Utilization of absolute monocyte counts to predict cardiovascular events in people living with HIV.

OBJECTIVES: Cardiovascular risk is increased in people living with HIV (PLWH). In HIV-uninfected populations, total absolute monocyte count (AMC) has been shown to be predictive of future cardiovascular events (CVEs). We sought to determine whether AMC predicts CVEs in PLWH independent of established and HIV-related cardiovascular risk factors. METHODS: We identified all PLWH within the Partners HIV Cohort without factors that could confound the monocyte count. CVE was defined as fatal or non-fatal acute myocardial infarction or ischaemic stroke. Baseline-measured AMC was defined as the average of all outpatient AMC counts a year before and after the baseline date. Multivariable Cox proportional hazards models were used to assess the association of baseline AMC with CVEs. RESULTS: Our cohort consisted of 1980 patients, with median follow-up of 10.9 years and 182 CVEs. Mean (± SD) age was 41.9 ± 9.3 years; 73.0% were male. Mean CD4 count was 506.3 ± 307.1 cells/µL, 48% had HIV viral load (VL) < 400 copies/mL, and 87% were on antiretroviral therapy. Mean AMC was 0.38 × 103  ± 0.13 cells/µL. In multivariable modelling adjusted for traditional CV risk factors, CD4 cell count, and HIV VL, AMC quartile 2 (Q2) (HR = 1.01, P = 0.98), Q3 (HR = 1.07, P = 0.76), and Q4 (HR = 0.97, P = 0.89) were not significantly predictive of CVE compared with Q1. DISCUSSION: Baseline AMC was not associated with long-term CVEs in PLWH. AMC obtained in routine clinical encounters does not appear to enhance CV risk stratification in PLWH.

Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Transfer from paediatric to adult care for young adults with Type 2 diabetes: the SEARCH for Diabetes in Youth Study.

AIM: To describe factors associated with transfer from paediatric to adult care and poor glycaemic control among young adults with Type 2 diabetes, using the SEARCH for Diabetes in Youth study. METHODS: Young adults with Type 2 diabetes were included if they had a baseline SEARCH visit while in paediatric care at < 18 years and ≥ 1 follow-up SEARCH visit thereafter at 18-25 years. At each visit, HbA1c , BMI, self-reported demographic and healthcare provider data were collected. Associations of demographic factors with transfer of care and poor glycaemic control (HbA1c ≥ 75 mmol/mol; 9.0%) were explored with multivariable logistic regression. RESULTS: 182 young adults with Type 2 diabetes (36% male, 75% minority, 87% with obesity) were included. Most (n = 102, 56%) reported transfer to adult care at follow-up; a substantial proportion (n = 28, 15%) reported no care and 29% did not transfer. Duration of diabetes [odds ratio (OR) 1.4, 95% confidence interval (95% CI) 1.1, 1.8] and age at diagnosis (OR 1.8, 95% CI 1.4, 2.4) predicted leaving paediatric care. Transfer to adult or no care was associated with a higher likelihood of poor glycaemic control at follow-up (adult: OR 4.5, 95% CI 1.8, 11.2; none: OR 4.6, 95% CI 1.4, 14.6), independent of sex, age, race/ethnicity or baseline HbA1c level. CONCLUSIONS: Young adults with Type 2 diabetes exhibit worsening glycaemic control and loss to follow-up during the transfer from paediatric to adult care. Our study highlights the need for development of tailored clinical programmes and healthcare system policies to support the growing population of young adults with youth-onset Type 2 diabetes.

Pepsin in saliva as a biomarker for oropharyngeal reflux compared with 24-hour esophageal impedance/pH monitoring in pediatric patients.

BACKGROUND: Pepsin in saliva is a proposed biomarker for oropharyngeal reflux. Pepsin may be prevalent in saliva from subjects with gastro-esophageal reflux and may correlate with proximal reflux by intraluminal impedance/pH monitoring (MII/pH). METHODS: Patients (3 days to 17.6 years, n=90) undergoing 24-hour MII/pH monitoring and asymptomatic controls (2 months to 13.7 years, n=43) were included. Salivary pepsin was determined using a pepsin enzyme-linked immunosorbent assay. Eight saliva samples were collected from patients undergoing 24-hr MII/pH: (i) before catheter placement, (ii) before and 30 minutes after each of three meals, and (iii) upon awakening. One sample was collected from each control. KEY RESULTS: In MII/pH subjects, 85.6% (77/90) had at least one pepsin-positive sample compared with 9.3% (4/43) in controls. The range of pepsin observed in individual subjects varied widely over 24 hours. The average pepsin concentration in all samples obtained within 2 hours following the most recent reflux event was 30.7±135 ng/mL, decreasing to 16.5±39.1 ng/mL in samples collected more than 2 hours later. The frequency of pepsin-positive samples correlated significantly with symptom index (rS =0.332, P=.0014), proximal (rS =0.340, P=.0010), and distal (rS =0.272, P=.0095) MII events. CONCLUSIONS & INFERENCES: Concentration of salivary pepsin may not be an accurate measure of severity of reflux because of the wide range observed in individuals over 24 hours. Saliva samples must be obtained soon after a reflux event. Defining a regimen for optimal saliva collection may help to achieve the goal of using salivary pepsin as a biomarker for oropharyngeal reflux. CLINICAL TRIAL REGISTRY: NCT01091805.

Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study.

INTRODUCTION: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. METHODS: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. RESULTS: PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113). CONCLUSION: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.

Retrospective analysis of the impact of HPV status and smoking on mucositis in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemotherapy and radiotherapy.

OBJECTIVES: The standard concurrent radiotherapy and chemotherapy regimens for patients with oropharyngeal cancer are highly toxic. Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has recently emerged as a distinct biological and clinical entity with improved response to treatment and prognosis. A tailored therapeutic approach is needed to optimize patient care. The aim of our study was to investigate the impact of HPV and smoking status on early toxicities (primarily mucositis) associated with concurrent chemotherapy and radiotherapy in patients with OPSCC. MATERIALS AND METHODS: We retrospectively evaluated 72 consecutive patients with OPSCC and known HPV status treated with concurrent radiotherapy and chemotherapy at our institution. Treatment-related toxicities were stratified by smoking and HPV status and compared using univariate and multivariate logistic regression. RESULTS: HPV-positive patients had a 6.86-fold increase in the risk of having severe, grade 3-4 mucositis. This effect was preserved after adjusting for patient smoking status, nodal stage, radiotherapy technique and radiotherapy maximum dose. Additionally, HPV status had significant effect on the objective weight loss during treatment and at three months after treatment. Consistently, non-smokers had a significant 2.70-fold increase in the risk of developing severe mucositis. CONCLUSION: Risk factors for OPSCC modify the incidence of treatment-related early toxicities, with HPV-positive and non-smoking status correlating with increased risk of high grade mucositis and associated outcomes. Retrospective single-institution studies need to be interpreted cautiously. However, this finding is important to consider when designing therapeutic strategies for HPV-positive patients and merits further investigation in prospective clinical trials.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

A systems analysis of age-related changes in some cardiac aging traits.

Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling-a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals.

A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials.

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Vitamin D in youth with Type 1 diabetes: prevalence of insufficiency and association with insulin resistance in the SEARCH Nutrition Ancillary Study.

AIMS: To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. METHODS: Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. RESULTS: Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57-0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64-1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63-1.14). CONCLUSIONS: Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.