38 research outputs found
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis
The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance
INTRODUCTION
Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic.
RATIONALE
We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs).
RESULTS
Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants.
CONCLUSION
Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century
Microbial contamination potential of solutions in prefilled disposable syringes used with a syringe pump
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Adjuvant Therapy is Associated with Improved Survival in pT1N1 Gastric Cancer in a Heterogeneous Western Patient Population
Background
Two recent South Korean studies showed adjuvant therapy (AT) was not associated with improved survival in pT1N1 gastric adenocarcinoma (GAC). We established the prognostic utility of lymph node status, determined the pattern of use of AT, and compared survival stratified by type of AT in pT1N1 GAC in a Western patient population.
Methods
We identified patients with pT1N0 and pT1N1 GAC using the National Cancer Database from 2004 to 2012. Clinicopathologic variables, treatment regimens, and overall survival (OS) were compared.
Results
We compared 4516 (86.6%) pT1N0 to 696 (13.4%) pT1N1 patients. pT1N1 tumors were larger (median size 2.5 vs. 1.8Â cm,
p
 < 0.001), more often poorly differentiated (56.2% vs. 39.6%,
p
 < 0.001), and had higher median retrieved lymph nodes (RLN) (14 vs. 12,
p
 < 0.001) compared with pT1N0. pT1N1 was associated with worse median overall survival (OS) (6.9 vs. 9.9 years for pT1N0,
p
 < 0.001). pN1 was independently associated with worse OS (hazard ratio [HR] 2.17, 95% confidence interval [CI] 1.84–2.56). Increased RLN was associated with improved OS (HR 0.73, 95% CI 0.65–0.83). Among pT1N1 patients, 330 (47.4%) had observation (OBS), 77 (11.1%) received adjuvant chemotherapy (ACT), 68 (9.8%) received adjuvant radiation therapy (ART), and 221 (31.8%) received adjuvant chemoradiation therapy (ACRT). ACT and ACRT were independently associated with improved OS (HR 0.37, 95% CI 0.22–0.65 and HR 0.40, 95% CI 0.28–0.57).
Conclusions
pN1 was associated with worse survival and RLN ≥ 15 was associated with improved survival in pT1 GAC. ACT and ACRT were independently associated with improved survival in pT1N1 gastric cancer suggesting a valuable role in Western patients
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Incidence and comparative outcomes of periampullary cancer: A population-based analysis demonstrating improved outcomes and increased use of adjuvant therapy from 2004 to 2012
Background and Objectives Periampullary adenocarcinoma (PAC) is stratified anatomically: ampullary adenocarcinoma (AA), distal cholangiocarcinoma (DCC), duodenal adenocarcinoma (DA), and pancreatic ductal adenocarcinoma (PDAC). We aimed to determine differences in incidence, prognosis, and treatment in stage-matched PAC patients in a longitudinal study. Methods PAC patients were identified in The National Cancer Database from 2004 to 2012. Clinicopathological variables were compared between subtypes. Covariate-adjusted treatment use and OS were compared. Results The 116 705 patients with PAC were identified: 1320 (9%) AA, 3732 (3%) DCC, 7142 (6%) DA, and 95 511 (82%) PDAC. DA, DCC, and PDAC were associated with worse survival compared with AA (hazard ratio [HR], 1.10; 95% CI, 1.1-1.1; HR, 1.50; 95% CI, 1.4-1.6, and HR, 1.90; 95% CI, 1.8-1.9). Among resected patients, DA was associated with improved survival compared with AA (HR, 0.70; 95% CI, 0.67-0.75); DCC and PDAC were associated with worse survival (HR, 1.41; 95% CI, 1.31-1.53 and HR, 2.041; 95% CI, 1.07-2.12). Resected AA, PDAC, and DA, but not DCC, demonstrated significantly improved survival over the studied period. While all patients had increased adjuvant therapy (AT) receipt over time (P < 0.001), only patients with PDAC had increased neoadjuvant therapy (NAT) receipt (P < 0.001). Conclusion Resected PDAC, AA, and DA were associated with clinically significant improved survival over time, mirroring a concurrent associated increased receipt of AT
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Clinicopathologic Features and Outcomes of Early-Onset Pancreatic Adenocarcinoma in the United States
Limited research has been performed regarding pancreatic ductal adenocarcinoma (PDAC) diagnosed in early-onset patients. This study defined early-onset disease as cancer diagnosed before the age of 50Â years and aimed to characterize the clinicopathologic factors associated with early- versus late-onset patients.
The National Cancer Database was queried to identify early- and late-onset PDAC patients with cancer diagnosed from 2004 to 2013. Patient demographics, tumor characteristics, treatment regimens, and overall survival (OS) were compared between the groups.
The study enrolled 207,062 patients, including 12,137 early-onset patients (5.9%) and 194,925 late-onset patients (94.1%). The early-onset patients (stage 3 or 4 cancer) were more likely to present with a later stage of disease (62.1% vs. 55.2%; p < 0.001) and to be male (57.1% vs. 50.0%; p < 0.001) than those with late-onset PDAC. The early-onset patients also presented with a lower Charlson/Deyo comorbidity score (80.9% vs. 66.6% had a score of 0; p < 0.001) and received higher rates of treatment (22.8% vs. 40.1% received no treatment, p < 0.001) than the late-onset patients. Furthermore, early-onset PDAC was associated with improved OS among all the PDAC patients (9.2 vs. 6.0 months; p < 0.001) and among the surgically resected patients (27.3 vs. 24.3 months; p < 0.001). Early-onset PDAC also was found to be independently associated with improved OS after adjustment for other significant clinicopathologic factors.
Despite features suggestive of aggressive tumor biology at presentation, early-onset PDAC was independently associated with better OS than late-onset PDAC among all patients and among curatively resected stage-matched patients
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Improved Survival in Surgically Resected Distal Cholangiocarcinoma Treated with Adjuvant Therapy: a Propensity Score Matched Analysis
Background Data on the efficacy of adjuvant therapy (AT) in distal cholangiocarcinoma (dCCA) is limited. This study aimed to determine the role of AT in resected dCCA and identify subgroups that benefit from AT.
Methods We conducted a retrospective review of surgically resected dCCA in the NCDB from 2004 to 2013. Patients who received AT or observation (OB) were matched by propensity score. Log-rank test was used to compare OS.
Results Of 1782 patients with resected dCCA, 840 (47%) were in the OB group and 942 (53%) in the AT group. AT was younger (64.0 vs. 68.7 years, p < 0.001), had less comorbidities (Charlson Deyo score 0) (74.6 vs. 68.0%, p < 0.001), and more likely to have private insurance (p < 0.001). AT was more likely to present with T3/T4 stage (72 vs. 57%, p < 0.001), N1/N2 disease (58 vs. 37%, p < 0.001), and positive surgical margins (26 vs. 16%, p < 0.001). After 1: 1 propensity score matching, 500 OB and 500 AT patients were compared. AT was associated with better OS (HR 0.79; 95% CI 0.67-0.93). Median OS was 31 and 25 months for the AT and OB (p = 0.006). The 1-, 3-, and 5-year survival rates were 87, 46, and 31% for AT; 79, 39, and 24% for OB. Subgroup analysis revealed an associated survival advantage for AT in T3/T4 tumors (HR = 0.72; 95% CI 0.59-0.89), node positive disease (HR 0.70; 95% CI 0.56-0.87), and positive margins (HR 0.58; 95% CI 0.42-0.81).
Conclusion AT is associated with improved OS in resected dCCA, especially in T3/T4 tumors, node positive disease, and positive margins