American Cohort Research Articles

SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma.

Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.

In This Issue

In This Issue

285 (PB-109) Poster - A retrospective evaluation of factors associated with upstage to malignancy for breast lesions of uncertain malignant potential (B3): findings from an American cohort

Background: The management of breast lesions of uncertain malignant potential (B3) diagnosed by core needle biopsy (CNB) remains controversial and varies by country, institution, lesion characteristics, and patient preference. Due to the risk of upstage (the discovery of cancer not detected by CNB) management includes surgical excision (SE), vacuum assisted core needle biopsy, and observation.

O1.1 Clinical presentation and outcome of HPV-positive nasopharyngeal carcinoma in a North American cohort

O1.1 Clinical presentation and outcome of HPV-positive nasopharyngeal carcinoma in a North American cohort

Modified Juvenile Spondyloarthritis Disease Activity Index in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.

To validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA), and modified versions thereof, in a North American cohort of patients with enthesitis-related arthritis (ERA). We utilized the Childhood Arthritis and Rheumatology Research Alliance Registry database ERA cohort to validate the JSpADA and its modifications (JSpADA6-no Schober, no C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR]; JSpADA7-no Schober; and JSpADA7-no CRP/ESR) using the Outcome Measures in Rheumatology principles of face validity, discriminative validity, and responsiveness to change. There were 51 subjects (64 visits) with complete JSpADA data with a mean age of 13.7 years and disease duration of 30.9 months. Subjects were predominantly White (84.3%), and 56.9% were male and 50% were HLA-B27 positive. The JSpADA showed high correlation with the clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10; r = 0.81), moderate-to-high correlation with physician global assessment (PGA; r = 0.69), and low-to-fair correlation with Childhood Health Assessment Questionnaire (CHAQ; r = 0.22). The modifications of the JSpADA (JSpADA7-no Schober; JSpADA7-no CRP/ESR; and JSpADA6-no Schober, no CRP/ESR) performed similarly with high correlation with cJADAS10 (r = 0.81, 0.79, and 0.80, respectively), moderate-to-high correlation with PGA (r = 0.65, 0.67, 0.64, respectively), and low-to-fair correlation with CHAQ (r = 0.35, 0.34, 0.39, respectively). All modified versions of JSpADA had good responsiveness to change. All versions of JSpADA had excellent discriminative validity. We propose the term modified JSpADA for the modification of JSpADA with 6 elements (JSpADA6-no Schober, no CRP/ESR). This shorter disease activity index may improve implementation of JSpADA in both clinical practice and research trials.

Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium

IntroductionThe mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. MethodsWe evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. ResultsThere were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. ConclusionsNearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Trans-ancestry, Bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian and European cohort.

Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal disorder with major phenotypes: ulcerative colitis (UC) and Crohn's disease (CD). Multiple studies have identified over 240 IBD susceptibility loci. However, most studies have centered on European (EUR) and East Asian (EAS) populations. The prevalence of IBD in non-EUR, including African Americans (AAs), has risen in recent years. Here we present the first attempt to identify loci in AAs using a trans-ancestry Bayesian approach (MANTRA) accounting for heterogeneity between diverse ancestries while allowing for the similarity between closely related populations. We meta-analyzed genome-wide association studies (GWAS) and Immunochip data from a 2015 EUR meta-analysis of 38 155 IBD cases and 48 485 controls and EAS Immunochip study of 2824 IBD cases and 3719 controls, and our recent AA IBD GWAS of 2345 cases and 5002 controls. Across the major IBD phenotypes, we found significant evidence for 92% of 205 loci lead SNPs from the 2015 meta-analysis, but also for three IBD loci only established in latter studies. We detected 20 novel loci, all containing immunity-related genes or genes with other evidence for IBD or immune-mediated disease relevance: PLEKHG5;TNFSFR25 (encoding death receptor 3, receptor for TNFSF15 gene product TL1A), XKR6, ELMO1, BC021024;PI4KB;PSMD4 and APLP1 for IBD; AUTS2, XKR6, OSER1, TET2;AK094561, BCAP29 and APLP1 for CD; and GABBR1;MOG, DQ570892, SPDEF;ILRUN, SMARCE1;CCR7;KRT222;KRT24;KRT25, ANKS1A;TCP11, IL7, LRRC18;WDFY4, XKR6 and TNFSF4 for UC. Our study highlights the value of combining low-powered genomic studies from understudied populations of diverse ancestral backgrounds together with a high-powered study to enable novel locus discovery, including potentially important therapeutic IBD gene targets.

