Faculty Bibliography

INTRODUCTION/UNASSIGNED:The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). OBJECTIVE/UNASSIGNED:The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. METHODS/UNASSIGNED:In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. RESULTS/UNASSIGNED:In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. CONCLUSION/UNASSIGNED:Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

PURPOSE/UNASSIGNED:Early intervention for high-risk smoldering multiple myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to the treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. EXPERIMENTAL DESIGN/UNASSIGNED:In this study, we interrogated whole-genome and whole-exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480 and NCT02279394). RESULTS/UNASSIGNED:We reveal that the genomic landscape of treated HR-SMM is generally simple as compared with newly diagnosed multiple myeloma counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. CONCLUSIONS/UNASSIGNED:Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy. See related commentary by Weinhold and Rasche, p. 4263.

BACKGROUND:A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. METHODS:Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight < 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach. RESULTS:When the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1-5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated. CONCLUSIONS:Vulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals.

BACKGROUND:Over the last 20 years, fructose has gradually emerged as a potential metabolic substrate capable of promoting the growth and progression of various cancers, including prostate cancer (PCa). The biological and molecular mechanisms that underlie the effects of fructose on cancer are beginning to be elucidated. METHODS:This review summarizes the biological function of fructose as a potential carbon source for PCa cells and its role in the functionality of the male reproductive tract under normal conditions. RESULTS:The most recent biological advances related to fructose transport and metabolism as well as their implications in PCa growth and progression suggest that fructose represent a potential carbon source for PCa cells. Consequently, fructose derivatives may represent efficient radiotracers for obtaining PCa images via positron emission tomography and fructose transporters/fructose-metabolizing enzymes could be utilized as potential diagnostic and/or predictive biomarkers for PCa. CONCLUSION/CONCLUSIONS:The existing data suggest that restriction of fructose from the diet could be a useful therapeutic strategy for patients with PCa.

DNA characterisation in people with tuberculosis (TB) is critical for diagnostic and microbiome evaluations. However, extracellular DNA, more frequent in people on chemotherapy, confounds results. We evaluated whether nucleic acid dyes [propidium monoazide (PMA), PEMAX] and DNaseI could reduce this. PCR [16S Mycobacterium tuberculosis complex (Mtb) qPCR, Xpert MTB/RIF] was done on dilution series of untreated and treated (PMA, PEMAX, DNaseI) Mtb. Separately, 16S rRNA gene qPCR and sequencing were done on untreated and treated sputa before (Cohort A: 11 TB-negatives, 9 TB-positives; Cohort B: 19 TB-positives, PEMAX only) and 24-weeks after chemotherapy (Cohort B). PMA and PEMAX reduced PCR-detected Mtb DNA for dilution series and Cohort A sputum versus untreated controls, suggesting non-intact Mtb is present before treatment-start. PEMAX enabled sequencing-based Mycobacterium-detection in 7/12 (58%) TB-positive sputa where no such reads otherwise occurred. In Cohort A, PMA- and PEMAX-treated versus untreated sputa had decreased α- and increased β-diversities. In Cohort B, β-diversity differences between timepoints were only detected with PEMAX. DNaseI had negligible effects. PMA and PEMAX (but not DNaseI) reduced extracellular DNA in PCR and improved pathogen detection by sequencing. PEMAX additionally detected chemotherapy-associated taxonomic changes that would otherwise be missed. Dyes enhance microbiome evaluations especially during chemotherapy.

Our study in the Nurses' Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer. C-peptide was inversely associated with percent MD and positively with non-dense area, but no associations were found with dense area and V measure. C-peptide was associated with an increased risk of invasive BC risk (top vs. bottom quartile, odds ratio = 1.46, 95% CI: 1.12-1.91). No multiplicative interactions were found between C-peptide, MD parameters, and BC risk. Our results suggest a positive association between C-peptide and BC risk, and MD parameters do not seem to modify this association.

OBJECTIVE:This study was conducted to investigate the impact of antiplatelet administration in the periprocedural period on the occurrence of thromboembolic complications (TECs) in patients undergoing treatment using the Woven EndoBridge (WEB) device for intracranial wide-necked bifurcation aneurysms. The primary objective was to assess whether the use of antiplatelets in the pre- and postprocedural phases reduces the likelihood of developing TECs, considering various covariates. METHODS:A retrospective multicenter observational study was conducted within the WorldWideWEB Consortium and comprised 38 academic centers with endovascular treatment capabilities. Univariable and multivariable logistic regression analyses were performed to determine the association between antiplatelet use and TECs, adjusting for covariates. Missing predictor data were addressed using multiple imputation. RESULTS:The study comprised two cohorts: one addressing general thromboembolic events and consisting of 1412 patients, among whom 103 experienced TECs, and another focusing on symptomatic thromboembolic events and comprising 1395 patients, of whom 50 experienced symptomatic TECs. Preprocedural antiplatelet use was associated with a reduced likelihood of overall TECs (OR 0.32, 95% CI 0.19-0.53, p < 0.001) and symptomatic TECs (OR 0.49, 95% CI 0.25-0.95, p = 0.036), whereas postprocedural antiplatelet use showed no significant association with TECs. The study also revealed additional predictors of TECs, including stent use (overall: OR 4.96, 95% CI 2.38-10.3, p < 0.001; symptomatic: OR 3.24, 95% CI 1.26-8.36, p = 0.015), WEB single-layer sphere (SLS) type (overall: OR 0.18, 95% CI 0.04-0.74, p = 0.017), and posterior circulation aneurysm location (symptomatic: OR 18.43, 95% CI 1.48-230, p = 0.024). CONCLUSIONS:The findings of this study suggest that the preprocedural administration of antiplatelets is associated with a reduced likelihood of TECs in patients undergoing treatment with the WEB device for wide-necked bifurcation aneurysms. However, postprocedural antiplatelet use did not show a significant impact on TEC occurrence.

