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Aim The aim of this study was to define the functional correlates of reversibilitiy following restoration of blood flow in the murine 2K1C model of renovascular hypertension. Method : Renal artery stenosis surgery (RAS) was performed by placement of a polytetrafluoroethylene cuff on the right renal artery (N=18). Sham surgery was performed without cuff placement (N=6). In two groups the cuff was removed at 7 days (7D cuff‐off, N=6) and 14 days (14D cuff‐off, N=6) after surgery. In the RAS group, cuff was left in place for 28 days (28D RAS, N=6). Kidneys were harvested at 28 days for assessment of histology and microvessel density (MVD). Renal blood perfusion and oxygenation were measured using 16.4T MRI. Blood pressure measurements were done using tail cuff method. Results In 7D cuff‐off group, baseline intra‐renal perfusion (891±142.8 ml/100g/min) was significantly reduced (311±73.4 ml/100g/min, p<0.0001) following cuff placement. Perfusion was restored to normal level (810±81.2 ml/100g/min) at 28 days following cuff removal at 7 days after RAS. In 14D cuff‐off group, baseline intra‐renal perfusion (846±74.5 ml/100g/min) was also significantly reduced (304±45.9 ml/100g/min, p=0.0002) following cuff placement with non‐significant improvement (579±112.9 ml/100g/min) at 28 days after cuff removal at 14 days after RAS. Baseline intra‐renal perfusion (905±54.9 ml/100g/min) in the 28D RAS group was significantly reduced (455±56.4 ml/100g/min, p<0.0034) following cuff placement and the reduction was maintained throughout the study period (478±22.2 ml/100g/min). 7D cuff‐off group (142±8.2 mg) showed no significant difference in kidney weights measured at 28 days compared to the sham group (154±4.8 mg), but was significantly higher compared to the 28D RAS group (67±10.5 mg, p=0.0010). The kidney weights of the 14D cuff‐off group (86±18.3 mg) measured at 28 days was not significantly different from the 28D RAS group. The 7D cuff‐off group had a significantly lower % atrophy (7±2.2%, p=0.0042) and higher MVD count (152±6.5, p=0.0045) compared to 28D RAS group (% atrophy 66±13%, MVD count 78±15.2). The 14D cuff‐off group had severe atrophy (56±16.6%) and reduced MVD count (94±20.1) similar to that seen in 28D RAS group. 50% of mice that developed hypoxia at day 3 had an improvement in their oxygenation after cuff removal at day 7, whereas, mice undergoing cuff removal at day 14 and 28 day ras mice remained hypoxic. Conclusion Based on these results, we conclude that the renal architecture and microvessel density are preserved when the cuff is removed no longer than 7 days post surgery. We Identified that 2 weeks after cuff placement is the “point of no return” in the renal injury in murine RAS model due to their reduction in microvessel density. Studies to identify biomarkers associated with irreversible renal injury in this model are currently being performed. Support or Funding Information NIH AI 100911 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The objective of this study was to define a role for chemokine generation by parenchymal cells versus circulating inflammatory cells in the initiation of renal damage in the 2K1C model of renovascular hypertension. 129 SV mice were subjected to renal artery stenosis (RAS) by placement of a polytetraethylene cuff on the right renal artery. Systolic blood pressure increased within 2 days of surgery. The cuffed kidney developed tubular atrophy, whereas the contralateral kidney developed compensatory enlargement. Immunohistochemical staining of the cuffed kidney revealed less than 2 CD3+ T cells per 200x field, and rare F4/80+ macrophages or CD20+ B cells in the first 2 weeks following RAS, with progressive increases in macrophages and T cells throughout the 6‐week observation period. Despite the relative paucity of infiltrating inflammatory cells, there was a dramatic increase in chemokine generation within the first week following RAS, as assessed by qPCR analysis of renal cortical homogenates, with 25‐fold induction of MCP‐1, 47‐fold induction of RANTES, and 15‐fold induction of MIP‐2. Chemokine generation continued to increase throughout the 6 weeks, during which circulating inflammatory cells infiltrated the cuffed kidney. Increased expression of MCP‐1 was detected in tubular epithelial cells within 1 week of RAS. We conclude that chemokine generation precedes inflammatory cell influx in RAS.

