Duke University Medical Center Research Articles

Racial disparities in Alzheimer’s Disease and Related Dementias (ADRD): The association between early life adversity and ADRD

AbstractBackgroundAdverse childhood experiences (ACEs) are an important public health concern that predict neuroanatomical changes in development such as decreased prefrontal cortex and hippocampal volumes, and can lead to poor health outcomes in adulthood, including cognitive impairment. Alzheimer’s disease (AD) is the most common cause of dementia, and it disproportionately affects racial and ethnic minoritized (REM) individuals. Research demonstrates that some of the mechanisms underlying these racial disparities may include differences in exposure to specific types of ACEs (i.e. parental remarriage and/or death). A significant ACE burden can lead to disruption of the hypothalamic‐pituitary adrenal (HPA) axis, our fight‐or‐flight response system to environmental threats and stressors. Growing evidence has shown an association between ACEs and the development of cognitive impairment in older adulthood, including AD and related dementias (ADRD). We do not know, however, how biomarkers related to HPA axis dysregulation in association with ACEs are correlated to ADRD biomarkers (pathology) in a nationally representative, diverse cohort of individuals.MethodsA preliminary study is being conducted to evaluate the associations between early life adversity (measured retrospectively through surveys) and ADRD in several cohorts, including the Minority Aging in Research Study (MARS) from the Rush University Alzheimer’s Disease Research Center, the Stress and Resilience in Dementia (STRIDE) cohort from the University of Wisconsin, and the Duke University Medical Center clinics using DEDUCE, an on‐line query system in MaestroCare, Duke University Hospital’s electronic medical record system. Statistical analyses will be performed using R software.ResultsPending statistical analyses.ConclusionValidation of ACEs as independent risk factors for AD and contributors to the racial disparities seen in this condition will offer new potential therapeutic targets at the molecular level, new clinical screening modalities for specific ACEs instigating cognitive decline, and public policy insights to address a history of childhood trauma in patients with a clinical diagnosis of ADRD. This is especially for those REM individuals who have historically had a delayed or missed diagnosis and have been disproportionately impacted by ADRD.The research project described is supported by the National Institute On Aging of the National Institutes of Health under Award Number P30AG072958.

Tumor-Infiltrating Normal B Lymphocytes Have Remarkable Prognostic Effects and Are Crucial for Antitumor Immune Responses in Diffuse Large B-Cell Lymphoma

