Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery.
\n \n\n \n \n\n Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33\u2013activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25\u2013activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor\n IL25\n expression had reduced survival and increased IL-25R\u2013expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an\n Apc\n mutation\u2013driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-\u03b3 (IFN-\u03b3)\u2013mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25\u2013ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.\n
\n \n\n \n \nStatic cold storage (SCS) is the standard method for pancreas preservation prior to transplantation; however, it does not permit organ assessment. Normothermic reperfusion (NR) is utilized clinically for other organs to assess viability. Our aim was to develop NR using normothermic machine perfusion technique to simulate reperfusion at the time of transplantation, enabling evaluation of oxygenated hypothermic machine perfusion (HMPO2) as a newer strategy to optimize pancreas preservation. 13 porcine pancreases procured after circulatory death were divided into 3 groups: 4 pancreases preserved using SCS, and 2 groups preserved by HMPO2 (n\u00a0=\u00a04 and n\u00a0=\u00a05, differing by type of preservation solution). Duration of perfusion or cold storage was 6\u00a0hours before the 1-hour assessment using NR. Outcome measures were perfusion characteristics, biochemistry and change in tissue water mass as oedema assessment. During NR, the HMPO2 groups demonstrated better perfusion characteristics, normal macroscopic appearances, decreased water mass and one HMPO2 group demonstrated a response to glucose stimulation. Conversely, the SCS group showed an increased water mass and developed early macroscopic appearances of oedema, interstitial haemorrhage and minimal portal outflow. This study suggests that ex situ assessment of pancreases by NR is promising, and that HMPO2 may be better than SCS.
\n \n\n \n \nThis commentary outlines the development and current status of the UK Islet Transplant Programme in the UK. The author makes the case that it is now time for similar fully funded beta-cell programmes to be made available in many other countries as well.
\n \n\n \n \nOptimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of \u03b2-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet\u00a0allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate
\n \n\n \n \nBACKGROUND: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management. METHODS: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR). RESULTS: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth. CONCLUSIONS: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.
\n \n\n \n \nThe UK islet allotransplant program is nationally funded to deliver one or two transplants over 12\u00a0months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10\u00a0years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50\u00a0pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12\u00a0months was attained in 23 (68%) single and 47 (94%) (p\u00a0=\u00a0.002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12\u00a0months sustained graft function at 6\u00a0years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12\u00a0months (p\u00a0
\n \n\n \n \nIntussusception is the most common cause of intestinal obstruction in infancy and early childhood. It occurs when one segment of bowel (the intussusceptum) invaginates into an adjacent distal segment of bowel (the intussuscepien). The classical presentation is with intermittent abdominal pain, vomiting and redcurrant jelly like stool. Diagnosis can be accurately confirmed with an ultrasound scan. Initial management is with fluid resuscitation and antibiotics. Following adequate resuscitation, treatment is usually with a non-operative air enema reduction under fluoroscopic guidance. If this fails to completely reduce the intussusception, the air enema may be repeated in patients that are clinically stable. The main risks associated with an air enema are bowel perforation, failed reduction and recurrence. Surgical intervention is indicated in patients presenting with perforation, those that are clinically unstable or where multiple air enemas have failed to reduce the intussusception. Surgery can be performed open or laparoscopic and involves attempted manual reduction of the intussusception and may require bowel resection and anastomosis.
\n \n\n \n \nIntroduction: The provision of patient information leaflets (PILs) for cancer treatment options is primarily via a paper format. PILs can now be provided on an electronic tablet with the added benefits of providing audio-visual information. Materials and Methods: Between February 2017 and August 2019, 112 patients with newly diagnosed prostate cancer (PCa) were enrolled into our prospective cohort study. The control group (n = 56) were all given PILs on a paper as the standard of care (SoC). The intervention (tablet) group (n = 56) were given the same paper PILs as that of the control group plus an electronic tablet computer with an application containing all SoC paper PILs in an electronic format and supplementary videos detailing treatments. Both groups were asked to complete a validated questionnaire (Telemedicine, Satisfaction and Usefulness questionnaire) with regard to satisfaction with care, provided information, and tablet usage. Results: The response rate for our study was 78/112 (70%). The control and tablet groups were highly satisfied with their care (91%-100% agreed or strongly agreed) and with the information they received (80%-100% agreed or strongly agreed). In the tablet group, 41/46 (89%) reported its utilization. Of those 41, 38 (92%) considered the tablet easy to use and 13 (32%) reported a preference for the paper format. Conclusions: The provision of electronic PILs in PCa treatment is an innovative method of providing oncological care, with positive feedback from our patients. With further development as a mobile application, electronic PILs may allow a more environmentally and fiscally advantageous method of providing PCa care.
\n \n\n \n \nPancreatic \u03b2 cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca(2+) action potentials due to the activation of voltage-dependent Ca(2+) channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic \u03b2 cells. NAADP-regulated Ca(2+) release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca(2+) from the endolysosomal system, resulting in localized Ca(2+) signals. We show here that NAADP-mediated Ca(2+) release from endolysosomal Ca(2+) stores activates inward membrane currents and depolarizes the \u03b2 cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca(2+) release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca(2+) signals, and insulin secretion. Our findings implicate NAADP-evoked Ca(2+) release from acidic Ca(2+) storage organelles in stimulus-secretion coupling in \u03b2 cells.
\n \n\n \n \nAbstractLynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
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