Search

Background: The predictive validity of components of the Graduate Record Examination (GRE) on student success is inconsistent, and the test itself has been shown to be a barrier for prospective students historically underrepresented in graduate programs.Policy Options and Recommendations: We analyzed three admissions cycles for the Master of Public Health degree at the Boston University School of Public Health before (2016, 2017, 2018) and after (2019, 2020, 2021) eliminating the GRE for diversity and quality of applications, student success, and employment outcomes. We observed increases in diversity (e.g., 7.1% and 7.0% self-identified as African American/Black and Hispanic before eliminating the GRE as compared to 8.5% and 8.2% after), but no loss of quality, as measured by undergraduate grade point averages (GPAs) (e.g., median undergraduate GPA before and after eliminating the GRE of 3.4). We also saw no difference in performance in required core courses (e.g., more than 93.5% of students earned passing grades in required courses before and 94.5% after eliminating the GRE) and graduate employment (i.e., 93.1% employed within 6 months of graduation before and 93.8% after eliminating the GRE). We recommend removing the GRE as an admission requirement for the MPH as a step toward diversifying the public health workforce. This change alone is necessary but insufficient. We also need to develop support programs, tailored specifically to the needs of our future students, to ensure their success.Conclusion: Eliminating the GRE as an admissions requirement for prospective students does not result in loss of student quality or worse program performance.

Achieving a diverse and inclusive community requires establishing a culture of genuine equality for all members. Our purpose in writing this book is to share our collective knowledge about how to challenge the forces that enable and sustain discrimination in the workplace as informed by our experience developing and implementing the UC Davis ADVANCE program. The program’s goal is to create an inclusive academic community that reflects and serves the diverse population of California. In this introductory chapter, we emphasize the need to move from affirmative action programs, which have played an important role in fostering diversity, to a focus on institutional transformation, which requires not only changes in policy but also shifts in academic culture. Much of what we cover in this book is broadly applicable beyond academia and will interest those wanting to understand and address challenges to diversity, equity, and inclusion in their own organizations. Since workplaces differ in their goals, priorities, and culture, the book is not a “how to” manual but rather a collective effort to share with readers the approaches we took, the information we gathered, what we observed and experienced, and the lessons we learned along the way.

Addressing barriers to inclusion requires understanding the nature of the problem at the institutional level. Data collection and assessment are both crucial for this aim. In this chapter, we describe two important classes of data: (1) data on diversity that define the potential nature of the issues at stake and the need for change, and (2) data on assessing the usefulness of new programs, processes, and policies in creating a more diverse institution. Both sets of data are important for effective decision-making. At the same time, data analyses can be challenging because issues of equity and inclusion are complex and determining the basis of comparison or the “ideal” diversity target can be difficult. Nevertheless, data gathering and analysis are critical to assess progress and to provide a basis for both accountability and efficacy. Moreover, the ability to document that a problem indeed exists will help justify the need for change and, ideally, spur corrective action.

Key Points Question Is prenatal exposure to maternal drinking and smoking associated with the risk of stillbirth? Findings In this cohort study of 8506 pregnant women (with 11 892 pregnancies) in Cape Town, South Africa, and the Northern Plains in the US, dual exposure to drinking and smoking after the first trimester of pregnancy had 2.78 times the risk of late stillbirth compared with those with no exposure or who had quit before the end of the first trimester of pregnancy. Meaning These findings suggest that dual exposure to drinking and smoking after the first trimester of pregnancy is associated with nearly 3 times the risk of late stillbirth., Importance Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures The main outcomes were stillbirth, defined as fetal death at 20 or more weeks’ gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks’ gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth., This cohort study assesses whether prenatal exposure to alcohol, tobacco cigarettes, or both is associated with the risk of stillbirth in pregnant women from Cape Town, South Africa, and the Northern Plains region of the US.

