TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining.

Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.

Performance and reliability assessment of a lower dose, task-based scoliosis radiography protocol in pediatric patients.

BACKGROUND: Follow-up scoliosis radiographs are performed to assess the degree of spinal curvature and skeletal maturity, which can be done at lower radiation exposures than those in standard-dose radiography. OBJECTIVE: Describe and evaluate a protocol that reduced the radiation in follow-up frontal-view scoliosis radiographs. MATERIALS AND METHODS: We implemented a postero-anterior lower dose modified-technique for scoliosis radiography with task-based definition of adequate image quality and use of technique charts based on target exposure index and patient's height and weight. We subsequently retrospectively evaluated 40 consecutive patients who underwent a follow-up radiograph using the modified-technique after an initial standard-technique radiograph. We evaluated comparisons of proportions for subjective assessment with chi-squared tests, and agreements of reader's scores with intraclass correlation coefficients and Bland-Altman plots. We determined incident air kerma, exposure index, deviation index/standard deviation, dose-area product (DAP), and effective dose for each radiograph. We set statistical significance at P<0.05. RESULTS: Forty patients (65% female), aged 4-17 years. Median effective dose was reduced from 39 to 10 µSv (P<0.001), incident air kerma from 139 to 29 µSv (P<0.001), and DAP from 266 to 55 mGy*cm2 (P<0.001). All modified-technique parameters were rated with a mean score of acceptable or above. All modified-technique measurements obtained inter- and intra-observer correlation coefficient agreements of 0.86 ("Good") or greater. CONCLUSION: Substantial dose reduction on follow-up scoliosis imaging with existing radiography units is achievable through task-based definition of adequate image quality and tailoring of radiation to each patient's height and weight, while still allowing for reliable assessment and reproducible measurements.

Sex and molecular differences in cardiovascular parameters at peak influenza disease in mice.

There is a growing interest in the detection of subtle changes in cardiovascular physiology in response to viral infection to develop better disease surveillance strategies. This is not only important for earlier diagnosis and better prognosis of symptomatic carriers but also useful to diagnose asymptomatic carriers of the virus. Previous studies provide strong evidence of an association between inflammatory biomarker levels and both blood pressure (BP) and heart rate (HR) during infection. The identification of novel biomarkers during an inflammatory event could significantly improve predictions for cardiovascular events. Thus, we evaluated changes in cardiovascular physiology induced in A/Puerto Rico/8/34 (PR8) influenza infections in female and male C57BL/6J mice and compared them with the traditional method of influenza disease detection using body weight (BW). Using radiotelemetry, changes in BP, HR, and activity were studied. Change in BW of infected females was significantly decreased from 5 to 13 days postinfection (dpi), yet alterations in normal physiology including loss of diurnal rhythm and reduced activity was observed starting at about 3 dpi for HR and 4 dpi for activity and BP; continuing until about 13 dpi. In contrast, males had significantly decreased BW 8 to 12 dpi and demonstrated altered physiological measurements for a shorter period compared with females with a reduction starting at 5 dpi for activity, 6 dpi for BP, and 7 dpi for HR until about 12 dpi, 10 dpi, and 9 dpi, respectively. Finally, females and males exhibited different patterns of inflammatory maker expression in lungs at peak disease by analyzing bulk RNA-sequencing data for lungs and Bio-plex cytokine assay for blood collected from influenza-infected and naïve C57BL/6J female and male mice at 7 dpi. In total, this study provides insight into cardiovascular changes and molecular markers to distinguish sex differences in peak disease caused by influenza virus infection.NEW & NOTEWORTHY This study performed longitudinal cardiovascular measurements of influenza viral infection and identified sex difference in both physiological and molecular markers at peak disease.

Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus.

Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with an increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day) for 4 wk. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T-cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, homeostatic model assessment for insulin resistance, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.NEW & NOTEWORTHY SLE is an autoimmune disease that is associated with obesity, insulin resistance, and elevated endothelin-1. The present study demonstrated that pharmacological inhibition of endothelin receptors decreased body weight, insulin resistance, and adipose tissue inflammation in a murine model of SLE. The therapeutic potential of endothelin receptor antagonists to treat obesity-related diseases and pathophysiological conditions, such as autoimmune diseases and insulin resistance, has become increasingly clear.

Prominent Structural Dependence of Quantum Capacitance Unraveled by Nitrogen-Doped Graphene Mesosponge.

Porous carbons are important electrode materials for supercapacitors. One of the challenges associated with supercapacitors is improving their energy density without relying on pseudocapacitance, which is based on fast redox reactions that often shorten device lifetimes. A possible solution involves achieving high total capacitance (Ctot ), which comprises Helmholtz capacitance (CH ) and possibly quantum capacitance (CQ ), in high-surface carbon materials comprising minimally stacked graphene walls. In this work, a templating method is used to synthesize 3D mesoporous graphenes with largely identical pore structures (≈2100 m2 g-1 with an average pore size of ≈7 nm) but different concentrations of oxygen-containing functional groups (0.3-6.7 wt.%) and nitrogen dopants (0.1-4.5 wt.%). Thus, the impact of the heteroatom functionalities on Ctot is systematically investigated in an organic electrolyte excluding the effect of pore structures. It is found that heteroatom functionalities determine Ctot , resulting in the cyclic voltammetry curves being rectangular or butterfly-shaped. The nitrogen functionalities are found to significantly enhance Ctot owing to increased CQ .

Leptin antagonism attenuates hypertension and renal injury in an experimental model of autoimmune disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by B- and T-lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin has various immunomodulatory properties, including promoting the expansion of proinflammatory T lymphocytes and the proliferation and survival of B cells. In the present study, we hypothesized that leptin antagonism would improve B- and T-cell dysfunction and attenuate hypertension in an experimental model of SLE, the NZBWF1 mouse. To test this hypothesis, 28-week-old female control and SLE mice were administered 5 mg/kg of murine leptin superantagonist (LA) or vehicle via ip injection every other day for four weeks. Analysis of peripheral blood immune cell populations showed no changes in total CD45R+ B and CD3+ T cell percentages after treatment with LA. However, SLE mice treated with LA had an improved CD4/CD8 ratio and decreased CD3+CD4-CD8- double negative (DN) T cells. Blood pressure was higher in SLE than in control, and treatment with LA decreased blood pressure in SLE mice. Treatment with LA also delayed the onset of albuminuria and decreased glomerulosclerosis in SLE mice. Renal immune cell infiltration was significantly higher in SLE mice as compared with control, but LA treatment was associated with decreased levels of renal CD4+ T cells. In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in SLE, in part, by promoting the expansion of inflammatory DN T cells and the infiltration of T cells into the kidneys.

Systematic Identification and Categorization of Opioid Prescribing and Dispensing Policies in 16 States and Washington, DC.

OBJECTIVES: State policies can impact opioid prescribing or dispensing. Some state opioid policies have been widely examined in empirical studies, including prescription drug monitoring programs and pain clinic licensure requirements. Other relevant policies might exist that have received limited attention. Our objective was to identify and categorize a wide range of state policies that could affect opioid prescribing/dispensing. METHODS: We used stratified random sampling to select 16 states and Washington, DC, for our sample. We collected state regulations and statutes effective during 2020 from each jurisdiction, using search terms related to opioids, pain management, and prescribing/dispensing. We then conducted qualitative template analysis of the data to identify and categorize policy categories. RESULTS: We identified three dimensions of opioid prescribing/dispensing laws: the prescribing/dispensing rule, its applicability, and its disciplinary consequences. Policy categories of prescribing/dispensing rules included clinic licensure, staff credentials, evaluating the appropriateness of opioids, limiting the initiation of opioids, preventing the diversion or misuse of opioids, and enhancing patient safety. Policy categories related to applicability of the law included the pain type, substance type, practitioner, setting, payer, and prescribing situation. The disciplinary consequences dimension included specific consequences and inspection processes. DISCUSSION: Policy categories within each dimension of opioid prescribing/dispensing laws could become a foundation for creating variables to support empirical analyses of policy effects, improving operationalization of policies in empirical studies, and helping to disentangle the effects of multiple state laws enacted at similar times to address the opioid crisis. Several of the policy categories we identified have been underexplored in previous empirical studies.

