAL-measured out-of-bed mobilization increased steadily to a median of 9 sessions by postoperative day 6, the number of Johns Hopkins Highest Level of Mobility documentation remained around twice daily. ActivPAL measurements demonstrated that Johns Hopkins Highest Level of Mobility documentation of ambulatory sessions (scores 6-8) was accurate. CONCLUSIONS: We found that routine Johns Hopkins Highest Level of Mobility documentation did not accurately detect preambulatory activities or the overall frequency of out-of-bed mobility sessions, poorly reflecting the highly sedentary behaviors of the acute postoperative inpatients and highlighting the need to improve clinical documentation or use alternative methods to track postoperative mobilization.

Tubular Secretory Solute Clearance and HIV Infection.

BACKGROUND: Tubular secretion is an important kidney function responsible for the clearance of numerous medications, including antibiotics and antivirals. It is unknown whether persons living with HIV have lower secretion compared with HIV-uninfected persons, which might predispose them to the risk of progressive kidney disease or adverse drug events. SETTING AND METHODS: We evaluated a panel of 6 endogenous secretory solutes in 199 women living with HIV (WLWH) and 100 women without HIV enrolled in the Women's Interagency HIV Study. Secretory clearance was estimated as the urine-to-plasma ratio of each solute, with adjustment for urine tonicity. Using multivariable linear regression analysis, we compared differences in levels of secretory solute clearance between women with and without HIV and evaluated characteristics associated with secretion. RESULTS: WLWH were older (median 40 vs. 38 years) but had similar estimated glomerular filtration rate (eGFR, 96 vs. 100 mL/minute/1.73 m 2 ) compared with those without HIV. African American and Latino race, diabetes, diastolic blood pressure, smoking, hepatitis C, peak HIV viral load, and current and nadir CD4 count were associated with differences in clearance of at least 1 marker after multivariable adjustment. The secretory clearance of 3 solutes (cinnamoylglycine, kynurenic acid, and pyridoxic acid) were on average 10%-15% lower among WLWH compared with those without HIV independent of eGFR, albuminuria and chronic kidney disease risk factors, including HCV, and injection drug use. CONCLUSIONS: HIV is associated with reduced secretion among women with preserved eGFR. The implications of these findings for drug dosing and adverse events need to be evaluated.

Effect of Adopting the New Race-Free 2021 Chronic Kidney Disease Epidemiology Collaboration Estimated Glomerular Filtration Rate Creatinine Equation on Racial Differences in Kidney Disease Progression Among People With Human Immunodeficiency Virus: An Observational Study.

BACKGROUND: The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. METHODS: We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. RESULTS: With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73-.82), an equal risk of progressing from stage 2 to 3 (1.00; .92-.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60-3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. CONCLUSIONS: The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

Associations among Visual, Auditory, and Olfactory Functions in Community-Based Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

Purpose: Objective examination of relationships among visual, hearing, and olfactory function may yield mechanistic insights and inform our understanding of the burden of multiple-sensory impairments. Methods: This cross-sectional study capitalized on continuous measures of visual acuity (VA), contrast sensitivity, pure tone audiometry, Quick Speech-in-Noise (QuickSIN), and Sniffin' Sticks from a subset of ARIC participants at two community sites (EyeDOC Study, 2017-2019). Scales of all measures were aligned such that higher values indicated greater impairment. Intersensory bivariate associations were assessed graphically, and correlations assessed using Kendall's tau. Intersensory associations, independent of age, education, smoking, diabetes, and hypertension, were examined using linear regression. Analyses were stratified by community/race (Washington County/White vs Jackson/Black) and sex (men vs women) to explore community-sex heterogeneity. Results: We included 834 participants (mean age, 79 years); 39% were from Jackson and 63% females. We found weak intersensory correlations (tau generally ≤0.15). In the demographics-adjusted regression models, results were heterogeneous across communities and sex. Worse near VA, contrast sensitivity, and olfaction were associated with worse QuickSIN and worse near VA was associated with worse olfaction in some but not all community/race-sex groups (e.g., Jackson/Black women, 0.1 logMAR worse near VA was associated with 0.27 units increase in QuickSIN [95% confidence interval, 0.10-0.45]). Associations were modestly attenuated by adjustment for the shared risk factors of smoking, diabetes, and hypertension. Conclusions: Visual dysfunction showed little or no association with hearing or olfaction impairments, suggesting a modest role for shared risk factors. Translational Relevance: Visually impaired individuals have only a modestly higher risk of other sensory impairment.

