Consortium Participants Research Articles

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium.

Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry. MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) in transforming growth factor-β pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched in SMAD3 PV compared with other transforming growth factor-β PV (prevalence ratio 1.8 [1.1-2.8], P <0.02). Severe disjunction (>10 mm) was only observed in the transforming growth factor-β subgroup and was further enriched in participants with SMAD3 PV (prevalence ratio 3.1 [1.1-8.6]). MVP (prevalence ratio 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9]) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events. Pathological mitral valve phenotypes are more prevalent in individuals with PV in transforming growth factor-β pathway genes, particularly SMAD3. MR and MVP but not MAD are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for heritable thoracic aortic disease should be considered for such individuals, especially if they also have a family history of heritable thoracic aortic disease.

Association of depression with longitudinal changes in brain structure across the lifespan: A mendelian randomization study.

Understanding the impact of depression on brain aging benefits the prognosis of this disease and of the risk that other age-related brain disorders will develop in the same population. The aim of the present study was to explore the genetic effect of depression on longitudinal changes in brain structure throughout the lifespan using a Mendelian randomization approach. Summary data from a genome-wide association study of 195,321 to 377,277 participants in the FinnGen consortium were used to predict depression, anxiety disorders, mood disorders, and antidepressant use genetically. Data from 15,640 participants in the ENIGMA consortium were included to predict changes in 15 brain structures throughout the lifespan. The causal relationship between these depressive traits and the brain structure parameters was assessed by two-sample Mendelian randomization (including inverse-variance weighted). Sensitivity analyses were conducted for quality control. Depression slowed the decrease of cortical gray matter volume significantly throughout the lifespan (p = 0.001). Depression, anxiety, and mood disorders nominally decreased the rates of change of volume in the cerebellum gray matter, lateral ventricles, and cortical gray matter throughout the lifespan (p = 0.048, p = 0.021, p = 0.038, respectively). Antidepressants did not affect these rates of change significantly (p > 0.05). Sensitivity analyses confirmed the reliability of this study. Depression and its main symptoms have a slight effect on longitudinal changes in a few brain structures throughout the lifespan at the genetic level. These findings do not support the notion that depression affects macro-aging in the brain crucially.

Influence of Contract Management on Purchasing Consortia at County Referral Hospitals in the Coast Region, Kenya

The Purchasing consortium has been used to describe a form of cooperation in a diversified view to pool resources and manage supply risk. Depending on the anticipated advantages, the function of a purchasing group might be expanded more or less. The objective of the study was to determine the influence of contract management on purchasing consortium. The study was done in the County Referral Hospital in the Coast Region, Kenya. Theoretically, the study was anchored on competency theory, MacNeil Relational Theory. The study used the descriptive research design in undertaking this study. The study population comprised of 212 officials drawn from across the county referral hospitals in the coastal region of Kenya. The stratified random sampling technique resulted into having a total sample size of 139 units of analysis. Data was collected by use of questionnaires, analyzed, and presented scientifically in tables and graphs. The study findings revealed that Contract Management has a significant positive on the purchasing consortium. The study recommends that government and regulatory authorities implement policies and incentives to encourage healthcare organizations to adopt a portfolio approach to procurement. Given the significant financial and operational implications of purchasing consortiums, robust regulatory mechanisms are essential to safeguard against corruption, fraud, and collusion. Regulators should establish clear guidelines, standards, and monitoring mechanisms to govern consortium formation, operation, and performance evaluation. The study also recommends that government and regulatory bodies leverage technology and data analytics to enhance procurement efficiency and effectiveness in the healthcare sector. Furthermore, the study recommends that hospital management adopt a strategic approach to contract management that aligns with their organizational objectives and resource constraints. While the correlation analysis revealed a weak relationship between contract management and consortium participation, it is imperative for hospitals to prioritize effective contract management practices to mitigate risks and maximize value from procurement activities.

