Canadian Pediatric Surgeon Workforce: Characterization of Training, Trends Over Time, and 10-year Model for Pediatric Surgery Need.

BACKGROUND: Graduate and fellowship training trends for Canadian pediatric surgeons remain uncharacterized. Similarly, updated workforce planning for pediatric surgeons is required. We aimed to characterize graduate degree and fellowship trends for Canadian pediatric surgeons, with modelling to inform workforce planning. METHODS: We performed a cross sectional observational study evaluating Canadian pediatric surgeons in January 2022. Surgeon demographics collected included year of medical degree (MD) conferment, MD location, fellowship location, and graduate degree achievement. Our primary outcome was to evaluate training characteristics over time. Secondary outcomes evaluated surgeon supply and demand from 2021 to 2031. Supply was extrapolated from current Canadian pediatric surgery fellows assuming static fellowship matriculation, while retirement was estimated using a 31-, 36-, or 41-year career following MD conferral. RESULTS: Of included surgeons (n = 77), 64 (83%) completed fellowship training in Canada and 46 (60%) have graduate degrees. No surgeons graduating ≤1980 hold graduate degrees, compared to 8 (100%) surgeons with MD ≥ 2011 (p < 0.001). Similarly, more surgeons with MD ≥ 2011 appear to have a Canadian MD (n = 7, 87.5%) and Canadian fellowship (n = 8, 100%). Modelling predicts that 19-49 (25%-64%) surgeons will retire between 2021 and 2031, while 37 fellows will graduate with intention to work in Canada, creating between a 12 surgeon deficit up to an 18 surgeon surplus depending on career length. CONCLUSIONS: Trends in graduate degree achievement and fellowship location suggest increasing competition for Canadian pediatric surgery positions. Additionally, a substantial number of Canadian-trained fellows will need positions outside of Canada in the next decade. Overall, results support previous work demonstrating saturation of the Canadian pediatric workforce. LEVEL OF EVIDENCE: Level IV. ACGME COMPETENCY ADDRESSED: Medical Knowledge.

Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies?

The vermiform appendix is generally considered a redundant organ, but recent evidence suggests that the appendix could contribute to the pathogenesis of inflammatory bowel diseases, in particular ulcerative colitis (UC), and may even have a therapeutic role; however, mechanisms of the appendix involvement remain unclear. Here, we highlight current evidence on the link between the appendix and UC and consider plausible therapeutic implications. A literature search was conducted using PubMed and PubMed Central from inception to Nov 2021 using the terms "Appendix", "UC", "Appendix & UC," "Appendectomy", and "Peri-appendicular patch," including only articles published in English. Reference lists from the selected studies were manually searched and reviewed to gather additional related reports. Inflammation around the appendix ("peri-appendicular patch") has been frequently observed in UC patients without other cecal involvement, and this inflammation can even precede the onset of UC. Epidemiologic studies propose that appendectomy reduces the risk of developing UC or even the risk of flare after UC is diagnosed, although this remains controversial. We reviewed studies showing altered host-microbe interactions in the appendix in UC, which suggest that the appendix could act as a priming site for disease via alterations in the immune response and changes in microbiota carried distally to the colon. In summary, recent literature suggests a possible role for microbes and immune cells within the appendix; however, the role of the appendix in the pathogenesis of UC remains unclear. Further research could clarify the therapeutic potential related to this organ.

Surgical repair of massive hemorrhage secondary to button battery ingestion causing aortoesophageal fistula.

BACKGROUND: In pediatrics, foreign body ingestion poses unique challenges. Each case is unique given variability in timing, type, and size of object, compounded by underlying comorbidities and age. In the mid-1990s, mortality and morbidity associated with button battery (BB) ingestion (BBI) emerged corresponding to modification in battery fabrication towards higher voltage, large-diameter lithium cells. AIMS: To describe the case and management of a BBI in a pediatric patient necessitating the use of cardiopulmonary bypass and deep hypothermic circulatory arrest (DHCA). MATERIALS AND METHODS: A 17-month-old female presented with the sudden loss of consciousness at home. Chest X-ray revealed an esophageal foreign body suspicious for BBI. A massive upper gastrointestinal bleeding was temporized with packing. The patient was urgently taken to the operating room for sternotomy, establishment of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), removal of BB, repair of the left common carotid artery, esophageal, and tracheal injuries. DISCUSSION: Successful management of BBI requires coordinated care and a multidisciplinary approach. A high degree of clinical suspicion for BBI is imperative to facilitate early aggressive interventions. Lateral and anteroposterior chest films should be obtained in any suspected BBI. CONCLUSION: This case demonstrates the utility of CPB and DHCA where control of bleeding secondary to BBI is not otherwise possible.

Endospore forming bacteria may be associated with maintenance of surgically-induced remission in Crohn's disease.