Background There is heterogeneity in the names and anatomical descriptions of regional anesthetic techniques. This may have adverse consequences on education, research, and implementation into clinical practice. We aimed to produce standardized nomenclature for abdominal wall, paraspinal, and chest wall regional anesthetic techniques. Methods We conducted an international consensus study involving experts using a three-round Delphi method to produce a list of names and corresponding descriptions of anatomical targets. After long-list formulation by a Steering Committee, the first and second rounds involved anonymous electronic voting and commenting, with the third round involving a virtual round table discussion aiming to achieve consensus on items that had yet to achieve it. Novel names were presented where required for anatomical clarity and harmonization. Strong consensus was defined as ≥75% agreement and weak consensus as 50% to 74% agreement. Results Sixty expert Collaborators participated in this study. After three rounds and clarification, harmonization, and introduction of novel nomenclature, strong consensus was achieved for the names of 16 block names and weak consensus for four names. For anatomical descriptions, strong consensus was achieved for 19 blocks and weak consensus was achieved for one approach. Several areas requiring further research were identified. Conclusions Harmonization and standardization of nomenclature may improve education, research, and ultimately patient care. We present the first international consensus on nomenclature and anatomical descriptions of blocks of the abdominal wall, chest wall, and paraspinal blocks. We recommend using the consensus results in academic and clinical practice.

INTRODUCTION: Gastroenterologists at all levels of practice benefit from formal mentoring. Much of the current literature on mentoring in gastroenterology is based on expert opinion rather than data. In this study, we aimed to identify gender-related barriers to successful mentoring relationships from the mentor and mentee perspectives. METHODS: A voluntary, web-based survey was distributed to physicians at 20 academic institutions across the United States. Overall, 796 gastroenterology fellows and faculty received the survey link, with 334 physicians responding to the survey (42% response rate), of whom 299 (90%; 129 women and 170 men) completed mentorship questions and were included in analysis. RESULTS: Responses of women and men were compared. Compared with men, more women preferred a mentor of the same gender (38.6% women vs 4.2% men, P < 0.0001) but less often had one (45.5% vs 70.2%, P < 0.0001). Women also reported having more difficulty finding a mentor (44.4% vs 16.0%, P < 0.0001) and more often cited inability to identify a mentor of the same gender as a contributing factor (12.8% vs 0.9%, P = 0.0004). More women mentors felt comfortable advising women mentees about work-life balance (88.3% vs 63.8%, P = 0.0005). Nonetheless, fewer women considered themselves effective mentors (33.3% vs 52.6%, P = 0.03). More women reported feeling pressured to mentor because of their gender (39.5% vs 0.9% of men, P < 0.0001). Despite no gender differences, one-third of respondents reported negative impact of the COVID-19 pandemic on their ability to mentor and be mentored. DISCUSSION: Inequities exist in the experiences of women mentees and mentors in gastroenterology, which may affect career advancement and job satisfaction.

Context.— Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios. Objective.— To evaluate the performance of DOAC-specific assays for various concentrations of dabigatran and rivaroxaban, assess the interlaboratory variability in measurement of these DOACs, and investigate the responsiveness of the routine clotting assays to various concentrations of these oral anticoagulants. Design.— College of American Pathologists proficiency testing survey data from 2013 to 2016 were summarized and analyzed. Results.— For dabigatran, the interlaboratory coefficient of variation (CV) of ecarin chromogenic assay was broad (ranging from 7.5% to 29.1%, 6.3% to 15.5%, and 6.8% to 9.0% for 100-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The CV for diluted thrombin time for dabigatran was better overall (ranging from 11.6% to 17.2%, 9.3% to 12.3, and 7.1% to 11.2% for 100 ng/mL, 200 ng/mL, and 400 ng/mL, respectively). The rivaroxaban-calibrated anti-Xa assay CVs also showed variability (ranging from 11.5% to 22.2%, 7.2% to 10.9%, and 6.4% to 8.1% for 50-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The prothrombin time (PT) and activated partial thromboplastin time (aPTT) showed variable dose- and reagent-dependent responsiveness to DOACs: PT was more responsive to rivaroxaban and aPTT to dabigatran. The undiluted thrombin time showed maximum prolongation across all 3 dabigatran concentrations, making it too sensitive for drug-level monitoring, but supporting its use as a qualitative screening assay. Conclusions.— DOAC-specific assays performed reasonably well. While PT and aPTT cannot be used safely to determine DOAC degree of anticoagulation, a normal thrombin time excludes the presence of dabigatran.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.