Introduction: In recent years, increasing evidence suggests an important role of tumor-infiltrating B lymphocytes (TIL-Bs) in cancer immunity. In various types of solid tumors, high density of TIL-Bs and presence of mature tertiary lymphoid structures consistently correlate with better prognosis and response to immune checkpoint blockade therapies. Diffuse large B-cell lymphoma (DLBCL) is a type of aggressive lymphoma arising from mature B cells. TIL-Bs have been identified in DLBCL based on single-cell gene-expression data in several previous studies, but their prognostic significance in DLBCL is unknown. In this study, we determined the clinical significance of TIL-B abundance and investigated the potential underlying mechanisms. Patients and Methods: This abstract includes a discovery study in which we distinguished TIL-Bs from malignant B-cells by immunoglobulin gene (IG) clonotype analysis and a validation study using flow cytometry. In the discovery study, a molecularly well-characterized DLBCL cohort assembled by the International DLBCL R-CHOP Consortium Program was analyzed. DNA samples from DLBCL patients were sequenced by high-throughput ultra-deep sequencing assays using multiplexed forward and reverse primers. Based on the IG heavy chain (IGH) sequencing results, malignant B-cell and TIL-B VDJ clonotypes were identified for 138 patients, and the frequencies and numbers of TIL-B clonotypes in individual sequence repertoires were calculated. In 79 DLBCL cases, a DJ-only sequence was predominant and no productive VDJ sequences met the criteria for diagnostic sequences. Total frequencies of productive VDJ sequences in the sequence repertoires were then used to access high and low TIL-B frequencies. TIL-B frequencies were also evaluated by IG light chain clonotypes for these 217 patients and additional 52 patients. The TIL-B frequencies were correlated with patient survival, gene-expression profiling (GEP) data GSE31312, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex immunohistochemistry (mIHC). To validate the prognostic significance of TIL-B frequencies, we assembled a validation cohort of 94 DLBCL patients treated at Duke University Medical Center. TIL-Bs in tissues were quantified by flow cytometry immunophenotyping. Ratios of TIL-Bs to abnormal B cells were assessed for prognostic effects. Results: First, we found thathigh frequencies of TIL-Bs and clonotypic diversity were associated with significantly favorable prognostic effects in 138 DLBCL patients with their malignant B-cell IGH-VDJ clonotypes identified (Figure A). The prognostic effects of TIL-Bs outweighed those of the germinal center B-cell-like/activated B-cell-like classification (Figure B). Second, patients with high frequencies of TIL-Bs compared with those without had significant upregulation of immune response genes by GEP (Figure C), higher CD4 T cell infiltration quantified by fluorescent mIHC (Figure D), and enrichment of EcoTyper-defined specific cell states, including significantly increased frequencies of B cell state S2 (pre-memory), CD4 T cell state S3 (naïve), follicular helper T cell state S3, and endothelial cell state S3, whereas lower frequencies of B cell state S5 (plasmablast) and follicular helper T cell state S1. Third, high TIL-B abundance in 79 ‘DJ-only’ clonotype cases and additional 52 cases assessed by light chain clonotype analysis showed similar favorable prognostic effects and associations with upregulated immune gene expression and CD4 T cell infiltration. Fourth, the identified GEP signatures, prominent with genes involved in T-dependent B cell activation and T cell activation and differentiation, showed significant prognostic effects in two GEO datasets. Fifth, TIL-B abundance showed significant prognostic effects in DLBCL cases infiltrated with T-cells in both the discovery study (Figure E) and validation study (Figure F, flow cytometry cohort). Conclusions: TIL-B frequencies and clonotypic diversity have remarkable prognostic and biological effects in DLBCL, which has significant implications for developing novel therapeutic strategies. Our study identified a new prognostic biomarker in DLBCL and an important player in anti-lymphoma immune responses, providing a new point of view to analyze the tumor biology in aggressive B-cell lymphoma and precisely identify prognostic determinants.

Scaling the Library Resources with Zscaler

More and more institutions and universities are implementing security measures to prevent wide-spread cyberattacks. When institutions initiate new security applications, the library is often overlooked. Libraries have complex ecosystems where multiple applications and systems converge with user data and online library resources. These ecosystems have various considerations including multi-factor authentication, proxies, multiple virtual private networks (VPNs), knowledgebases, and vendor inconsistencies. Duke University Health recently launched data security software called Zscaler, which prevented on-campus users from accessing the library e-resources. This presentation describes how Duke University Medical Center Library staff discovered the access issue and tested various workarounds to allow patrons to access library e-resources. The discussion covered how staff continue to work with Duke University Health IT security staff and university administration to find resolutions for the complex integration of security software with the library’s online resources.

Real-world Experiences in the Transplantation of Hepatitis C-NAAT-positive Organs.

Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals. This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed. Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection. One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option.

An interview with Purushothama Rao Tata.

Purushothama Rao Tata is an Assistant Professor in the Department of Cell Biology at Duke University Medical Center. His lab is focussed on understanding the cellular basis of cell plasticity and self-organization in regeneration and tumorigenesis, using the lung as a model system. In 2022, Tata was awarded a Rising Star award from the International Society for Regenerative Biology. We caught up with Tata over Zoom to learn how an early plant tissue culture experiment led to a career working on human lung regeneration, the role serendipity has played in his research and the importance of switching off.

