Comparing Right-sided Colon Adenoma and Serrated Polyp Miss Rates with Water Exchange and CO2 Insufflation: A Randomized Controlled Trial.

INTRODUCTION: Postcolonoscopy colorectal cancers primarily occur in the right-sided colon because of missed adenomas and serrated polyps (SPs). Water exchange (WE) improves cleanliness and visibility of the right-sided colon. We hypothesized that WE could reduce the right-sided colon adenoma (rAMR) and SP miss rate (rSPMR) compared to standard colonoscopy. METHODS: We randomly assigned 386 colonoscopy patients to insertion with either WE or CO2 insufflation. During the first withdrawal, polypectomies were performed up to the hepatic flexure. A second endoscopist, blinded to the insertion technique, reexamined the right-sided colon. The miss rate was determined by dividing the number of additional adenomas or SPs by the total number detected in both examinations. The primary outcome was the combined rAMR and rSPMR. RESULTS: WE significantly decreased the combined rAMR and rSPMR (22.2% vs 32.2%, P < 0.001) and rSPMR alone (22.5% vs 37.1%, P = 0.002) compared to CO2 insufflation, but not rAMR (21.8% vs 29.8%, P = 0.079). Additionally, WE significantly increased the detection of SP per colonoscopy (SPPC) in the right-sided colon (0.95 ± 1.56 vs 0.50 ± 0.79, P < 0.001). Multivariate logistic regression analysis showed that ≥2 SPs in the right-sided colon was an independent predictor of rSPMR (odds ratio [OR], 3.47; 95% confidence interval [CI], 1.89─6.38), along with a higher right-sided colon Boston Bowel Preparation Scale score (OR, 0.55; 95% CI, 0.32─0.94). CONCLUSIONS: The significant reduction in rSPMR and increase in right-sided colon SPPC suggest that colonoscopy insertion using WE is a valid alternative to CO2 insufflation (Clinical trial registration number: NCT04124393).

Long term clinical outcomes of home parenteral nutrition in Singapore.

BACKGROUND AND OBJECTIVES: Home parenteral nutrition (HPN) is a life sustaining therapy for patients with chronic intestinal failure. Reported outcomes for Asian HPN patients are scarce. We aim to review the clinical outcomes of adult and paediatric HPN patients in our cohort which caters for 95% of Singaporean HPN patients. METHODS AND STUDY DESIGN: This is a retrospective review of HPN patients from an adult (2002-2017) and paediatric cohort (2011-2017) from the largest tertiary PN centres in Singapore. Patient demographics and clinical outcomes were reviewed. RESULTS: There were 41 adult and 8 paediatric HPN patients. Mean age was 53.0(±15.1) (adults) and 8(±1.8) years-old (paediatrics). Mean duration of HPN was 2.6(±3.5) and 3.5(±2.5) years. Leading indications for adult HPN were short bowel syndrome (SBS) (n=19,46.3%), mechanical obstruction (n=9,22.0%), and gastrointestinal dysmotility disorders (GID) (n=5,12.2%). Thirteen adult (31.7%) patients had underlying malignancy, with seven (17.3%) receiving palliative HPN. Indications for HPN amongst paediatric patients was GID (n=5,62.5%) and SBS (n=3,37.5%). Central line-associated bloodstream infection (CLABSI)/1000catheter-days was 1.0(±2.1) and 1.8(±1.3). Catheter associated venous thrombosis (CAVT)/1000catheter-days was 0.1(±0.4) and 0.7(±0.8). Biochemical Intestinal Failure Associated Liver Disease (IFALD) was found in 21.9% and 87.5%. For adults, median overall survival was 90-months (4.3,175.7,95%CI), with actuarial survival of 70.7%(1-year) and 39.0%(5-years). Median survival for adult patients with malignancy was 6-months (4.2,7.7,95%CI), actuarial survival of 85.7%(3-months) and 30.7%(1-year). One adult patient died from PN related complications. No paediatric deaths were noted. CONCLUSIONS: Whilst patient numbers were modest, we report comparable complication and survival rates to other international centres in both our adult and paediatric cohorts.