Abstract Purpose:Quantify in vivo biomechanical tissue properties in various breast densities and in normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk.Methods: Patients with normal risk or high risk of breast cancer underent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (normal versus high). A multivariable logistic regression model was used to evaluate whether the MRE parameters (separately for stiffness, elasticity, and viscosity) predicted risk status after controlling for clinical factors.Results: 50 normal risk and 86 high risk patients were included. Risk groups were similar on age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients (N = 55) compared to normal risk patients (N = 34; all p < 0.001). Stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity.Conclusion: A structurally-based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.

Aggregation and accumulation of amyloid-β (Aβ) is a defining feature of Alzheimer’s disease pathology. To study microglial responses to Aβ, we applied exogenous Aβ peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system-level transcriptional changes and then compared these with transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change in response to Aβ. Transcriptomic responses to oligomeric or fibrillar Aβ in primary microglia, although partially overlapping, are distinct and are not recapitulated in vivo where Aβ progressively accumulates. Furthermore, although classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar Aβ can be distinguished.

Melanoma is the sixth most common cancer in the US. Immunotherapies, such as anti‐CTLA‐4 and anti‐PD‐1, have transformed the treatment of advanced melanoma; however, a subset of patients fail to respond to immunotherapy. Thus, improved predictors of the anti‐melanoma immune response and response to immunotherapy are needed. We have previously shown that 1) gamma‐interferon‐inducible lysosomal thiol reductase (GILT) is critical for MHC class II‐restricted presentation of a melanoma antigen, 2) there is variable GILT protein expression in melanoma cells from primary and cutaneous metastatic melanoma specimens, and 3) high GILT mRNA expression in melanoma specimens is associated with improved overall survival. Here, we created a database of n = 43 metastatic melanoma patients (stage III or IV) annotated with clinical outcome. Formalin‐fixed, paraffin‐embedded sections of pre‐treatment metastatic melanoma specimens were tested for GILT protein expression using immunohistochemistry and scored by a dermatopathologist and dermatologist. GILT expression in melanoma cells was detected in 65% of lymph node and distant organ metastases, consistent with our prior finding of GILT expression in 58% of cutaneous metastases. The frequency of GILT‐staining melanoma cells was determined by the ratio of the area of tumor cells with positive GILT staining to the total area of tumor cells. The frequency of GILT‐staining melanoma cells among specimens with positive GILT staining was 15.2% ± 24.7% (mean ± SD). The median frequency of GILT staining was used to divide the patients into no/low and high GILT expression groups. The median overall survival was 52.8 months in the no/low GILT expression group, while the median overall survival was not reached in the high GILT expression group (log‐rank, p = 0.67). For the n = 34 patients who were treated with immunotherapy targeting CTLA‐4 and/or PD‐1, the median overall survival was 38.2 months in the no/low GILT expression group, while the median overall survival was not reached in the high GILT expression group (log‐rank, p = 0.83). These data suggest that high GILT expression in melanoma cells may be associated with improved overall survival, although a statistically significant association of GILT with survival was not observed in the whole group or the subset of patients treated with immunotherapy. A limitation of the current analysis is that 65% of patients have incomplete clinical outcome data. This study demonstrates variable GILT protein expression in tumor cells in metastatic melanoma specimens. Updated clinical outcome data will allow us to better evaluate the association of GILT protein expression in melanoma cells with overall survival and response to immunotherapy in metastatic melanoma patients.