As noted by JAHA Editor-in-Chief Barry London1, the views presented in the recently retracted article "Diversity, Inclusion, and Equity: Evolution of Race and Ethnicity Considerations for the Cardiology Workforce in the United States of America From 1969 to 2019"2,3 do not reflect the views of the JAHA Editorial Board, the Editor-in-Chief, or the American Heart Association. We, the JAHA editors, are strong advocates of increasing equity, diversity and inclusiveness in cardiovascular medicine and in healthcare broadly.

We, the Editors of the Journal of the American Heart Association , sincerely regret the publication of the article “Diversity, Inclusion, and Equity: Evolution of Race and Ethnicity Considerations for the Cardiology Workforce in the United States of America From 1969 to 2019”. 1 We are aware that the publication of this flawed and biased article has caused a great deal of unnecessary pain and anguish to a number of parties, and reflects extremely poorly on us. We fully support the retraction of this article.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach-Merritt phenomenon that, through deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin.

// Allison M. Martin 1 , Christopher J. Nirschl 2 , Magda J. Polanczyk 1 , W Robert Bell 3 , Thomas R. Nirschl 4 , Sarah Harris-Bookman 5 , Jillian Phallen 6 , Jessica Hicks 7 , Daniel Martinez 8 , Aleksandra Ogurtsova 9 , Haiying Xu 9 , Lisa M. Sullivan 10 , Alan K. Meeker 7 , Eric H. Raabe 1, 11 , Kenneth J. Cohen 1 , Charles G. Eberhart 11 , Peter C. Burger 11 , Mariarita Santi 8 , Janis M. Taube 9 , Drew M. Pardoll 2 , Charles G. Drake 12 and Michael Lim 13 1 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA 2 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA 3 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA 4 Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA 5 Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA 6 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA 7 Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA 8 Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA 9 Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA 10 In Jackson, MS, USA 11 Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA 12 Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA 13 Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA Correspondence to: Allison M. Martin, email: amarti65@jhmi.edu Keywords: medulloblastoma; PD-1; brain tumor; PD-L1; B7-H1 Received: August 03, 2017 Accepted: March 13, 2018 Published: April 10, 2018 ABSTRACT Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro , IFN-γ robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-γ), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, T H 1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9,912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

// Abhilasha Sinha 1, * , Bibbin T. Paul 2, * , Lisa M. Sullivan 3 , Hillary Sims 3 , Ahmed El Bastawisy 4 , Hend F. Yousef 5 , Abdel-Rahman N. Zekri 6 , Abeer A. Bahnassy 7 , Wael M. ElShamy 1, 3 1 Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA 2 Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA 3 Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA 4 Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt 5 Cytogenetics and Molecular Genetics, National Cancer Institute, Cairo University, Cairo, Egypt 6 Virology and Immunology, National Cancer Institute, Cairo University, Cairo, Egypt 7 Molecular Pathology and Cytogenetics, National Cancer Institute, Cairo University, Cairo, Egypt * These authors have contributed equally to this work Correspondence to: Wael M. ElShamy, email: welshamy@umc.edu Keywords: breast cancer, BRCA1-IRIS, metastasis, early lesion, TNBC Received: September 27, 2016 Accepted: December 13, 2016 Published: December 29, 2016 ABSTRACT Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44 + /CD24 - /ALDH1 + phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.

Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid–binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C-reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid–binding protein 4, and leptin concentrations (all P P =0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels ( P P =0.02), but inversely with leptin and leptin receptor levels ( P ≤0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension.

Plexiform fibromyxoma tumor (PFT) is an exceedingly rare tumor, particularly in children where only four cases have been reported to date. The patient reported herein presented with abdominal pain and vomiting related to gastric outlet obstruction caused by a large, polypoid PFT. We describe the clinical features, diagnostic evaluation, and surgical treatment of this rare tumor in our patient. Further, we review the literature of FPT to bring attention to this rare gastric tumor to the Pediatric Surgeon.

