Comparing the Real-World Effectiveness of High- Versus Low-Volume Split Colonoscopy Preparations: An Experience Through the British Columbia Colon Cancer Screening Program.

BACKGROUND: The British Columbia Colon Screening Program (BCCSP) is a population-based colon cancer screening program. In December 2018, physicians in Vancouver, Canada agreed to switch from a low-volume split preparation to a high-volume polyethylene glycol preparation after a meta-analysis of studies suggested superiority of the higher volume preparation in achieving adequate bowel cleansing and improving adenoma detection rates. AIMS: To compare the quality of bowel preparation and neoplasia detection rates using a high-volume split preparation (HVSP) versus a low-volume split preparation (LVSP) in patients undergoing colonoscopy in the BCCSP. METHODS: A retrospective review of patients undergoing colonoscopy through the BCCSP at St. Paul's Hospital from July 2017 to November 2018 and December 2018 to November 2019 was conducted. Inclusion criteria included age 50 to 74 and patients undergoing colonoscopy through the BCCSP. Variables collected included patient demographics and bowel preparation quality. Rates of bowel preparation and neoplasia detection were analyzed using chi-squared test. RESULTS: A total of 1453 colonoscopies were included, 877 in the LVSP group and 576 in the HVSP group. No statistically significant difference was noted between rates of inadequate bowel preparation (LVSP 3.6% versus HVSP 2.8%; P = 0.364). Greater rates of excellent (48.4% versus 40.1%; P = 0.002) and optimal (90.1% versus 86.5%; P = 0.041) bowel preparation were achieved with HVSP. The overall adenoma detection rate was similar between the two groups (LVSP 53.1% versus HVSP 54.0%; P = 0.074). LVSP demonstrated higher overall sessile serrated lesion detection rate (9.5% versus 5.6%; P = 0.007). CONCLUSIONS: Compared to LVSP, HVSP was associated with an increase in excellent and optimal bowel preparations, but without an improvement in overall neoplasia detection.

High rate of re-bleeding after application of Hemospray for upper and lower gastrointestinal bleeds.

BACKGROUND & AIMS: Hemospray (TC-325, Cook Medical) has recently been approved for use in GI bleeding. Specific clinical indications and predictors of success or failure have not been well delineated. METHODS: We conducted a retrospective cohort study of Hemospray use at a tertiary center. We assessed demographics and characteristics of Hemospray use. We analyzed outcomes of hemostasis, rebleeding, need for embolization or surgery, and death. RESULTS: 86 applications of Hemospray were identified. The most common etiology of upper GI bleeds were ulcers (67.1%) whilst the etiology of lower GI bleeds varied. Hemospray was applied as monotherapy in 28 procedures (32.6%). Immediate hemostasis rate was 88.4%, but there was a high rate of re-bleeding (33.7%). Most re-bleeds occurred within 7 days (86.2%). Syncope was an independent predictive factor re-bleeding at 7 days for EGD (OR = 12.16, 95% CI = 1.51-97.75, P = 0.019). Bleeding refractory to endoscopic treatment with hemospray required radiological embolization in 9 instances, and surgery in 9 instances. Hemospray therapy was protective against need for embolization (p < 0.05). 2 patients underwent liver transplantation and there was a total of 5 deaths. Hepatic disease was an independent predictor of death (OR = 47.15, 95% CI = 2.42-916.89, P = 0.011). CONCLUSION: Hemospray is effective in achieving immediate hemostasis but is plagued by high rates of rebleeding. Syncope is a predictor of rebleeding, and hepatic disease is a predictor of death in patients undergoing Hemospray therapy. Despite high rates of embolization and surgery, Hemospray may reduce need for embolization. Hemospray use during endoscopy should prompt physicians to consider early re-look endoscopy and more aggressive therapy.

Survival benefit of a low ratio of visceral to subcutaneous adipose tissue depends on LDL clearance versus production in sepsis.

BACKGROUND: Patients with sepsis with a high ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) have increased mortality. Our goal was to investigate the mechanism of this effect, noting that low LDL levels are also associated with increased sepsis mortality. Accordingly we tested for association between VAT/SAT, low-density lipoprotein (LDL) levels, and mortality. Then we examined the effect of statin treatment, which decreases LDL production, and the effect of PCSK9 genotype, which increases LDL clearance. METHODS: We performed retrospective analysis of a cohort of patients with sepsis from a tertiary care adult intensive care unit in Vancouver, Canada, who underwent abdominal computed tomography (CT) (n = 75) for clinical reasons. We compared LDL levels in patients with sepsis according to high versus low VAT/SAT and 90-day survival. We next examined the effects of statin therapy and PCSK9 loss-of-function genotype on survival. RESULTS: Patients with a low VAT/SAT had increased 90-day survival and were relatively protected against low LDL levels in sepsis compared to high VAT/SAT. Statin treatment abrogated the beneficial effects of low VAT/SAT; eliminating the difference in LDL levels and survival between patients with low and high VAT/SAT. PSCK9 loss-of-function genotype similarly eliminated the increased LDL levels in low VAT/SAT patients but, in contrast, increased the survival advantage of low VAT/SAT compared to high VAT/SAT. CONCLUSIONS: Low LDL levels per se are not simply associated with decreased sepsis survival because lowering LDL levels by inhibiting LDL production (statin treatment) is associated with adverse outcomes, while increased LDL clearance (PCSK9 loss-of-function genotype) is associated with improved outcomes in patients with low VAT/SAT.