The association of female sex with management and mortality in patients with Staphylococcus aureus bacteraemia

ObjectivesThe association of biological female sex with outcome in patients with Staphylococcus aureus bacteraemia remains unresolved. The aim of this study was to determine the independent association of female sex with management and mortality in patients with S. aureus bacteraemia. MethodsThis is a post hoc analysis of prospectively collected data from the S. aureus Bacteraemia Group Prospective Cohort Study. Adult patients with monomicrobial S. aureus bacteraemia at Duke University Medical Center were enrolled from 1994 to 2020. Univariable and multivariable Cox regression analyses were performed to assess differences in management and mortality between females and males. ResultsAmong 3384 patients with S. aureus bacteraemia, 1431 (42%) were women. Women were, as compared with men, more often Black (581/1431 [41%] vs. 620/1953 [32%], p < 0.001), haemodialysis dependent (309/1424 [22%] vs. 334/1940 [17%], p 0.001) and more likely to be infected with methicillin-resistant S. aureus (MRSA) (697/1410 [49%] MRSA in women vs. 840/1925 [44%] MRSA in men, p 0.001). Women received shorter durations of antimicrobial treatment (median 24 [interquartile range 14–42] vs. 28 [interquartile range 14–45] days, p 0.005), and were less likely to undergo transesophageal echocardiography as compared with men (495/1430 [35%] vs. 802/1952 [41%], p < 0.001). Despite these differences, female sex was not associated with 90-day mortality in either univariable (388/1431 [27%] in women vs. 491/1953 [25%] in men, p 0.204) or multivariable analysis (adjusted hazard ratio for women 0.98 [95% CI, 0.85–1.13]). DiscussionDespite significant differences in patient characteristics, disease characteristics, and management, women and men with S. aureus bacteraemia have a similar mortality risk.

Spatial genomics to reveal an immunosuppressive tumor microenvironment after chemoradiation in head and neck cancer patients.

6059 Background: Although chemoradiotherapy (CRT) remains the cornerstone of management for locoregionally advanced head and neck squamous cell carcinomas (HNSCC), recurrence occurs in ~50% of patients. We sought to characterize the impact of CRT on the tumor microenvironment (TME) and identify factors associated with progression. Emerging spatial biology technologies, such as NanoString GeoMx Digital Spatial Profiler (DSP), enable spatially defined whole-transcriptomic profiling of cells along the tumor-stromal interface in tumor biopsies to resolve immune cell identities, activation states and signaling pathways in adjacent tumor cells. We used a multimodal approach including immunohistochemistry (IHC), bulk tumor gene expression and spatial genomics to characterize paired pre- and post-CRT tumor samples from HNSCC patients. Methods: 20 patients with locoregionally advanced HNSCC who had undergone curative intent CRT and developed subsequent recurrence requiring salvage surgery from June 14, 2010 to June 14, 2020 were retrospectively identified at Duke University Medical Center. Matched formalin-fixed paraffin embedded tumor specimens collected prior to CRT and at salvage surgery were compared via IHC for markers of immune infiltration and PDL1 expression, bulk tumor whole transcriptomic profiling, and spatial transcriptomic analysis of tumor and stroma using DSP were further examined in “early” progressors ( &lt; 6 months after CRT) and “late” progressors (≥6 months after CRT). Results: IHC analyses demonstrated significant reductions in T-cell immune populations (total CD3+, CD8+, 4-1BB+ cell density [ p &lt; 0.001]) after CRT. PDL1+ expression was similar before and after CRT. Neither T-cell infiltrate nor tumor PDL1 levels at surgery were associated with progression. Bulk tumor gene expression analysis demonstrated that macrophage and fibroblast markers were increased post-CRT. In early progressors, molecular dissection of the tumor-stromal interface using DSP expression profiling revealed macrophage associated genes ( CD68, MRC1/CD206, CD163, F13A1) at salvage surgery had a more pronounced increase in macrophage markers in stroma with enriched M2 genes compared to late progressors. Conclusions: Integrated spatial analysis with high resolution transcriptomics and IHC suggest CRT induces an immunosuppressive environment characterized by decreased T-cell infiltration and an influx of putative immunosuppressive macrophages. We hypothesize that tumor associated macrophages and/or fibroblasts may contribute to immunosuppression due to “reprogramming” of the TME after CRT. This exploratory study suggests that patients with progressive disease after chemoradiation may benefit from additional immunoregulatory therapies that ameliorate the immunosuppressive TME. These findings will be further validated in a larger cohort of patients.