Intragastric injection of botulinum toxin A for weight loss: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Intragastric botulinum toxin A (BTA) injection is a potential treatment for weight reduction in obese patients. Current studies yielded conflicting results. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of intragastric BTA injection for weight management. METHODS: We searched several databases to identify RCTs evaluating intragastric BTA injections for obesity. We applied random-effects models for all meta-analyses due to heterogeneity in the included studies. The mean difference (MD) and 95% confidence interval (CI) were calculated for continuous outcomes. RESULTS: A total of 6 RCTs including 192 subjects met the inclusion criteria and were included for the meta-analysis. Although the pooled data from six studies showed no difference in the absolute weight loss between intragastric BTA injection and control, subgroup analysis showed a significantly decreased absolute weight after a BTA injection dose ≥ 200 U (MD, -2.04 kg; 95% CI, -3.96 to -0.12) and after multiple injection regions in the stomach combined with diet control (MD, -4.44 kg; 95% CI, -6.54 to -2.33 kg) compared with the control. Regarding absolute weight loss, the impact of endoscopic ultrasound-guided injection and follow-up duration showed no difference. Intragastric BTA injection had a significant change in body mass index (MD, -1.25 kg/m2 ; 95% CI, -2.18 to -0.32 kg/m2 ) and prolonged gastric half-emptying time (MD, 11.37 min; 95% CI, -3.69 to 19.06 min). CONCLUSION: Intragastric BTA injection is effective for obesity treatment, and adequate doses (≥ 200 U), multiple gastric injection regions, and combined diet control are crucial. However, given the small sample size and limited power, caution should be exercised.

Seizure from water intoxication following bowel preparation: a case report.

BACKGROUND: Bowel preparation prior to colonoscopic examination is generally considered a safe process. Hyponatremia is a complication that has been reported in literature during bowel preparation. Individuals who develop severe symptomatic hyponatremia are often older and have comorbidities such as hypothyroidism, chronic kidney disease, or adrenal insufficiency. However, other mechanisms and circumstances can also lead to this potentially fatal complication. CASE PRESENTATION: We present a unique case of a patient who developed seizure prior to colonoscopy due to acute hyponatremia without any well-known risk factors. With the subsequent diagnosis of water intoxication, the use of desmopressin was believed to have contributed to this serious complication. CONCLUSION: In addition to the use of certain well-documented medications and the presence of comorbidities that can lead to hyponatremia, clinicians should also be aware of the use of desmopressin as an important risk factor. Thorough history taking can guide individualized bowel preparation regimens to minimize the risk of undesired complications.

Mucormycosis causing massive lower gastrointestinal bleeding: a case report.

BACKGROUND: Lower gastrointestinal bleeding (LGIB) is very common in the hospital setting. Most bleedings stop spontaneously, but rare infectious causes of LGIB may lead to rapid and serious complications if left untreated and are sometimes very difficult to diagnose preoperatively. CASE PRESENTATION: We described a young man with poorly controlled Type I diabetes mellitus and chronic alcohol abuse who presented with acute altered mental status. During his hospitalization for treatment of diabetic ketoacidosis, acute renal failure, and sepsis, he suddenly developed massive hematochezia of 1500 mL. Colonoscopy was performed and a deep ulcer covered with mucus with peripheral elevation was noted at the transverse colon. Biopsy of the ulcer later revealed nonpigmented, wide (5-20 µm in diameter), thin-walled, ribbon-like hyphae with few septations and right-angle branching suggestive of mucormycosis demonstrated by Periodic acid-Schiff stain. He received 2 months of antifungal treatment. Follow up colonoscopy post-treatment was normal with no ulcer visualized. CONCLUSIONS: Early diagnosis and treatment of gastrointestinal (GI) mucormycosis infection is critical but can be challenging, especially in the setting of massive hematochezia. Therefore, clinical awareness for immunocompromised patients and prompt antifungal prophylaxis in cases with high suspicion of infection are essential.

Association between esophagogastric varices in hepatocellular carcinoma and poor prognosis after transarterial chemoembolization: A propensity score matching analysis.

