Angelo Elmi

Effects of Sex, Race, and Puberty on Cortical Bone and the Functional Muscle Bone Unit in Children, Adolescents, and Young Adults

CONTEXT Sex and race differences in bone development are associated with differences in growth, maturation, and body composition. OBJECTIVE The aim of the study was to determine the independent effects of sex, race, and puberty on cortical bone development and muscle-bone relations in children and young adults. DESIGN AND PARTICIPANTS We conducted a cross-sectional study of 665 healthy participants (310 male, 306 black) ages 5-35 yr. OUTCOMES Tibia peripheral quantitative computed tomography measures were made of cortical bone mineral content (BMC) and bone mineral density (BMD), periosteal (Peri) and endosteal circumferences, section modulus (Zp), and muscle area. Regression models were adjusted for tibia length, age, race, sex, and Tanner stage. RESULTS All cortical measures were greater in blacks than whites (all P < or = 0.001) in Tanner stages 1-4; however, differences in BMC, Peri, and Zp were negligible in Tanner stage 5 (all interactions, P < 0.01). Cortical BMC, Peri, and Zp were lower in females than males in all Tanner stages (all P < 0.001), and the sex differences in Peri and Zp were greater in Tanner stage 5 (interaction, P < 0.02). Cortical BMD was greater (P < 0.0001) and endosteal circumference was lower (P < 0.01) in Tanner 3-5 females, compared with males. Adjustment for muscle area attenuated but did not eliminate sex and race differences in cortical dimensions. Associations between muscle and bone outcomes did not differ according to sex or race. CONCLUSION Sex and race were associated with maturation-specific differences in cortical BMD and dimensions that were not fully explained by differences in bone length or muscle. No race or sex differences in the functional muscle bone unit were identified.

Consumer Product Chemicals in Indoor Dust: A Quantitative Meta-analysis of U.S. Studies.

Indoor dust is a reservoir for commercial consumer product chemicals, including many compounds with known or suspected health effects. However, most dust exposure studies measure few chemicals in small samples. We systematically searched the U.S. indoor dust literature on phthalates, replacement flame retardants (RFRs), perfluoroalkyl substances (PFASs), synthetic fragrances, and environmental phenols and estimated pooled geometric means (GMs) and 95% confidence intervals for 45 chemicals measured in ≥3 data sets. In order to rank and contextualize these results, we used the pooled GMs to calculate residential intake from dust ingestion, inhalation, and dermal uptake from air, and then identified hazard traits from the Safer Consumer Products Candidate Chemical List. Our results indicate that U.S. indoor dust consistently contains chemicals from multiple classes. Phthalates occurred in the highest concentrations, followed by phenols, RFRs, fragrance, and PFASs. Several phthalates and RFRs had the highest residential intakes. We also found that many chemicals in dust share hazard traits such as reproductive and endocrine toxicity. We offer recommendations to maximize comparability of studies and advance indoor exposure science. This information is critical in shaping future exposure and health studies, especially related to cumulative exposures, and in providing evidence for intervention development and public policy.

Risk Factors for Melanoma Among Survivors of Non-Hodgkin Lymphoma

PURPOSE Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. PATIENTS AND METHODS We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. RESULTS A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n=18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n=10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n=36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n=49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). CONCLUSION Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma.

Who listens to our advice? A secondary analysis of data from a clinical trial testing an intervention designed to decrease delay in seeking treatment for acute coronary syndrome

OBJECTIVE Prolonged prehospital delay in persons experiencing acute coronary syndrome (ACS) remains a problem. Understanding which patients respond best to particular interventions designed to decrease delay time would provide mechanistic insights into the process by which interventions work. METHODS In the PROMOTION trial, 3522 at-risk patients were enrolled from 5 sites in the United States (56.4%), Australia and New Zealand; 490 (N=272 intervention, N=218 control) had an acute event within 2 years. Focusing on these 490, we (1) identified predictors of a rapid response to symptoms, (2) identified intervention group subjects with a change in these predictors over 3 months of follow-up, and (3) compared intervention group participants with and without the favorable response pattern. Hypothesized predictors of rapid response were increased perceived control and decreased anxiety. Knowledge, attitudes, and beliefs were hypothesized to differ between responders and non-responders. RESULTS Contrary to hypothesis, responders had low anxiety and low perceived control. Only 73 (26.8%) subjects showed this pattern 3 months following the intervention. No differences in ACS knowledge, attitudes, or beliefs were found. CONCLUSION The results of this study challenge existing beliefs. PRACTICE IMPLICATIONS New intervention approaches that focus on a realistic decrease in anxiety and perceived control are needed.