Four Decades of Foot and Ankle Research Activity: A Scientometric study of Subspecialty Foot and Ankle Journals.

To evaluate foot and ankle documents using scientometric methods and provide insight into global research activities. This scientometric study was conducted at the Department of Spine Surgery, Ganzhou People's Hospital, China. Documents on foot and ankle from 1980 to 2019 were retrieved from the Scopus database. The number of documents, year of publication, journal, country, institution, author, h-index, and top-cited documents were analyzed. In total, 11313 documents were retrieved. The annual research output on foot and ankle showed a dramatic increase over the past four decades, especially in the past decade (p = 0.000). Foot & Ankle International published the biggest number of documents (44.48%). The United States contributed more than half (52.17%) of the global production, followed by the United Kingdom (11.39%), and Germany (3.62%). The United States had the highest h-index (109). The Hospital for Special Surgery (1.87%) ranked first in terms of productivity, followed by Union Memorial Hospital (1.37%), and Duke University Medical Center (1.24%). The most productive author was Myerson MS (1.25%), followed by Schon LC (0.77%), and Hyer CF (0.74%). Research on foot and ankle has thrived rapidly over the past four decades, particularly in the last decade. The United States contributes the most to the quantity and quality of foot and ankle documents.

Role of complement activation in cellular activation by systemic lupus erythematosus (SLE) immune complexes (ICs)

Abstract Complement (C’) activation is a prominent feature of SLE ICs, but the mechanism by which C’ mediates cellular activation by ICs is not well understood. To investigate this question, we formed SLE ICs in situ in healthy donor (HD) whole blood (WB) by adding SLE plasma (n=1–3;10% v/v) or HD plasma (as a control) along with apoptotic bodies (generated from RAW 264.7 cells) or RNP-Sm antigen (Arotec Diagnostics, New Zealand) with and without C’ inhibitors (CI). For cellular binding studies, WB was incubated for 45 minutes at 37°C and deposition of C3c and human IgG (ICs) on blood cells was examined by flow cytometry. In these studies, we noted that C’ inhibition significantly reduced deposition of C3c and ICs on B cells {% reduction: C3c (97%) and IgG (97%)}, monocytes {% reduction: C3c (40%) and IgG (49%)} and neutrophils {% reduction: C3c (69%) and IgG (70%)}. To investigate cellular activation, WB was incubated for 22 hours and cellular activation was measured by HLA-DR expression on monocytes by flow cytometry and cytokine release (IL-8, IL-6 and TNF) by ELISA. Incubation of WB with SLE ICs, but not ICs made with HD plasma (control ICs), resulted in increased HLA-DR expression on monocytes (MFI control ICs: 1609 V SLE ICs: 11096), which was susceptible to C’ inhibition (MFI SLE ICs with CI: 4975). Similarly, inflammatory cytokine release by SLE ICs was also significantly inhibited with C’ inhibition {% inhibition: IL-8 (75 %), IL-6 (99%) and TNF (99 %)}. Taken together, our results show significant C’-dependent effects of SLE ICs on cellular binding and activation. Additional studies are underway to investigate the prevalence of C’ activating ICs in SLE patient and correlate their presence with clinical disease. Wendell F. Rosse Complement Research Award, Duke University Medical Center (SK) and Duke Scholars Award, Duke University Medical Center (GMA)

The Association Between Sociodemographic Factors, Social Determinants of Health, and Spine Surgical Patient Portal Utilization.