Urine drug testing in the context of opioid analgesic prescribing for chronic pain: a content analysis of U.S. state laws in 2022.

BACKGROUND: In response to the opioid crisis, U.S. states have passed laws requiring urine drug testing (UDT) when opioid analgesics are prescribed for chronic pain. We sought to identify state law UDT requirements. METHODS: We searched NexisUni legal database using terms related to UDT, chronic pain, and opioids. We included laws effective during spring 2022 that required UDT when opioids were prescribed for chronic pain. We performed deductive content analysis, coding laws for mandated UDT frequency, type of clinician and type of payer to whom the law applied, and circumstances under which UDT was mandated. RESULTS: We found 32 laws across 13 states that met our inclusion criteria. UDT requirements varied substantially by state, including with regard to the type of clinician to whom the law applied, the mandated frequency of UDT (eg, at initiation/assessment, at least annually, more than once per year), and the circumstances in which UDT was mandated (eg, patient had substance use disorder; dosage/day threshold). DISCUSSION: Relatively few states have UDT mandates associated with prescribing opioids as chronic pain treatment. When developing policy indicators for empirical studies, researchers evaluating how UDT policy affects health outcomes must consider the complexity and lack of uniformity of UDT requirements. In addition, even if states mandate UDT, it is unclear whether clinicians understand the best way to use the test results.

Factors Associated With Low Procedural Pain Scores Among 1- to 5-Year-Old Patients Undergoing Facial Laceration Repair.

OBJECTIVES: Our objectives were to quantify pain experienced by young children undergoing facial laceration repair and identify factors associated with low procedural pain scores. METHODS: We conducted a prospective cohort study of children's distress among a convenience sample of children aged 1 to 5 years undergoing facial or scalp laceration repair in 2 pediatric emergency departments. We reviewed video recordings and documented pain scores at 15-second intervals using the Face, Leg, Activity, Cry, Consolability-Revised (FLACC-r) scale. We dichotomized FLACC-r into low/high scores (≤3 and >3) to evaluate practice variables. RESULTS: We included 11,474 FLACC-r observations from 258 procedures in the analysis. Two-thirds of 3- to 5-year-olds completed their laceration repair without the use of restraint, sedation, or anxiolytics. Mean distress scores were low (≤2.5 out of 10) across all procedure phases for 2- to 5-year-old patients. One-year-old patients experienced significantly more distress than their older counterparts (mean ≤4.2 out of 10). Odds of having low FLACC scores (≤3) were greater for patients with an expert clinician (adjusted odds ratio [aOR]: 1.72; 95% confidence interval [CI], 1.05-2.84). Wound infiltration (aOR, 0.35; 95% CI, 0.13-0.93), patient observation of a needle (aOR, 0.21; 95% CI, 0.14-0.33), and restraint (aOR, 0.04; 95% CI, 0.02-0.06) were negatively associated with low FLACC score. CONCLUSION: The majority of 3- to 5-year-old patients were able to undergo facial laceration repair without restraint, sedation, or anxiolytics and with low mean distress scores. Our findings suggest that children's risk of experiencing moderate and severe distress during facial and scalp laceration repair may be reduced by prioritizing wound closure by expert-level clinicians, ensuring effective lidocaine-epinephrine-tetracaine application, avoiding restraint, and concealing needles from patient view.

Do Financial Incentives Affect Utilization for Chronically Ill Medicare Beneficiaries?