Association between Abdominal CT Measurements of Body Composition before Deceased Donor Liver Transplant with Posttransplant Outcomes.

Background Pre-liver transplant (LT) sarcopenia is associated with poor survival. Methods exist for measuring body composition with use of CT scans; however, it is unclear which components best predict post-LT outcomes. Purpose To quantify the association between abdominal CT-based body composition measurements and post-LT mortality in a large North American cohort. Materials and Methods This was a retrospective cohort of adult first-time deceased-donor LT recipients from 2009 to 2018 who underwent pre-LT abdominal CT scans, including at the L3 vertebral level, at Johns Hopkins Hospital. Measurements included sarcopenia (skeletal muscle index [SMI] <50 in men and <39 in women), sarcopenic obesity, myosteatosis (skeletal muscle CT attenuation <41 mean HU for body mass index [BMI] <25 and <33 mean HU for BMI ≥25), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT ratio. Covariates in the adjusted models were selected with use of least absolute shrinkage and selection operator regression with lambda chosen by means of 10-fold cross-validation. Cox proportional hazards models were used to quantify associations with post-LT mortality. Model discrimination was quantified using the Harrell C-statistic. Results A total of 454 recipients (median age, 57 years [IQR, 50-62 years]; 294 men) were evaluated. In the adjusted model, pre-LT sarcopenia was associated with a higher hazard ratio (HR) of post-LT mortality (HR, 1.6 [95% CI: 1.1, 2.4]; C-statistic, 0.64; P = .02). SMI was significantly negatively associated with survival after adjustment for covariates. There was no evidence that myosteatosis was associated with mortality (HR, 1.3 [95% CI: 0.86, 2.1]; C-statistic, 0.64; P = .21). There was no evidence that BMI (HR, 1.2 [95% CI: 0.95, 1.4]), VAT (HR, 1.0 [95% CI: 0.98, 1.1]), SAT (HR, 1.0 [95% CI: 0.97, 1.0]), and VAT/SAT ratio (HR, 1.1 [95% CI: 0.90, 1.4]) were associated with mortality (P = .15-.77). Conclusions Sarcopenia, as assessed on routine pre-liver transplant (LT) abdominal CT scans, was the only factor significantly associated with post-LT mortality. © RSNA, 2022 See also the editorial by Ruehm in this issue.

RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL).

RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

Per- and polyfluoroalkyl substances and psychosocial stressors have a joint effect on adverse pregnancy outcomes in the Atlanta African American Maternal-Child cohort

BackgroundAfrican Americans (AAs) experience high rates of adverse pregnancy outcomes relative to Whites. Differential in utero exposure to environmental chemicals and psychosocial stressors may explain some of the observed health disparities, as exposures to per- and polyfluoroalkyl substances (PFAS) and experiences of discrimination have been linked to adverse birth outcomes. Few studies have examined chemicals and non-chemical stressors together as an exposure mixture, which may better reflect real-life exposure patterns. Here, we adapted methods designed for the analysis of exposure mixtures to examine joint effects of PFAS and psychosocial stress on birth outcomes among AAs. Methods348 participants from the Atlanta African American Maternal-Child cohort were included in this study. Four PFAS were measured in first trimester serum samples. Self-report questionnaires were administered during the first trimester and were used to assess psychosocial stress (perceived stress, depression, anxiety, gendered racial stress). Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to estimate the joint effects between PFAS and psychosocial stressors on gestational age at delivery and birthweight for gestational age z-scores. All models were adjusted for maternal education, maternal age, parity, and any alcohol, tobacco and marijuana use. ResultsOur analytic sample included a socioeconomically diverse group of pregnant women, with 79 % receiving public health insurance. In quantile g-computation models, a simultaneous one-quartile increase in all PFAS, perceived stress, depression, anxiety, and gendered racial stress was associated with a reduction in birthweight z-scores (mean %change per quartile increase = −0.24, 95 % confidence interval = −0.43, −0.06). BKMR similarly showed that increasing all exposures in the mixture was associated with a modest decrease in birthweight z-scores, but not a reduced length of gestation. DiscussionUsing methods designed for analyzing exposure mixtures, we found that a simultaneous increase in in utero PFAS and psychosocial stressors was associated with reduced birthweight for gestational age z-scores.

