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.

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.

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.

Nutritional Assessment in Patients after Gastric Electrical Stimulation (GES).

BACKGROUND: Gastric electrical stimulation (GES) is used for patients with drug-refractory gastroparesis (Gp) symptoms. Approximately two-thirds of patients with Gp symptoms are either overweight or obese. We aimed to assess symptoms and nutritional status pre-GES and post-GES placement in a large sample of drug-refractory Gp patients. METHODS: We conducted a chart review of 282 patients with drug-refractory Gp who received temporary followed by permanent GES at an academic medical center. Gastrointestinal symptoms were collected by a traditional standardized PRO (0-4, 0 being asymptomatic and 4 being worst symptoms), baseline nutritional status by BMI plus subjective global assessment (SGA score A, B, C, for mild, moderate, and severe nutritional deficits), ability to tolerate diet, enteral tube access, and parenteral therapy were assessed at baseline and after permanent GES placement. RESULTS: Comparing baseline with permanent, GES was found to significantly improve upper GI symptoms in all quartiles. Of the 282 patients with baseline body mass index (BMI) information, 112 (40%) patients were severely malnourished at baseline, of which 36 (32%) patients' nutritional status improved after GES. Among all patients, 76 (68%) patients' nutritional status remained unchanged. Many patients with high BMI were malnourished by SGA. CONCLUSION: We conclude that symptomatic patients of different BMIs showed improvement in their GI symptoms irrespective of baseline nutritional status. Severely malnourished patients were found to have an improvement in their nutritional status after GES therapy. We conclude that BMI, even if high, is not by itself a contraindication for GES therapy for symptomatic patients.

Characterization of endoscopic features and histology of a distinct mucosal transition zone on the ileocecal valve (with video).

BACKGROUND AND AIMS: We have endoscopically encountered a zone of transitional mucosa between the colonic and ileal mucosa located in a 3- to 10-mm-wide ring around the ileocecal valve (ICV) orifice. We aimed to describe the features of the ICV transitional zone mucosa. METHODS: We used videos and photographs from normal ICVs and biopsy samples from normal colonic mucosa, transitional zone mucosa, and normal ileal mucosa to characterize the endoscopic and histologic features of the ICV transitional zone mucosa. RESULTS: The ICV transitional zone is identifiable on every ICV without a circumferential adenoma or inflammation that obliterates the zone. The zone is characterized endoscopically by an absence of villi, which distinguishes it from the ileal mucosa, but the pits are more tubular and with more prominent blood vessels compared with normal colonic mucosa. Histologically, the villi of the transitional zone are blunted, and the amount of lymphoid tissue is intermediate between the colonic mucosa and ileal mucosa. CONCLUSIONS: This is the first description of the normal transitional zone of mucosa on the ICV. This zone has unique endoscopic features that should be recognized by colonoscopists and that can potentially create difficulty in identifying the margins of adenomas located on the ICV.

Use of a Cirrhosis Admission Order Set Improves Adherence to Quality Metrics and May Decrease Hospital Length of Stay.

INTRODUCTION: Quality metrics for inpatient cirrhosis management have been created to improve processes of care. We aimed to improve adherence to quality metrics by creating a novel clinical decision support (CDS) tool in the electronic health record (EHR). METHODS: We developed and piloted an alert system in the EHR that directs providers to a cirrhosis order set for patients who have a known diagnosis of cirrhosis or are likely to have cirrhosis. Adherence to process measures and outcomes when the CDS was used were compared with baseline performance before the implementation of the CDS. RESULTS: The use of the order set resulted in a significant increase in adherence to process measures such as diagnostic paracentesis (29.6%-51.1%), low-sodium diet (34.3%-77.8%), and social work involvement (36.6%-88.9%) ( P < 0.001 for all). There were also significant decreases in both intensive care and hospital lengths of stay ( P < 0.001) as well as in-hospital development of infection ( P = 0.002). There was no difference in hospital readmissions at 30 or 90 days between the groups ( P = 0.897, P = 0.640). DISCUSSION: The use of CDS in EHR-based interventions improves adherence to quality metrics for patients with cirrhosis and could easily be shared by institutions through EHR platforms. Further studies and larger sample sizes are needed to better understand its impact on additional outcome measures.

Primary lung sarcoma with gastric metastasis and morphological divergence presenting as melena.