OBJECTIVE: The objective of this study was to examine the price sensitivity for provider visits among Medicare Advantage beneficiaries. DATA SOURCES: We used Medicare Advantage encounter data from 2014 to 2017 accessed as part of an evaluation for the Center for Medicare & Medicaid Innovation. STUDY DESIGN: We analyzed the effect of cost-sharing on the utilization of 2 outcome categories: number of visits (specialist and primary care) and the probability of any visit (specialist and primary care). Our main independent variable was the size of the copayment for the visit, which we regressed on the outcomes with several beneficiary-level and plan-level control variables. DATA COLLECTION/EXTRACTION METHODS: We included beneficiaries with at least 1 of 4 specific chronic conditions and matched comparison beneficiaries. We did not require beneficiaries to be continuously enrolled from 2014 to 2017, but we required a full year of data for each year they were observed. This resulted in 371,140 beneficiary-year observations. PRINCIPAL FINDINGS: Copay reductions were associated with increases in utilization, although the changes were small, with elasticities <-0.2. We also found evidence of substitution effects between primary care provider (PCP) and specialist visits, particularly cardiology and endocrinology. When PCP copays declined, visits to these specialists also declined. CONCLUSIONS: We find that individuals with chronic conditions respond to changes in copays, although these responses are small. Reductions in PCP copays lead to reduced use of some specialists, suggesting that lowering PCP copays could be an effective way to reduce the use of specialist care, a desirable outcome if specialists are overused.

Rapid Discontinuation of Chronic, High-Dose Opioid Treatment for Pain: Prevalence and Associated Factors.

PURPOSE: To examine the prevalence of rapid discontinuation of chronic, high-dose opioid analgesic treatment, and identify associated patient, clinician, and community factors. METHODS: Using 2017-2018 retail pharmacy claims data from IQVIA, we identified chronic, high-dose opioid analgesic treatment episodes discontinued during these years and determined the percent of episodes meeting criteria for rapid discontinuation. We used multivariable logistic regression to estimate the probability of rapid discontinuation, conditional on having a discontinued chronic, high-dose opioid treatment episode, as a function of patient, provider, and county characteristics. RESULTS: We identified 810,120 new, chronic, high-dose opioid treatment episodes discontinued in 2017 or 2018, of which 72.0% (n=583,415) were rapidly discontinued. Rapid discontinuation was significantly more likely among Medicare (aOR 1.14, 95% CI 1.12 to 1.15) and Medicaid enrollees (aOR 1.03, 95% CI 1.02 to 1.05) compared to the commercially insured; in counties with higher fatal overdose rates (aOR 1.03, 95% CI 1.01 to 1.04) compared to counties with the lowest fatal overdose rates; and in counties with a higher percentage of non-white residents (aOR 1.21 for counties in the highest quartile relative to the lowest, 95% CI 1.19 to 1.24). Likelihood of rapid discontinuation also varied by prescriber specialty. CONCLUSIONS: Most chronic, high-dose opioid treatment episodes that ended in 2017 or 2018 were discontinued more rapidly than recommended by clinical guidelines, raising concerns about adverse patient outcomes. Our findings highlight the need to understand what drives discontinuation and to inform safer opioid tapering and discontinuation practices.

Casting a wide NET: an update on uncontrolled NETosis in response to COVID-19 infection.

Dysregulation of neutrophil extracellular trap (NET) formation has been shown to mediate disease pathology in multiple viral infections, including SARS-CoV-2. At the beginning of COVID-19 pandemic, Thierry and Roch wrote a perspective on the mechanisms by which severe SARS-CoV-2 infection may lead to uncontrolled NET formation that leads to acute respiratory distress syndrome (ARDS), systemic vascular permeability, and end organ damage. In this commentary, the progress that has been made in regards to the ideas postulated by the perspective will be discussed, with a focus on the therapeutics that target NET formation.

Does boron or nitrogen substitution affect hydrogen physisorption on open carbon surfaces?