Background: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. Methods: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. Findings: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59–53·7, p

In observational studies with censored data, exposure-outcome associations are commonly measured with adjusted hazard ratios (HRs) from multivariable Cox proportional hazards models. The difference in restricted mean survival times (RMST) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. We derive the adjusted RMST by integrating an adjusted Kaplan-Meier estimator with inverse probability weighting (IPW). The adjusted difference in RMSTs is the area between the two IPW-adjusted survival functions. In a Monte Carlo-type simulation study, we demonstrate that the proposed estimator performs as well as two regression-based approaches: the ANCOVA-type method of Tian et al(1) and the pseudo-observation method of Andersen et al.(2–4) We illustrate the methods by re-examining the association between total cholesterol and the 10-year risk of coronary heart disease in the Framingham Heart Study.

The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia.We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×10No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion.We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).

Background/Aims: Pediatric Graves' disease (GD) accounts for 10-15% of all thyroid disorders in patients ≤18 years and is treated with antithyroid medication or definitive therapy [radioactive iodine (RAI) ablation vs. surgery]. Patients with GD may have concurrent differentiated thyroid cancer (DTC). DTC prevalence in pediatric GD is not well established. We examined the prevalence of DTC in pediatric GD and the role of preoperative thyroid ultrasound (US) in selecting the appropriate definitive therapy. Methods: This is a single-institution, retrospective, cross-sectional study of 32 GD patients with a median age of 11 years (range 3-18) who underwent total thyroidectomy as the definitive treatment between 2005 and 2014. Results: DTC was identified in 22% of the GD patients. A total of 97% completed preoperative thyroid US, and thyroid nodules were identified in 13/32 patients (41%). Preoperative fine needle aspiration (FNA) biopsy was performed in 6/13 patients, accounting for four preoperative diagnoses of concurrent DTC. Extra-thyroidal extension was present in 4/7 (63%), regional lymph node metastasis in 3/7 (43%), and lung metastasis in 2/7 patients (29%). Conclusions: Concurrent DTC occurs in pediatric GD patients. Thyroid US is an efficient tool for selecting patients for thyroidectomy. For patients with a nodule on US before definitive therapy, FNA should be performed to appropriately select thyroidectomy versus RAI ablation.

Background— Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l -arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers. Methods and Results— This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci ( DDAH1, MED23, Arg1 , and AGXT2 ) associated with the interindividual variability in ADMA, l -arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Conclusions— These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l -arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. The disorder is classified into nine different subtypes (HPS1–HPS9) based on genetic mutations in 9 unique genes. Here we describe the generation of an HPS1 iPSC line (CHOPHPS1) using a Cre-excisable polycistronic STEMCCA lentivirus. This line was derived from human fibroblasts isolated from a patient carrying a duplicative mutation in the HPS1 gene. The patient presented with oculocutaneous albinism, early pulmonary fibrosis, and hemorrhagic diathesis.

Thyroid nodules are less common in pediatric patients (i.e., those ≤18 years) than they are in adults. The Bethesda System for Reporting Thyroid Cytopathology allows for individual risk stratification, but a significant number of nodules are indeterminate. Incorporating gene mutation panels and gene expression classifiers may aid in preoperative diagnosis. The overall aim of this study was to assess the prevalence of oncogene alterations in a representative pediatric population and across a broad-spectrum of thyroid tumor diagnoses.This was a retrospective cross-sectional evaluation of 115 archived samples, including: 47 benign (29 follicular adenoma, 11 diffuse hyperplasia, four thyroiditis, and three multinodular goiter), six follicular thyroid carcinomas (FTC), 24 follicular variant of papillary thyroid carcinomas (fvPTC), 27 classic variant of PTC (cPTC), eight diffuse sclerosing variant of PTC (dsvPTC), and three other PTC. Molecular testing was performed by multiplex qualitative polymerase chain reaction followed by bead array cytometry. Oncogene results were analyzed for association with age, sex, histology, lymph node metastasis, and intrathyroidal spread.A mutation in one of the 17 molecular markers evaluated was found in: 2/6 (33%) FTC, 8/24 (33%) fvPTC, 17/27 (63%) cPTC, and 4/8 (50%) dsvPTC. Mutations in RAS or PAX8/PPARG were exclusive to FTC and fvPTC. BRAF was the most common mutation in cPTC (12/17; 71%), and RET/PTC was the only mutation associated with dsvPTC. Overall, a mutation was found in 32/68 (47%) malignant specimens, with a single follicular adenoma positive for PAX8/PPARG. The relative distribution of gene alterations in pediatric lesions was similar to adults. The presence of a BRAF mutation in pediatric cPTC did not predict a more invasive phenotype.Of 33 nodules with genetic alterations, 32 were malignant. Mutations in RAS were most frequently associated with FTC, RET/PTC rearrangements with dsvPTC, and invasive fvPTC, and BRAF with cPTC. These results suggest a clinical role for mutational analysis of pediatric nodules to guide the surgical approach.

