Low Mass Blood Peptides Discriminative of Inflammatory Bowel Disease (IBD) Severity: A Quantitative Proteomic Perspective.

Breakdown of the protective gut barrier releases effector molecules and degradation products into the blood stream making serum and plasma ideal as a diagnostic medium. The enriched low mass proteome is unexplored as a source of differentiators for diagnosing and monitoring inflammatory bowel disease (IBD) activity, that is less invasive than colonoscopy. Differences in the enriched low mass plasma proteome (<25 kDa) were assessed by label-free quantitative mass-spectrometry. A panel of marker candidates were progressed to validation phase and "Tier-2" FDA-level validated quantitative assay. Proteins important in maintaining gut barrier function and homeostasis at the epithelial interface have been quantitated by multiple reaction monitoring in plasma and serum including both inflammatory; rheumatoid arthritis controls, and non-inflammatory healthy controls; ulcerative colitis (UC), and Crohn's disease (CD) patients. Detection by immunoblot confirmed presence at the protein level in plasma. Correlation analysis and receiver operator characteristics were used to report the sensitivity and specificity. Peptides differentiating controls from IBD originate from secreted phosphoprotein 24 (SPP24, p = 0.000086, 0.009); whereas those in remission and healthy can be differentiated in UC by SPP24 (p = 0.00023, 0.001), α-1-microglobulin (AMBP, p = 0.006) and CD by SPP24 (p = 0.019, 0.05). UC and CD can be differentiated by Guanylin (GUC2A, p = 0.001), and Secretogranin-1 (CHGB p = 0.035). Active and quiescent disease can also be differentiated in UC and CD by CHGB (p ≤ 0.023) SPP24 (p ≤ 0.023) and AMBP (UC p = 0.046). Five peptides discriminating IBD activity and severity had very little-to-no correlation to erythrocyte sedimentation rate, C-reactive protein, white cell or platelet counts. Three of these peptides were found to be binding partners to SPP24 protein alongside other known matrix proteins. These proteins have the potential to improve diagnosis and evaluate IBD activity, reducing the need for more invasive techniques. Data are available via ProteomeXchange with identifier PXD002821.

Concordance of maternal and paternal decision-making and its effect on choice for vaginal birth after caesarean section.

BACKGROUND: The proportion of women who plan for a repeat elective caesarean section (CS) is one of the major determinants of the overall rate of CS, and programs aiming to reduce the rate of CS have not been greatly successful. To date, there appear to have been no large studies directly addressing paternal influences on decision-making regarding vaginal birth after caesarean (VBAC). This study aimed to compare the reactions of fathers and mothers to the prospect of VBAC. METHODS: Couples were recruited from three Australian hospitals and were eligible with a singleton pregnancy, a normal morphology ultrasound, and where there was no condition in the new pregnancy that would preclude a vaginal birth. Questionnaires were scheduled for 20 weeks' gestation, 32-36 weeks' gestation and six weeks postnatal and were sent separately to each partner. RESULTS: Seventy-five couples completed the full sets of questionnaires during the study period. In total, 31 women (41%) ultimately attempted vaginal delivery, and 44 (59%) were delivered by planned CS. When the paternal rating of risk fell between the second and third trimesters, the couple were likely to attempt VBAC (P < 0.05). Where the maternal rating of importance was 3 or less, 92% had a planned CS compared to 63% for the same paternal scores (P = 0.02). CONCLUSION: This study suggests that interventions that improve the paternal perceptions of risk during a pregnancy might increase the chance that a couple will attempt VBAC.

Aerosol risk with noninvasive respiratory support in patients with COVID-19.

Objectives: This study evaluates aerosol production with high-flow nasal cannula (HFNC) and noninvasive positive pressure ventilation (NIPPV) compared to 6 L/min by low-flow nasal cannula. Methods: Two healthy volunteers were randomized to control (6 L/min by low-flow nasal cannula), NIPPV, or HFNC using block randomization. NIPPV conditions were studied using continuous positive airway pressures of 5, 10, and 15 cm H2O with an FiO2 of 1.0 delivered via full-face mask. HFNC conditions included flow rates of 30 and 40 L/min with an FiO2 of 1.0 with and without coughing. HFNC and low-flow nasal cannula conditions were repeated with and without participants wearing a surgical mask. Six aerosol sizes (0.3, 1.0, 2.5, 5, and 10 µm) and total aerosol mass were measured at 2 and 6 ft from the participant's nasopharynx. Results: There was no significant difference in aerosol production between either HFNC or NIPPV and control. There was also no significant difference with the use of a procedural mask over the HFNC. There was significant variation between the 2 participants, but in neither case was there a difference compared to control. There was an aerosol-time trend, but there does not appear to be a difference between either flow rate, pressure, or control. Furthermore, there was no accumulation of total aerosol particles over the total duration of the experiment in both HFNC and NIPPV conditions. Conclusions: HFNC and NIPPV did not increase aerosol production compared to 6 L/min by low-flow nasal cannula in this experiment involving healthy volunteers.