Incorporation of heteroatoms in carbon materials is commonly expected to influence their physical or chemical properties. However, contrary to previous results for methane adsorption, no technologically significant effect was identified for the hydrogen physisorption energies (measured 4.1-4.6 kJ mol-1 and calculated qst = -ΔHads = 4.1 ± 0.7 kJ mol-1 using a comprehensive set of levels of theory) as a function of B- and N-substitution of a mid-plane C-site on open carbon surfaces.

Sir2 suppresses transcription-mediated displacement of Mcm2-7 replicative helicases at the ribosomal DNA repeats.

Repetitive DNA sequences within eukaryotic heterochromatin are poorly transcribed and replicate late in S-phase. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). Despite the widespread association between transcription and replication timing, it remains unclear how transcription might impinge on replication, or vice versa. Here we show that, when silencing of an RNA polymerase II (RNA Pol II)-transcribed non-coding RNA at the rDNA is disrupted by SIR2 deletion, RNA polymerase pushes and thereby relocalizes replicative Mcm2-7 helicases away from their loading sites to an adjacent region with low nucleosome occupancy, and this relocalization is associated with increased rDNA origin efficiency. Our results suggest a model in which two of the major defining features of heterochromatin, transcriptional silencing and late replication, are mechanistically linked through suppression of polymerase-mediated displacement of replication initiation complexes.

Taming Wickedness: Towards an Implementation Framework for Medical Ethics.

"Wicked" problems are characterized by intractable complexity, uncertainty, and conflict between individuals or institutions, and they inhabit almost every corner of medical ethics. Despite wide acceptance of the same ethical principles, we nevertheless disagree about how to formulate such problems, how to solve them, what would count as solving them, or even what the possible solutions are. That is, we don't always know how best to implement ethical ideals in messy real-world contexts. I sketch an implementation framework for medical ethics that can help clarify wicked problems and organize further ethics research toward their resolutions. This framework describes the procedural variables that work alongside substantive ethical ideals to deliver ethical decisions in complex real-world situations. Using controversial GM mosquito research as an example, I illustrate how the generalizable relationships between the variables clarify emerging ethical guidelines of research governance and provide a pathway to extend these guidelines in a way consistent with our ethical intuitions across a wide range of research and public health ethics.

Immunological comparison of pregnant Dahl salt-sensitive and Sprague-Dawley rats commonly used to model characteristics of preeclampsia.

The pregnant Dahl salt-sensitive (S) rat is an established preclinical model of superimposed spontaneous preeclampsia characterized by exacerbated hypertension, increased urinary protein excretion, and increased fetal demise. Because of the underlying immune system dysfunction present in preeclamptic pregnancies in humans, we hypothesized that the pregnant Dahl S rat would also have an altered immune status. Immune system activation was assessed during late pregnancy in the Dahl S model and compared with healthy pregnant Sprague-Dawley (SD) rats subjected to either a sham procedure or a procedure to reduce uterine perfusion pressure (RUPP). Circulating immunoglobulin and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA) and Milliplex bead assay, respectively, and percentages of circulating, splenic, and placental immune cells were determined using flow cytometry. The pregnant Dahl S rat exhibited an increase in CD4+ T cells, and specifically TNFα+CD4+ T cells, in the spleen compared with virgin Dahl S rats. The Dahl also had increased neutrophils and decreased B cells in the peripheral blood as compared with Dahl virgin rats. SD rats that received the RUPP procedure had increases in circulating monocytes and increased IFN-É£+CD4+ splenic T cells. Together these findings suggest that dysregulated T cell activity is an important factor in both the pregnant Dahl S rats and SD rats after the RUPP procedure.

The complex role of adipokines in obesity, inflammation, and autoimmunity.

