Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals

BACKGROUND: Clinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown. METHODS: We measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL). RESULTS: There was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient −0.04, P = 0.021), supporting our previous findings in vitro. CONCLUSIONS: Together, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0288-6) contains supplementary material, which is available to authorized users

Correlation of coagulation parameters with clinical outcomes in Coronavirus-19 affected minorities in United States: Observational cohort

ABSTRACTImportanceCOVID-19 has caused a worldwide illness and New York has become the epicenter of COVID-19 in the United States. Currently Bronx has the highest prevalence per capita in New York.ObjectiveTo investigate the coagulopathic presentation of COVID and its natural course and to investigate whether hematologic and coagulation parameters can be used to assess illness severity and death.DesignRetrospective case study of positive COVID inpatients between 3/20/2020-3/31/2020.SettingMontefiore Health System main hospital, Moses, a large tertiary care center in the Bronx.ParticipantsAdult inpatients with positive COVID tests hospitalized at MHS.Exposure (for observational studies)Datasets of participants were queried for physiological, demographic (age, sex, socioeconomic status and self-reported race and/or ethnicity) and laboratory data.Main Outcome and MeasuresRelationship and predictive value of measured parameters to mortality and illness severity.ResultsOf the 217 in this case review, 70 died during hospitalization while 147 were discharged home. Only the admission PT and first D-Dimer could very significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 1.65 μg/mLConclusionsWe describe here a comprehensive assessment of hematologic and coagulation parameters in COVID and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments.</jats:sec

Validation Data-based Adjustments for Outcome Misclassification in Logistic Regression

Misclassification of binary outcome variables is a known source of potentially serious bias when estimating adjusted odds ratios. Although researchers have described frequentist and Bayesian methods for dealing with the problem, these methods have seldom fully bridged the gap between statistical research and epidemiologic practice. In particular, there have been few real-world applications of readily grasped and computationally accessible methods that make direct use of internal validation data to adjust for differential outcome misclassification in logistic regression. In this paper, we illustrate likelihood-based methods for this purpose that can be implemented using standard statistical software. Using main study and internal validation data from the HIV Epidemiology Research Study, we demonstrate how misclassification rates can depend on the values of subject-specific covariates, and illustrate the importance of accounting for this dependence. Simulation studies confirm the effectiveness of the maximum likelihood approach. We emphasize clear exposition of the likelihood function itself, to permit the reader to easily assimilate appended computer code that facilitates sensitivity analyses as well as the efficient handling of main/external and main/internal validation-study data. These methods are readily applicable under random cross-sectional sampling, and we discuss the extent to which the main/internal analysis remains appropriate under outcome-dependent (case-control) sampling

Correlation of Coagulation Parameters With Clinical Outcomes During the Coronavirus-19 Surge in New York: Observational Cohort

ImportanceCOVID-19 has caused a worldwide illness and New York became the epicenter of COVID-19 in the United States from Mid-March to May 2020.ObjectiveTo investigate the coagulopathic presentation of COVID and its natural course during the early stages of the COVID-19 surge in New York. To investigate whether hematologic and coagulation parameters can be used to assess illness severity and death.DesignRetrospective case study of positive COVID inpatients between March 20, 2020-March 31, 2020.SettingMontefiore Health System main hospital, Moses, a large tertiary care center in the Bronx.ParticipantsAdult inpatients with positive COVID tests hospitalized at MHS.Exposure (for observational studies)Datasets of participants were queried for demographic (age, sex, socioeconomic status, and self-reported race and/or ethnicity), clinical and laboratory data.Main Outcome and MeasuresRelationship and predictive value of measured parameters to mortality and illness severity.ResultsOf the 225 in this case review, 75 died during hospitalization while 150 were discharged home. Only the admission PT, absolute neutrophil count (ANC) and first D-Dimer could significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 2.1 μg/mL. 15% of discharged patients required readmission and more than a third of readmitted patients died (5% of all initially discharged).ConclusionWe describe here a comprehensive assessment of hematologic and coagulation parameters in COVID-19 and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments. Furthermore, D-Dimer may be useful to follow up discharged patients.</jats:sec

Phase I Randomized Safety Study of Twice Daily Dosing of Acidform Vaginal Gel: Candidate Antimicrobial Contraceptive

BACKGROUND: Acidform gel, an acid-buffering product that inactivates spermatozoa, may be an effective topical non-hormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota. METHODS: Thirty-six sexually abstinent U.S. women were randomized to apply Acidform or hydroxyethylcellulose (HEC) placebo gel twice daily for 14 consecutive days. Safety was assessed by symptoms and pelvic examination. The impact of gel on mucosal immunity was assessed by quantifying cytokines, chemokines, antimicrobial proteins and antimicrobial activity of genital secretions collected by cervicovaginal lavage (CVL) at screening, 2 hours after gel application, and on days 7, 14 and 21. Vaginal microbiota was characterized at enrollment and day 14 using species-specific quantitative PCR assays. RESULTS: The median vaginal and cervical pH was significantly lower 2 hours after application of Acidform and was associated with an increase in the bactericidal activity of CVL against E. coli. However, 65% of women who received Acidform had at least one local adverse event compared with 11% who received placebo (p = 0.002). While there was no increase in inflammatory cytokines or chemokines, CVL concentrations of lactoferrin and interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory protein, were significantly lower following Acidform compared to HEC placebo gel application. There were no significant changes in Lactobacillus crispatus or Lactobacillus jensenii in either group but there was a decrease in Gardnerella vaginalis in the Acidform group (p = 0.08). CONCLUSIONS: Acidform gel may augment mucosal defense as evidenced by an increase in bactericidal activity of genital secretions against E. coli and a decrease in Gardnerella vaginalis colonization. However, Acidform was associated with more irritation than placebo and lower levels of antimicrobial (lactoferrin) and anti-inflammatory (IL-1ra) proteins. These findings indicate the need for additional safety studies of this candidate non-hormonal contraceptive. TRIAL REGISTRATION: ClinicalTrials.gov NCT0085083

Trial profile.

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