Retrospective cohort study. To examine patient portal use among the surgical spine patient population across different sociodemographic groups and assess the impact of patient portal use on clinical outcomes. Patient portals (PP) have been shown to improve outcomes and quality of care. Engaging them requires internet access, technological literacy, and dexterity, which may serve as access barriers. After exclusion criteria were applied, the study included data for 9211 encounters from 7955 patients. PP utilization was defined as having activated and used the Duke University Medical Center patient portal system, MyChart, at least once. Sociodemographic characteristics included urbanicity, age, race, ethnicity, language, employment, and primary insurer. Clinical outcomes included the length of hospital stay during the procedure, 30-day return to the emergency department, 30-day readmission, and being discharged somewhere other than home. Being older than 65, non-White, unemployed, non-English-speaking, male, not-partnered, uninsured or publicly insured (Medicaid, Medicare and under 65 years of age, or other government insurance), and living in a rural environment were all risk factors for decreased PP utilization among surgical spine patients. A one-risk factor decrease in the number of social risk factors was associated with a 78% increase in the odds of PP utilization [odds ratio (OR): 1.78; 95% Confidence interval (CI): 1.69-1.87; P <0.001]. Patients not utilizing the portal at the time of their procedure had higher odds of 30-day readmission (OR: 1.59; 95% CI: 1.26-2.00), discharge somewhere other than home (OR: 2.41, 95% CI: 1.95-2.99), and an increased length of hospital stay (geometric mean ratio: 1.21; 95% CI: 1.12-1.30) compared with those who utilized it. In patients undergoing spine procedures, PPs are not equally utilized among different sociodemographic groups. PP utilization is also associated with better outcomes. Interventions aimed at increasing PP uptake may improve care for certain patients.

Low contralateral neck recurrence risk with ipsilateral neck radiotherapy in N2b tonsillar squamous cell carcinoma

ObjectivesTo characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes. MethodsPatients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990–10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed. Results120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7–209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2–9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3–4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %–98 %). ConclusionsFor patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.

Impact of diagnostic guidelines on the diagnosis of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease from exposure to environmental antigens. Diagnosing HP could be challenging. The American College of Chest Physicians (CHEST) and American Thoracic Society/Japanese Respiratory Society/and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) have published diagnostic guidelines in 2021 and 2020 respectively. The CHEST guideline uses four grades of confidence: confident (>90%), provisional high (70-89%), provisional low (51-69%), and unlikely (≤50%). The ATS/JRS/ALAT guideline uses five grades of confidence: definite (>90%), high (80-89%), moderate (70-79%), low (51-69%) and not excluded (≤50%). In this study, we determined how these two guidelines could have affected the diagnosis of HP made before the guidelines. Two hundred and fifty-nine adult patients from a previous cohort with HP (ICD-9:495) made between Jan. 1, 2008, and Dec. 31, 2013, at Duke University Medical Center were included. We simplified the diagnostic confidence into three categories so we could compare the guidelines: high (≥90%), intermediate (51-89%), and low (≤50%). There were 156 female and 103 male. Mean age was 58 (range: 20-90). 68.8% of the patients had restrictive defects (FVC < 80% pred) and 48.6% had lung biopsy. The CHEST guideline classified 33.6% of the patients into high, 59.5% into intermediate and 6.9% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.7% of the patients into high, 21.2% into intermediate and 49.0% into low confidence categories (p < 0.0001 vs. CHEST). Cohen's kappa was 0.331. In patients with identifiable inciting agents (IAs) (N = 168), the CHEST guideline classified 32.1% of the patients into high, 64.3% into intermediate and 3.6% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.2% of the patients into high, 20.8% into intermediate, and 50.0% into low confidence categories. Cohen's kappa was 0.314. In our HP cohort with two-thirds of the patients with restrictive defects, we found the two guidelines had fair agreement in diagnosing HP with or without identifiable IAs. They agreed more when the diagnostic confidence was high. When the diagnostic confidence was lower, however, the ATS/JRS/ALAT guideline was more stringent. Clinicians should be aware of the differences between the two guidelines when evaluating patients suspicious of HP.

Congenital Athymia: Unmet Needs and Practical Guidance.