Abstract PO5-09-03: Multi-tissue transcriptome-wide association studies identified genes for intrinsic subtypes of breast cancer

Abstract Background: Though several genome-wide association studies (GWAS) of breast cancer (BC) have identified common variants which differ between intrinsic subtypes, the genes through which these variants act through to impact BC risk have not been fully established. Furthermore, transcriptome-wide association studies (TWAS) have thus far been primarily employed to identify genes associated with overall BC risk, while overlooking how the influence of common variation on gene expression may contribute to subtype-specific differences. Methods: In this study, we performed two complementary multi-tissue TWASs for each of the following BC intrinsic subtypes: Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, Triple Negative BC. These two approaches included 1) an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues using the Aggregated Cauchy Association Test (ACAT) and 2) a splicing-based approach that utilized two applications of ACAT to collate splicing QTLs (sQTLs) for a given gene in a tissue and then across tissues. To perform these two TWASs, we utilized e/sQTL models trained in 11 tissues from the Genotype-Tissue Expression Project including breast, ovary, uterus, vagina, EBV-transformed lymphocytes, whole blood, spleen, liver, subcutaneous adipose, visceral adipose, and cell-cultured fibroblasts. GWAS summary statistics were previously generated from 133,384 BC cases and 113,789 controls who were participants in the Breast Cancer Association Consortium (BCAC). We further performed our TWAS while conditioning e/sQTL effect sizes on nearby GWAS index SNPs. Additionally, we utilized gene-based fine-mapping of eQTLs and sQTL to identify candidate causal genes for each intrinsic subtype. Results: Overall, we identified 164 genes in 69 loci that were associated with Luminal A-like, 19 genes in 9 loci with Luminal B-like, 18 genes in 11 loci with Luminal B/HER2-negative-like, 10 genes in 7 loci with HER2-enriched-like, and 29 genes in 12 loci with TNBC. Among these genes, 17 genes had not been reported in previous TWAS of BC, and 140 genes, 1 gene, 2 genes, 2 genes, and 16 genes were uniquely associated with each of the intrinsic subtypes, respectively. Additionally, we identified one gene associated with Luminal A-like and one gene with Luminal B-like BC that were each in a locus located at least 1.4 Mb from published GWAS hits. Furthermore, we identified 106, 11, 10, 5, and 21 candidate causal genes for each of the intrinsic subtypes, respectively, that had a posterior inclusion probability of 0.9 in at least one e/sQTL. Conclusion: In summary, our multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation impacts BC etiology by modulating the expression and splicing of genes in multiple tissue types. Citation Format: James Li, Julian McClellan, Haoyu Zhang, Guimin Gao, Dezheng Huo. Multi-tissue transcriptome-wide association studies identified genes for intrinsic subtypes of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-03.

Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease

BackgroundMillions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs.MethodsAmong the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis.ResultsGenetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80–0.95); P < 0.01) and UC risk (0.83 (0.73–0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of LDLR and LPL enhancements, respectively (odds ratioLDLR: 1.18 (1.03–1.36); P = 0.018; odds ratioCD: 1.26 (1.11–1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was associated with increased CD risk (0.68 (0.50–0.94); P = 0.018). These findings were confirmed through Mendelian analysis of the cross-combination of four separate datasets. APOC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglycerides, Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs partly through increasing Lactobacillaceae.ConclusionVigilance is required to prevent adverse effects on IBDs (UC) for patients receiving volanesorsen (an antisense oligonucleotide targeting ApoC3 mRNA) and adverse effects on CD for statin users. LPL and LDLR show promise as candidate drug targets for CD and IBD, respectively, with mechanisms that are potentially independent of their lipid-lowering effects.

State capacity impact on COVID-19 mortality in Brazil.

This study addresses the State's capacity to combat the COVID-19 pandemic and contributes to the literature on crisis management in health care. We analyzed whether the capacity level impacted the State response to COVID-19 in Brazilian healthcare regions in 2020 using a set of statistical analysis techniques and public health impact analysis, including propensity score matching (PSM). Results revealed that a low COVID-19 mortality was associated with participation in municipal health consortia, schooling level of municipal health managers and the resources allocated by the Brazilian National Program for Improvement of Access and Quality of Basic Care (PMAQ). Conversely, the number of intensive care units (ICU) and life-sustaining equipment available were associated with higher mortality, as locations with a larger population concentrated operational capacity to treat the most severe cases. In conclusion, the different levels of State capacity in health regions led to different outcomes in combating the pandemic. This reinforces the importance of discussing State capacity and crisis management, since the COVID-19 confrontation in Brazil related to the level of existing resources concerning health system capacity, bureaucratic capacity and participation in consortia for sharing inputs and ensuring the provision of health services to the population.

