Dye Chromoendoscopy Outperforms High-Definition White Light Endoscopy in Dysplasia Detection for Patients With Inflammatory Bowel Disease: An Updated Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Whether dye spray chromoendoscopy (DCE) adds value in surveillance colonoscopy with high-definition (HD) scopes remains controversial. This updated meta-analysis compares dysplasia detection using DCE and high-definition white light endoscopy (HD-WLE) in patients with inflammatory bowel disease (IBD) undergoing surveillance colonoscopy. METHODS: A comprehensive search was performed for randomized controlled trials (RCT) comparing HD-WLE and DCE in patients with IBD. The primary outcome was to compare the proportion of patients with at least 1 dysplastic lesion detected by DCE vs HD-WLE. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using the random-effects model, with I2 > 60% indicating substantial heterogeneity. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to assess the certainty of evidence (CoE). RESULTS: Six RCT involving 978 patients were analyzed (DCE = 479 vs HD-WLE = 499 patients). DCE detected significantly more patients with dysplasia than HD-WLE (18.8% vs 9.4%), OR 1.94 (95% CI 1.21-3.11, I2 = 28%, P = 0.006, high CoE). This remained significant after excluding 2 RCT published as abstracts. A sensitivity analysis excluding a noninferiority RCT with a single experienced operator eliminated the results' heterogeneity, OR 2.46 (95% CI 1.56-3.90, I2 = 0%). Although high-grade dysplasia detection was numerically higher in the DCE group (2.8% vs 1.1%), the difference was statistically insignificant, OR 2.21 (95% CI 0.64-7.62, I2 = 0%, low CoE). DISCUSSION: Our updated meta-analysis supports DCE as a superior strategy in overall dysplasia detection in IBD, even with HD scopes. When expertise is available, DCE should be considered for surveillance colonoscopy in patients with high-risk IBD, with the acknowledgment that virtual chromoendoscopy shows equivalence in recent studies. Further multicenter trials with multiple endoscopists with varying expertise levels and longer-term outcome data showing a reduction in cancer or cancer-related death are needed.

A new oxidative pathway of nitric oxide production from oximes in plants.

Nitric oxide (NO) is an essential reactive oxygen species and a signal molecule in plants. Although several studies have proposed the occurrence of oxidative NO production, only reductive routes for NO production, such as the nitrate (NO-3) -upper-reductase pathway, have been evidenced to date in land plants. However, plants grown axenically with ammonium as the sole source of nitrogen exhibit contents of nitrite and NO3-, evidencing the existence of a metabolic pathway for oxidative production of NO. We hypothesized that oximes, such as indole-3-acetaldoxime (IAOx), a precursor to indole-3-acetic acid, are intermediate oxidation products in NO synthesis. We detected the production of NO from IAOx and other oximes catalyzed by peroxidase (POD) enzyme using both 4-amino-5-methylamino-2',7'-difluorescein fluorescence and chemiluminescence. Flavins stimulated the reaction, while superoxide dismutase inhibited it. Interestingly, mouse NO synthase can also use IAOx to produce NO at a lower rate than POD. We provided a full mechanism for POD-dependent NO production from IAOx consistent with the experimental data and supported by density functional theory calculations. We showed that the addition of IAOx to extracts from Medicago truncatula increased the in vitro production of NO, while in vivo supplementation of IAOx and other oximes increased the number of lateral roots, as shown for NO donors, and a more than 10-fold increase in IAOx dehydratase expression. Furthermore, we found that in vivo supplementation of IAOx increased NO production in Arabidopsis thaliana wild-type plants, while prx33-34 mutant plants, defective in POD33-34, had reduced production. Our data show that the release of NO by IAOx, as well as its auxinic effect, explain the superroot phenotype. Collectively, our study reveals that plants produce NO utilizing diverse molecules such as oximes, POD, and flavins, which are widely distributed in the plant kingdom, thus introducing a long-awaited oxidative pathway to NO production in plants. This knowledge has essential implications for understanding signaling in biological systems.

Drug-Induced Acute Pancreatitis: An Evidence-Based Classification (Revised).

