Development of American Society for Gastrointestinal Endoscopy standards for training in advanced endoscopy within dedicated advanced endoscopy fellowship programs.

BACKGROUND AND AIMS: Training in interventional endoscopy is offered by nonaccredited advanced endoscopy fellowship programs (AEFPs). The number of these programs has increased dramatically with a concurrent increase in the breadth and complexity of interventional endoscopy procedures. Accreditation is governed by competency-based education, yet what constitutes a "high-quality" nonaccredited AEFP has not been defined. Using an evidence-based consensus process, we aimed to establish standards for AEFPs. METHODS: The RAND UCLA appropriateness method, a well-described modified Delphi process to develop quality indicators, was used. A task force established by the American Society for Gastrointestinal Endoscopy drafted potential quality indicators (structure, process, and outcome) in 6 categories: activity preceding training; structure of AEFPs; training in ERCP, EUS, and EMR; and luminal stent placement. Three rounds of iterative feedback from 20 experts were conducted. Round 0 involved discussion of project details. In round 1, experts independently ranked proposed quality indicators on a 9-point interval scale ranging from highly inappropriate (1) to highly appropriate (9). Next, proposed quality indicators were discussed and reworded in a group meeting followed by round 2, in which experts independently reranked proposed quality indicators and provided benchmarks (when applicable). The median score for each quality indicator was calculated. Mean absolute deviation from the median was calculated, and appropriateness of potential quality indicators was assessed using the BIOMED concerted action on appropriateness definition, P value method, and interpercentile range adjusted for symmetry definition. A quality indicator was deemed appropriate if the median score was ≥7 and met criteria for appropriateness using all 3 defined statistical methods. RESULTS: Of 89 proposed quality indicators, 37 statements met criteria as appropriate for a quality indicator (activity preceding training, 2; structure of AEFPs, 10; training in ERCP, 7; training in EUS, 8; training in EMR, 7; luminal stent placement, 3). Minimum thresholds were defined for 19 relevant quality indicators for number of trainers, procedures during fellowship, and procedures before assessment of competence. Among the final appropriate quality indicators were that all trainees should undergo qualitative and quantitative competence assessments using validated tools at least quarterly with documented feedback throughout the training period and that trainees should track outcomes and relevant quality metrics for specific procedures. CONCLUSIONS: This consensus process using validated methodology established standards for an AEFP in an effort to ensure adequate training in the most commonly taught interventional endoscopic procedures (ERCP, EUS, EMR, and luminal stent placement) during fellowship. An important component of an AEFP is the use of competency-based assessments that are compliant with the Accreditation Council for Graduate Medical Education's Next Accreditation System, with the goal of ensuring that trainees achieve specific milestones in their progression to achieving cognitive and technical competency.

Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception.

The direct blockade of CB1 cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB1 negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB1. We recently reported that GAT358, a CB1-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB1-allosteric mechanism of action. Whether a CB1-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted opioid side-effects remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine in male rats. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar spinal cord. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors in male mice. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception and reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 also produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal cord. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with arrestin-biased CB1-NAMs.

Negative allosteric modulation of cannabinoid CB 1 receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception.

The direct blockade of CB 1 cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB 1 negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB 1 . We recently reported that GAT358, a CB 1 -NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB 1 -allosteric mechanism of action. Whether a CB 1 -NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted side-effects of opioids remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar dorsal horn. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception. GAT358 also reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal dorsal horn. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing in mice. Our results support the therapeutic potential of CB 1 -NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB 1 -NAMs. Highlights: CB 1 negative allosteric modulator (NAM) GAT358 attenuated morphine tolerance GAT358 reduced morphine-induced slowing of colonic motility but not fecal productionGAT358 was antinociceptive for formalin pain alone and when combined with morphineGAT358 reduced formalin-evoked Fos protein expression in the lumbar spinal cordGAT358 mitigated naloxone precipitated withdrawal after chronic morphine dosing.

Pilot Study on Gut Microbiota Profile in Indian Children with Type 1 Diabetes.