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

BACKGROUND: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). METHODS: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. RESULTS: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites. CONCLUSION: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.

Variability in CKD Biomarker Studies: Soluble Urokinase Plasminogen Activator Receptor (suPAR) and Kidney Disease Progression in the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Biomarker studies are important for generating mechanistic insight and providing clinically useful predictors of chronic kidney disease (CKD) progression. However, variability across studies can often muddy the evidence waters. Here we evaluated real-world variability in biomarker studies using two published studies, independently conducted, of the novel plasma marker soluble urokinase-type plasminogen activator receptor (suPAR) for predicting CKD progression in children with CKD. STUDY DESIGN: A comparison of 2 prospective cohort studies. SETTING & PARTICIPANTS: 541 children from the Chronic Kidney Disease in Children (CKiD) study, median age 12 years, median glomerular filtration rate (GFR) of 54 mL/min/1.73m2. OUTCOME: The first occurrence of either a 50% decline in GFR from baseline or incident end-stage kidney disease. ANALYTICAL APPROACH: The suPAR plasma marker was measured using the Quantikine ELISA immunoassay in the first study and Meso Scale Discovery (MSD) platform in the second. The analytical approaches varied. We used suPAR data from the 2 assays and mimicked each analytical approach in an overlapping subset. RESULTS: We found that switching assays had the greatest impact on inferences, resulting in a 38% to 66% change in the magnitude of the effect estimates. Covariate and modeling choices resulted in an additional 8% to 40% variability in the effect estimate. The cumulative variability led to different inferences despite using a similar sample of CKiD participants and addressing the same question. LIMITATIONS: The estimated variability does not represent optimal repeatability but instead illustrates real-world variability that may be present in the CKD biomarker literature. CONCLUSIONS: Our results highlight the importance of validation, avoiding conclusions based on P value thresholds, and providing comparable metrics. Further transparency of data and equal weighting of negative and positive findings in explorations of novel biomarkers will allow investigators to more quickly weed out less promising biomarkers.

Metabolite Biomarkers of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. RESULTS: Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR <60 ml/min per 1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9). CONCLUSIONS: Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.

A New Panel-Estimated GFR, Including ß2-Microglobulin and ß-Trace Protein and Not Including Race, Developed in a Diverse Population.

RATIONALE AND OBJECTIVE: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. ß2-Microglobulin (B2M) and ß-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA. RESULTS: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 - P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 - P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups. LIMITATIONS: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. CONCLUSIONS: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Prevalence and Consequences of Perceived Vision Difficulty in Aging Adults with HIV Infection.

PURPOSE: Despite well-known ocular complications of HIV-related immune suppression, few studies have examined the prevalence and consequences of visual impairment among aging long-term survivors of HIV. DESIGN: Retrospective cohort study. METHODS: Aging HIV-infected (HIV+) men who have sex with men (MSM) and HIV-uninfected (HIV-) MSM controls reported their difficulty performing 6 vision-dependent tasks (difficulty defined as: no, a little, moderate, and extreme difficulty). Relationships were examined using logistic regression, regressing each outcome separately on categorical visual function responses, with missing data multiply imputed. RESULTS: There were 634 age-matched pairs for a total sample of 1,268 MSM of 1,700 MSM with available data. The median age was 60 years old (interquartile range [IQR], 54, 66), and 23% were African American. Among HIV+ men, 95% were virally suppressed (viral load <400 copies/mL). HIV+ men were more likely to report moderate or extreme difficulty performing at least 1 task (21% for HIV+ compared to 13% for HIV-; P < .01). Participants reporting extreme vision-related difficulty performing at least 1 task had 11.2 times the odds of frailty (95% confidence interval [CI], 5.2-23.9), 2.6 times the odds of a slow gait speed (95% CI, 1.4-4.8), and 3.2 times the odds of impaired instrumental activities of daily living (95% CI: 1.6-6.3) compared to those reporting no vision-related difficulty on any task. CONCLUSIONS: Perceived vision difficulty was more common among older HIV+ MSM than age-matched HIV- MSM controls and was associated with higher risk of depression and physical function loss among MSM.

Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children.