Crohn's disease (CD) patients who undergo ileocolonic resection (ICR) typically have disease recurrence at the anastomosis which has been linked with a gut dysbiosis. The aims of this study were to define the mucosa-associated microbiota at the time of ICR and to determine if microbial community structure at the time of surgery was predictive of future disease relapse. Ileal biopsies were obtained at surgery and after 6 months from CD subjects undergoing ICR. Composition and function of mucosal-associated microbiota was assessed by 16S rRNA sequencing and PICRUSt analysis. Endoscopic recurrence was assessed using the Rutgeerts score. Analysis of mucosal biopsies taken at the time of surgery showed that decreased Clostridiales together with increased Enterobacteriales predicted disease recurrence. An increase in the endospore-forming Lachnospiraceae from surgery to 6 months post-ICR was associated with remission. A ratio of 3:1 between anaerobic endospore-forming bacterial families and aerobic families within the Firmicutes phylum was predictive of maintenance of remission. Gut recolonization following ICR is facilitated by microbes which are capable of either aerobic respiration or endospore formation. The relative proportions of these species at the time of surgery may be predictive of subsequent microbial community restoration and disease recurrence.

Prebiotic Supplementation Following Ileocecal Resection in a Murine Model is Associated With a Loss of Microbial Diversity and Increased Inflammation.

Background: Individuals with Crohn's disease frequently require ileocecal resection (ICR), and inflammation often recurs in the neoterminal ileum following surgery. Fructooligosaccharide (FOS) is a fermentable prebiotic that stimulates the growth of bifidobacteria and may promote anti-inflammatory activity. The aim of this study was to determine if supplementation of a postICR diet with FOS in a mouse model would be effective in stimulating the growth of bifidobacteria and reducing systemic and local inflammation. Methods: ICR was performed in IL10-/- mice (129S1/SvlmJ) with colitis. Following surgery, nonICR control and ICR mice were fed a chow diet ± 10% FOS for 28 days. Serum, colon, and terminal ileum (TI) were analyzed for cytokine expression by MesoScale discovery platform. DNA extracted from stool was analyzed using 16s rRNA sequencing and qPCR. Expression of occludin and ZO1 was assessed using qPCR. Short-chain fatty acid (SCFA) concentrations were assessed using gas chromatography. Results: ICR led to increased systemic inflammation (P < 0.05) and a significant decline in fecal microbial diversity (P < 0.05). Mice on the FOS diet had a greater reduction in microbial diversity and also had worsened inflammation as evidenced by increased serum IL-6 (P < 0.05) and colonic IFNγ and TNFα (P < 0.05). Expression of occludin and ZO1 were significantly reduced in FOS-supplemented mice. There was a correlation between loss of diversity and the bifidogenic effectiveness of FOS (r = -0.61, P < 0.05). Conclusions: FOS-supplementation of a postICR diet resulted in a decrease in fecal bacterial diversity, reduction in barrier function, and increased gut inflammation.

Ileocolic resection is associated with increased susceptibility to injury in a murine model of colitis.

Ileocolic resection (ICR) is the most common intestinal resection performed for Crohn's disease, with recurrences commonly occurring at the site of the anastomosis. This study used an animal model of ICR in wild-type mice to examine immunologic changes that developed around the surgical anastomosis and how these changes impacted gut responses to minor acute injury. ICR was performed in adult 129S1/SvlmJ mice and results compared with mice receiving sham or no surgery. Dextran sodium sulfate was given either on post-operative day 9 or day 24 to evaluate immune responses in the intestine both immediately following surgery and after a period of healing. Fecal occult blood measurements and animal weights were taken daily. Cytokine levels were measured in ileal and colonic tissue. Bacterial load in the neo-terminal ileum was measured using qPCR. Immune cell populations in the intestinal tissue, mesenteric lymph nodes, and spleen were assessed using flow cytometry. Cytokine secretion in response to microbial products was measured in isolated mesenteric lymph nodes and spleen cells. ICR resulted in an initial elevation of inflammatory markers in the terminal ileum and colon followed by enhanced levels of bacterial growth in the neo-terminal ileum. Intestinal surgical resection resulted in the recruitment of innate immune cells into the colon that exhibited a non-responsiveness to microbial stimuli. DSS colitis phenotype was more severe in the ileocolic resection groups and this was associated with local and systemic immunosuppression as evidenced by a reduced cytokine responses to microbial stimuli. This study reveals the development of an immune non-responsiveness to microbial products following ileocolic resection that is associated with enhanced levels of bacterial growth in the neo-terminal ileum. These surgical-induced altered immune-microbial interactions in the intestine may contribute to disease recurrence at the surgical anastomosis site following ileocolic resections in patients with Crohn's disease.

Characterization of the Gut Microbiome Using 16S or Shotgun Metagenomics.