Background: Non-genetic factors like microbial dysbiosis may be contributing to the increasing incidence/progression of type 1 diabetes mellitus (T1DM). Objectives: To analyse the gut microbiota profile in Indian children with T1DM and its effect on glycaemic control. Methodology: Faecal samples of 29 children with T1DM were collected and faecal microbial DNA was extracted and subjected to 16S rRNA (ribosomal RNA) sequencing and further analysis. Results: The dominant phyla in children with T1DM were Firmicutes and Bacteroidetes. Butyrate-producing bacteria Blautia and Ruminococcus showed a significant negative correlation with the glycosylated haemoglobin (HbA1C) levels (p < 0.05). Coprococcus and Propionibacterium were important negative predictors of glycaemic control (p < 0.05). Conclusion: Our study suggests that Indian children with T1DM have a distinct gut microbiome taxonomic composition and that short-chain fatty acid-producing bacteria like Ruminococcus and Blautia (butyrate-producing) may play an important role in the glycaemic control of subjects with T1DM.

Iliac Artery-Inferior Vena Cava-Duodenal Fistula: An Unusual Cause of Massive Gastrointestinal Bleeding.

An arteriovenous-enteric fistula is a 3-way connection between the vascular and enteric system and associated with high mortality. We describe a case of iliac artery-inferior vena cava-duodenal fistula in a young female with a retroperitoneal mass presenting with sepsis and hemorrhagic shock with a catastrophic clinical course. These fistulas can be missed on endoscopy/colonoscopy and are usually diagnosed on computed tomography angiogram of the abdomen. Complex vasculoenteric fistula should be among differentials in patients presenting with gastrointestinal bleeding, especially with a history of malignancy, radiation, foreign bodies, and trauma. The management is complex and should involve a multidisciplinary approach involving vascular surgery, intervention radiology, and gastroenterologist.

GAT107-mediated α7 nicotinic acetylcholine receptor signaling attenuates inflammatory lung injury and mortality in a mouse model of ventilator-associated pneumonia by alleviating macrophage mitochondrial oxidative stress via reducing MnSOD-S-glutathionylation.

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). Compromised host defense and inflammatory lung injury are mediated, in part, by high extracellular concentrations of HMGB1, which can be decreased by GTS-21, a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). Here, we report that a novel α7nAChR agonistic positive allosteric modulator (ago-PAM), GAT107, at 3.3 mg/kg, i.p., significantly decreased animal mortality and markers of inflammatory injury in mice exposed to hyperoxia and subsequently infected with Pseudomonas aeruginosa. The incubation of macrophages with 3.3 µM of GAT107 significantly decreased hyperoxia-induced extracellular HMGB1 accumulation and HMGB1-induced macrophage phagocytic dysfunction. Hyperoxia-compromised macrophage function was correlated with impaired mitochondrial membrane integrity, increased superoxide levels, and decreased manganese superoxide dismutase (MnSOD) activity. This compromised MnSOD activity is due to a significant increase in its level of glutathionylation. The incubation of hyperoxic macrophages with 3.3 µM of GAT107 significantly decreases the levels of glutathionylated MnSOD, and restores MnSOD activity and mitochondrial membrane integrity. Thus, GAT107 restored hyperoxia-compromised phagocytic functions by decreasing HMGB1 release, most likely via a mitochondrial-directed pathway. Overall, our results suggest that GAT107 may be a potential treatment to decrease acute inflammatory lung injury by increasing host defense in patients with VAP.

Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated reward.

Blockade of cannabinoid type 1 (CB1)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB1 antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB1 signaling by decreasing affinity and/or efficacy of CB1 ligands. We hypothesized that a CB1-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB1 antagonists. GAT358, a CB1-NAM, failed to elicit cardinal signs of direct CB1 activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB1 agonist CP55,940, suggesting that a CB1-NAM blocked cardinal signs of CB1 activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB1 positive allosteric modulator (CB1-PAM), and absent in CB1-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.

Effect of cigarette smoking on serum anti-Mullerian hormone and antral follicle count in women seeking fertility treatment: a prospective cross-sectional study.