BACKGROUND/PURPOSE: Whether esophagogastric varices (EGV) can determine the outcome of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) remains unknown. This study aimed to assess the impact of EGV on the prognosis of HCC patients after TACE. METHODS: From 2007 to 2012, we retrospectively enrolled 251 treatment-naïve HCC patients who underwent TACE and received esophagogastroduodenoscopy when HCC was diagnosed. The prognostic factors were analyzed using a Cox proportional hazards model and propensity score-matching analysis. RESULTS: There were 120 (47.8%) patients with EGV. Compared to those without EGV, patients with EGV had worse liver functional reserve. After a median follow-up of 14.7 months (25th-75th percentiles, 6.4-35.6 months), 152 patients died. The cumulative 5-year overall survival (OS) rates were 11.2% and 38.8% in patients with and without EGV, respectively (p < 0.001). Multivariate analysis showed that presence of EGV, presence of ascites, tumor size >5 cm, serum alpha-fetoprotein >20 ng/mL, progressive disease by modified Response Evaluation Criteria in Solid Tumors, Assessment for Retreatment with TACE score ≥2.5, and higher albumin-bilirubin grades were the independent predictors of poor OS. Subgroup analysis also demonstrated that EGV was associated with poor OS in most of the subgroups. After propensity score matching, the EGV group still had a lower OS rate than their counterparts (p = 0.004). CONCLUSION: HCC patients with EGV had worse liver functional reserve compared to those without EGV. Moreover, EGV was an independent risk factor to predict poor prognosis in patients with HCC after TACE.

Hypogammaglobulinemia and bacterial infections following pediatric post-transplant lymphoproliferative disorder in the rituximab era.

INTRODUCTION: Treatment of PTLD using immune-depleting agents such as RTX may be associated with increased risk of infections. The aim of this report was to describe the incidence of hypogammaglobulinemia and bacterial infections in children with PTLD after SOT at a single center since the introduction of RTX. METHODS: A retrospective review was conducted over a study period of 2000-2016 in pediatric patients diagnosed with biopsy-proven PTLD based on the WHO histologic criteria. Hypogammaglobulinemia was defined by serum IgG <4 g/L; CPBI was defined by clinically significant infection by an identified pathogenic bacteria isolated from a normally sterile body site. RESULTS: Twenty-eight patients were included, comprising 16 LTx and 12 ITx patients, and 17 patients received RTX therapy. Total of 31 episodes of CPBI occurred in 16 patients. Incidence of CPBI was 31.4 infections per 100 patient-years in RTX-treated patients, as compared to 8.4 infections per 100 patient-years in non-RTX-treated patients (P < 0.001). Hypogammaglobulinemia was significantly more prevalent after 6 months (P = 0.001) and 2 years (P = 0.005) in RTX-treated patients, as compared to none in the group that did not receive RTX. Hypogammaglobulinemia (P = 0.047), ITx (P = 0.027), and monomorphic PTLD (P = 0.024) were significantly associated with recurrent (≥2) CPBI and/or CPBI-related deaths within the first year post-PTLD. CONCLUSION: While RTX is an effective treatment for PTLD, hypogammaglobulinemia can persist for up to 2 years following RTX therapy, which may be associated with the higher cumulative rates of CPBI observed in RTX-treated patients.

Exclusive enteral nutrition with concomitant early thiopurine use was effective in maintaining steroid-free remission in a Southeast Asian cohort of children with Crohn's disease.

