Faculty Bibliography

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10^-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10^-17), rs219779 adjacent to CLDN14 (P=3.5 × 10^-16), rs4443100 near RTDR1 (P=8.7 × 10^-9), and rs73186030 near CASR (P=4.8 × 10^-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

BACKGROUND:The 2020 American Heart Association Impact Goal aims to improve cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%. A large step toward this goal would be to better understand and take advantage of the significant intersection between behavior and biology across the entire life-span. In the proposed FAMILIA studies, we aim to directly address this major knowledge and clinical health gap by implementing an integrated family-centric health promotion intervention and focusing on the intersection of environment and behavior, while understanding the genetic and biologic basis of cardiovascular disease. METHODS:We plan to recruit 600 preschool children and their 600 parents or caregivers from 12-15 Head Start schools in Harlem, NY, and perform a 2:1 (2 intervention/1 control) cluster randomization of the schools. The preschool children will receive our intensive 37-hour educational program as the intervention for 4 months. For the adults, those in the "intervention" group will be randomly assigned to 1 of 2 intervention programs: an "individual-focused" or "peer-to-peer based." The primary outcome in children will be a composite score of knowledge (K), attitudes (A), habits (H), related to body mass index Z score (B), exercise (E), and alimentation (A) (KAH-BEA), using questionnaires and anthropometric measurements. For adults, the primary outcome will be a composite score for behaviors/outcomes related to blood pressure, exercise, weight, alimentation (diet) and tobacco (smoking; Fuster-BEWAT score). Saliva will be collected from the children for SNP genotyping, and blood will be collected from adults for RNA sequencing to identify network models and predictors of primary prevention outcomes. CONCLUSION/CONCLUSIONS:The FAMILIA studies seek to demonstrate that targeting a younger age group (3-5 years) and using a family-based approach may be a critical strategy in promoting cardiovascular health across the life-span.

RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.

PURPOSE OF REVIEW/OBJECTIVE:This article intends to review biomarkers derived from blood, urine, and tissue that can aid in the diagnosis of prostate cancer (PCa). RECENT FINDINGS/RESULTS:PCa screening requires tools that complement prostate-specific antigen (PSA) with a higher specificity for clinically significant disease. Novel blood biomarkers, such as the Prostate Health Index (phi) and 4Kscore, utilize isoforms of PSA to more accurately predict high-grade PCa than traditional tools such as PSA and the percentage free-to-total PSA. Several gene products associated with PCa can be detected in the urine through commercially available assays. PCa antigen 3 (PCA3), though approved for repeat biopsy decisions, appears inferior to other biomarkers such as phi for identifying aggressive disease. However, combinations of PCA3 with other urine assays have shown promising results. One tissue-based hypermethylation test, named ConfirmMDx, can also be used to determine the need for repeat biopsy in men with a prior negative biopsy. SUMMARY/CONCLUSIONS:Several biomarkers have been developed to aid in the screening and diagnosis of PCa. Such tests are often indicated in men with moderately elevated PSA or history of a prior negative biopsy. Their use facilitates reduction of unnecessary biopsies without sacrificing the early diagnosis of clinically significant PCa.

Background/Purpose: Parent anxiety can affect infant experiences of procedural pain. However, little is known about other parent psychological factors associated with parent anxiety related to infant/toddler cleft and craniofacial surgery, and to what degree preoperative parent anxiety affects infant/toddler experiences of postoperative pain. Objectives 1. To identify psychological factors associated with preoperative anxiety for parents with young infants/toddlers undergoing craniofacial surgery 2. To determine whether preoperative parent anxiety is associated with infant/toddler postoperative pain Methods/Description: This was a prospective cohort study of all patients undergoing primary cleft and craniofacial surgery at a tertiary care medical center. Seventy-one consecutive parents of infants/toddlers 2-18 months were recruited for this study. Preoperative parent assessment included: anxiety (Hospital Anxiety and Depression Scale [HADS]), coping (Brief COPE), Parent Health Locus of Control scale, de novo self-efficacy around child pain, and pain knowledge. Sociodemographic data included child's age, gender; previous surgery, NICU or feeding tube; and parent age, gender, socioeconomic status, and race. Subsequent nurse-assessed child pain scores were collected for patients admitted postoperatively. Analyses included hierarchical multivariable logistic and linear regression models. Results: Parents (n=71, 90% female) of young children (mean age 6.6 mo) undergoing cleft lip/palate (n=59) or cranial vault repair (n=13) were enrolled. Only maladaptive coping (OR 1.3, p<0.01, 95% CI 1.1, 1.6), low pain management parent self-efficacy (OR 2.4, p<0.01, 95% CI 1.3, 4.5), and external locus of control (1.74, p 0.024, 95% CI 11, 2.9) were associated with high anxiety on bivariable analysis. In the final model, odds of parent preoperative anxiety was associated with differences in maladaptive coping score (aOR). Moderate/severe preoperative parental anxiety (HADS>10) was correlated with significantly higher child mean hospital pain scores in families of children undergoing cleft lip repair (1.87 point on 0-10 scale, 95% CI.42, 3.70, p =0.045). Conclusions: Infants/toddlers undergoing cleft and craniofacial surgery with highly anxious parents prior to surgery are at greater risk for higher hospital pain. Coping and self-efficacy are modifiable factors that contribute to parent anxiety before and during hospitalization and may be targets for intervention. Health locus of control could be incorporated into preoperative screening for vulnerable families

