Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer's disease-associated metabolites.

Type 2 diabetes (T2D) is implicated as a risk factor for Alzheimer's disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood-brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex. We employed unsupervised clustering, inferential statistics, and partial least squares discriminant analysis to identify relationships between cytokine concentration and disease-associations of metabolites. We identified MCP-1, a cytokine associated with monocyte recruitment, as differentially abundant between neurons stimulated by metabolites associated with protective and detrimental properties of AD and T2D. We also identified IL-9, a cytokine that promotes mast cell growth, to be differentially associated with T2D. Indeed, cytokines, such as MCP-1 and IL-9, released from neurons in response to BBB-permeable metabolites associated with T2D may contribute to AD development by downstream effects of neuroinflammation.

A new through-the-scope clip with anchor prongs is safe and successful for a variety of endoscopic uses.

Background and study aims Endoscopic through-the-scope clips (TTSC) are used for hemostasis and closure. We documented the performance of a new TTSC with anchor prongs. Patients and methods We conducted a prospective case series of the new TTSC in 50 patients with an indication for endoscopic clipping at three hospitals in the United States and Canada. Patients were followed for 30 days after the index procedure. Outcomes included defect closure and rate of serious adverse events (SAEs) related to the device or procedure. Results Fifty patients had 56 clipping procedures. Thirty-four procedures were clipping after endoscopic mucosal resection (EMR) in the colon (33) or stomach (1), 16 after polypectomy, two for hemostasis of active bleeding, and one each for fistula closure, per-oral endoscopic myotomy mucosal closure, or anchoring a feeding tube. Complete defect closure was achieved in 32 of 33 colon EMR defects and 21 of 22 other defects. All clips were placed per labeled directions for use. In 41 patients (82.0%), prophylaxis of delayed bleeding was reported as an indication for endoscopic clipping. There were three instances of delayed bleeding. There were no device-related SAEs. The only technical difficulty was one instance of premature clip deployment. Conclusions A novel TTSC with anchor prongs showed success in a range of defect closures, an acceptable safety profile, and low incidence of technical difficulties.

Racial Implicit Associations in Child Psychiatry.

OBJECTIVE: Racial disparities in diagnosis and treatment are prevalent in child psychiatry, including disparate diagnosis rates of internalizing and externalizing disorders in Black and White children. However, limited research has investigated mechanisms that contribute to these disparities. This study examined child racial implicit associations in psychiatric clinicians and medical students to address this gap. METHOD: Psychiatrists and trainees completed an online survey including 2 race Implicit Association Tests (IATs) pairing child faces to words with either positive or negative valence, and words related to internalizing or externalizing behavioral problems. We further investigated psychiatrists' and trainees' demographic predictors of implicit associations. RESULTS: Data were analyzed from 235 psychiatrists and trainees (112 child and adolescent psychiatrists and fellows) who met inclusion criteria. Psychiatrists and trainees demonstrated greater moderate-to-strong association between Black child faces and "bad" words (44.3%) vs "good" words (6.4%), and between externalizing words (41.7%) and internalizing words (7.2%). Psychiatrists' and trainees' demographic characteristics including being female (ß = -0.12; 95% CI = -0.23 to -0.01; p < .05), Black (ß = -0.36; 95% CI = -0.54 to -0.18; p < .001), or an attending physician (ß = -0.26; 95% CI = -0.45 to -0.06; p = .01) were significant predictors of decreased association between Black child faces and negative valence words. Being female was a significant predictor of decreased association between Black child faces and externalizing words (ß = -0.26; 95% CI = -0.45 to -0.06; p = .01). CONCLUSION: Participating psychiatrists and trainees demonstrated bias toward associating Black rather than White child faces with negative words and externalizing behavioral problems. Future research should examine the following: (1) racial implicit associations in a more generalizable sample, (2) the relationship between race IATs and provider behavior, and (3) interventions to reduce racial inequities in psychiatry, including individual and systemic solutions. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

TEMPORARY REMOVAL: Quality indicators common to all GI endoscopic procedures.

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Genomic Characterization of Preclinical Prostate Cancer Cell Line Models.