BACKGROUND: Exclusive enteral nutrition (EEN) is as effective as corticosteroids in inducing remission in children with Crohn's disease (CD). However, over 50% of these children relapse by 12 months of diagnosis. Thiopurines are commonly prescribed as maintenance therapy for CD, but evidence for its efficacy is controversial. Data on the effectiveness of EEN in Southeast Asian (SEA) children with CD is scarce. This study aims to evaluate the efficacy of EEN induction therapy in a cohort of SEA children with newly diagnosed CD. The secondary aim was to evaluate concomitant early azathioprine (EAZ) use in determining remission rate at 6 and 12 months. METHODS: Case records of all children with newly diagnosed CD from 2011 to 2014 were reviewed and relevant demographic as well as clinical data were extracted. The primary outcome measure was the number of patients who completed EEN induction therapy and achieved remission (Paediatric Crohn's Disease Activity Index; PCDAI≤10). Factors influencing duration of remission were evaluated in particular early azathioprine (EAZ) defined as starting azathioprine within one month of diagnosis versus late azathioprine (LAZ) use. RESULTS: Forty children with newly diagnosed CD were identified. Thirty-three children: 67% boys, median age 13y (range 3-17) completed 8 weeks of EEN induction therapy and 91% achieved remission. Significant improvements were seen in PCDAI scores (32.7 ± 9.2 to 4.2 ± 5.1; p < 0.001), mean BMI z-score (- 1.38 ± 1.57 to - 0.82 ± 1.27; p = 0.004) and baseline inflammatory markers: Erythrocyte Sedimentation Rate (51.6 ± 30.1 mm/h to 13.3 ± 7.1 mm/h; p < 0.0001) C-Reactive Protein (44.6 ± 51.0 mg/L to 5.2 ± 7.6 mg/L; p = 0.001), Albumin (30.7 ± 7.5 g/L to 38.7 ± 3.9 g/L; p < 0.0001), Platelets (464 ± 161 × 109 to 370 ± 111 × 109; p < 0.0001),. Early azathioprine initiation was associated with a remission rate of 80 and 73% at 6 and 12 months respectively. Remission was also maintained for longer duration in EAZ vs LAZ groups (p = 0.048). CONCLUSION: EEN effectively induces remission in this cohort of SEA children with newly diagnosed CD. Early initiation of thiopurine with EEN induction therapy is effective in maintaining steroid-free remission for at least one year.

Cytotoxic T-lymphocyte therapy for post-transplant lymphoproliferative disorder after solid organ transplantation in children.

EBV-CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV-CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third-party EBV-CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV-CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV-CTLs were derived from human leukocyte antigen-typed, EBV-seropositive third-party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV-CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12-144) and median post-transplant interval of 8 months (range: 2-107). Seven had monomorphic, two had polymorphic, and one had Hodgkin-type PTLD. All were of B-cell origin and EBV-positive on histology. EBV-CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft-versus-host disease or opportunistic infections. EBV-CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity.

Hepatocellular Carcinoma: Nomograms Based on the Albumin-Bilirubin Grade to Assess the Outcomes of Radiofrequency Ablation.

Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naïve patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10-year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, α-fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long-term survival data for patients with early-stage HCC who undergo RFA. © RSNA, 2017 Online supplemental material is available for this article.

The impact of clinically significant portal hypertension on the prognosis of patients with hepatocellular carcinoma after radiofrequency ablation: a propensity score matching analysis.

OBJECTIVES: To assess the impact of clinically significant portal hypertension (CSPH) on the prognosis of patients with hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). METHODS: We retrospectively enrolled 280 treatment-naïve early-stage HCC patients who had Child-Pugh grade A or B and received upper gastrointestinal endoscopy at the time of HCC diagnosis. CSPH was defined as (1) a platelet count < 100,000/mm3 associated with splenomegaly and/or (2) the presence of oesophageal/gastric varices by endoscopy. Factors determining poor overall survival and recurrence after RFA were analysed by Cox proportional hazards model and propensity score matching analysis. RESULTS: A total of 192 (68.6 %) patients had CSPH. The cumulative 5-year survival rates were 50.6 % and 76.7 % in patients with and without CSPH, respectively (p = 0.015). Based on multivariate analysis, age > 65 years (hazard ratio (HR) 1.740, p = 0.025), serum albumin levels ≤ 3.5 g/dL (HR 3.268, p < 0.001) and multiple tumours (HR 1.693, p = 0.046), but not CSPH, were independent risk factors associated with poor overall survival after RFA. Moreover, the overall survival rates were comparable between patients with and without CSPH after adjusting for confounding factors via propensity score matching analysis. CONCLUSIONS: CSPH was not associated with poor outcomes after RFA. KEY POINTS: • CSPH was common in HCC patients who underwent RFA therapy. • CSPH was not an independent risk factor in determining poor prognosis. • Serum albumin level was more important to determine the outcomes.