UNLABELLED:Leishmaniasis is a group of infectious diseases caused by protozoa of the Leishmania genus and its immunopathogenesis results from an unbalanced immune response during the infection. Diabetes is a chronic disease resulting from dysfunction of the body's production of insulin or the ability to use it properly, leading to hyperglycemia causing tissue damage and impairing the immune system. AIMS:The objective of this work was to evaluate the effects of hyperglycemia and diabetes during Leishmania amazonensis infection and how these conditions alter the immune response to the parasite. METHODS:An in vitro hyperglycemic stimulus model using THP-1-derived macrophages and an in vivo experimental diabetes with streptozotocin (STZ) in C57BL/6 mice was employed to investigate the impact of diabetes and hyperglicemia in Leishmania amazonensis infection. RESULTS:We observed that hyperglycemia impair the leishmanicidal capacity of macrophages derived from THP-1 cells and reverse the resistance profile that C57BL/6 mice have against infection by L. amazonensis, inducing more exacerbated lesions compared to non-diabetic animals. In addition, the hyperglycemic stimulus favored the increase of markers related to the phenotype of M2 macrophages. The induction of experimental diabetes in C57BL/6 mice resulted in a failure in the production of nitric oxide (NO) in the face of infection and macrophages from diabetic animals failed to process and present Leishmania antigens, being unable to activate and induce proliferation of antigen-specific lymphocytes. CONCLUSION:Together, these data demonstrate that diabetes and hyperglycemia can impair the cellular immune response, mainly of macrophages, against infection by parasites of the genus Leishmania.

BACKGROUND:Many patients with mildly to moderately reduced left ventricular ejection fraction (LVEF) who require permanent pacemaker (PPM) implantation do not have a concurrent indication for implantable cardioverter-defibrillator (ICD) therapy. However, the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in this population is unknown. OBJECTIVE:The aim of this study was to describe the risk of VT/VF after PPM implantation in patients with mildly to moderately reduced LVEF. METHODS:Retrospective analysis was performed of 243 patients with LVEF between 35% and 49% who underwent PPM placement and did not meet indications for an ICD. The primary end point was occurrence of sustained VT/VF. Competing risks regression was performed to calculate subhazard ratios for the primary end point. RESULTS:Median follow-up was 27 months; 73% of patients were male, average age was 79 ± 10 years, average LVEF was 42% ± 4%, and 70% were New York Heart Association class II or above. Most PPMs were implanted for sick sinus syndrome (34%) or atrioventricular block (50%). Of 243 total patients, 11 (4.5%) met the primary end point of VT/VF. Multivessel coronary artery disease (CAD) was associated with significantly higher rates of VT/VF, with a subhazard ratio of 5.4 (95% CI, 1.5-20.1; P = .01). Of patients with multivessel CAD, 8 of 82 (9.8%) patients met the primary end point for an annualized risk of 4.3% per year. CONCLUSION:Patients with mildly to moderately reduced LVEF and multivessel CAD undergoing PPM implantation are at increased risk for the development of malignant ventricular arrhythmias. Patients in this population may benefit from additional risk stratification for VT/VF and consideration for upfront ICD implantation.

BACKGROUND:Outcomes of inflammatory bowel disease (IBD) following flare complicated by enteric infection (EI) are limited by follow-up duration and insufficient assessment of the role of non-Clostridioides difficile pathogens. We compared 2-year IBD outcomes following flare with and without EI. METHODS:We performed a retrospective cohort study of adults evaluated with stool PCR testing for IBD flare. Subjects were stratified by presence of EI at flare and were matched for age, sex, and date to those without EI. The primary outcome was a composite of steroid-dependent IBD, colectomy, and/or IBD therapy class change/dose escalation at 2 years. Additional analyses were performed by dividing the EI group into C. difficile infection (CDI) and non-CDI EI, and further subdividing non-CDI EI into E. coli subtypes and other non-CDI EI. RESULTS:We identified 137 matched subjects, of whom 62 (45%) had EI (40 [29%] CDI; 17 [12%] E. coli). Enteric infection at flare was independently associated with the primary outcome (adjusted odds ratio, 4.14; 95% confidence interval [CI], 1.62-11.5). After dividing EI into CDI and non-CDI EI, only CDI at flare was independently associated with the primary outcome (adjusted odds ratio, 4.04; 95% CI, 1.46-12.6). After separating E. coli subtypes from non-CDI EI, E. coli infection and CDI at flare were both independently associated with the primary outcome; other EI was not. CONCLUSIONS:Enteric infection at flare-specifically with CDI-is associated with worse IBD outcomes at 2 years. The relationship between E. coli subtypes at flare and subsequent IBD outcomes requires further investigation.