OBJECTIVES: The relationship between smoking and ovarian reserve markers is inconclusive. The primary objective of our study was to assess the effect of cigarette smoking on the quantitative ovarian reserve parameters, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) as relevant to prediction of fertility outcomes in women seeking fertility treatment. Our secondary aims were to validate self-reported smoking behaviour using biomarkers and evaluate the association between biomarkers of ovarian reserve (serum AMH and AFC) with biomarkers of smoking exposure (breath carbon monoxide (CO) and urine cotinine levels). DESIGN: Prospective, cross-sectional study. SETTING: Single tertiary care fertility centre. PARTICIPANTS: Women ≤35 years seeking fertility treatment. PRIMARY OUTCOME MEASURES: Serum AMH and AFC. RESULTS: Significant differences were found among current smokers, ex-smokers and never smokers for breath CO (F(2,97)=33.32, p<0.0001) and urine cotinine levels (p<0.001). However, no significant differences were found either for serum AMH (F(2,91)=1.19, p=0.309) or total AFC (F(2,81)=0.403, p=0.670) among the three groups. There was no significant correlation between pack years of smoking and serum AMH (r=-0.212, n=23, p=0.166) or total AFC (r=-0.276, n=19, p=0.126). No significant correlation was demonstrated between breath CO and serum AMH (r=0.082, n=94, p=0.216) or total AFC (r=0.096, n=83, p=0.195). Similarly, no significant correlation was demonstrated between urine cotinine levels and serum AMH (r=0.146, n=83, p=0.095) or total AFC (r=-0.027, n=77, p=0.386). CONCLUSION: We did not find a statistically significant difference in quantitative ovarian reserve markers between current smokers, ex-smokers and never smokers which would be clinically meaningful in our study population. We confirmed that self-reported smoking correlates well with quantitatively measured biomarkers of smoking. This validated the self-reported comparison groups to ensure a valid comparison of outcome measures. There was no significant association between biomarkers of smoking and biomarkers of ovarian reserve. We were also unable to demonstrate a correlation between the lifetime smoking exposure and ovarian reserve.

Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study.

BACKGROUND: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. OBJECTIVE: This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. STUDY DESIGN: This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. RESULTS: Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of <3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and <1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of >3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. CONCLUSION: A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages.

Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.

EUS-directed transgastric endoscopic retrograde cholangiopancreatography versus laparoscopic-assisted ERCP versus deep enteroscopy-assisted ERCP for patients with RYGB.

Background and study aims Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (ERCP) (EDGE) is a novel technique for managing pancreaticobiliary diseases in patients with a history of Roux-en-Y Gastric Bypass (RYGB). It has shown to have high technical success rates and fewer adverse events as compared to laparoscopic-assisted ERCP (LA-ERCP). We compared the technical success and clinical outcomes of EDGE vs. LA-ERCP vs. E-ERCP. Patients and methods A retrospective chart review was performed for 56 patients, of whom 18 underwent LA-ERCP, 12 underwent E-ERCP, and 26 had EDGE, and a comparison of technical success and complication rates was done. Results Baseline demographic characteristics of patients undergoing these procedures, including age and gender, were comparable. The technical success rate for patients in the EDGE group were 100 % (n = 26), compared with 94 % (n = 17) and 75 % (n = 9) in the LA-ERCP and E-ERCP groups ( P  = 0.02). In the EDGE group, 8 % of patients (n = 2) had bleeding, and 4 % of patients (n = 1) had lumen-apposing metal stent migration occur during the procedure. In the LA-ERCP group 6 % (n = 1) of patient had bleeding, 6 % (n = 1) post-ERCP pancreatitis and 6 % (n = 1) were diagnosed with an intra-abdominal infection post-procedure. Time to complete the EDGE procedure was significantly shorter at 79 ±â€Š31 mins, compared with 158 ±â€Š50 mins for LA-ERCP and 102 ±â€Š43 mins for E-ERCP ( P  < 0.001). Conclusion EDGE is a novel procedure with short procedure times and an effective alternative to LA-ERCP and E-ERCP in management of pancreaticobiliary diseases in patients with a history of RYGB.