Open cholecystectomy: Exposure and confidence of surgical trainees and new fellows.

BACKGROUND: The laparoscopic approach to cholecystectomy has overtaken open procedures in terms of frequency, despite open procedures playing an important role in certain clinical situations. This study explored exposure and confidence of Australasian surgical trainees and new fellows in performing an open versus laparoscopic cholecystectomy. MATERIALS AND METHODS: An online survey was disseminated via the Royal Australasian College of Surgeons to senior general surgery trainees (years 3-5 of surgical training) and new fellows (fellowship within the previous 5 years). The survey included questions regarding level of experience and confidence in performing an open cholecystectomy and converting from a laparoscopic to an open approach. RESULTS: A total of 135 participants responded; 58 (43%) were surgical trainees, 58 (43%) were fellows and 19 (14%) did not specify their level of training. Respondents who were involved in more than 20 open cholecystectomy procedures as an assistant or independent operator compared with those less exposed were more likely to feel confident to independently perform an elective open cholecystectomy (87.8% vs. 57.3%, P = 0.001), independently convert from a laparoscopic to open cholecystectomy (87.8% vs. 58.7%, P = 0.001) and independently perform an open cholecystectomy as a surgical consultant based on their level of exposure as a trainee (73.2% vs. 45.3%, P = 0.004). CONCLUSION: This study suggests the need to ensure surgical trainees are exposed to sufficient open cholecystectomies to enable confidence and skill with performing these procedures when indicated. Greater recognition of the need for exposure during training, including meaningful simulation, may assist.

Laparoscopic adjustable gastric band revisional surgery: a single surgeon series.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a safe and proven surgical option for morbid obesity; however, the need for revisional surgery is being increasingly reported. This study reports outcomes and incidence for a large cohort of patients requiring revisional LAGB surgery for various indications. METHODS: A retrospective review of prospectively collected data for 1524 primary LAGB placed between 2003 and 2013 by a single surgeon at a single institution was performed, analysing data for all patients in this cohort requiring revisional LAGB surgery. RESULTS: A total of 434 revisions were performed on 349 patients. A total of 278 patients had a single revision, with 71 patients having two or more revisions. Revisions amounting to 213 were band repositions, 68 were band removal only and 153 were band removal with conversion to another bariatric procedure, mostly Roux-en-Y gastric bypass (n = 143). A total of 47 (35.1%) 'band-to-band' revision patients were lost to follow-up. Patients undergoing 'band-to-band' revision for a slipped band, patient intolerance and mechanical band failure had mean excess weight loss (EWL) at 4 years of 49.9% (n = 35), 38.6% (n = 10) and 67.4% (n = 6), respectively. Port or tubing revisions were not included. Mean follow-up for 'band-to-band' revision patients was 33.4 months (standard deviation 26.4 months). 22.9% of patients required one or more band revision procedures by 2013, increased from 13% in 2008. CONCLUSION: Continued EWL is achieved with repositioning or replacement of a LAGB. However, a significant and increasing rate of re-operation over time exists.

Local epigenetic reprogramming induced by G-quadruplex ligands.

DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here, we demonstrate that impeding replication by small-molecule-mediated stabilization of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterization of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps: the loss of H3K4me3 and then subsequent DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming.

Bimodal plasma metabolomics strategy identifies novel inflammatory metabolites in inflammatory bowel diseases.

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. MATERIALS AND METHODS: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. RESULTS: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA 50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). CONCLUSIONS: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism.

A case study of ileal metaplasia and neoplasia in a patient with an ileal-rectal anatomosis / Um caso de estudo de metaplasia ileal e neoplasia em paciente com anastomose ileal-retal

ABSTRACT A clear link between ulcerative colitis and the formation of dysplasia and neoplasia has been described. This increased risk remains even after subtotal colectomy and ileo-rectal anastomosis, necessitating life-long surveillance of the remaining ano-rectum. This case study highlights the importance in long-term follow up in this population, including proximal to the anastomosis as dysplastic changes can occur in the distal ileum.

RESUMO Uma ligação clara entre colite ulcerativa e a formação de displasia e neoplasia tem sido descrita. Ese risco aumentado permanece mesmo após colectomia subtotal e ileo-retal, necesitando de uma vigilância ao longo da vida do ano-recto restante. Este caso de estudo realça a importância no acompanhamento a longo prado dessa população, incluindo áqueles próximos à anastomose já que podem ocorrer alteraçoes displásicas no íleo distal.