Increased Ratio of Visceral to Subcutaneous Adipose Tissue in Septic Patients Is Associated With Adverse Outcome.

OBJECTIVES: Visceral and subcutaneous adipose tissue may contribute differentially to the septic inflammatory response. Accordingly, we tested the hypothesis that the ratio of visceral to subcutaneous adipose tissue is associated with altered sepsis outcome. DESIGN: A retrospective analysis from a cohort of sepsis patients admitted between 2004 and 2009. SETTING: A mixed medical-surgical ICU at St. Paul's Hospital in Vancouver, Canada. PATIENTS: Patients older than 16 years old who had sepsis and underwent abdominal CT scan (n = 257) for clinical reasons. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the visceral adipose tissue and subcutaneous adipose tissue areas and calculated the visceral adipose tissue-to-subcutaneous adipose tissue ratio. Visceral adipose tissue/subcutaneous adipose tissue was not correlated with body mass index (r = -0.015, p = NS) and therefore provides additional unique information independent of body mass index. Sepsis patients with higher visceral adipose tissue/subcutaneous adipose tissue had greater 90-day mortality than patients with lower visceral adipose tissue/subcutaneous adipose tissue (log-rank test, linear-by linear association p < 0.005). After adjustment for significant covariates using Cox regression, increased visceral adipose tissue/subcutaneous adipose tissue quartile was significantly associated with increased 90-day mortality with hazard ratios of 2.01 (95% CI, 1.01-3.99) for the third visceral adipose tissue/subcutaneous adipose tissue quartile compared with the first quartile and 2.32 (95% CI, 1.15-4.69) for the highest visceral adipose tissue/subcutaneous adipose tissue quartile when compared with the first quartile. Increased mortality for patients with higher visceral adipose tissue/subcutaneous adipose tissue was found for both patients with body mass index less than 25 kg/m (p = 0.004) and for body mass index greater than or equal to 25 kg/m (p = 0.023). Furthermore, we found significantly greater need for mechanical ventilation, renal replacement therapy, and ICU stay in patients in the highest visceral adipose tissue/subcutaneous adipose tissue quartile. The ratio of proinflammatory (interleukin-8) to anti-inflammatory (interleukin-10) plasma cytokine levels was greater in patients with higher visceral adipose tissue/subcutaneous adipose tissue than in those with lower visceral adipose tissue/subcutaneous adipose tissue (p = 0.043). CONCLUSIONS: Visceral obesity, defined by a high visceral adipose tissue-to-subcutaneous adipose tissue ratio, contributes to adverse outcome in sepsis patients perhaps because of a greater pro- versus anti-inflammatory response.

Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFß) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFß activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFß signaling.

Growth factor signaling results in dramatic phenotypic changes in cells, which require commensurate alterations in cellular metabolism. Mutations in SLC2A10/GLUT10, a member of the facilitative glucose transporter family, are associated with altered transforming growth factor-ß (TGFß) signaling in patients with arterial tortuosity syndrome (ATS). The objective of this work was to test whether SLC2A10/GLUT10 can serve as a link between TGFß-related transcriptional regulation and metabolism during development. In zebrafish embryos, knockdown of slc2a10 using antisense morpholino oligonucleotide injection caused a wavy notochord and cardiovascular abnormalities with a reduced heart rate and blood flow, which was coupled with an incomplete and irregular vascular patterning. This was phenocopied by treatment with a small-molecule inhibitor of TGFß receptor (tgfbr1/alk5). Array hybridization showed that the changes at the transcriptome level caused by the two treatments were highly correlated, revealing that a reduced tgfbr1 signaling is a key feature of ATS in early zebrafish development. Interestingly, a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function. Consistent with these results, slc2a10 morphants showed decreased respiration and reduced TGFß reporter gene activity. Finally, co-injection of antisense morpholinos targeting slc2a10 and smad7 (a TGFß inhibitor) resulted in a partial rescue of smad7 morphant phenotypes, suggesting scl2a10/glut10 functions downstream of smads. Taken together, glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFß signaling.