A B-Spline Based Semiparametric Nonlinear Mixed Effects Model

The Semiparametric Nonlinear Mixed Effects Model (SNMM) (Ke and Wang 2001) provides a flexible framework for longitudinal comparisons of curve shapes between groups. In this article, we develop an alternative method for fitting the SNMM by reformulating Ke and Wang’s smoothing spline based model in terms of B-splines. The existing algorithm is based on a backfitting procedure that iterates between two mixed models whose corresponding likelihoods are not equivalent to the likelihood of all model parameters. The consequence is a lack of reliable convergence and statistical inference. Using B-splines, however, overcomes these disadvantages by simplifying the likelihood computations without sacrificing model flexibility. Therefore, the algorithm can be expressed in terms of existing, accurate techniques based on Adaptive Gaussian Quadrature. The model is applied to labor curves, cervical dilation measured longitudinally, from women attempting a vaginal birth after cesarean. Only partial curves were measured on cases of uterine rupture given the need for emergency c-section while controls completed delivery naturally. The model allowed us to estimate and compare the average labor curve shape between cases and controls and also determine the earliest time at which clinicians could distinguish between the average labor curves in different groups. Supplemental materials are available online.

Low-dose Ketamine for Children and Adolescents with Acute Sickle Cell Disease Related Pain: A Single Center Experience

Background: Opioids are the mainstay of therapy for painful vasoocclusive episodes (VOEs) in sickle cell disease (SCD). Based on limited studies, low-dose ketamine could be a useful adjuvant analgesic for refractory SCD pain, but its safety and efficacy has not been evaluated in pediatric SCD. Procedure: Using retrospective chart review we recorded and compared characteristics of hospitalizations of 33 children with SCD hospitalized with VOE who were treated with low-dose ketamine and opioid PCA vs. a paired hospitalization where the same patients received opioid PCA without ketamine. We seek to 1) describe a single center experience using adjuvant low-dose ketamine with opioid PCA for sickle cell related pain, 2) retrospectively explore the safety and efficacy of adjuvant low-dose ketamine for pain management, and 3) determine ketamine’s effect on opioid consumption in children and adolescents hospitalized with VOE. Results: During hospitalizations where patients received ketamine, pain scores and opioid use were higher (6.48 vs. 5.99; p=0.002 and 0.040 mg/kg/h vs. 0.032 mg/kg/h; p=0.004 respectively) compared to hospitalizations without ketamine. In 3 patients, ketamine was discontinued due to temporary and reversible psychotomimetic effects. There were no additional short term side effects of ketamine. Conclusions: Low-dose ketamine has an acceptable short-term safety profile for patients with SCD hospitalized for VOE. Lack of an opioid sparing effect of ketamine likely represents use of low-dose ketamine for patients presenting with more severe VOE pain. Prospective randomized studies of adjuvant low-dose ketamine for SCD pain are warranted to determine efficacy and long-term safety.

Left ventricular assist device outcomes based on flow configuration and pre-operative left ventricular dimension: An Interagency Registry for Mechanically Assisted Circulatory Support Analysis

BACKGROUND Axial configuration (AC) and centrifugal configuration (CC) left ventricular assist devices (LVAD) have different flow characteristics, and whether the interaction between device flow configuration and the pre-operative left ventricular internal diastolic diameter (LVIDD) mediates adverse events after LVAD implantation is unknown. METHODS We queried 9,424 continuous-flow LVAD recipients who received LVADs from April 2008 to June of 2015 in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The pre-operative LVIDD * flow configuration interaction term was tested in multivariable models to determine its relationship to adverse events. RESULTS The pre-operative LVIDD * flow configuration interaction was a significant predictor of device thrombosis. As the LVIDD increased, the risk of AC device thrombosis increased compared with CC devices (p = 0.0099). At 7.0 cm, the hazard ratio (HR) for AC device thrombosis compared with the CC device was 1.61 (95% confidence interval [CI], 1.17-2.22; p = 0.004) and continued to rise as the LVIDD increased. The LVIDD * flow configuration interaction did not predict stroke, gastrointestinal bleeding, or patient survival. In multivariable models, the hazard of stroke was higher with the CC device regardless of the LVIDD (HR, 1.96; 95% CI, 1.64-2.36; p < 0.0001). Adjusted analyses showed LVAD implantation into a larger left ventricle was associated with a lower risk of death (HR, 0.90; 95% CI, 0.85-0.95; p = 0.0004) per centimeter of LVIDD. CONCLUSIONS Our study suggests that the pre-operative LVIDD, flow configuration, and interaction terms should be considered individually when choosing the appropriate LVAD to mitigate the rates of device thrombosis, stroke, and death.