INTRODUCTION: Drug induced acute pancreatitis is a difficult diagnosis for clinicians. We previously published an "Evidence-Based Classification System" on Drug-Induced Acute Pancreatitis widely used by clinicians to assist in the identification of drugs. Unfortunately, this prior analysis based only on published case reports has been misunderstood. The prior review did not include studies with higher evidentiary value, such as randomized trials, case-control studies, and/or pharmacoepidemiologic studies. The use of the prior classification system has led to many patients being inappropriately labeled as having drug-induced acute pancreatitis. We now propose a "Revised" Evidence- Based Classification System for the purpose of determining which drugs cause acute pancreatitis based on the Grading of Recommendations, Development, and Evaluation criteria. METHODS: A search of the English Language literature was performed to identify all case reports with medication and/or drug induced acute pancreatitis. We divided the drugs implicated as causing acute pancreatitis into four groups based on the quality of evidence as defined by GRADE quality parameters. RESULTS: Although 141 drugs were identified in the literature as causing acute pancreatitis, only 106 drugs published in the literature as causing acute pancreatitis were high quality case reports. Only 3 drugs had evidence as causing acute pancreatitis from randomized controlled clinical trials, including 6-mercaptopurine and azathioprine. DISCUSSION: The vast majority of drugs implicated as causing acute pancreatitis in the literature have low or very low quality of evidence supporting those claims.

Interaction of ammonium nutrition with essential mineral cations.

Plant growth and development depend on sufficient nutrient availability in soils. Agricultural soils are generally nitrogen (N) deficient, and thus soils need to be supplemented with fertilizers. Ammonium (NH4+) is a major inorganic N source. However, at high concentrations, NH4+ becomes a stressor that inhibits plant growth. The cause of NH4+ stress or toxicity is multifactorial, but the interaction of NH4+ with other nutrients is among the main determinants of plants' sensitivity towards high NH4+ supply. In addition, NH4+ uptake and assimilation provoke the acidification of the cell external medium (apoplast/rhizosphere), which has a clear impact on nutrient availability. This review summarizes current knowledge, at both the physiological and the molecular level, of the interaction of NH4+ nutrition with essential mineral elements that are absorbed as cations, both macronutrients (K+, Ca2+, Mg2+) and micronutrients (Fe2+/3+, Mn2+, Cu+/2+, Zn2+, Ni2+). We hypothesize that considering these nutritional interactions, and soil pH, when formulating fertilizers may be key in order to boost the use of NH4+-based fertilizers, which have less environmental impact compared with nitrate-based ones. In addition, we are convinced that better understanding of these interactions will help to identify novel targets with the potential to improve crop productivity.

Choledocholithiasis Can Present with Marked Transaminases Elevation: Systematic Review and Meta-Analysis.

BACKGROUND: Extreme transaminase elevation > 1000 international units per liter (IU/L) is typically caused by hepatocellular injury due to ischemia, drugs, or viral infection. Acute choledocholithiasis can also present with marked transaminase elevation mimicking severe hepatocellular injury, contrary to the presumed cholestatic pattern. METHODS: We searched PubMed/Medline, EMBASE, Cochrane Library, and Google Scholar for studies reporting the proportion of marked elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1000 IU/L in patients with common bile duct (CBD) stones. A proportion meta-analysis with a corresponding 95% confidence interval (CI) was used to pool the proportion of patients with extreme transaminase elevation. I2 was used to examine heterogeneity. We used CMA software utilizing a random effect model for statistical analysis. RESULTS: Three studies (n = 1328 patients) were included in our analysis. The reported frequency of ALT or AST > 1000 IU/L in choledocholithiasis patients ranged between 6 and 9.6%, with pooled frequency of 7.8% (95% CI 5.5-10.8%, I2 61%). The frequency of patients with ALT or AST > 500 IU/L was higher, ranging between 28 and 47%, with pooled frequency of 33.1% (95% CI 25.3-42%, I2 88%). CONCLUSION: This is the first meta-analysis to study prevalence of severe hepatocellular injury in patients with CBD stones. Results revealed that approximately one-third of patients with choledocholithiasis present with ALT or AST > 500 IU/L. Furthermore, levels > 1000 IU/L are not uncommon. An elaborate work-up for alternative etiologies of severe transaminase elevation is likely unwarranted in cases with clear evidence of choledocholithiasis.

Etiologies and Outcomes of Transaminase Elevation > 1000 IU/L: A Systematic Review and Meta-Analysis.