As we move into the era of precision medicine, the growing relevance of genetic alterations to prostate cancer (PCa) development and treatment demonstrates the importance of characterizing preclinical models at the genomic level. Our study investigated the genomic characterization of eight PCa cell lines to understand which models are clinically relevant. We designed a custom AmpliSeq DNA gene panel that encompassed key molecular pathways targeting AR signaling, apoptosis, DNA damage repair, and PI3K/AKT/PTEN, in addition to tumor suppressor genes. We examined the relationship between cell line genomic alterations and therapeutic response. In addition, using DepMap's Celligner tool, we identified which preclinical models are most representative of specific prostate cancer patient populations on cBioPortal. These data will help investigators understand the genetic differences in preclinical models of PCa and determine which ones are relevant for use in their translational research.

International consensus on the management of large (≥20 mm) colorectal laterally spreading tumors: World Endoscopy Organization Delphi study.

OBJECTIVES: There have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices. METHODS: Two experts in interventional endoscopy spearheaded an evidence-based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three-round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5-point Likert scale. RESULTS: Forty-two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision-making; seven statements on postresection evaluation; and eight statements on postresection care. CONCLUSIONS: An international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow-up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

Medicare volume and reimbursement trends in lingual and hyoid procedures for obstructive sleep apnea.

OBJECTIVES: This study aims to analyze utilization and reimbursement trends in lingual and hyoid surgery for obstructive sleep apnea (OSA). METHODS: Annual retrospective data on lingual and hyoid OSA surgeries was obtained from the 2000-2021 Medicare Part B National Summary Datafiles. Current Procedural Terminology (CPT) codes utilized included 21,685 (hyoid myotomy and suspension [HMS]), 41,512 (tongue base suspension [TBS]), 41,530 (radiofrequency ablation of the tongue [RFT]) and 42,870 (lingual tonsillectomy [LT]). RESULTS: The number of lingual and hyoid OSA surgeries rose 2777 % from 121 in 2000 to 3481 in 2015, before falling 82.9 % to 594 in 2021. Accordingly, Medicare payments rose 17,899 % from an inflation-adjusted $46,958 in 2000 to $8.45 million in 2015, before falling drastically to $341,011 in 2021. As the number of HMSs (2000: 91; 2015: 84; 2021: 165), TBS (2009: 48; 2015: 31; 2021: 16), and LTs (2000: 121; 2015: 261; 2021: 234) only experienced modest changes in utilization, this change was largely driven by RFT (2009: 340; 2015: 3105; 2021: 179). Average Medicare payments for RFT rose from $1110 in 2009 to $2994 in 2015, before falling drastically to $737 in 2021. CONCLUSION: Lingual and hyoid surgery for OSA has overall fallen in utilization among the Medicare population from 2000 to 2021. However, there was a brief spike in usage, peaking in 2015, driven by the adoption (and then quick dismissal) of RFT. The rise and fall in RFT use coincide with the rise and fall in reimbursement.

Artificial Intelligence for Real-Time Prediction of the Histology of Colorectal Polyps by General Endoscopists.

BACKGROUND: Real-time prediction of histologic features of small colorectal polyps may prevent resection and/or pathologic evaluation and therefore decrease colonoscopy costs. Previous studies showed that computer-aided diagnosis (CADx) was highly accurate, though it did not outperform expert endoscopists. OBJECTIVE: To assess the diagnostic performance of histologic predictions by general endoscopists before and after assistance from CADx in a real-life setting. DESIGN: Prospective, multicenter, single-group study. (ClinicalTrials.gov: NCT04437615). SETTING: 6 centers across the United States. PARTICIPANTS: 1252 consecutive patients undergoing colonoscopy and 49 general endoscopists with variable experience in real-time prediction of polyp histologic features. INTERVENTION: Real-time use of CADx during routine colonoscopy. MEASUREMENTS: The primary end points were the sensitivity and specificity of CADx-unassisted and CADx-assisted histologic predictions for adenomas measuring 5 mm or less. For clinical purposes, additional estimates according to location and confidence level were provided. RESULTS: The CADx device made a diagnosis for 2695 polyps measuring 5 mm or less (96%) in 1252 patients. There was no difference in sensitivity between the unassisted and assisted groups (90.7% vs. 90.8%; P = 0.52). Specificity was higher in the CADx-assisted group (59.5% vs. 64.7%; P < 0.001). Among all 2695 polyps measuring 5 mm or less, 88.2% and 86.1% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be resected and discarded without pathologic evaluation. Among 743 rectosigmoid polyps measuring 5 mm or less, 49.5% and 47.9% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be left in situ without resection. LIMITATION: Decision making based on CADx might differ outside a clinical trial. CONCLUSION: CADx assistance did not result in increased sensitivity of optical diagnosis. Despite a slight increase, the specificity of CADx-assisted diagnosis remained suboptimal. PRIMARY FUNDING SOURCE: Olympus America Corporation served as the clinical study sponsor.