BACKGROUND: After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS: We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS: Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS: Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Association Between Microvascular Retinal Signs and Age-Related Hearing Loss in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

Importance: Given that age-related hearing loss is highly prevalent and treatable, understanding its causes may have implications for disease prevention. Objective: To investigate whether microvascular retinal signs are associated with age-related hearing loss attributable to a hypothesized underlying shared pathologic entity involving microvascular disease. Design, Setting, and Participants: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) is a community-based prospective cohort study of 15 792 men and women aged 45 to 64 years at baseline. The ARIC-NCS participants returned for a fifth clinic visit in 2011-2013 and a sixth clinic visit in 2016-2017. Participants were recruited from 4 US communities (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). Participants included a subset of the ARIC-NCS cohort with complete covariate data who underwent retinal fundus photography at visit 5 (2011-2013) and completed hearing assessment at visit 6 (2016-2017) (N = 1458). Overall, 453 participants had diabetes; of those, 68 had retinopathy. Of 1005 participants without diabetes, 42 had retinopathy. Exposures: Microvascular retinal signs included retinopathy, arteriovenous (AV) nicking, and generalized arteriolar narrowing measured using the central retinal arteriolar equivalent (CRAE). Main Outcomes and Measures: Hearing was measured using the better-hearing ear pure-tone average (PTA) of air conduction speech thresholds (0.5, 1, 2, and 4 kHz). Multivariable-adjusted linear and ordered logistic regression was used to estimate the association between microvascular retinal signs and age-related hearing loss to describe the precision of the estimates and provide a plausible range for the true association. Results: After full adjustment among 1458 individuals in the analytic cohort (mean [SD] age, 76.1 [5.0] years [age range, 67-90 years]; 825 women [56.6%]; 285 black [19.5%]), the difference in PTA per dB hearing level in persons with and without retinopathy was 2.21 (95% CI, -0.22 to 4.63), suggesting that retinopathy is associated with poorer hearing, although the width of the 95% CI prevents definitive conclusions about the strength of the observed association. Restricting the analysis to participants without diabetes, the difference in PTA associated with retinopathy was even greater (4.14; 95% CI, 0.10-8.17 dB hearing level), but the large width of the 95% CI prevents definitive conclusions about the association. In analyses quantifying the mean differences in hearing thresholds at individual frequencies by retinopathy status, the estimates trended toward retinopathy being associated, contrary to expectation, with better high-frequency hearing. At 8 kHz, the estimated difference in hearing thresholds in persons with retinopathy vs those without was -4.24 (95% CI, -7.39 to -1.09). Conclusions and Relevance: In this population-based study, an association between the presence of microvascular retinal signs and hearing loss was observed, suggesting that retinopathy may have the potential to identify risk for hearing loss in persons without diabetes. The precision of these estimates is low; therefore, additional epidemiologic studies are needed to better define the degree of microvascular contributions to age-related hearing loss.

Inflammation and Risk of Depression in HIV: Prospective Findings From the Multicenter AIDS Cohort Study.

Studies suggest that inflammation might be involved in the pathogenesis of depression. Individuals with human immunodeficiency virus (HIV) have a higher risk of depression and elevated inflammatory profiles. Despite this, research on the link between inflammation and depression among this high-risk population is limited. We examined a sample of men who have sex with men from the Multicenter AIDS Cohort Study in prospective analyses of the association between inflammation and clinically relevant depression symptoms, defined as scores >20 on Center for Epidemiological Studies Depression Scale. We included 1,727 participants who contributed 9,287 person-visits from 1984 to 2010 (8,218 with HIV (HIV+) and 1,069 without (HIV-)). Exploratory factor analysis (EFA) was used to characterize underlying inflammatory processes from 19 immune markers. Logistic regression with generalized estimating equations was used to evaluate associations between inflammatory processes and depressive symptoms stratified by HIV serostatus. Three EFA-identified inflammatory processes (EIPs) were identified. EIP-1 scores-described by soluble tumor necrosis factor receptor 2 (sTNF-R2), soluble interleukin-2 receptor α (sIL-2Rα), sCD27, B-cell activating factor, interferon γ-induced protein 10 (IP-10), soluble interleukin-6 receptor (sIL-6R), sCD14, and sGP130-were significantly associated with 9% higher odds of depressive symptoms in HIV+ participants (odds ratio = 1.09; 95% confidence interval: 1.03, 1.16) and 33% higher odds in HIV- participants (odds ratio = 1.33; 95% confidence interval: 1.09, 1.61). Findings suggest that immune activation might be involved in depression risk among both HIV+ and HIV- men who have sex with men.

