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Background: Lynch syndrome (LS) is the most common colorectal cancer (CRC) predisposition syndrome. While patients (pts) with MLH1/ MSH2-associated LS are recommended to start colonoscopy ...between age 20-25, recent guidelines recommend delaying initiation in pts with MSH6/ PMS2-associated LS to age 30-35. However, data on findings from colonic surveillance in young MSH6/ PMS2-LS pts are limited. Methods: We performed a retrospective review of a multi-institutional cohort of pts with MSH6/ PMS2-associated LS who underwent any colonic surveillance prior to age 50, and assessed corresponding pathology results. Neoplastic lesions were defined as a CRC, adenomas, or non-hyperplastic serrated lesions. Clinicopathologic variables were reported with summary statistics and compared using non-parametric tests at the patient level and among pooled procedures. Results: We identified 285 pts 161(56%) MSH6; 124(44%) PMS2 with history of colonic surveillance prior to age 50. 190 (67%) pts were female, with similar sex distribution among the MSH6 and PMS2 groups. 107 (38%) pts had personal history (hx) of any cancer, 67 (42%) MSH6 and 40 (32%) PMS2, including 58 (20%) with CRC 35(22%) MSH6; 23 (19%) PMS2. Median age at CRC diagnosis (dx) was 39 and did not differ between groups (41 MSH6 vs. 37 PMS2, p = 0.47) with 16 (5.6%) pts dx prior to age 35. 157 (57%) pts had a family hx of CRC, and there was no difference in the rate of CRC between pts with or without family hx of CRC 50%(n = 25) vs 60%(n = 31), p = 0.33. Pts underwent a median of 2 colonic surveillance procedures (range 1-12) with 824 total procedures, 806 (98%) colonoscopies and 18 (2%) sigmoidoscopies, with 691 (85%) occurring at an academic/tertiary center. Among the 824 pooled procedures, there were 194 (24%) procedures with neoplastic lesions identified, including 19 (2.3%) with advanced adenomas or advanced serrated lesions and 34 (4.1%) with CRC. Among 247 procedures completed at age < 35, 43 (18%) detected neoplastic lesions, including 4 (1.6%) with advanced adenomas or advanced serrated lesions and 9 (3.6%) with CRCs. Notably, in 123 procedures performed prior to LS diagnosis, 43 (35%) had a neoplastic finding with 28 (23%) showing CRC. These findings did not differ between the MSH6 and PMS2 groups. Conclusions: Among this large, multi-institutional cohort of pts with MSH6/ PMS2-associated LS with history of colonic surveillance performed prior to age 50, colonic neoplasia was found at similar rates in both MSH6 and PMS2-associated LS. 20% of overall pts had CRC, with 48% presenting prior to LS dx. In surveillance procedures performed < age 35, the upper threshold of initiation of colonic surveillance as per NCCN, 18% found a neoplastic finding with 3.6% finding CRC, highlighting the need to optimize the age of colonic surveillance initiation in MSH6/ PMS2-associated LS.
Michael S. Barker1,2, Katrina M. Dlugosch1, Louie Dinh1, R. Sashikiran Challa2, Nolan C. Kane1, Matthew G. King1 and Loren H. Rieseberg1,21The Biodiversity Research Centre and Department of Botany, ...University of British Columbia, Vancouver, BC V6T 1Z4, Canada. 2Department of Biology, Indiana University, Bloomington, IN 47405, USA. AbstractRecent increases in the production of genomic data are yielding new opportunities and challenges for biologists. Among the chief problems posed by next-generation sequencing are assembly and analyses of these large data sets. Here we present an online server, http://EvoPipes.net, that provides access to a wide range of tools for bioinformatic analyses of genomic data oriented for ecological and evolutionary biologists. The EvoPipes.net server includes a basic tool kit for analyses of genomic data including a next-generation sequence cleaning pipeline (SnoWhite), scaffolded assembly software (SCARF), a reciprocal best-blast hit ortholog pipeline (RBH Orthologs), a pipeline for reference protein-based translation and identification of reading frame in transcriptome and genomic DNA (TransPipe), a pipeline to identify gene families and summarize the history of gene duplications (DupPipe), and a tool for developing SSRs or microsatellites from a transcriptome or genomic coding sequence collection (findSSR). EvoPipes.net also provides links to other software developed for evolutionary and ecological genomics, including chromEvol and NU-IN, as well as a forum for discussions of issues relating to genomic analyses and interpretation of results. Overall, these applications provide a basic bioinformatic tool kit that will enable ecologists and evolutionary biologists with relatively little experience and computational resources to take advantage of the opportunities provided by next-generation sequencing in their systems.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To perform an in‐depth analysis of opioid‐related ADRs reported by consumers, manufacturers and healthcare professionals. Delving into the depth and breadth of reported opioid‐related adverse drug ...reactions (ADRs) provides an opportunity to strategize better clinical management and alleviate safety concerns. Retrospective pharmacovigilance disproportionality analysis for opioid‐related ADRs in the FDA Adverse Event Reporting System (FAERS) database was performed. Detailed analysis of patient (sex, age) and report (year of report; reporter: healthcare worker vs consumer) characteristics were conducted using reports from 2004 quarter 1 to 2018 quarter 4. Reporting odds ratios and confidence intervals (RORs,CI) were calculated. Of the 1 916 674 ADR reports, 300 985 indicated opioids as the primary medication. There was a surge in opioid‐related ADRs reported in 2018 with six times more reports compared to 2004 and twice the number of reports compared to 2017. The largest ROR among the 20 common ADRs was depression and suicide‐self‐injury (ROR 3.12, 95% CI 3.01‐3.22) for reports in age group ≥65 compared to age group 18 to 64, and lack of efficacy (ROR 6.80, 95% CI 6.61‐7.00) for males compared to females. ADRs with the largest RORs for consumers included lack of efficacy/effect (ROR 3.37, 95% CI 3.28‐3.46), administration site reactions (ROR 3.21, 95% CI 3.11‐3.32), depression and suicide self‐injury (ROR 2.26, 95% CI 2.14‐2.38) compared to healthcare professionals. Important aspects of opioid ADR voluntary reporting included suicidal ideation in elderly patients and lack of efficacy, especially in male patients. This examination provides insight to better manage safety concerns of opioids.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The majority of emerging infectious diseases are zoonotic (transmissible between animals and humans) in origin, and therefore integrated surveillance of disease events in humans and animals has been ...recommended to support effective global response to disease emergence. While in the past decade there has been extensive global surveillance for highly pathogenic avian influenza (HPAI) infection in both animals and humans, there have been few attempts to compare these data streams and evaluate the utility of such integration.