Inborn errors of thymic stromal cell development and function which are associated with congenital athymia result in life-threatening immunodeficiency with susceptibility to infections and autoimmunity. Athymic patients can be treated by thymus transplantation using cultured donor thymus tissue. Outcomes in patients treated at Duke University Medical Center and Great Ormond Street Hospital (GOSH) over the past three decades have shown that sufficient T-cell immunity can be recovered to clear and prevent infections, but post-treatment autoimmune manifestations are relatively common. Whilst thymus transplantation offers the chance of long-term survival, significant challenges remain to optimise the outcomes for the patients. In this review, we will discuss unmet needs and offer practical guidance based on the experience of the European Thymus Transplantation programme at GOSH. Newborn screening (NBS) for severe combined immunodeficiency (SCID) and routine use of next-generation sequencing (NGS) platforms have improved early recognition of congenital athymia and increasing numbers of patients are being referred for thymus transplantation. Nevertheless, there remain delays in diagnosis, in particular when the cause is genetically undefined, and treatment accessibility needs to be improved. The majority of athymic patients have syndromic features with acute and chronic complex health issues, requiring life-long multidisciplinary and multicentre collaboration to optimise their medical and social care. Comprehensive follow up after thymus transplantation including monitoring of immunological results, management of co-morbidities and patient and family quality-of-life experience, is vital to understanding long-term outcomes for this rare cohort of patients. Alongside translational research into improving strategies for thymus replacement therapy, patient-focused clinical research will facilitate the design of strategies to improve the overall care for athymic patients.

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

Brominated flame retardants and legacy organochlorines in archived human placenta samples: Sex differences, temporal analysis and associations with infant birth weight.

Perinatal exposure to persistent organic pollutants (POPs) has been suggested to play a role in the etiology of adverse pregnancy outcomes. This study evaluated temporal changes in the accumulation of several classes of POPs, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and several organochlorine pesticides in human placenta and examined their associations with birth outcomes at delivery. Placental tissues (n = 99) previously collected and archived at the Duke University Medical Center from 2009 to 2015 were analyzed for 22 POPs using gas chromatography mass spectrometry. The mean age of mothers was 30.6 years; 8% of newborns were characterized as low birthweight (<2500 g). Of the 22 POPs targeted in the analysis, only p,p’-DDE, BDE-47 and BDE-100 were detected in more than 50% of the samples, with median concentrations of 0.110, 0.310, and 0.033 ng/g wet weight, respectively. Placental PBDE concentrations generally decreased over time, particularly BDE-47. Placental tissues associated with female infants had significantly higher levels of BDE-100 than placental tissues associated with male infants (p = 0.02) and a similar, but not statistically significant trend was observed for BDE-47 (p = 0.07). Multivariate regression models revealed that placental BDE-47 concentrations were associated with a significantly lower birthweight among male, but not female infants. A similar, although non-statistically significant, trend was observed for other POPs, further suggesting sex-specific associations between gestational exposure to POPs and birthweight.

Editorial introductions.