The Impact of Past and Current Alcohol Consumption Patterns on Progression of Carotid Intima-Media Thickness Among Women and Men Living with HIV Infection.

BACKGROUND: The relationship between alcohol consumption and atherosclerosis has not been sufficiently examined among people living with HIV (PLWH). METHODS: We analyzed data from PLWH in the Women's Interagency HIV Study (WIHS; n = 1,164) and the Multicenter AIDS Cohort Study (MACS; n = 387) with no history of cardiovascular disease (CVD). Repeated measures of intima-media thickness of the right common carotid artery (CCA-IMT) were assessed using B-mode ultrasound from 2004 to 2013. Current alcohol consumption was collected at time of CCA-IMT measurement and was categorized according to gender-specific weekly limits. Group-based trajectory models categorized participants into past 10-year consumption patterns (1994 to 2004). Multivariate generalized estimating equations were conducted to assess the association of past and current alcohol use patterns on change in CCA-IMT by cohort, controlling for age, race, cigarette and illicit drug use, probable depression, HIV RNA viral load, antiretroviral therapy exposure, and hepatitis C coinfection. RESULTS: Among the WIHS, past heavy alcohol consumption was associated with increased CCA-IMT level over time (ß = 8.08, CI 0.35, 15.8, p = 0.04), compared to abstinence. Among the MACS, compared to abstinence, all past consumption patterns were associated with increased CCA-IMT over time (past low: ß = 15.3, 95% CI 6.46, 24.2, p < 0.001; past moderate: ß = 14.3, CI 1.36, 27.2, p = 0.03; past heavy: ß = 21.8, CI 4.63, 38.9, p = 0.01). Current heavy consumption was associated with decreased CCA-IMT among the WIHS (ß = -11.4, 95% CI -20.2, -2.63, p = 0.01) and MACS (ß = -15.4, 95% CI -30.7, -0.13, p = 0.04). No statistically significant time by consumption pattern effects were found. CONCLUSIONS: In both cohorts, 10-year heavy consumption was associated with statistically significant increases in carotid artery thickness, compared to abstinence. Long-term patterns of drinking at any level above abstinence were particularly significant for increases in IMT among men, with heavy consumption presenting with the greatest increase. Our results suggest a potentially different window of risk among past and current heavy drinkers. Further studies are needed to determine whether alcohol consumption level is associated with intermediate measures of atherosclerosis. Alcohol screening and interventions to reduce heavy consumption may benefit PLWH who are at risk of CVD.

Prescription drug use and misuse in a cohort of people who inject drugs (PWID) in Baltimore.

BACKGROUND: Prescription drug misuse and its consequences (e.g., overdose) are a major public health concern. While national focus has been on opioids, misuse of sedatives/tranquilizers also occurs. Here we describe the use, correlates, and sources of prescription drugs in a community-based cohort of people who inject drugs (PWID). METHODS: We included participants of the AIDS Linked to the IntraVenous Experience (ALIVE) study in follow-up in 2014. We defined prescription drug use as use of opioids or sedatives/tranquilizers considering both medical "prescribed by a doctor" and non-medical sources "obtained from the street/friend/relative." Correlates were evaluated separately for opioids and sedatives/tranquilizers using logistic regression and included socioeconomic factors, health conditions, substance use, and health care access. RESULTS: 823 predominantly African-American (90.6%) and male (66.3%) ALIVE participants with a median age of 55 were included. Prevalence of prescription opioid and sedative/tranquilizer use was 25.3% and 16.3% respectively. While the majority (70%) obtained prescription drugs exclusively through medical sources, the 30% who reported any non-medical source were also more likely to use other substances by injection and non-injection routes. PWID reporting prescription drug use (from medical and non-medical sources) were significantly more likely to report other substance use, mental health disorder, and recent contact with health care providers or detoxification facilities. CONCLUSIONS: Prescription drug use was highly prevalent among PWID. While it is difficult to distinguish medically indicated from non-medical use, high levels of prescription drug use in conjunction with other drugs and alcohol heightens the risk for drug overdose and other adverse consequences.