The global obesity epidemic is a major contributor to chronic disease and disability in the world today. Since the discovery of leptin in 1994, a multitude of studies have characterized the pathological changes that occur within adipose tissue in the obese state. One significant change is the dysregulation of adipokine production. Adipokines are an indispensable link between metabolism and optimal immune system function; however, their dysregulation in obesity contributes to chronic low-grade inflammation and disease pathology. Herein, I will highlight current knowledge on adipokine structure and physiological function, and focus on the known roles of these factors in the modulation of the immune response. I will also discuss adipokines in rheumatic and autoimmune diseases.

Endothelin receptor antagonism improves glucose handling, dyslipidemia, and adipose tissue inflammation in obese mice.

Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. We hypothesized that high ET-1 levels cause dyslipidemia, inflammation, and insulin resistance within the adipose tissue of obese mice. To test this hypothesis, male C57BL/6J mice were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day) or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day). Atrasentan and bosentan lowered circulating non-esterified free fatty acids and triglycerides seen in HFD mice, while atrasentan-treated mice had significantly lower liver triglycerides compared with non-treated HFD mice. ET-1 receptor blockade significantly improved insulin tolerance compared with insulin-resistant HFD mice and lowered expression of genes in epididymal white adipose tissue (eWAT) associated with insulin resistance and inflammation. Flow cytometric analyses of eWAT indicated that HFD mice had significantly higher percentages of both CD4+ and CD8+ T cells compared with NMD mice, which was attenuated by treatment with atrasentan or bosentan. Atrasentan treatment also abolished the decrease in eosinophils seen in HFD mice. Taken together, these data indicate that ETA and ETA/ETB receptor blockade improves peripheral glucose homeostasis, dyslipidemia and liver triglycerides, and also attenuates the pro-inflammatory immune profile in eWAT of mice fed HFD. These data suggest a potential use for ETA and ETA/ETB receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

Clinical Importance of Incidental Homogeneous Renal Masses That Measure 10-40 mm and 21-39 HU at Portal Venous Phase CT: A 12-Institution Retrospective Cohort Study.

BACKGROUND. Incidental homogeneous renal masses are frequently encountered at portal venous phase CT. The American College of Radiology Incidental Findings Committee's white paper on renal masses recommends additional imaging for incidental homogeneous renal masses greater than 20 HU, but single-center data and the Bosniak classification version 2019 suggest the optimal attenuation threshold for detecting solid masses should be higher. OBJECTIVE. The purpose of this article is to determine the clinical importance of small (10-40 mm) incidentally detected homogeneous renal masses measuring 21-39 HU at portal venous phase CT. METHODS. We performed a 12-institution retrospective cohort study of adult patients who underwent portal venous phase CT for a nonrenal indication. The date of the first CT at each institution ranged from January 1, 2008, to January 1, 2014. Consecutive reports from 12,167 portal venous phase CT examinations were evaluated. Images were reviewed for 4529 CT examinations whose report described a focal renal mass. Eligible masses were 10-40 mm, well-defined, subjectively homogeneous, and 21-39 HU. Of these, masses that were shown to be solid without macroscopic fat; classified as Bosniak IIF, III, or IV; or confirmed to be malignant were considered clinically important. The reference standard was renal mass protocol CT or MRI, ultrasound of definitively benign cysts or solid masses, single-phase contrast-enhanced CT or unenhanced MRI showing no growth or morphologic change for 5 years or more, or clinical follow-up 5 years or greater. A reference standard was available for 346 masses in 300 patients. The 95% CIs were calculated using the binomial exact method. RESULTS. Eligible masses were identified in 4.2% of patients (514/12,167; 95% CI, 3.9-4.6%). Of 346 masses with a reference standard, none were clinically important (0%; 95% CI, 0-0.9%). Mean mass size was 17 mm; 72% (248/346) measured 21-30 HU, and 28% (98/346) measured 31-39 HU. CONCLUSION. Incidental small homogeneous renal masses measuring 21-39 HU at portal venous phase CT are common and highly likely benign. CLINICAL IMPACT. The change in attenuation threshold signifying the need for additional imaging from greater than 20 HU to greater than 30 HU proposed by the Bosniak classification version 2019 is supported.