Offending and the Long-Term Risk of Death: An Examination of Mid-Life Mortality Among an Urban Black American Cohort.

Research on the long-term relationship between offending and mortality is limited, especially among minorities who have higher risk of premature mortality and criminal offending, particularly arrest. Using Cox proportional hazard models, we estimate the relationship between young adult offending and later mortality (to age 58) among a community cohort of Black Americans (n = 1,182). After controlling for a wide range of covariates, results indicate that violent offenders are at heightened risk of mortality from young adulthood through midlife compared with both non-violent only offenders and non-offenders. Further analysis shows that this result is driven by the frequent, largely non-violent, arrests incurred among violent offenders. Criminal justice reform and collaboration with public health practitioners might be fruitful avenues to reduce mortality disparities.

Association between obesity and hypertrophic cardiomyopathy phenotype, validation in a latin american cohort

Abstract Objectives Hypertrophic Cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The influence of obesity on the disease phenotype is not well established. A recent publication sought to answer this gap. Our objective is to assess the relationship of a obesity on the phenotype of our cohort and compare it to the published literature. Methods We performed a retrospective observational study of consecutive patients diagnosed with HCM at a single center in Argentina. We included 1331 patients between March 1993 and December 2021. We excluded patients &amp;lt;18 years of age, metabolic diseases &amp; syndromes and patients who were lost on follow up. We defined Obesity as a body mass index ≥30 kg/m2. Results 1168 patients had available data for analysis. 54 (10.4%) patients were obese. Mean age was 54±28 years and 33 (61%) were male. Average maximal left ventricular wall thickness (LVWT) in this group was 20 mm ± 5 mm. When comparing obese vs non-obese patients we found no statistically significant differences for gender, age, family history of HCM, family history of sudden death (SD), previous VF/VT/NSVT, ESC low, intermediate or high risk for SD groups, fibrosis, apical aneurism, LV diameter, maximum LVWT, high risk genetic mutation, abnormal BP response to exercise, device implant, septal alcohol ablation, reduced EF on follow up, nor death/HF/Stroke/AICD appropriate therapy/AF development. We did find that obese patients had less unexplained syncope (6% vs 13%, OR 0.43, p=0.03), had more frequently an NYHA &amp;gt; III/IV (15.3% vs 8.9%, OR 1.8, p=0,03), a trend to having less frequently a LVWT &amp;gt;30 mm (3.5% vs 8.1%, OR 0.41, p=0.07) but more frequently had systolic anterior motion of the mitral valve on echocardiography (45% vs 34%, OR 1.58, p=0.04). We noted a trend to being more frequently indicated LV myectomy (9.2% vs 5%, OR 1.9, p=0,07) and significantly having elevated ultrasensitive troponin I (7.8% vs 3.7%, OR 2.2, p=0,04). Conclusions We found that obese patients from our cohort, as described in other series, had more advanced symptoms. In our set of obese patients they were more frequently sent to myectomy rather than alcohol septal ablation as described in other series. AF was not more prevalent among our obese patients and maximum wall thickness and fibrosis were not higher either. We did find that obese patients had more frequently elevated biomarkers. As HCM is so frequent it is important to characterize cohorts and compare data. Funding Acknowledgement Type of funding sources: None.