Risk factors for second acute myeloid leukemia/myelodysplastic syndrome among survivors of non-Hodgkin lymphoma.

Risk factors for second acute myeloid leukemia/myelodysplastic syndrome among survivors of non-Hodgkin lymphoma

Association between persistent endocrine-disrupting chemicals (PBDEs, OH-PBDEs, PCBs, and PFASs) and biomarkers of inflammation and cellular aging during pregnancy and postpartum

BACKGROUND Endocrine-disrupting chemicals (EDCs) can target immune and metabolic pathways. However, few epidemiologic studies have examined the influence of EDCs on measures of inflammation and cellular aging during pregnancy and postpartum. OBJECTIVE We investigated associations between prenatal exposures to polybrominated diphenyl ethers (PBDEs), hydroxylated PBDE metabolites (OH-PBDEs), polychlorinated biphenyls (PCBs), and per- and polyfluorochemicals (PFASs) with repeated biomarker measurements of inflammation and cellular aging in women during pregnancy and the postpartum period. METHODOLOGY Overweight or obese pregnant women were recruited from the San Francisco Bay area (n = 103) during their first or second trimester of pregnancy. Blood samples were collected from participants at baseline (median 16 weeks gestation) and at three and nine months postpartum. Serum concentrations of PBDEs, OH-PBDEs, PCBs, and PFASs were measured at baseline. Inflammation biomarkers (interleukin 6 [IL-6], interleukin 10 [IL-10], and tumor necrosis factor [TNF-α]) and leukocyte telomere length (LTL), a biomarker of cellular aging, were measured at all three time points. Associations between serum chemical concentrations and repeated measures of IL-6, IL-10, TNF-α, and LTL were examined using linear mixed models. We also examined the potential for effect modification by time (visit) and obesity. RESULTS In adjusted models, we observed positive relationships between PBDEs and pro-inflammatory cytokines (IL-6 and TNF-α). A doubling in ∑PBDEs was associated with a 15.26% (95% CI 1.24, 31.22) and 3.74% (95% CI -0.19, 7.82) increase in IL-6 and TNF-α, respectively. Positive associations were also observed for PFASs and IL-6. A two-fold increase in ∑PFASs was associated with a 20.87% (95% CI 3.46, 41.22) increase in IL-6. 5-OHBDE-47 was inversely associated with anti-inflammatory cytokine IL-10. Some EDC-outcome associations, including those of PBDEs with TNF-α, were stronger during pregnancy (compared to three or nine months postpartum) and among obese (compared to overweight) women (p-interaction <0.05). CONCLUSIONS These findings suggest that exposure to specific EDCs is associated with increased inflammation among women during pregnancy and the postpartum period. Future studies should replicate these findings in additional study populations and examine the implications of these associations for maternal and child health.

First trimester dating by fetal heart rate assessment: a comparison with crown-rump length measurement.

Abstract Objective: The purpose of this study was to determine whether fetal heart rate (FHR) can be used to date pregnancies in the early first trimester using the gold standard of crown-rump length (CRL) dating as a reference. Methods: This single center study evaluated women undergoing obstetrical ultrasounds between 4.5 and 8.5 weeks. FHR and gestational age (GA) based on CRL were obtained. Linear regression analysis and a Bland–Altman plot were used to demonstrate the relationship between the two measurements. A further simplified version of the relationship between CRL and FHR that may be clinically useful was calculated. Results: 176 patients were included in the study. The Pearson correlation coefficient was 0.95, indicating a strong correlation between the two dating methods. The Bland–Altman plot demonstrated agreement across GA tested. A simple arithmetic formula of GA(weeks) = FHR (beats per minute)/20 was calculated. 169/176 patients had <4 days discrepancy between FHR- and CRL-based dating using this formula. Conclusion: We found that a simple formula based on FHR may accurately date early pregnancies. This method, if further validated, may represent an important tool for pregnancy dating.