High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors; Four cases of homozygous deletions of the CDKN2A gene

BACKGROUND: Neuroblastoma is a very heterogeneous pediatric tumor of the sympathetic nervous system showing clinically significant patterns of genetic alterations. Favorable tumors usually have near-triploid karyotypes with few structural rearrangements. Aggressive stage 4 tumors often have near-diploid or near-tetraploid karyotypes and structural rearrangements. Whole genome approaches for analysis of genome-wide copy number have been used to analyze chromosomal abnormalities in tumor samples. We have used array-based copy number analysis using oligonucleotide single nucleotide polymorphisms (SNP) arrays to analyze the chromosomal structure of a large number of neuroblastoma tumors of different clinical and biological subsets. RESULTS: Ninety-two neuroblastoma tumors were analyzed with 50 K and/or 250 K SNP arrays from Affymetrix, using CNAG3.0 software. Thirty percent of the tumors harbored 1p deletion, 22% deletion of 11q, 26% had MYCN amplification and 45% 17q gain. Most of the tumors with 1p deletion were found among those with MYCN amplification. Loss of 11q was most commonly seen in tumors without MYCN amplification. In the case of MYCN amplification, two types were identified. One type displayed simple continuous amplicons; the other type harbored more complex rearrangements. MYCN was the only common gene in all cases with amplification. Complex amplification on chromosome 12 was detected in two tumors and three different overlapping regions of amplification were identified. Two regions with homozygous deletions, four cases with CDKN2A deletions in 9p and one case with deletion on 3p (the gene RBMS3) were also detected in the tumors. CONCLUSION: SNP arrays provide useful tools for high-resolution characterization of significant chromosomal rearrangements in neuroblastoma tumors. The mapping arrays from Affymetrix provide both copy number and allele-specific information at a resolution of 10–12 kb. Chromosome 9p, especially the gene CDKN2A, is subject to homozygous (four cases) and heterozygous deletions (five cases) in neuroblastoma tumors

Cohort profile: the British Columbia COVID-19 Cohort (BCC19C)—a dynamic, linked population-based cohort

PurposeThe British Columbia COVID-19 Cohort (BCC19C) was developed from an innovative, dynamic surveillance platform and is accessed/analyzed through a cloud-based environment. The platform integrates recently developed provincial COVID-19 datasets (refreshed daily) with existing administrative holdings and provincial registries (refreshed weekly/monthly). The platform/cohort were established to inform the COVID-19 response in near “real-time” and to answer more in-depth epidemiologic questions.ParticipantsThe surveillance platform facilitates the creation of large, up-to-date analytic cohorts of people accessing COVID-19 related services and their linked medical histories. The program of work focused on creating/analyzing these cohorts is referred to as the BCC19C. The administrative/registry datasets integrated within the platform are not specific to COVID-19 and allow for selection of “control” individuals who have not accessed COVID-19 services.Findings to dateThe platform has vastly broadened the range of COVID-19 analyses possible, and outputs from BCC19C analyses have been used to create dashboards, support routine reporting and contribute to the peer-reviewed literature. Published manuscripts (total of 15 as of July, 2023) have appeared in high-profile publications, generated significant media attention and informed policy and programming. In this paper, we conducted an analysis to identify sociodemographic and health characteristics associated with receiving SARS-CoV-2 laboratory testing, testing positive, and being fully vaccinated. Other published analyses have compared the relative clinical severity of different variants of concern; quantified the high “real-world” effectiveness of vaccines in addition to the higher risk of myocarditis among younger males following a 2nd dose of an mRNA vaccine; developed and validated an algorithm for identifying long-COVID patients in administrative data; identified a higher rate of diabetes and healthcare utilization among people with long-COVID; and measured the impact of the pandemic on mental health, among other analyses.Future plansWhile the global COVID-19 health emergency has ended, our program of work remains robust. We plan to integrate additional datasets into the surveillance platform to further improve and expand covariate measurement and scope of analyses. Our analyses continue to focus on retrospective studies of various aspects of the COVID-19 pandemic, as well as prospective assessment of post-acute COVID-19 conditions and other impacts of the pandemic

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

An examination of contemporary challenges in deceased donor kidney allocation

Transplantation is the preferred treatment for patients with kidney failure, but the need for transplantation exceeds the organ supply. Strategies to address the organ shortage include: preventing end-organ failure, increasing the number of deceased donor kidneys (DDK) for transplantation, and ensuring appropriate allocation to avoid organ waste. This thesis: develops an improved metric for deceased donation activity; describes an age-matching allocation strategy to reduce organ waste; and examines the impact of selected wait-list policies on disparities in access to DDK transplantation. Using national administrative databases, we: Estimated and validated the number of potential deceased organ donors among in-hospital deaths using diagnostic codes; Calculated differences in DDK and transplant candidate survival by age using Cox regression to determine the area between survival curves (ABSC), and combined these measures with information on DDK and candidate ages to define age cut-points for DDK allocation; Described the use and outcomes of older DDKs (≥ 65 years) in countries with different allocation systems using Cox regression and ABSC, and identified patients that achieved a lifetime of transplant function from older DDKs; and Examined longitudinal use and outcomes of wait-listing candidates at multiple transplant centres using logistic and Cox regression. Three percent of Canadians who die in-hospital were identified as potential organ donors, suggesting significant potential to increase deceased donation. We determined DDK and candidate age cut-points for Canadian allocation, and estimated that implementation of these cut-points could have eliminated 500 years of wasted donor kidney function, and prevented 800 years of post-transplant dialysis compared to the current allocation strategy. We found that older DDKs provided a lifetime of kidney function for patients aged >60 years, suggesting targeted use of these organs could safely increase transplantation. Finally, we determined that multiple wait-listing helped minimize geographic disparities in accessing transplantation and may be an important policy consideration in countries that do not currently allow multiple listing. As transplantation wait-lists grow at unprecedented rates, the potential to increase deceased donation, implement allocation policies to decrease organ wastage, safely expand the use of older deceased donors and promulgate wait-list policies to increase access to transplantation will become more important.Medicine, Faculty ofPopulation and Public Health (SPPH), School ofGraduat