Background Adipokines are implicated in the development of obesity‐related traits. We hypothesized that nonobese participants without diabetes mellitus (DM) whose parents were obese or had DM would have altered circulating adipokines compared with those without parental history of these conditions. Methods and Results Participants in the community‐based Framingham Third Generation cohort who were not obese (body mass index DM was defined as occurring before age 60 years, and obesity was defined as body mass index ≥30 before age 60 years. General estimating equations were used to compare concentrations of adipokines among participants with 0, 1, or 2 parents affected by obesity or DM (separate analyses for each), adjusting for known correlates of adipokines. Overall, 44% had at least 1 parent who was obese and 15% had parents with DM . Parental obesity was associated with higher serum levels of FABP 4 and LEP ‐R in their offspring ( P =0.02 for both). Parental DM was associated with lower adiponectin but higher RBP 4 concentrations in offspring ( P ≤0.02 for both). Conclusions In our community‐based sample, a parental history of DM or obesity was associated with an altered adipokine profile in nonobese nondiabetic offspring. Additional studies are warranted to evaluate whether such preclinical biomarker alterations presage future risk of disease.

Background Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross‐sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS. Methods and Results Participants in the community‐based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002–2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin‐A, fatty acid–binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in follow‐up (mean 6 years). The adipokines were compared among individuals with excess body weight (body mass index ≥25 kg/m 2 ) and prevalent MetS, excess body weight without MetS (metabolically healthy obese), and normal‐weight with MetS (metabolically obese, normal‐weight) with normal‐weight participants without MetS as a referent. Metabolically healthy obese individuals (n=1467) had higher circulating levels of fetuin‐A and fatty acid–binding protein 4 but lower levels of leptin, leptin receptor, and adiponectin ( P P =0.002). Higher circulating concentrations of retinol‐binding protein 4 and fetuin‐A were associated with incidence of MetS (odds ratio per 1‐ SD increment log marker, 1.21; 95% CI , 1.03–1.41 [ P =0.02] and 1.17; 95% CI, 1.01–1.34 [ P =0.03], respectively). Conclusions In our community‐based sample of young to middle‐aged adults, metabolically healthy obese individuals demonstrated an adverse adipokine profile. Higher circulating levels of retinol‐binding protein 4 and fetuin‐A marked future cardiometabolic risk.

Background: The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. Methods: The results provided are based on an interim assessment of 6004 women enrolled, out of the 12 000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. Results: Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. Conclusions: The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/ infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.

It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest) and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous net reclassification index (NRI), the integrated discrimination index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to the following: null model, model including a published risk score, model including a composite risk score estimated from the sample of interest, and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by the Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.

Ectopic production of β-human chorionic gonadotropin (β-hCG) by nontrophoblastic tumors has been reported but mostly in carcinomas. We report a case of an adolescent female patient with a epithelioid osteosarcoma that was discovered to secrete β-hCG after routine pregnancy testing. Immunohistochemical staining of her primary tumor biopsy demonstrated immunoreactivity for β-hCG. Levels of serum β-hCG were monitored throughout her therapy and demonstrated normalization with effective systemic therapy and local control. She remains disease free 6 months off therapy, with undetectable hormone levels. A review of the available literature on β-hCG production by sarcomas is also presented.