BACKGROUND: Among liver injury causes, few result in marked elevation of liver enzymes to a level > 1,000 international units per liter (IU/L). This review summarizes common etiologies of marked transaminase elevation and associated prognostic factors. METHODS: We performed a comprehensive search on PubMed, EMBASE, Cochrane Library, and Google Scholar from inception through December 2022 using MOOSE guidelines for studies reporting frequency of etiologies of marked transaminase elevation. We used a proportion meta-analysis to pool frequencies with corresponding 95% confidence interval (CI). I2 was used to adjudicate heterogeneity. We used CMA software for statistical analysis. RESULTS: Seven relevant studies (n = 1608 patients) were included. The pooled frequency of ischemic hepatitis was 51% (95% CI 42-60%, I2 = 91%), viral hepatitis was 13.1% (95% CI 9.7-17.6%, I2 = 80%), toxins or drug-induced liver injury (DILI) was 13% (95% CI 8-18%, I2 = 85%), and pancreaticobiliary-related injury was 7.8% (95% CI 4.4-13.6%, I2 = 89%). Mortality was significantly higher in ischemic hepatitis versus other causes of marked transaminase elevation, with an odds ratio of 21 (95% CI 9.9-44.8, P value < 0.0001, I2 = 64% Q 11.1). DISCUSSION: This is the first meta-analysis to examine etiologies of marked transaminase elevation > 1000 IU/L. Liver ischemia is the most common cause, while other causes include DILI or toxins, viral hepatitis, and biliary pathologies. We found biliary pathologies to be the fourth most common cause. This is clinically relevant as it has been traditionally linked to a cholestatic pattern of liver injury. Being aware of this presentation may help prevent delayed or missed diagnoses and unnecessary testing.

Oxygenator impact on peramivir in extra-corporeal membrane oxygenation circuits.

INTRODUCTION: This study aims to determine the oxygenator impact on alterations of peramivir (PRV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra-corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. METHODS: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of PRV was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5-min and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-h time points. PRV was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS: For the 1/4-in. circuit with an oxygenator, there was < 15% PRV loss, and for the 1/4-in. circuit without an oxygenator, there was < 3% PRV loss during the study period. For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss, and for the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. CONCLUSION: There was no significant PRV loss over the 24-h study period in either the 1/4-in. or 3/8-in circuit, regardless of the presence of the oxygenator. The concentrations obtained pre- and post-oxygenator appeared to approximate each other, suggesting there may be no drug loss via the oxygenator. This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings.

Gastrointestinal histopathology of acute colchicine toxicity after lower dose treatment of pericarditis: A case report.

Colchicine is an anti-inflammatory alkaloid drug with anti-microtubule activity. Colchicine toxicity is a serious and potentially fatal complication associated with hallmark histopathological features most conspicuous in proliferative tissues such as the gastrointestinal tract. These features have only been reported in patients treated with high doses. We report a patient who experienced acute colchicine toxicity with gastrointestinal histologic changes after treatment with the lowest dose of colchicine. Knowledge of drug-drug interactions and the organs involved in colchicine metabolism is imperative when using colchicine, even when administered at its lowest dose.

Impaired cell growth under ammonium stress explained by modeling the energy cost of vacuole expansion in tomato leaves.

Ammonium (NH4 + )-based fertilization efficiently mitigates the adverse effects of nitrogen fertilization on the environment. However, high concentrations of soil NH4 + provoke growth inhibition, partly caused by the reduction of cell enlargement and associated with modifications of cell composition, such as an increase of sugars and a decrease in organic acids. Cell expansion depends largely on the osmotic-driven enlargement of the vacuole. However, the involvement of subcellular compartmentation in the adaptation of plants to ammonium nutrition has received little attention, until now. To investigate this, tomato (Solanum lycopersicum) plants were cultivated under nitrate and ammonium nutrition and the fourth leaf was harvested at seven developmental stages. The vacuolar expansion was monitored and metabolites and inorganic ion contents, together with intracellular pH, were determined. A data-constrained model was constructed to estimate subcellular concentrations of major metabolites and ions. It was first validated at the three latter developmental stages by comparison with subcellular concentrations obtained experimentally using non-aqueous fractionation. Then, the model was used to estimate the subcellular concentrations at the seven developmental stages and the net vacuolar uptake of solutes along the developmental series. Our results showed ammonium nutrition provokes an acidification of the vacuole and a reduction in the flux of solutes into the vacuoles. Overall, analysis of the subcellular compartmentation reveals a mechanism behind leaf growth inhibition under ammonium stress linked to the higher energy cost of vacuole expansion, as a result of alterations in pH, the inhibition of glycolysis routes and the depletion of organic acids.

Treat-to-Target: The Era of Targeted Immunosuppressive Agents in IBD Management.