Current Opinion in Endocrinology and Diabetes was launched in 1994, with Obesity added to the title in 2007. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The fields of endocrinology and diabetes are divided into 9 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR IN CHIEF David M. HarlanDavid M. HarlanDr David M. Harlan is a graduate of the University of Michigan (Bachelor of Science) and the Duke University School of Medicine, USA. He completed his internal medicine internship and residency at the Duke University Medical Center. This was before serving for 4 years as a staff internist at the Navy Hospital, San Diego, CA, USA. He then returned to Duke for his fellowship training in diabetes, endocrinology, and metabolism. In 1991 he established his laboratory at the Navy Medical Research Institute, USA, where he rose to become the Director of Combat Casualty Care. He was then appointed to the faculty of the Uniformed Services University of the Health Sciences. In 1999, he moved his laboratory to the National Institutes of Health, where he became the Diabetes Branch Chief within the National Institute of Diabetes, Digestive, and Kidney Diseases. In 2010, he moved to the University of Massachusetts School of Medicine, USA, where he is the William and Doris Krupp Professor of Medicine and Diabetes Division Chief. Dr Harlan also co-directs the UMass Diabetes Center of Excellence. His research interests all relate to diabetes and include the immunopathogenesis underlying type 1 diabetes and improved care delivery models for the disease. SECTION EDITORS Matthew FreebyMatthew FreebyMatthew Freeby, MD, is Health Sciences Associate Clinical Professor of Medicine in the Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine at the University of California Los Angeles, USA. Dr Freeby received his MD from Virginia Commonwealth University, USA and completed his internal medicine internship and residency training at the University of California San Diego. He subsequently completed training in an endocrinology fellowship at Columbia University Medical Center in New York, USA. Dr Freeby is involved in community leadership for the American Diabetes Association and serves on planning committees for the Endocrine Society's annual meetings. His research has focused on a number of diabetes related topics including non-invasive in vivo measurement of beta cell mass as well as the evaluation of general care and complications. He has also collaborated with researchers evaluating iPS as a method for beta cell replacement in type 1 and other rare forms of diabetes. Lynne L. LevitskyLynne L. LevitskyDr Lynne L. Levitsky is a graduate of Bryn Mawr College and Yale Medical School, USA. She received her pediatric training at the Albert Einstein College of Medicine in New York, USA, and at the Children's Hospital of Philadelphia, USA. She was trained in pediatric endocrinology at the University of Maryland in Baltimore, USA. She was a Pediatric Endocrinologist and Professor of Pediatrics at the Pritzker School of Medicine, University of Chicago, USA, until 1990. She then came to Massachusetts General Hospital, USA, as Chief of the Pediatric Endocrine Unit and Associate Professor of Pediatrics at Harvard Medical School. She is now Emeritus Chief and co-director of the Turner Syndrome Wellness Center, USA. Her research interests in carbohydrate metabolism span laboratory studies of transcriptional control of beta cell function, and a role as an investigator in the NIH-sponsored TODAY treatment study of type 2 diabetes in the young. She is a past President of the Pediatric Endocrine Society and was the first head of the Education Council for that organization.

Risk factors for persistent pain after breast cancer surgery: a multicentre prospective cohort study.

Identifying factors associated with persistent pain after breast cancer surgery may facilitate risk stratification and individualised management. Single-population studies have limited generalisability as socio-economic and genetic factors contribute to persistent pain development. Therefore, this prospective multicentre cohort study aimed to develop a predictive model from a sample of Asian and American women. We enrolled women undergoing elective breast cancer surgery at KK Women's and Children's Hospital and Duke University Medical Center. Pre-operative patient and clinical characteristics and EQ-5D-3L health status were recorded. Pain catastrophising scale; central sensitisation inventory; coping strategies questionnaire-revised; brief symptom inventory-18; perceived stress scale; mechanical temporal summation; and pressure-pain threshold assessments were performed. Persistent pain was defined as pain score ≥ 3 or pain affecting activities of daily living 4months after surgery. Univariate associations were generated using generalised estimating equations. Enrolment site was forced into the multivariable model, and risk factors with p < 0.2 in univariate analyses were considered for backwards selection. Of 210 patients, 135 (64.3%) developed persistent pain. The multivariable model attained AUC=0.807, with five independent associations: age (OR 0.85 95%CI 0.74-0.98 per 5 years); diabetes (OR 4.68, 95%CI 1.03-21.22); pre-operative pain score at sites other than the breast (OR 1.48, 95%CI 1.11-1.96); previous mastitis (OR 4.90, 95%CI 1.31-18.34); and perceived stress scale (OR 1.35, 95%CI 1.01-1.80 per 5 points), after adjusting for: enrolment site; pre-operative pain score at the breast; pre-operative overall pain score at rest; postoperative non-steroidal anti-inflammatory drug use; and pain catastrophising scale. Future research should validate this model and evaluate pre-emptive interventions to reduce persistent pain risk.

Foot Drop: The Importance of Imaging as Part of the Peripheral Nerve Evaluation

Dr. Smith is Assistant Professor of Neurosurgery, Duke University Medical Center, Durham, North Carolina; Dr. Jack is Associate Staff, Neurological Surgery, Cleveland Clinic, Cleveland, Ohio; and Dr. Spinner is Chair of Neurosurgery, Department of Neurologic Surgery, Burton M Onofrio MD Professor of Neurosurgery, and Professor of Orthopedics and Anatomy, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, E-mail: [email protected]. All authors, faculty, and staff have no relevant financial relationships with any ineligible organizations regarding this educational activity. Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Category: Peripheral Nerve Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed form, answering at least 70% of the quiz questions correctly. This activity expires on December 29, 2024.