Silence of inositol 1,4,5-trisphosphate receptor expression decreases cyantraniliprole susceptibility in Bemisia tabaci.

Cyantraniliprole is the second active ingredient of anthranilic diamide insecticide, and the first to control a cross-spectrum of chewing and sucking pests such as sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). The inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are two families of Ca2+ release channels to raise the cytoplasmic free calcium concentration when it is activated by various extracellular stimuli. Previous study proved the over-expression of ryanodine receptor (RyR) was associated with the resistance to diamide insecticides, while the roles of IP3R in diamide resistance remain unknown. In this study, a full-length cDNA sequence of IP3R was cloned from B. tabaci through RT-PCR and rapid amplification of cDNA ends (RACE). The gene (named BtIP3R) is 9922bps long, with an open reading frame (ORF) of 8202bps, encoding a predicted IP3R of 2733 amino acids. The BtIP3R shares 47-78% identity with other insect IP3Rs. Quantitative real-time PCR (qRT-PCR) analysis showed that the BtIP3R was highly expressed in larva, pseudopupa, and female adult, while lowly expressed in egg and male adult. RNA interference (RNAi) by dietary introduction of double-stranded RNA (dsRNA) of BtIP3R significantly reduced the mRNA levels of the target gene in the adult, and dramatically decreased the susceptibility of adult B. tabaci to cyantraniliprole. The results shed light on further understanding of cyantraniliprole resistance mechanisms in B. tabaci as well as in other insects.

Reduction of CD200 expression in glioma cells enhances microglia activation and tumor growth.

CD200, a type I transmembrane glycoprotein, can interact with its receptor CD200R, which plays an inhibitory role in the activation of microglia-the resident macrophages of the central nervous system. In this study, the rat C6 glioma cell line (C6-1) that was previously characterized with high in vivo tumorigenicity was found to generate CD200 mRNA abundantly. However, CD200 expression was barely detected in another C6 glioma cell clone (C6-2) that was previously found to display low tumorigenic behavior. The results from CD200 immunohistochemistry on human glioma tissue array also showed that tumor cells in Grade I-II astrocytoma expressed a lower level of CD200 immunoreactivity than those detected in Grade III-IV glioblastoma multiforme. C6-1 transfectants with stable downregulation of CD200 gene expression using lentivirus knockdown approach were generated (C6-KD). Microglia and iNOS+ cells were increased when microglia were co-cultured with C6-KD cells. The colony formation of C6-KD was also augmented when those cells were co-cultured with microglia. Yet, increased colony formation of C6-KD transfectants in the co-culture with microglia was effectively suppressed by interleukin (IL)-4 and IL-10. The in vivo results indicated that the tumor formation of C6-1 cells in rat brain was promoted after CD200 gene knockdown. Moreover, CD11b+ activated microglia and iNOS+ microglia were highly accumulated in the tumor site formed by C6-KD. In conclusion, our findings demonstrate that the downregulation of CD200 expression in CD200-rich glioma cells could foster the formation of an activated microglia-associated tumor microenvironment, leading to glioma progression. © 2016 Wiley Periodicals, Inc.

Colchicine derivative as a potential anti-glioma compound.