The advent of next generation sequencing (NGS) has enabled investigations of the gut microbiome with unprecedented resolution and throughput. This has stimulated the development of sophisticated bioinformatics tools to analyze the massive amounts of data generated. Researchers therefore need a clear understanding of the key concepts required for the design, execution and interpretation of NGS experiments on microbiomes. We conducted a literature review and used our own data to determine which approaches work best. The two main approaches for analyzing the microbiome, 16S ribosomal RNA (rRNA) gene amplicons and shotgun metagenomics, are illustrated with analyses of libraries designed to highlight their strengths and weaknesses. Several methods for taxonomic classification of bacterial sequences are discussed. We present simulations to assess the number of sequences that are required to perform reliable appraisals of bacterial community structure. To the extent that fluctuations in the diversity of gut bacterial populations correlate with health and disease, we emphasize various techniques for the analysis of bacterial communities within samples (α-diversity) and between samples (ß-diversity). Finally, we demonstrate techniques to infer the metabolic capabilities of a bacteria community from these 16S and shotgun data.

Fecal Microbial Transplant After Ileocolic Resection Reduces Ileitis but Restores Colitis in IL-10-/- Mice.

BACKGROUND: Ileocolic resection (ICR) is frequently performed for Crohn's disease; however, disease commonly recurs early in the neoterminal ileum. The aim of this study was to use the IL-10(-/-) mouse to determine the effects of ICR on gut microbiome and immune function and if postoperative fecal microbial transplant (FMT) would improve disease. METHODS: ICR was performed in 129S1/SvlmJ IL10(-/-) mice followed by FMT using stool from wild-type mice. Sham-transplant mice received their own stool. Stool samples were collected on day 0, day 13 (after ICR), and day 27 (after FMT) for whole metagenome shot-gun sequencing. Mucosal-associated bacteria were quantified with quantitative PCR and visualized by fluorescent in situ hybridization. Tissue cytokines were measured with multiplex arrays and mononuclear phagocyte populations by flow cytometry. RESULTS: Surgery induced microbial functional and taxonomic shifts, decreased diversity, and depleted Bacteroidia and Clostridia. ICR mice had reduced colitis but worse ileitis with bacterial overgrowth, increased translocation, and reduction in tissue macrophages. FMT prevented ileitis but restored colitis and allowed for a bloom of γ-proteobacteria. In the colon, ICR and sham transplant were associated with recruitment of tolerogenic dendritic cells, whereas FMT shifted these immune cell subsets to control profiles along with increasing cytokine levels. CONCLUSIONS: This study suggests that surgical-induced immune dysfunction and microbial dysbiosis with impaired clearance may be the underlying cause of the early ulcerations found in the ileum of patients with Crohn's disease after ICR. FMT has an immunostimulatory effect on the postoperative intestine, which was beneficial in preventing ileitis, but detrimental in restoring colonic injury after surgery.

Should We Routinely Investigate Incidental Head and Neck Findings on 18-Fluorodeoxyglucose Positron Emission Tomography in Patients Being Staged for Non-small Cell Lung Cancer? A Retrospective Analysis.

BACKGROUND: Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) is routinely performed for investigating suspected lung cancers. Despite the known potential for false-positive FDG uptake in the head and neck, most suspicious lesions on FDG-PET are investigated. METHODS: Between October 2002 and January 2010, FDG-PET/PET-computed tomography (CT) reports showing significant incidental uptake were retrospectively analyzed using controls to compare time to treatment for lung cancer and the rate of secondary malignancy in those with and without incidental head and neck FDG uptake. RESULTS: In this study, 48/1,846 PET/PET-CT scan reports reviewed, and demonstrated nonthyroidal head and neck abnormalities. A total of 30 patients had proven non-small cell lung cancer (1.6%); 3/30 (10%) went on to have biopsy proven malignancy. Furthermore, there was a significant increase in time to treatment in those patients with incidental head and neck findings (p = 0.002). CONCLUSION: These unexpected findings are mostly of no clinical significance and the patient should continue treatment without delay; however, aggressive work-up should be pursued if concerns for head and neck pathology are raised following clinical assessment.

Murine ileocolic bowel resection with primary anastomosis.

Intestinal resections are frequently required for treatment of diseases involving the gastrointestinal tract, with Crohn's disease and colon cancer being two common examples. Despite the frequency of these procedures, a significant knowledge gap remains in describing the inherent effects of intestinal resection on host physiology and disease pathophysiology. This article provides detailed instructions for an ileocolic resection with primary end-to-end anastomosis in mice, as well as essential aspects of peri-operative care to maximize post-operative success. When followed closely, this procedure yields a 95% long-term survival rate, no failure to thrive, and minimizes post-operative complications of bowel obstruction and anastomotic leak. The technical challenges of performing the procedure in mice are a barrier to its wide spread use in research. The skills described in this article can be acquired without previous surgical experience. Once mastered, the murine ileocolic resection procedure will provide a reproducible tool for studying the effects of intestinal resection in models of human disease.