With the advent of biologic agents, the treatment of patients with Inflammatory Bowel Diseases (IBD) has changed from managing symptoms to achieving remission of disease. Disease remission is associated with better outcomes than symptomatic care alone. The Treat-to-Target paradigm provides targets that serve as surrogates for achieving disease remission. The most important target is endoscopic mucosal healing and other targets include symptomatic response, symptomatic remission, biomarker normalization, and normalization of patient's quality of life. Targets are reached via utilization of biologic medications that may be modified or substituted as goals are not met. IBD Qorus represents a national collaborative of academic IBD centers and private gastroenterology practices using the Treat-to-Target approach and patient-centered communication methods to provide better care for all patient's suffering from IBD.

Endoscopic Treatment of Reflux: A Comprehensive Review.

The last decade has seen the rise of multiple novel endoscopic techniques to treat gastroesophageal reflux disease, many of which are efficacious when compared with traditional surgical options and allow relief from long-term dependence on antacid medications. This review will explore the latest endoscopic treatment options for gastroesophageal reflux disease including a description of the technique, review of efficacy and safety, and future directions.

Knock-down of phosphoenolpyruvate carboxylase 3 negatively impacts growth, productivity, and responses to salt stress in sorghum (Sorghum bicolor L.).

Phosphoenolpyruvate carboxylase (PEPC) is a carboxylating enzyme with important roles in plant metabolism. Most studies in C4 plants have focused on photosynthetic PEPC, but less is known about non-photosynthetic PEPC isozymes, especially with respect to their physiological functions. In this work, we analyzed the precise roles of the sorghum (Sorghum bicolor) PPC3 isozyme by the use of knock-down lines with the SbPPC3 gene silenced (Ppc3 lines). Ppc3 plants showed reduced stomatal conductance and plant size, a delay in flowering time, and reduced seed production. In addition, silenced plants accumulated stress indicators such as Asn, citrate, malate, and sucrose in roots and showed higher citrate synthase activity, even in control conditions. Salinity further affected stomatal conductance and yield and had a deeper impact on central metabolism in silenced plants compared to wild type, more notably in roots, with Ppc3 plants showing higher nitrate reductase and NADH-glutamate synthase activity in roots and the accumulation of molecules with a higher N/C ratio. Taken together, our results show that although SbPPC3 is predominantly a root protein, its absence causes deep changes in plant physiology and metabolism in roots and leaves, negatively affecting maximal stomatal opening, growth, productivity, and stress responses in sorghum plants. The consequences of SbPPC3 silencing suggest that this protein, and maybe orthologs in other plants, could be an important target to improve plant growth, productivity, and resistance to salt stress and other stresses where non-photosynthetic PEPCs may be implicated.

Is plastidic glutamine synthetase essential for C3 plants? A tale of photorespiratory mutants, ammonium tolerance and conifers.

Agriculture faces the considerable challenge of having to adapt to a progressively changing climate (including the increase in CO2 levels and temperatures); environmental impact must be reduced while at the same time crop yields need to be maintained or increased to ensure food security. Under this scenario, increasing plants' nitrogen (N) use efficiency and minimizing the energy losses associated with photorespiration are two goals of crop breeding that are long sought after. The plastidic glutamine synthetase (GS2) enzyme stands at the crossroads of N assimilation and photorespiration, and is therefore a key candidate for the improvement of crop performance. The GS2 enzyme has long been considered essential for angiosperm survival under photorespiratory conditions. Surprisingly, in Arabidopsis GS2 is not essential for plant survival, and its absence confers tolerance towards ammonium stress, which is in conflict with the idea that NH4+ accumulation is one of the main causes of ammonium stress. Altogether, it appears that the 'textbook' view of this enzyme must be revisited, especially regarding the degree to which it is essential for plant growth under photorespiratory conditions, and the role of NH4+ assimilation during ammonium stress. In this article we open the debate on whether more or less GS2 is a desirable trait for plant productivity.

Ammonium nutrition interacts with iron homeostasis in Brachypodium distachyon.