BACKGROUND:Rural settings in Sub-Saharan Africa (SSA) consistently report low participation in non-communicable disease (NCD) treatment programs and poor outcomes. OBJECTIVE:The objective of this study is to assess the impact of the implementation of a patient-centered rural NCD care delivery model called Bridging Income Generation through grouP Integrated Care (BIGPIC). DESIGN/METHODS:The study prospectively tracked participation and health outcomes for participants in a screening event and compared linkage frequencies to a historical comparison group. PARTICIPANTS/METHODS:Rural Kenyan participants attending a voluntary NCD screening event were included within the BIGPIC model of care. INTERVENTIONS/METHODS:The BIGPIC model utilizes a contextualized care delivery model designed to address the unique barriers faced in rural settings. This model emphasizes the following steps: (1) find patients in the community, (2) link to peer/microfinance groups, (3) integrate education, (4) treat in the community, (5) enhance economic sustainability and (6) generate demand for care through incentives. MAIN MEASURES/METHODS:The primary outcome is the linkage frequency, which measures the percentage of patients who return for care after screening positive for either hypertension and/or diabetes. Secondary measures include retention frequencies defined as the percentage of patients remaining engaged in care throughout the 9-month follow-up period and changes in systolic (SBP) and diastolic blood pressure (DBP) and blood sugar over 12 months. KEY RESULTS/RESULTS:Of the 879 individuals who were screened, 14.2 % were confirmed to have hypertension, while only 1.4 % were confirmed to have diabetes. The implementation of a comprehensive microfinance-linked, community-based, group care model resulted in 72.4 % of screen-positive participants returning for subsequent care, of which 70.3 % remained in care through the 12 months of the evaluation period. Patients remaining in care demonstrated a statistically significant mean decline of 21 mmHg in SBP [95 % CI (13.9 to 28.4), P < 0.01] and 5 mmHg drop in DBP [95 % CI (1.4 to 7.6), P < 0.01]. CONCLUSIONS:The implementation of a contextualized care delivery model built around the unique needs of rural SSA participants led to statistically significant improvements in linkage to care and blood pressure reduction.

BACKGROUND: There is a need for screening and brief assessment instruments to identify primary care patients with substance use problems. This study's aim was to examine the performance of a two-step screening and brief assessment instrument, the TAPS Tool, compared to the WHO ASSIST. METHODS: Two thousand adult primary care patients recruited from five primary care clinics in four Eastern US states completed the TAPS Tool followed by the ASSIST. The ability of the TAPS Tool to identify moderate- and high-risk use scores on the ASSIST was examined using sensitivity and specificity analyses. RESULTS: The interviewer and self-administered computer tablet versions of the TAPS Tool generated similar results. The interviewer-administered version (at cut-off of 2), had acceptable sensitivity and specificity for high-risk tobacco (0.90 and 0.77) and alcohol (0.87 and 0.80) use. For illicit drugs, sensitivities were >0.82 and specificities >0.92. The TAPS (at a cut-off of 1) had good sensitivity and specificity for moderate-risk tobacco use (0.83 and 0.97) and alcohol (0.83 and 0.74). Among illicit drugs, sensitivity was acceptable for moderate-risk of marijuana (0.71), while it was low for all other illicit drugs and non-medical use of prescription medications. Specificities were 0.97 or higher for all illicit drugs and prescription medications. CONCLUSIONS: The TAPS Tool identified adult primary care patients with high-risk ASSIST scores for all substances as well moderate-risk users of tobacco, alcohol, and marijuana, although it did not perform well in identifying patients with moderate-risk use of other drugs or non-medical use of prescription medications. The advantages of the TAPS Tool over the ASSIST are its more limited number of items and focus solely on substance use in the past 3months.