Colchicine, an anti-microtubule and antimitotic drug, is a common therapeutically agent for gout, which is thought to have potential anti-tumor effects. Owing to concerns of colchicines poisoning, the development of derivatives with low dose efficacy and less side effects is of obvious interest. In this study, we characterized the inhibitory effects of a colchicine derivative named AD1 on the cell proliferation of human malignant glioblastoma (MG) cell lines, U87MG and U373MG. We found that 50 % of U87MG and U373MG cells were reduced in the cultures after exposure to AD1 for 24 h at 10 and 50 nM, respectively. Moreover, α-tubulin immunostaining indicated that AD1 induced the disruption of the microtubule polymerization in glioma cells with apoptotic features including membrane budding/blebbing or fragmented nuclei. Increased levels of reactive oxygen species (ROS) were also detected in AD1-treated U87MG and U373MG cells compared to that observed in the control culture. Moreover, examination of microtubule-associated protein 1A/1B-light chain 3 (LC3I)/LC3II conversion and acridine orange staining for autophagic vesicles, combined with flow cytometry, showed that treatment with AD1 induced the autophagic pathway in U87MG and U373MG cells. Furthermore, we found that the intermittent intravenous administration of AD1 suppressed glioma growth in rat brain receiving intracerebral injection with rat C6 glioma cells. Taken together, our findings reveal that treatment with AD1 at nanomolar scales can reduce glioma cell viability effectively, with the occurrence of a rise in ROS and cellular autophagy. In conjunction with the observations from in vivo study, the colchicine derivative AD1 has chemotherapeutic potential to suppress glioma progression.

Activation of VCAM-1 and its associated molecule CD44 leads to increased malignant potential of breast cancer cells.

VCAM-1 (CD106), a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4ß1). In the present study, we observed that VCAM-1 expression can be induced in many breast cancer epithelial cells by cytokine stimulation in vitro and its up-regulation directly correlated with advanced clinical breast cancer stage. We found that VCAM-1 over-expression in the NMuMG breast epithelial cells controls the epithelial and mesenchymal transition (EMT) program to increase cell motility rates and promote chemoresistance to doxorubicin and cisplatin in vitro. Conversely, in the established MDAMB231 metastatic breast cancer cell line, we confirmed that knockdown of endogenous VCAM-1 expression reduced cell proliferation and inhibited TGFß1 or IL-6 mediated cell migration, and increased chemosensitivity. Furthermore, we demonstrated that knockdown of endogenous VCAM-1 expression in MDAMB231 cells reduced tumor formation in a SCID xenograft mouse model. Signaling studies showed that VCAM-1 physically associates with CD44 and enhances CD44 and ABCG2 expression. Our findings uncover the possible mechanism of VCAM-1 activation facilitating breast cancer progression, and suggest that targeting VCAM-1 is an attractive strategy for therapeutic intervention.

Earthworms-enhanced bacterial degradation of the chiral fungicide penflufen R-enantiomer.

The widespread application of chiral fungicides as seed-coating agents in agriculture has led to serious residue accumulation in soil, increasingly drawing attention to soil pollution remediation strategies for chiral pesticides. This study explored the role of earthworms and soil microorganisms in selectively accelerating the degradation of penflufen in soil. The results showed that soil microorganisms significantly accelerated penflufen enantiomer degradation, particularly the R-enantiomer. Nocardioides, Variovorax, Arthrobacter, and Pseudomonas were identified as key degrading microorganisms associated with the preferential degradation of the R-enantiomer. The addition of earthworms further significantly enhanced the preferential degradation of the R-enantiomer. Importantly, earthworms markedly promoted the growth and reproduction of the four aforementioned degrading microorganisms in soil treated with enantiomers. Notably, the relative abundance of these degrading microorganisms was significantly higher in R-enantiomer-treated soil with earthworms than in soil treated with the S-enantiomer. Additionally, earthworms significantly increased the relative abundance of degradation genes p450, bphA1, and benA in the soil, especially in the R-enantiomer treated soil. Nocardioides, Variovorax, Arthrobacter, and Pseudomonas were identified as potential hosts for the degradation gene benA. More importantly, twelve strains of penflufen-degrading bacteria were isolated from the treated soil, of which eight belonged to the aforementioned four microorganisms and exhibited a remarkable ability to preferentially degrade the R-enantiomer. This finding highlights the potential of adding earthworms to soil, in conjunction with key degrading microorganisms, which preferentially accelerates penflufen R-enantiomer degradation.

Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice.

Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.

Clinical profile, referral trends, and real-world application of vibration-controlled transient elastography in children with non-alcoholic fatty liver disease in Singapore.