S1211 Peripheral Immune Markers Can Detect Hepatocellular Carcinoma in Blood in a Latin American Cohort

Introduction: Late detection of hepatocellular carcinoma (HCC) due to suboptimal surveillance with ultrasound is a major problem worldwide but with further importance in resource-limited settings. Blood biomarkers are urgently needed and currently alpha-fetoprotein (AFP) is the only accepted biomarker. However, AFP has poor accuracy for early HCC detection and has mainly been studied in resource-rich settings. We prospectively investigated circulating immune markers to detect HCC in 2 different groups of Latin American patients acting as discovery and validation cohorts. Methods: Through the ESCALON network we prospectively evaluated a discovery cohort of 127 individuals with HCC and 113 cirrhotic controls from 3 countries in Latin America (Argentina, Brazil and Ecuador) as well as a validation cohort of 145 HCCs and 75 cirrhotic individuals from a different set of institutions in Latin America (Chile, Peru, Argentina, Ecuador, Colombia). Blood samples were analyzed for 37 unique immune markers using the multiplex Bio-Rad platform. Differences between HCC and cirrhosis were analyzed via t-test and ANOVA, and tuned with lasso coefficient-bootstrap computing. We used leave-one-out cross-validation (LOOCV) to compute an ROC curve. Results: In the discovery cohort 22 markers showed a significant difference between cases and controls for all size tumors and 15 for those tumors < 5cm. A set of 5 markers which were highly differential in HCC vs cirrhosis controls identified via Lasso and bootstrap: HGF, MIP-3a, MIG, CCL-25, and MDC. The AUROC for this top-5 set in detecting HCC was 0.83 (CI 0.78-0.88) for all tumors and 0.75 (CI 0.66-0.83) for tumors < 5cm. In this same cohort, the AUROC for AFP was only 0.69 for all tumors and 0.66 for tumors < 5cm. The addition of AFP to the top-5 markers did not significantly increase the AUROC (0.83 to 0.85). We investigated the set of top-5 markers in the validation cohort and found that they could detect HCC with an AUROC of 0.73 (CI 0.642-0.810). The main differences between both cohorts were in the underlying liver diseases in HCC, with viral hepatitis being the most common in the validation cohort (42%) and non-alcoholic fatty liver disease in the validation cohort (56%). Conclusion: Our study identified a set of 5 cytokines that can detect HCC by means of blood measurement in a discovery and validation cohort in Latin America. To our knowledge this is the first study assessing immune markers with a high degree of accuracy in a unique Latin American cohort.

THE IMPACT OF OBESITY AND ADIPOSITY ON ANTI-MULLERIAN HORMONE (AMH) LEVELS IN A LATINA/LATINX POPULATION

Research suggests that obesity has an adverse effect on ovarian reserve, as assessed by AMH. Previous studies have explored this association predominantly in Caucasian non-Hispanic and African American cohorts. Additionally, studies have predominantly utilized BMI to categorize patients as having obesity. The objective of this study was to examine the association of obesity/adiposity with AMH in a Latina/LatinX population using multiple measures of obesity/adiposity.

AGE 75 YEARS, CLINICAL STAGE III/IV, NEUTROPHILIA AND HIGH LYMPHOCYTE/MONOCYTE RATIO PREDICT DECREASED OVERALL SURVIVAL IN ELDERLY PATIENTS WITH DLBCL, NOS OLDER THAN 70 YEARS