OBJECTIVE: Hispanic parents in the United States are disproportionately affected by low health literacy and limited English proficiency (LEP). We examined associations between health literacy, LEP, and liquid medication dosing errors in Hispanic parents. METHODS: Cross-sectional analysis of data from a multisite randomized controlled experiment to identify best practices for the labeling/dosing of pediatric liquid medications (SAFE Rx for Kids study); 3 urban pediatric clinics. Analyses were limited to Hispanic parents of children aged 20% dose deviation. Predictor variables included health literacy (Newest Vital Sign) (limited = 0-3; adequate = 4-6) and LEP (speaks English less than "very well"). RESULTS: A total of 83.1% made dosing errors (mean [SD] errors per parent = 2.2 [1.9]). Parents with limited health literacy and LEP had the greatest odds of making a dosing error compared to parents with adequate health literacy who were English proficient (trials with errors per parent = 28.8 vs 12.9%; adjusted odds ratio = 2.2 [95% confidence interval 1.7-2.8]). Parents with limited health literacy who were English proficient were also more likely to make errors (trials with errors per parent = 18.8%; adjusted odds ratio = 1.4 [95% confidence interval 1.1-1.9]). CONCLUSIONS: Dosing errors are common among Hispanic parents; those with both LEP and limited health literacy are at particular risk. Further study is needed to examine how the redesign of medication labels and dosing tools could reduce literacy- and language-associated disparities in dosing errors.

Background: Asian Americans are one of the fastest growing minority populations in the United States. With increases in the older adult population too, there needs to be research dedicated to their health. Past studies have shown that social isolation and loneliness predict greater physical, mental, and cognitive decline. This literature review was conducted to address this emerging need to understand the scope of research focused on social isolation and Asian American older adults. Methods: The PRISMA guidelines were used to guide this review. Four interdisciplinary databases searched were: PubMed, CINAHL, PsychINFO, and AgeLine. Search terms included variations on the words social isolation, loneliness, Asian Americans, and older adults. The date of the last search was July 6th, 2016. Articles were reviewed based on 5 eligibility criteria: (1) topic relevance, (2) study participants > 60 years of age, (3) Asian immigrants as main participants, (4) conducted in a Western country, and (5) published in the English language. The remaining studies were assessed on eight categories: ethnic group, health topic, geographic location, subject population, recruitment site, study design, outcomes accessed, and outcomes measures. Results: The search yielded 203 articles from the four databases. 49 articles were removed as duplicates. The 154 remaining studies were reviewed based on their abstract and 34 met the eligibility criteria and underwent full text review. Existing research has focused primarily on immigrant Chinese and Korean older adult populations located in major gateway cities (ex: Los Angeles, New York City). Studies were largely observational studies that were conducted using small community-based samples which makes generalizability difficult. There were zero interventional studies. Conclusions: There are critical gaps in the literature on social isolation in Asian immigrant populations. Future studies should prioritize health promotion intervention research and focus on diverse understudied Asian subgroups (e.g. South Asians, Cambodians, Filipinos). Potential pitfalls of this literature review include: accessing only four major databases, limiting searches to after 1995, and studies were conducted throughout countries with different healthcare systems

In a longitudinal population-based study of 2,905 children, we investigated if infants' neuromotor development was associated with autistic traits in childhood. Overall motor development and muscle tone were examined by trained research assistants with an adapted version of Touwen's Neurodevelopmental Examination between ages 2 and 5 months. Tone was assessed in several positions and items were scored as normal, low, or high tone. Parents rated their children's autistic traits with the Social Responsiveness Scale (SRS) and the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist at 6 years. We defined clinical PDP if scores were >98th percentile of the norm population. Diagnosis of autism spectrum disorder (ASD) was clinically confirmed in 30 children. We observed a modest association between overall neuromotor development in infants and autistic traits. Low muscle tone in infancy predicted autistic traits measured by SRS (adjusted beta = 0.05, 95% CI for B: 0.00-0.02, P = 0.01), and PDP (adjusted beta = 0.08, 95% CI for B: 0.04-0.10, P < 0.001). Similar results emerged for the association of low muscle tone and clinical PDP (adjusted OR = 1.36, 95% CI: 1.08-1.72, P = 0.01) at age 6 years. Results remained unchanged if adjusted for child intelligence. There was no association between high muscle tone and SRS or PDP. Exclusion of children with ASD diagnosis did not change the association. This large study showed a prospective association of infant muscle tone with autistic traits in childhood. Our findings suggest that early detection of low muscle tone might be a gateway to improve early diagnosis of ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.