A 61-year-old man was admitted to the medical intensive care unit following a 2-week history of weakness, lightheadedness and melena resulting in an acute anaemia. Upper endoscopy revealed multiple large gastric masses without evidence of active bleeding. CT of the chest revealed a large right upper lobe mass with bony destruction of the third rib and invasion into the anterior chest wall and mediastinum, as well as a soft-tissue density in the left kidney. Biopsy and histopathological review of both pulmonary and gastric masses revealed two distinct sarcomatous malignancies that, while both from a primary lung source, differed in their morphology. Natural history and behaviour are not well understood in sarcomas due to their rarity, but abdominal metastasis is considered an uncommon event in the progression of the disease. Gastrointestinal bleeding as the presenting symptom of a primary lung sarcoma is an atypical finding with no previously reported cases.

Plasma Metabolomics Analysis of Polyvinyl Chloride Workers Identifies Altered Processes and Candidate Biomarkers for Hepatic Hemangiosarcoma and Its Development.

BACKGROUND: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The purpose of this study is to address these knowledge gaps through plasma metabolomics. METHODS: Plasma samples from polyvinyl chloride polymerization workers who developed hemangiosarcoma (cases, n = 15) and VC exposure-matched controls (n = 17) underwent metabolomic analysis. Random forest and bioinformatic analyses were performed. RESULTS: Cases and controls had similar demographics and routine liver biochemistries. Mass spectroscopy identified 606 known metabolites. Random forest analysis had an 82% predictive accuracy for group classification. 60 metabolites were significantly increased and 44 were decreased vs. controls. Taurocholate, bradykinin and fibrin degradation product 2 were up-regulated by greater than 80-fold. The naturally occurring anti-angiogenic phenol, 4-hydroxybenzyl alcohol, was down-regulated 5-fold. Top affected ontologies involved: (i) metabolism of bile acids, taurine, cholesterol, fatty acids and amino acids; (ii) inflammation and oxidative stress; and (iii) nicotinic cholinergic signaling. CONCLUSIONS: The plasma metabolome was differentially regulated in polyvinyl chloride workers who developed hepatic hemangiosarcoma. Ontologies potentially involved in hemangiosarcoma pathogenesis and candidate biomarkers were identified.

Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.

Toll-like receptors (TLRs) are pathogen-recognition receptors that trigger the innate immune response. Recent reports have identified accessory proteins that provide essential support to TLR function through ligand delivery and receptor trafficking. Herein, we introduce leucine-rich repeats (LRRs) and calponin homology containing 4 (Lrch4) as a novel TLR accessory protein. Lrch4 is a membrane protein with nine LRRs in its predicted ectodomain. It is widely expressed across murine tissues and has two expression variants that are both regulated by lipopolysaccharide (LPS). Predictive modeling indicates that Lrch4 LRRs conform to the horseshoe-shaped structure typical of LRRs in pathogen-recognition receptors and that the best structural match in the protein database is to the variable lymphocyte receptor of the jawless vertebrate hagfish. Silencing Lrch4 attenuates cytokine induction by LPS and multiple other TLR ligands and dampens the in vivo innate immune response. Lrch4 promotes proper docking of LPS in lipid raft membrane microdomains. We provide evidence that this is through regulation of lipid rafts as Lrch4 silencing reduces cell surface gangliosides, a metric of raft abundance, as well as expression and surface display of CD14, a raft-resident LPS co-receptor. Taken together, we identify Lrch4 as a broad-spanning regulator of the innate immune response and a potential molecular target in inflammatory disease.

A 33-Year-Old Woman With Altered Mental Status and Elevated Ammonia Level.

CASE PRESENTATION: A 33-year-old woman was brought to the ED with altered mental status. She was combative on presentation but spontaneously progressed into a comatose state and was intubated for airway protection. Naloxone failed to improve her mental status. When family was reached, they reported a history of seizures that were controlled on treatment.

Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome.

BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. RESULTS: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. CONCLUSIONS: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.

p53 Integrates host defense and cell fate during bacterial pneumonia.

Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-κB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.

Kinetics of in vivo proliferation and death of memory and naive CD8 T cells: parameter estimation based on 5-bromo-2'-deoxyuridine incorporation in spleen, lymph nodes, and bone marrow.