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with a wide clinical and biological diversity, as well as a heterogeneous prognosis. It especially affects the elderly population, with an increasing incidence with advancing age. The DLBCL of elderly (≥ 60 years) and very-elderly (≥ 80 years) patients has numerous particularities, including high-risk molecular-genetic findings, greater association with Epstein-Barr (EBV) virus infection, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. Therefore, alternative therapeutic strategies have emerged for these patients, including immunochemotherapy in reduced doses and regimens without anthracyclines. Based on this premisse, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors and compare responses and toxicities in a large cohort of elderly patients with DLBCL, NOS older than 70 years. This is a retrospective, observational and single-center study, involving 185 patients with DLBCL, NOS aged ≥ 70 years, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2009 to December 2020. The median age at diagnosis was 75 years (70-97) and 58.9% (109/185) were female. Comorbidities were prevalent, including 19.5% (36/185) of immobility, 28.1% (52/185) of desnutrition, and 25% (46/185) of polypharmacy. Advanced clinical stage (III/IV) was observed in 73.6% (134/185), 48.6% (90/185) had bulky disease ≥ 7 cm, 63.2% (117/185) had B-symptoms, 76.2% (141/185) had ≥ 1 extranodal site involved by lymphoma, 67% (124/185) had intermediate-high/high-risk IPI, and 52.3% (57/109) had GCB-like phenotype detected by IHC. Ninety-eight percent of patients (182/185) received at least one line of therapy, 65.9% (120/182) underwent cytoreduction, 50.5% (92/182) received intrathecal CNS chemoprophylaxis, and 41.8% (76/185) experienced radiotherapy. The R-miniCHOP elderly regimen had a lower overall response rate (ORR) (p = 0.040), however patients in this group had unfavorable clinical and laboratory characteristics, including higher rates of hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013) and NCCN-IPI ≥ 3 (p = 0.002). For the entire cohort, ORR was 68.1% (95% CI: 60.8-74.8), 13.2% (95% CI: 8.6-18.9) were chemorefractory, early-mortality rate (< 100 days) was 18.7% (95% CI: 13.3-25.1), and overall mortality rate was 52.4% (97/185). With a median follow-up of 6.3 years (95% CI: 5.5-6.7), the estimated 5-year OS and PFS were 50.2% (95% CI: 42.4-57.5) and 44.6% (95% CI: 37.0-51.9), respectively. In multivariate analysis, age ≥ 75 years [HR 2.22, p = 0.001], advanced-stage III/IV [HR 2.36, p = 0.003], neutrophilia ≥ 7.0 × 109/L [HR 2.25, p = 0.001] and lymphocyte/monocyte ratio > 4 [HR 1.98, p = 0.01] were associated with decreased overall survival. Similarly, age ≥ 75 years [HR 2.33, p < 0.001], stage III/IV [HR 2.38, p = 0.002], B-symptoms [HR 1.62, p = 0.032], LDH ≥ 1.5 x UVN [HR 1.09, p = 0.047], neutrophilia [HR 2.25, p = 0.001] and high lymphocyte/monocyte ratio [HR 2.08, p = 0.005] predicted poor PFS. In the largest real-life Latin American cohort including patients with DLBCL, NOS older than 70 years, age ≥ 75 years, advanced clinical stage III/IV, neutrophilia and high lymphocyte/monocyte ratio were independent predictors associated with decreased overall survival.

2021 Asia-Pacific Graves' Disease Consortium Survey of Clinical Practice Patterns in the Management of Graves' Disease.

Although Graves' disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe. A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions. A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and β-blockers and adjunctive ATD-treatment during RAI in the APAC-group. Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts.

Negative impact of SARS-CoV-2 infection in acute coronary syndrome mortality in a Latin American cohort study.

PurposeCOVID-19 infection has been associated with a high risk of complications and death among patients with acute coronary syndrome (ACS). However, there is little information on the simultaneous involvement in Latin American countries.MethodsIn the period between May 2020 and February 2021, an observational, longitudinal, prospective cohort study with two parallel branches was conducted in private and public hospitals in Brasilia, Brazil, including patients with ACS with and without a positive SARS-CoV-2 test result during hospitalization.ResultsA total of 149 patients with ACS were included (75 with COVID-19 and 74 controls). Patients with COVID-19 exhibited an average of 62 years of age, 57% men, 40% diabetics, 67% hypertensive, 48% had an ACS with ST-segment elevation, Killip I was predominant, a low Syntax Score in 72%, with an average Grace Score of 117, and a length of hospitalization of 43 days in average. The control branch was similar in clinical characteristics, except for a lower proportion of ST-segment elevation ACS (16%, p < 0.01) and a higher incidence of arrhythmias (8 vs. 20 %, p = 0.03). Using the Cox regression method of analysis of covariates collected in the study, it was identified that patients with COVID-19 had a risk of death 2.34 times higher than patients without COVID-19 (p = 0.049).ConclusionIn this study conducted in a Latin American capital, SARS-CoV-2 infection predicted a higher chance of death in patients admitted with ACS, which is a finding that reinforces the need for greater care when diseases develop in overlapping ways.