Background and Aim: Pediatric non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that is increasing in incidence globally. The study aims to describe the clinical profile and longitudinal outcome, including the utility of vibration-controlled transient elastography (VCTE), in children with NAFLD at a single tertiary liver unit in Singapore. Methods: Retrospective review of patients aged 0-18 years referred for NAFLD from 2003 to 2020 was conducted. Diagnosis was based on persistent elevation of alanine transaminase ≥2× the upper limit of normal in at-risk patients, and/or radiologic detection of hepatic steatosis, with the exclusion of other etiologies. VCTE-derived liver stiffness measurements (LSMs) ≤7.0 , 7.1-9.0, and ≥9.1 kPa were used to differentiate normal (F0-F1), significant fibrosis (F2), and advanced fibrosis (F3-F4), respectively. Results: The study included 210 patients (72.4% male, mean age 11.6 years). New cases increased from 1.7/1000 referrals in 2003-2008 to 12.7 and 24.5/1000 referrals in 2009-2014 and 2015-2020, respectively. Significant proportion had dyslipidemia (41.4%), impaired glucose tolerance/diabetes (IGT/DM, 26.7%), and hypertension (17.1%). Only 6.2% had resolution of NAFLD after a mean follow-up of 3.7 years. Based on VCTE (n = 65), 41.5% had normal LSM, while 26.2% and 32.3% had increased likelihood of significant and advanced fibrosis, respectively. Age ≥16 years (odds ratio [OR] 8.9), IGT/DM (OR 6.5), and aspartate transaminase >70 U/L (OR 11.0) were independent risk factors associated with increased likelihood of advanced fibrosis. Conclusion: Incidence of pediatric NAFLD has increased dramatically in Singapore. Based on LSM estimation, pediatric NAFLD may be associated with an increased risk of developing advanced fibrosis by late adolescence.

Haemostatic spray in the management of acute nonvariceal upper gastrointestinal bleeding in children: A single-centre experience in Singapore.

Introduction/Objectives: Haemostatic spray (HS; Hemospray) is a powder agent for endoscopic haemostasis in patients with acute upper gastrointestinal bleeding (UGIB). It has been shown to be effective and easy to administer. However, published data on efficacy and safety in children remain scarce. Our aim was to describe our experience with the use of HS in the management of UGIB. Patients and Methods: A retrospective review was conducted of patients aged 0-18 receiving HS for endoscopic haemostasis from January 2017 to December 2021. Information was obtained on demographics, clinical presentation and comorbidities. Outcomes were successful initial haemostasis and rates of re-bleeding. Results: A total of 25 applications of HS occurred in 23 patients. The median patient age was 8 years (range: 4 months to 16 years). HS was used in 17/25 (68%) applications as monotherapy. Other treatments employed were clip application and adrenaline injection. One hundred per cent initial haemostasis was achieved with three (13.0%) patients who experienced re-bleeding. All patients tolerated HS applications with no adverse events. Conclusions: Our finding supports the use of HS in the management of UGIB in children. HS, either as monotherapy or in combination with other conventional therapy, could potentially be the treatment of choice in children with UGIB with its excellent feasibility and good safety profile.

To B(enign) or Not to B: functionalisation of variant in a mild form of argininosuccinate lyase deficiency identified through newborn screening.

Argininosuccinate lyase (ASL) deficiency is an autosomal recessive disorder of the urea cycle with a diverse spectrum of clinical presentation that is detectable in newborn screening. We report an 8-year-old girl with ASL deficiency who was detected through newborn screening and was confirmed using biochemical and functional assay. She is compound heterozygous for a likely pathogenic variant NM_000048.4(ASL):c.283C>T (p.Arg95Cys) and a likely benign variant NM_000048.4(ASL): c.1319T>C (p.Leu440Pro). Functional characterisation of the likely benign genetic variant in ASL was performed. Genomic sequencing was performed on the index patient presenting with non-specific symptoms of poor feeding and lethargy and shown to have increased serum and urine argininosuccinic acid. Functional assay using HEK293T cell model was performed. ASL enzymatic activity was reduced for Leu440Pro. This study highlights the role of functional testing of a variant that may appear benign in a patient with a phenotype consistent with ASL deficiency, and reclassifies NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) variant as likely pathogenic.