The clinical significance of incidental intra-abdominal findings on positron emission tomography performed to investigate pulmonary nodules.

BACKGROUND: Lung cancer is a common cause of cancer-related death. Staging typically includes positron emission tomography (PET) scanning, in which (18)F-fluoro-2-dexoy-D-glucose (FDG) is taken up by cells proportional to metabolic activity, thus aiding in differentiating benign and malignant pulmonary nodules. Uptake of FDG can also occur in the abdomen. The clinical significance of incidental intraabdominal FDG uptake in the setting of pulmonary nodules is not well established. Our objective was to report on the clinical significance of incidental intra-abdominal FDG activity in the setting of lung cancer. METHODS: Fifteen hundred FDG-PET reports for studies performed for lung cancer were retrospectively reviewed for the presence of incidental FDG-positive intraabdominal findings. Patient charts with positive findings were then reviewed and information extracted. RESULTS: Twenty-five patients (25/1500) demonstrated incidental intraabdominal FDG uptake thought to be significant (1.7%) with a mean patient age of 71 years. Colonic uptake was most common (n = 17) with 9 (52%) being investigated further. Of these 9 cases, a diagnosis of malignancy was made in 3 patients, pre-malignant adenomas in 2 patients, a benign lipoma in 1 patient and no abnormal findings in the remaining patients. 8 patients were not investigated further (3 diagnosed with metastatic lung cancer and 2 were of advanced age) secondary to poor prognosis. CONCLUSION: Incidental abdominal findings in the colon on FDG-PET scan for work-up of pulmonary nodules need to be further investigated by colonoscopy.

FACT, the Bur kinase pathway, and the histone co-repressor HirC have overlapping nucleosome-related roles in yeast transcription elongation.

Gene transcription is constrained by the nucleosomal nature of chromosomal DNA. This nucleosomal barrier is modulated by FACT, a conserved histone-binding heterodimer. FACT mediates transcription-linked nucleosome disassembly and also nucleosome reassembly in the wake of the RNA polymerase II transcription complex, and in this way maintains the repression of 'cryptic' promoters found within some genes. Here we focus on a novel mutant version of the yeast FACT subunit Spt16 that supplies essential Spt16 activities but impairs transcription-linked nucleosome reassembly in dominant fashion. This Spt16 mutant protein also has genetic effects that are recessive, which we used to show that certain Spt16 activities collaborate with histone acetylation and the activities of a Bur-kinase/Spt4-Spt5/Paf1C pathway that facilitate transcription elongation. These collaborating activities were opposed by the actions of Rpd3S, a histone deacetylase that restores a repressive chromatin environment in a transcription-linked manner. Spt16 activity paralleling that of HirC, a co-repressor of histone gene expression, was also found to be opposed by Rpd3S. Our findings suggest that Spt16, the Bur/Spt4-Spt5/Paf1C pathway, and normal histone abundance and/or stoichiometry, in mutually cooperative fashion, facilitate nucleosome disassembly during transcription elongation. The recessive nature of these effects of the mutant Spt16 protein on transcription-linked nucleosome disassembly, contrasted to its dominant negative effect on transcription-linked nucleosome reassembly, indicate that mutant FACT harbouring the mutant Spt16 protein competes poorly with normal FACT at the stage of transcription-linked nucleosome disassembly, but effectively with normal FACT for transcription-linked nucleosome reassembly. This functional difference is consistent with the idea that FACT association with the transcription elongation complex depends on nucleosome disassembly, and that the same FACT molecule that associates with an elongation complex through nucleosome disassembly is retained for reassembly of the same nucleosome.

Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells.

The expression of RHAMM and other centrosome-associated genes are known to correlate with the extent of centrosome amplification in multiple myeloma, and with poor prognosis. RHAMM has a significant interaction with TPX2, a protein which regulates the localization and action of Aurora A kinase (AURKA) at the spindle poles. AURKA is known to be a central determinant of centrosome and spindle function and is a target for cancer therapy. Given these observations, we investigated the role of Aurora kinases as therapeutic targets in myeloma. Here we report that AURKA is expressed ubiquitously in myeloma, to varying degrees, in both cell lines and patients' bone marrow plasma cells. siRNA targeting AURKA induces apoptotic cell death in myeloma cell lines. The Aurora kinase inhibitor VE-465 also induces apoptosis and death in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. The phenotype of myeloma cells treated with VE-465 is consistent with published reports on the effects of Aurora kinase inhibition. Aurora kinase inhibitors should be pursued as potential treatments for myeloma.