Computer-Aided Diagnosis for Leaving Colorectal Polyps In Situ : A Systematic Review and Meta-analysis.

BACKGROUND: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. PURPOSE: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. DATA SOURCES: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. STUDY SELECTION: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. DATA EXTRACTION: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. DATA SYNTHESIS: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). LIMITATION: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. CONCLUSION: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. PRIMARY FUNDING SOURCE: European Commission. (PROSPERO: CRD42023402197).

Using Computer-aided Optical Diagnosis and Expert Review to Evaluate Colorectal Polyps Diagnosed as Normal Mucosa in Pathology.

Pathological assessment of colorectal polyps is considered the current reference standard for histologic diagnosis. About 10% of polyps sent to the pathology lab are returned with the diagnosis of mucosal folds, mucosal prolapse, or normal mucosa.1,2 Two recent publications have indicated that disagreements between endoscopic optical diagnosis and the subsequent pathological diagnoses might be due to misdiagnosis in pathology.3,4 We were therefore interested in re-evaluating pathology-based diagnosis of "mucosal polyps" using expert endoscopists and computer-assisted diagnosis (CADx) evaluation.

Safety of first surveillance colonoscopy at 12 months after piecemeal endoscopic mucosal resection of large non-pedunculated colorectal lesions.

BACKGROUND AND AIMS: After piecemeal endoscopic mucosal resection (pEMR) of nonpedunculated colorectal lesions ≥ 20 mm, guidelines recommend first endoscopic surveillance at 6 months. However, initial surveillance at 12 months may be adequate for selected low-risk lesions, and could save the cost, risk and inconvenience of one surveillance examination. METHODS: We retrospectively examined a prospectively collected database of all colorectal lesions referred to our center for endoscopic resection between August 2019 and April 2023. We report recurrence rates of colorectal lesions ≥ 20 mm removed by pEMR who were assigned to 6-month first surveillance or assigned to 12-month first surveillance (or assigned to 6-month but did not return until after 10 months). RESULTS: There were 561 nonpedunculated lesions ≥ 20 mm that underwent first follow-up, including 490 lesions in 443 patients assigned to 6-month, and 71 lesions in 65 patients assigned to 12-month surveillance. Lesions assigned to 12-month surveillance were smaller (mean size 25.9 ± 6.1mm vs. 37.0 ± 17.4mm), more likely serrated (63.4% vs. 9.6%), and more often removed by cold pEMR (74.6% vs 20.4%). Twenty-nine lesions in 24 patients assigned 6-month surveillance presented after 10 months and their recurrence data were included in the group assigned 12-month surveillance. Overall recurrence rates at 6 months and 12 months were 10.0% (46/461) and 9.0% (9/100), respectively. Mean recurrence sizes at 6 and 12 months were 10.9 ± 6.2mm and 4.2 ± 1.9mm, respectively. One patient in the 6-month surveillance group had cancer at the pEMR site, but no other recurrences at 6 or 12 months had either cancer or high-grade dysplasia. CONCLUSION: Twelve-month surveillance appears acceptable for selected colorectal lesions ≥ 20 mm removed by pEMR. A randomized trial comparing initial 6-month to 12-month surveillance is warranted for selected lesions.

Optimizing clinical outcomes for bronchoscopic lung volume reduction with Zephyr® valves.

Bronchoscopic lung volume reduction treatment with Zephyr one-way valves is an effective guideline-based treatment option for patients with severe emphysema and hyperinflation. However, in some cases the treatment response is less than anticipated or there might be a loss of initial treatment effect. Reasons for the lack of response can include incorrect assessment of collateral ventilation, improper valve placement, or patient related factors. Loss of initial benefit can be due to granulation tissue formation and subsequent valve dysfunction, or there may be side effects such as excessive coughing or infectious problems. Careful follow-up after treatment with valves is important and evaluation with a CT scan and/or bronchoscopy is helpful if there is no improvement after treatment or loss of initial benefit. This paper aims to describe the most important causes and provide a strategy of how to approach and manage these patients.

Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors.

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.

Audit of hemostatic clip use after colorectal polyp resection in an academic endoscopy unit.