We compared reports of bird outbreaks of HPAI H5N1 in Egypt for 2006-2011 compiled by the World Organisation for Animal Health (OIE) and the UN Food and Agriculture Organization (FAO) EMPRESi reporting system with confirmed human H5N1 cases reported to the World Health Organization (WHO) for Egypt during the same time period.
Both human cases and bird outbreaks showed a cyclic pattern for the country as a whole, and there was a statistically significant temporal correlation between the data streams. At the governorate level, the first outbreak in birds in a season usually but not always preceded the first human case, and the time lag between events varied widely, suggesting regional differences in zoonotic risk and/or surveillance effectiveness. In a multivariate risk model, lower temperature, lower urbanization, higher poultry density, and the recent occurrence of a bird outbreak were associated with increased risk of a human case of HPAI in the same governorate, although the positive predictive value of a bird outbreak was low.
Integrating data streams of surveillance for human and animal cases of zoonotic disease holds promise for better prediction of disease risk and identification of environmental and regional factors that can affect risk. Such efforts can also point out gaps in human and animal surveillance systems and generate hypotheses regarding disease transmission.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spiral ganglion Schwann cells (SGSCs) myelinate spiral ganglion neurons (SGNs) and represent a potential source of neurotrophic support for SGNs. Deafening due to loss of hair cells results in ...gradual degeneration and death of SGNs. Successful efforts to maintain or regenerate a functional auditory nerve may depend on a healthy population of SGSCs, yet the responses of SGSCs to neural injury remain largely unknown. Here we investigate the role of p75(NTR) in SGSC responses to gradual denervation. Following deafening, SGSCs in the osseous spiral lamina (OSL) and, subsequently, in Rosenthal's canal (RC) expressed elevated p75(NTR) compared to hearing controls. p75(NTR)-positive cells co-labeled with S100 and RIP antibodies (Schwann cell markers), but not with anti-neurofilament. The pattern of p75(NTR) expression mirrored the pattern of neural degeneration, beginning in the OSL of the cochlea base and later extending into the apex. SGSCs expressed sortilin, a p75(NTR) co-receptor for pro-neurotrophins. Both pro-nerve growth factor (pro-NGF) and pro-brain derived neurotrophic factor (proBDNF) induced apoptosis in cultured SGSCs. Deafened animals exhibited significantly higher levels of SGSC proliferation (as measured by BrdU uptake) compared to hearing animals while total Schwann cell density remained stable, suggesting a tight regulation of SGSC proliferation and cell death. SGSCs undergoing cell division lose p75(NTR) expression from the cell surface and demonstrate nuclear localization of the intracellular domain (ICD), raising the possibility that p75(NTR) cleavage and ICD nuclear localization regulate SGSC proliferation. These results suggest that p75(NTR) contributes to SGSC responses to deafening and neural degeneration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Coastal strand and wetland habitats in the Hawaiian Islands are often intensively managed to restore and maintain biodiversity. Due to the low gradient of most coastal plain environments, the rate ...and aerial extent of sea-level rise (SLR) impact will rapidly accelerate once the height of the sea surface exceeds a critical elevation. Here, we develop this concept by calculating a SLR critical elevation and joint uncertainty that distinguishes between slow and rapid phases of flooding. We apply the methodology to three coastal wetlands on the Hawaiian Islands of Maui and O‘ahu to exemplify the applicability of this methodology for wetlands in the Pacific island region. Using high-resolution LiDAR digital elevation models, flooded areas are mapped and ranked from high (80 %) to low (2.5 %) risk based upon the percent probability of flooding under the B1, A2, and A1Fl emissions scenarios. As the rate of flooding transitioned from the slow to rapid phase, the area (expressed as a percentage of the total) at a high risk of flooding under the A1Fl scenario increased from 21.0 to 53.3 % (south Maui), 0.3 to 18.2 % (north Maui), and 1.7 to 15.9 % (north O‘ahu). At the same time, low risk areas increased from 34.1 to 80.2, 17.7 to 46.9, and 15.4 to 46.3 %. The critical elevation of SLR may have already passed (2003) on south Maui, and decision makers on North Maui and O‘ahu may have approximately 37 years (2050) to develop, and implement adaptation strategies that meet the challenges of SLR in advance of the largest impacts.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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