RIC3, the cholinergic anti-inflammatory pathway, and neuroinflammation.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels having many functions including inflammation control, as part of the cholinergic anti-inflammatory pathway. Genome wide association studies implicated RIC3, a chaperone of nAChRs, in multiple sclerosis (MS), a neuroinflammatory disease. To understand the involvement of RIC3 in inflammatory diseases we examined its expression, regulation, and function in activated immune cells. Our results show that immune activation leads to dynamic changes in RIC3 expression, in a mouse model of MS and in human lymphocytes and macrophages. We also show similarities in the expression dynamics of RIC3 and CHRNA7, encoding for the α7 nAChR subunit. Homomeric α7 nAChRs were shown to mediate the anti-inflammatory effects of cholinergic agonists. Thus, similarity in expression dynamics between RIC3 and CHRNA7 is suggestive of functional concordance. Indeed, siRNA mediated silencing of RIC3 in a mouse macrophage cell line eliminates the anti-inflammatory effects of cholinergic agonists. Furthermore, we show increased average expression of RIC3 and CHRNA7 in lymphocytes from MS patients, and a strong correlation between expression levels of these two genes in MS patients but not in healthy donors. Together, our results are consistent with a role for RIC3 and for the mechanisms regulating its expression in inflammatory processes and in neuroinflammatory diseases.

A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.

STUDY QUESTION: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY: Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION: A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE: During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births. LIMITATIONS, REASONS FOR CAUTION: Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected. WIDER IMPLICATIONS OF THE FINDINGS: Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS. STUDY FUNDING/COMPETING INTEREST(S): L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children's Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work. TRIAL REGISTRATION NUMBER: NA.

Survival Trends for Resectable Pancreatic Cancer Using a Multidisciplinary Conference: the Impact of Post-operative Chemotherapy.

PURPOSE: Despite advances in various treatment modalities, surgical resection for pancreatic ductal adenocarcinoma (PDA) remains the only curative treatment. Data remains limited regarding survival rates for resectable PDA when managed by a multidisciplinary pancreas conference (MDPC). The aim of this study is to assess survival rates, identify significant predictors of mortality, and assess the benefits of adjuvant chemotherapy for resectable PDA following presentation at a MDPC. METHODS: All patients presented from April 2013 to August 2016 with resectable PDA were discussed at a MDPC at a tertiary care center and were followed prospectively until November 2017. Survival analysis was performed using Kaplan-Meier for age, tumor size, tumor differentiation, T-stage, lymph node status, and completion of adjuvant chemotherapy cycles. Independent predictors of survival were determined using multivariate Cox regression modeling. RESULTS: After MDPC consensus and exclusions, total of 64 patients underwent successful surgery. Amongst this cohort, 1-, 2-, and 3-year survival was 78.13%, 46.30%, and 27.27%, respectively. A total of 37 patients (58%) initiated and 16 patients (25%) finished chemotherapy following surgery. Log-rank analysis revealed that tumor size, age, surgical margins, lymph node status, and number of adjuvant chemotherapy cycles received significantly influenced post-operative survival. Tumor size (p < 0.001), lymph node status (p = 0.035), and number of adjuvant chemotherapy cycles (p = 0.041) remained significant after multivariate Cox regression model. CONCLUSIONS: Our results suggest that patients with PDA with tumor size > 50 mm and/or lymph node involvement have poor outcomes despite being surgically resectable. Successful completion of adjuvant chemotherapy has better survival outcomes as compared with incomplete or no adjuvant chemotherapy. The role of alternative management such as down-staging with neoadjuvant therapy should be considered.

Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socio-economic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.

OBJECTIVES: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). DESIGN: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. RESULTS: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P < .01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P < .01). There was a significant trend to higher live birth rates of T21 with lower SES (P = .004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing. CONCLUSION: There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.

Distal Ileal Ulcers as Gastrointestinal Manifestation of Waldenstrom Macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a neoplastic disorder of the B-cell lymphoid system. A 69-year-old man with WM presented with diarrhea for 6 months. Magnetic resonance enterography showed thickening of the terminal ileum (TI). Colonosocopy with TI intubation showed a single TI ulcer, and small bowel enteroscopy revealed multiple ulcers in the TI. Biopsies from both were negative on hematoxylin and eosin staining. Immunoglobulin M immunofluorescence staining of the ulcers was positive for IgM deposits consistent with WM. After 6 cycles of chemotherapy with bendamustine and rituximab, symptoms resolved.

Defining Pancreatitis as a Risk Factor for Pancreatic Cancer: The Role, Incidence, and Timeline of Development.