Most plant species develop stress symptoms when exposed to high ammonium (NH4+) concentrations. The root is the first organ in contact with high NH4+ and therefore the first barrier to cope with ammonium stress. In this work, we focused on root adaptation to ammonium nutrition in the model plant Brachypodium distachyon. Proteome analysis revealed changes associated with primary metabolism, cell wall remodelling, and redox homeostasis. In addition, it showed a strong induction of proteins related to methionine (Met) metabolism and phytosiderophore (PS) synthesis in ammonium-fed plants. In agreement with this, we show how ammonium nutrition impacts Met/S-adenosyl-Met and PS metabolic pathways together with increasing root iron content. Nevertheless, ammonium-fed plants displayed higher sensitivity to iron deficiency, suggesting that ammonium nutrition triggers impaired iron utilization and root to shoot transport, which entailed an induction in iron-related responses. Overall, this work demonstrates the importance of iron homeostasis during ammonium nutrition and paves a new way to better understand and improve ammonium use efficiency and tolerance.

Per Oral Endoscopic Myotomy for Zenker's Diverticulum: A Novel and Superior Technique Compared With Septotomy?

INTRODUCTION: Endoscopic management of Zenker diverticuli (ZD) has traditionally been via septotomy technique. The recent development of tunneling technique has shown to be both efficacious and safe. The aim of this study is to evaluate the tunneling technique using per oral endoscopic myotomy (Z-POEM) versus septotomy. METHODS: Patients who underwent endoscopic management of ZD either by Z-POEM or septotomy from March 2017 until November 2020 from 9 international academic centers were included. Demographics, clinical data preprocedure and postprocedure, procedure time, adverse events, and hospital length of stay were analyzed. RESULTS: A total of 101 patients (mean age 74.9 y old, 55.4% male) were included: septotomy (n=49), Z-POEM (n=52). Preprocedure Functional Oral Intake Scale score and Eckardt score was 5.3 and 5.4 for the septotomy group and 5.9 and 5.15 for the Z-POEM group. Technical success was achieved in 98% of the Z-POEM group and 100% of the septotomy group. Clinical success was achieved in 84% and 92% in the septotomy versus Z-POEM groups. Adverse events occurred in 30.6% (n=15) in septotomy group versus 9.6% (n=5) in the Z-POEM group (P=0.017). Reintervention for ongoing symptoms occurred in 7 patients in the septotomy group and 3 patients in the Z-POEM group. Mean hospital length of stay was shorter for the Z-POEM group, at 1.5 versus 1.9 days. CONCLUSIONS: A tunneling technique via the Z-POEM procedure is an efficacious and safe endoscopic treatment for ZD. Z-POEM is a safer procedure with a statistically significant reduction in adverse events compared with traditional septotomy technique.

Oxygenator impact on meropenem/vaborbactam in extracorporeal membrane oxygenation circuits.

INTRODUCTION: To determine the oxygenator impact on alterations of meropenem (MEM)/vaborbactam (VBR) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. METHODS: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of MEM/VBR was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour time points. MEM/VBR was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS: For the 1/4-inch circuit, there was an approximate mean 55% MEM loss with the oxygenator in series and a mean 33%-40% MEM loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean 70% MEM loss with the oxygenator in series and a mean 30%-38% MEM loss without an oxygenator in series at 24 hours. For both the 1/4-inch circuit and 3/8-inch circuits with and without an oxygenator, there was <10% VBR loss for the duration of the experiment. CONCLUSIONS: This ex-vivo investigation demonstrated substantial MEM loss within an ECMO circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant VBR loss. Further evaluations with multiple dose in-vitro and in-vivo investigations are needed before specific MEM/VBR dosing recommendations can be made for clinical application with ECMO.

Combined renal proximal tubulopathy and crystal storing histiocytosis in a patient with κ light chain multiple myeloma.

Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the presence of a serum monoclonal spike (M-spike) of more than 3 g/dL or more than 10% clonal plasma cells in the bone marrow and at least one myeloma-defining event, such as hypercalcemia, anemia, bone lesions, or renal impairment. The kidney is a major target organ, and renal impairment is frequently the first manifestation of the disease. Renal damage occurs in up to 40% of patients and 10-20% will require dialysis. Monoclonal immunoglobulin light chains are the major causes of renal complications in multiple myeloma. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease, AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components, are constituted by light chain cast nephropathy, light chain proximal tubulopathy, and crystal-storing histiocytosis.We report the case of a 66-year-old woman who presented with albumin-predominant moderate proteinuria and renal failure. Serum and urine immunofixation electrophoresis showed monoclonal κ light chain in both. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving proximal tubular epithelial cells and crystal storing histiocytosis. Multiple myeloma with crystal storing histiocytosis was discovered in bone marrow biopsy. Thus, we present an unusual case of a myeloma patient presenting light chain proximal tubulopathy and crystal-storing histiocytosis both in the kidney and in the bone marrow.