To study naive and memory CD8 T cell turnover, we performed BrdU incorporation experiments in adult thymectomized C57BL/6 mice and analyzed data in a mathematical framework. The following aspects were novel: 1) we examined the bone marrow, in addition to spleen and lymph nodes, and took into account the sum of cells contained in the three organs; 2) to describe both BrdU-labeling and -delabeling phase, we designed a general mathematical model, in which cell populations were distinguished based on the number of divisions; 3) to find parameters, we used the experimentally determined numbers of total and BrdU(+) cells and the BrdU-labeling coefficient. We treated mice with BrdU continuously via drinking water for up to 42 days, measured by flow cytometry BrdU incorporation at different times, and calculated the numbers of BrdU(+) naive (CD44(int/low)) and memory (CD44(high)) CD8 T cells. By fitting the model to data, we determined proliferation and death rates of both subsets. Rates were confirmed using independent sets of data, including the numbers of BrdU(+) cells at different times after BrdU withdrawal. We found that both doubling time and half-life of the memory population were approximately 9 wk, whereas for the naive subset the doubling time was almost 1 year and the half-life was roughly 7 wk. Our findings suggest that the higher turnover of memory CD8 T cells as compared with naive CD8 T cells is mostly attributable to a higher proliferation rate. Our results have implications for interpreting physiological and abnormal T cell kinetics in humans.

Bone marrow CD8 cells down-modulate membrane IL-7Ralpha expression and exhibit increased STAT-5 and p38 MAPK phosphorylation in the organ environment.

By comparing mature CD8-cell turnover in different organs, we previously demonstrated that CD8 cells proliferate predominantly in the bone marrow (BM). To investigate the mechanisms underlying such increased turnover, we compared BM, lymph nodes, and spleen CD8 cells from untreated C57BL/6 mice regarding in vivo proliferation within the organ; in vitro response to interleukin-7 (IL-7), IL-15, IL-21; ex vivo expression of membrane CD127 (IL-7Ralpha), intracellular Bcl-2, phospho-STAT-5 (signal transducer and activator of transcription 5), phospho-p38 mitogen activated protein kinase (MAPK); and in vivo proliferation on adoptive transfer. In the BM, the proliferation rate was increased for either total CD8 cells or individual CD44 and CD122 subsets. In contrast, purified CD8(+) cells from the BM did not show an enhanced in vitro proliferative response to IL-7, IL-15, and IL-21 compared with corresponding spleen cells. After transfer and polyinosinic-polycytidylic acid (polyI:C) treatment, both spleen-derived and BM-derived CD8 cells from congenic donors proliferated approximately twice more in the recipient BM than in spleen and lymph nodes. Our results suggest that BM CD8 cells are not committed to self-renewal, but rather are stimulated in the organ. Molecular events constantly induced in the CD8 cells within the BM of untreated mice include increase of both phosphorylated STAT-5 and phosphorylated p38 intracellular levels, and the reduction of CD127 membrane expression.

CD8 cell division maintaining cytotoxic memory occurs predominantly in the bone marrow.

Long-term persistence of Ag-experienced CD8 cells, a class of T lymphocytes with cytotoxic function, contributes to immunological memory against intracellular pathogens. After Ag clearance, memory CD8 cells are maintained over time by a slow proliferation, primarily cytokine driven. In this article, we show that the bone marrow (BM) is the crucial organ where such basal division of memory CD8 cells occurs. BM memory CD8 cells contain a higher percentage of proliferating cells than their corresponding cells in either spleen or lymph nodes from C57BL/6 mice. This occurs both in the case of memory-phenotype CD44(high) CD8 cells and in the case of Ag-specific memory CD8 cells. Importantly, the absolute number of Ag-specific memory CD8 cells dividing in the BM largely exceeds that in spleen, lymph nodes, liver, and lung taken together. In the BM, Ag-specific memory CD8 cells express lower levels of CD127, i.e., the alpha-chain of IL-7R, than in either spleen or lymph nodes. We interpret these results as indirect evidence that Ag-specific memory CD8 cells receive proliferative signals by IL-7 and/or IL-15 in the BM and propose that the BM acts as a saturable "niche" for the Ag-independent proliferation of memory CD8 cells. Taken together, our novel findings indicate that the BM plays a relevant role in the maintenance of cytotoxic T cell memory, in addition to its previously described involvement in long-term Ab responses.

Peptide profiling in epithelial tumor plasma by the emerging proteomic techniques.

The plasma peptide component (PPC) from ten melanoma (Mel), breast cancer (BC) and healthy individuals was examined by a combination of RP-HPLC, surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and tandem mass spectrometry. A three peak pattern (2023, 2039, 2053.5 m/z) was primarily observed in melanoma. Two peaks (2236.1 and of 2356.3 m/z) were found only in BC samples. Fibrinogen alpha and inter-alpha-trypsin inhibitor heavy chain H4 fragments were absent in both tumor samples.