Background and study aims Prophylactic closure of endoscopic resection defects reduces delayed hemorrhage after resection of non-pedunculated colorectal lesions ≥ 20 mm that are located proximal to the splenic flexure and removed by electrocautery. The risk of delayed hemorrhage after cold (without electrocautery) resection is much lower, and prophylactic clip closure after cold resection is generally unnecessary. The aim of this study was to audit clip use after colorectal polyp resection in routine outpatient colonoscopies at two outpatient centers within an academic medical center. Patients referred for resection of known lesions were excluded. Patients and methods Retrospective chart analysis was performed as part of a quality review of physician adherence to screening and post-polypectomy surveillance intervals. Results Among 3784 total lesions resected cold by 29 physicians, clips were placed after cold resection on 41.7% of 12 lesions ≥ 20 mm, 19.3% of 207 lesions 10 to 19 mm in size, and 2.8% of 3565 lesions 1 to 9 mm in size. Three physicians placed clips after cold resection of lesions 1 to 9 mm in 18.8%, 25.5%, and 45.0% of cases. These physicians accounted for 8.1% of 1- to 9-mm resections, but 69.7% of clips placed in this size range. Electrocautery was used for 3.1% of all resections. Clip placement overall after cold resection (3.9%) was much lower than after resection with electrocautery (71.1%), but 62.4% of all clips placed were after cold resection. Conclusions Audits of clip use in an endoscopy practice can reveal surprising findings, including high and variable rates of unnecessary use after cold resection. Audit can potentially reduce unnecessary costs, carbon emissions, and plastic waste.

Chk2 homologue Mek1 limits Exo1-dependent DNA end resection during meiotic recombination in S. cerevisiae.

The conserved Rad2/XPG family 5'-3' exonuclease, Exonuclease 1 (Exo1), plays many roles in DNA metabolism including during resolution of DNA double strand breaks (DSBs) via homologous recombination. Prior studies provided evidence that the end-resection activity of Exo1 is downregulated in yeast and mammals by Cdk1/2 family cyclin-dependent and checkpoint kinases, including budding yeast kinase Rad53 which functions in mitotic cells. Here we provide evidence that the master meiotic kinase Mek1, a paralogue of Rad53, limits 5'-3' single strand resection at the sites of programmed meiotic DNA breaks. Mutational analysis suggests that the mechanism of Exo1 suppression by Mek1 differs from that of Rad53. Article Summary: Meiotic recombination involves formation of programmed DNA double strand breaks followed by 5' to 3' single strand specific resection by nucleases including Exo1. We find that the activity of budding yeast Exo1 is downregulated during meiotic recombination by the master meiotic kinase Mek1. The mechanism of downregulation of Exo1 by Mek1 in meiosis does not depend on the same phospho-sites as those used by the mitotic kinase Rad53, a relative of Mek1 that downregulates Exo1 in mitosis.

Perioperative Estrogen Hormonal Therapy Does Not Increase Venous Thromboembolism Risk In Facial Feminization Surgery.

BACKGROUND: Conflicting data exist regarding increased perioperative VTE risk while on feminizing hormone therapy. The effect has been poorly studied within the transgender population. Acute perioperative cessation of feminizing hormone therapy often leads to unpleasant side effects and exacerbates gender dysphoria in the perioperative period. We seek to identify the VTE incidence in patients undergoing facial feminization while continuing HRT throughout the time of surgery. METHODS: A 38-year retrospective cohort study within a two-surgeon practice (D.K.O. and J.C.D.) was designed to evaluate postoperative VTE in patients continuing hormone therapy. The primary outcome variable was identified as suffering a VTE postoperatively. RESULTS: 1,715 patients underwent facial feminization surgery within our search window. 953 patients met final inclusion criteria. 1 patient (0.10%) was diagnosed with a VTE postoperatively, comparable to reported literature rates for similar cosmetic and orthognathic procedures. The average Caprini score of all patients was 3.1±1.0 and the average case length was 491.9±111.0 minutes. Subgroup analysis of patients before and after internal practice changes identified 714 (77.7%) patients continuing full dose hormonal therapy perioperatively, 197 (20.7%) patients undergoing hormonal dose reduction to 25-50% perioperatively, and 8 patients who were either not taking hormonal therapy or stopped in the perioperative period. There was no significant difference in VTE incidence between the 3 subgroups (p > 0.99). CONCLUSIONS: Perioperative use of feminizing hormonal therapy does not increase risk for perioperative VTE in patients undergoing facial feminization surgery. Therefore, it is reasonable to continue these medications through the time of surgery.