Regulatory variants in a novel distal enhancer regulate the expression of CYP3A4 and CYP3A5.

The cytochrome P450 3As (CYP3As) are abundantly expressed in the liver and metabolize many commonly prescribed medications. Their expression is highly variable between individuals with little known genetic cause. Despite extensive investigation, cis-acting genetic elements that control the expression of the CYP3As remain uncharacterized. Using chromatin conformation capture (4C assays), we detected reciprocal interaction between a distal regulatory region (DRR) and the CYP3A4 promoter. The DRR colocalizes with a variety of enhancer marks and was found to promote transcription in reporter assays. CRISPR-mediated deletion of the DRR decreased expression of CYP3A4, CYP3A5, and CYP3A7, supporting its role as a shared enhancer regulating the expression of three CYP3A genes. Using reporter gene assays, we identified two single-nucleotide polymorphisms (rs115025140 and rs776744/rs776742) that increased DRR-driven luciferase reporter expression. In a liver cohort (n=246), rs115025140 was associated with increased expression of CYP3A4 mRNA (1.8-fold) and protein (1.6-fold) and rs776744/rs776742 was associated with 1.39-fold increased expression of CYP3A5 mRNA. The rs115025140 is unique to the African population and in a clinical cohort of African Americans taking statins for lipid control rs115025140 carriers showed a trend toward reduced statin-mediated lipid reduction. In addition, using a published cohort of Chinese patients who underwent renal transplantation taking tacrolimus, rs776744/rs776742 carriers were associated with reduced tacrolimus concentration after adjusting for CYP3A5*3. Our results elucidate a complex regulatory network controlling expression of three CYP3A genes and identify two novel regulatory variants with potential clinical relevance for predicting CYP3A4 and CYP3A5 expression.

Newborn Metabolomic Signatures of Maternal Serum Per- and Polyfluoroalkyl Substance Levels and Reduced Length of Gestation: A Prospective Analysis in the Atlanta African American Maternal-Child Cohort

Background and Aim: Preterm birth (PTB; 22–&amp;#x3c;37 gestational weeks) and early term birth (ETB; 37–38 gestational weeks) disproportionately affect marginalized populations. Exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to reduce length of gestation, but the underlying mechanisms are unknown. Our aim was to characterize the molecular signatures of prenatal PFAS exposure and gestational age at birth outcomes in the newborn dried blood spot (DBS) metabolome. Methods: This prospective cohort study included 267 African American pregnant people who gave birth to a singleton in Atlanta, Georgia between 2016 and 2020. Maternal PFAS concentrations were measured in serum samples obtained between 6–17 gestational weeks. Linear and logistic regression was used to assess associations between PFAS concentrations and gestational weeks at birth or PTB and ETB compared to full-term birth, respectively. Molecular signatures of the exposure-outcome relationships were phenotyped in newborn DBS samples with high-resolution metabolomics. Results: The mean gestational age was 38.7&amp;#xb1;2.0 weeks. Relative to the lowest quartile, the second quartile of serum perfluorooctanoic acid (PFOA) concentration was significantly associated with increased odds of ETB (odds ratio (OR), 2.85; 95% CI 1.16, 7.02) and the second quartile of perfluorohexane sulfonic acid (PFHxS) concentration was significantly associated with medically-indicated PTB or ETB (OR, 6.39; 95% CI 1.20, 34.09) versus healthy full-term birth. After false discovery rate correction, 8 pathways and 52 metabolites were associated with PFAS exposure and gestational age at birth outcomes. Discussion: In this study, pregnant people with higher PFOA and PFHxS concentrations had increased odds of an early birth prior to full-term. The effect of prenatal PFAS exposure on reduced length of gestation was associated with perturbed tissue neogenesis, neuroendocrine function, and redox homeostasis in the newborn DBS metabolome. These mechanisms may be translated into strategies for addressing maternal and child health disparities affecting African Americans.

Mixtures of persistent and non-persistent chemicals and associations with pregnancy outcomes in the Atlanta African American Maternal Child Cohort

Mixtures of persistent and non-persistent chemicals and associations with pregnancy outcomes in the Atlanta African American Maternal Child Cohort