Impact of Ventricular Dominance on Long-Term Fontan Outcomes: A 25-year Single-institution Study

BackgroundThe long-term impact of ventricular dominance on Fontan outcomes is controversial. This study examined this issue in a 25-year cohort. MethodsPatients undergoing the Fontan operation at a single institution (Duke University Medical Center, Durham, NC) from October 1998 to February 2022 were reviewed. Primary outcomes were transplant-free survival and Fontan failure (death, heart transplantation, takedown, protein-losing enteropathy, or plastic bronchitis). Secondary outcomes included hospital and intensive care lengths of stay. Kaplan-Meier methodology compared outcomes by ventricular dominance. Multiphase parametric risk hazard analysis identified risk factors for primary outcomes. ResultsThere were 195 patients (104 right ventricular dominant) included in the study. Baseline characteristics were comparable. Perioperative survival was similar (right ventricular dominant, 98%; non–right ventricular dominant, 100%; P = .51). The proportion of patients experiencing death or heart transplantation was 8.7%, and the rate of Fontan failure was 11.8% during a median follow-up of 4.5 years (interquartile range, 0.3-9.8 years). Right ventricular–dominant patients had reduced transplant-free survival (10-year estimates: 80% [95% CI, 70%-91%] vs 92% [95% CI, 83%-100%]; P = .04) and freedom from Fontan failure (73% [95% CI, 62%-86%] vs 92% [95% CI, 83%-100%]; P = .04). Multiphase hazard modeling resolved 2 risk phases. The early phase spanned from surgery to approximately 6 months afterward. The late phase spanned from approximately 6 months after surgery onward. In multivariable analysis, right ventricular dominance was an independent risk factor for death or heart transplantation (parameter estimate, 1.3 ± 0.6; P = .04) and Fontan failure (1.1 ± 0.5; P = .04) during the second phase, with no significant first-phase risk factors. ConclusionsRight ventricular dominance was associated with long-term complications after Fontan procedures, including mortality, heart transplantation, and Fontan failure. This cohort may benefit from heightened surveillance in a multidisciplinary Fontan clinic after the perioperative period.

Electrocardiographic parameters associated with pacemaker induced cardiomyopathy

BackgroundChronic right ventricular (RV) pacing can induce left ventricular (LV) dyssynchrony and cause pacemaker induced cardiomyopathy (PiCM). Identifying which patients are at risk for PiCM is limited. MethodsPatients receiving RV-only permanent pacemakers (PPMs) at Duke University Medical Center between 2011 and 2017 who had normal baseline ejection fractions (EFs) were identified. Patients who developed a subsequent decrease in EF, died, or underwent cardiac resynchronization therapy, left ventricular assist device, or heart transplant without a competing cause were considered as the primary endpoint. Pre-PPM and post-PPM electrocardiograms (ECGs) were analyzed to extract scalar measurements including the lead one ratio (LOR) as well as advanced-ECG (A-ECG) features to identify predictors of PiCM. Traditional and penalized Cox regression were used to identify variables predictive of the primary endpoint. ResultsPre-PPM ECGs were evaluated for 404 patients of whom 140 (35%) experienced the primary endpoint. Predictors included female sex (hazard ratio [HR] 1.14), a T' wave in V6 (HR 1.31), a P′ wave in aVL (HR 0.88), and estimated glomerular filtration rate (HR 0.88). Post-PPM ECGs were evaluated for 228 patients for whom 94 (41%) experienced the primary endpoint. Predictors included female sex (HR 0.50), age (HR 1.06), and a history of congestive heart failure (HR 1.63). Neither LOR nor A-ECG parameters were strong predictors of the primary endpoint. ConclusionsBaseline and paced ECG data provide limited insight into which patients are at high risk for developing PiCM.