OBJECTIVES: Acute and/or chronic pancreatitis has been implicated as an important risk factor for pancreatic cancer; however, the incidence and temporal relationship of pancreatitis before pancreatic cancer diagnosis are unclear. We aim to understand the role and incidence of pancreatitis temporally with the development of pancreatic cancer. METHODS: A population-based study was used to investigate a temporal relationship between pancreatitis and pancreatic cancer diagnoses. Intervals of 3, 6, 12, 24, and 36 months were developed. Demographical data including age, sex, and race were also recorded and analyzed. RESULTS: A total of 50,080 patients were found to have a diagnosis of pancreatic cancer, of which 7420 (14.8%) had prior diagnoses of pancreatitis. Of those, 92% were between the ages of 40 and 89 years. African Americans had a higher rate of pancreatitis before cancer diagnosis when compared with whites (21.2% vs 14.8%, P < 0.0001). Further analysis revealed that pancreatitis occurred in 81.3% of patients 3 months before a diagnosis of pancreas cancer and 98.9% had established diagnoses of pancreatic cancer within 3 years. CONCLUSIONS: Screening of patients older than 40 years who have pancreatitis and unclear etiology of pancreatitis may be warranted, especially in African Americans and male individuals.

Time to Adjuvant Systemic Therapy Following Pancreatic Cancer Resection and Effect on Outcome.

OBJECTIVES: The appropriate timing of chemotherapy following surgery for resectable pancreatic adenocarcinoma is controversial. Using the National Cancer Database we evaluated time to initiation of chemotherapy postresection and correlated with outcome. METHODS: We identified stage I-III pancreatic adenocarcinoma treated surgically with adjuvant chemoradiotherapy. Receiver operator curve analysis identified an interval of 66 days as the a priori value for largest discrepancy in outcome. Multivariable logistic regression analysis identified variables associated with increased time to chemotherapy postoperatively (>66 days). Propensity matching was performed to account for indication bias. RESULTS: In total, 6873 and 3348 patients received chemotherapy before and after the 66-day cutoff, respectively. Predictors of expedited chemotherapy included lower comorbidity, treatment outside a community program in an urban location, having insurance, white race, and treatment after 2009. Propensity-matched median survival was 21.8 months for all patients, and of these, 6462 were stage 1. Five-year survival was 20% in patients receiving chemotherapy within 66 days and 18% in those not (P = 0.0266). In stage 1 patients, 5-year survival was 23% versus 21% (P = 0.0116) in favor of expedited chemotherapy. CONCLUSIONS: The present propensity-matched analysis showed a significant association with survival for earlier delivery of chemotherapy in the adjuvant setting.

Endoscopic ultrasound guided fine-needle aspiration vs core needle biopsy for solid pancreatic lesions: Comparison of diagnostic accuracy and procedural efficiency.

BACKGROUND: Endoscopic ultrasound (EUS) guided core needle biopsies (CNB) are increasingly being performed to diagnose solid pancreatic lesions. However, studies have been conflicting in terms of CNB improving diagnostic accuracy and procedural efficiency vs fine-needle aspiration (FNA), which this study aims to elucidate. METHODS: Data were prospectively collected on consecutive patients with solid pancreatic or peripancreatic lesions at a single tertiary care center from November 2015 to November 2016 that underwent either FNA or CNB. Patient demographics, characteristics of lesions, diagnostic accuracy, final and follow-up pathology, use of rapid on-site evaluation (ROSE), complications, and procedure variables were obtained. RESULTS: A total of 75 FNA and 48 CNB were performed; of these, 13 patients had both. Mean passes were lower with CNB compared to FNA (2.4 vs 2.9, P = .02). Use of ROSE was higher for FNA (97.3% vs 68.1%, P = .001). Mean procedure time was shorter with CNB (34.1 minutes vs 51.2 minutes, P = .02) and diagnostic accuracy was similar (89.2% vs 89.4%, P = .98). There was no difference in diagnostic accuracy when ROSE was performed for CNB vs not performed (93.5% vs 85.7%, P = .58). Additionally, diagnostic accuracy of combined FNA and CNB procedures was 92.3%, which was comparable to FNA (P = .73) or CNB (P = .52) alone. CONCLUSION: FNA and CNB had comparable safety and diagnostic accuracy. Use of CNB resulted in less number of passes and shorter procedure time as compared to FNA. Moreover, diagnostic accuracy for CNB with or without ROSE was similar.