UPS of the CNS: Longitudinal profiling of mitochondrial DNA in neuronal‐enriched packages from plasma of individuals with cognitive decline

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder that disproportionately burdens Mexican Americans (MAs) due to a combination of population‐specific environmental exposures and genetic risk factors. In addition to AD, MAs have a higher prevalence of metabolic comorbidities such as type 2 diabetes (T2D) that have been implicated in accelerated age‐related cognitive impairment. Tissue‐specific mitochondrial dysfunction and oxidative stress are early and prominent features of both AD and T2D that propagate systemic inflammation as these diseases progress. Despite the shared pathophysiology, we do not fully understand the underlying molecular mechanisms linking cognitive decline and metabolic stress, especially in understudied minority populations. Mitochondrial dysfunction may serve as the biological basis of the AD health disparity in MAs who experience earlier onset of symptoms and have an overrepresentation of T2D compared to non‐Hispanic whites (NHWs). This project aims to study T2D‐related risk for cognitive impairment by assessing the packages that neurons secrete to communicate with cells in the periphery. These neuronal‐enriched exosomes (NEEs) can cross the blood‐brain barrier and are thus capable of mediating systemic inflammation in response to CNS‐sourced stress through their mitochondrial DNA (mtDNA) cargo. We hypothesize that plasma NEE mtDNA load will reflect cognitive status and T2D comorbidity over time.MethodsExosomes of neuronal origin were enriched via CD171‐based immunocapture in longitudinal plasma samples (two timepoints, 5 years apart) from 348 Texas Alzheimer’s Research and Care Consortium (TARCC) participants stratified by race/ethnicity (MA/NHW), cognitive status (AD/MCI/NC), and T2D comorbidity (+/‐). The success of NEE isolation was assessed using nanoparticle tracking analysis (NTA) and immunoblotting against CD171 and CD81 (canonical exosome surface marker). Following extraction of total DNA from NEEs, absolute mtDNA load and deletion ratio were estimated using a real‐time qPCR assay targeting sites within the minor (D‐loop) and major (ND4) arcs.ResultsHerein, we demonstrate the ability to isolate NEEs from plasma and quantify their mtDNA cargo. Resultant values were analyzed for longitudinal differences and correlation with disease status based on various neuropsychological measures.ConclusionAs the first effort to assess mtDNA in NEEs, this project provides novel insight into how T2D confers risk for AD across different populations over time.

Risk of Upper Extremity Musculoskeletal Injury Within the First Year After a Concussion.

Emerging evidence suggests that athletes and military personnel are at increased risk for lower extremity musculoskeletal injury after a concussion; however, the association between concussion and subsequent upper extremity (UE) musculoskeletal injury is unknown. To prospectively examine the association between concussion and UE musculoskeletal injury risk within the first year after returning to unrestricted activity. Cohort study; Level of evidence, 3. A total of 316 cases of concussion 42% (132/316 women) were observed among 5660 Concussion Assessment, Research and Education Consortium participants at the United States Military Academy from May 2015 to June 2018. Active injury surveillance within the cohort was conducted for 12 months after unrestricted return to activity to identify any incident cases of acute UE musculoskeletal injury. Injury surveillance during the follow-up period was also conducted for nonconcussed controls who were matched by sex and competitive sport level. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios between concussed cases and nonconcussed controls for time to UE musculoskeletal injury. During the surveillance period, 19.3% of concussed cases and 9.2% of nonconcussed controls sustained a UE injury. In the univariate model, concussed cases were 2.25 times (95% CI, 1.45-3.51) more likely to sustain a UE injury during the 12-month follow-up period when compared with the nonconcussed controls. In the multivariable model, adjusted for history of concussion, sport level, somatization, and history of UE injury, concussed cases were 1.84 times (95% CI, 1.10-3.07) more likely to sustain a UE injury during the surveillance period compared with nonconcussed controls. Sport level remained an independent risk factor for UE musculoskeletal injury; however, concussion history, somatization, and history of UE injury were not independent risk factors. Concussed cases were more than twice as likely to sustain an acute UE musculoskeletal injury within the first 12 months after unrestricted return to activity when compared with nonconcussed controls. The higher hazard of injury remained in the concussed group after adjusting for other potential risk factors.

Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2=0.100, p-value=2.69e-4, q-value=0.004) and suggestive associations with Visual Sensorimotor function (R2=0.039, p-value=0.024, q-value=0.180), but not with General Cognitive Ability (R2=0.015, p-value=0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2% of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

Biomarkers of cellular senescence in idiopathic pulmonary fibrosis

BackgroundCellular senescence is a cell fate in response to diverse forms of age-related damage and stress that has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The associations between circulating levels of candidate senescence biomarkers and disease outcomes have not been specifically studied in IPF. In this study we assessed the circulating levels of candidate senescence biomarkers in individuals affected by IPF and controls and evaluated their ability to predict disease outcomes.MethodsWe measured the plasma concentrations of 32 proteins associated with senescence in Lung Tissue Research Consortium participants and studied their relationship with the diagnosis of IPF, parameters of pulmonary and physical function, health-related quality of life, mortality, and lung tissue expression of P16, a prototypical marker of cellular senescence. A machine learning approach was used to evaluate the ability of combinatorial biomarker signatures to predict disease outcomes.ResultsThe circulating levels of several senescence biomarkers were significantly elevated in persons affected by IPF compared to controls. A subset of biomarkers accurately classified participants as having or not having the disease and was significantly correlated with measures of pulmonary function, health-related quality of life and, to an extent, physical function. An exploratory analysis revealed senescence biomarkers were also associated with mortality in IPF participants. Finally, the plasma concentrations of several biomarkers were associated with their expression levels in lung tissue as well as the expression of P16.ConclusionsOur results suggest that circulating levels of candidate senescence biomarkers are informative of disease status, pulmonary and physical function, and health-related quality of life. Additional studies are needed to validate the combinatorial biomarkers signatures that emerged using a machine learning approach.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Optimizing Concussion Care Seeking: The Influence of Previous Concussion Diagnosis Status on Baseline Assessment Outcomes

Background: The prevalence of unreported concussions is high, and undiagnosed concussions can lead to worse postconcussion outcomes. It is not clear how those with a history of undiagnosed concussion perform on subsequent standard concussion baseline assessments. Purpose: To determine if previous concussion diagnosis status was associated with outcomes on the standard baseline concussion assessment battery. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Concussion Assessment, Research, and Education (CARE) Consortium participants (N = 29,934) self-reported concussion history with diagnosis status and completed standard baseline concussion assessments, including assessments for symptoms, mental status, balance, and neurocognition. Multiple linear regression models were used to estimate mean differences and 95% CIs among concussion history groups (no concussion history [n = 23,037; 77.0%], all previous concussions diagnosed [n = 5315; 17.8%], ≥1 previous concussions undiagnosed [n = 1582; 5.3%]) at baseline for all outcomes except symptom severity and Brief Symptom Inventory–18 (BSI-18) score, in which negative binomial models were used to calculate incidence rate ratios (IRRs). All models were adjusted for sex, race, ethnicity, sport contact level, and concussion count. Mean differences with 95% CIs excluding 0.00 and at least a small effect size (≥0.20), and those IRRs with 95% CIs excluding 1.00 and at least a small association (IRR, ≥1.10) were considered significant. Results: The ≥1 previous concussions undiagnosed group reported significantly greater symptom severity scores (IRR, ≥1.38) and BSI-18 (IRR, ≥1.31) scores relative to the no concussion history and all previous concussions diagnosed groups. The ≥1 previous concussions undiagnosed group performed significantly worse on 6 neurocognitive assessments while performing better on only 2 compared with the no concussion history and all previous concussions diagnosed groups. There were no between-group differences on mental status or balance assessments. Conclusion: An undiagnosed concussion history was associated with worse clinical indicators at future baseline assessments. Individuals reporting ≥1 previous undiagnosed concussions exhibited worse baseline clinical indicators. This may suggest that concussion-related harm may be exacerbated when injuries are not diagnosed.

Optimizing Concussion Care Seeking: Identification of Factors Predicting Previous Concussion Diagnosis Status.

There is limited understanding of factors affecting concussion diagnosis status using large sample sizes. The study objective was to identify factors that can accurately classify previous concussion diagnosis status among collegiate student-athletes and service academy cadets with concussion history. This retrospective study used support vector machine, Gaussian Naïve Bayes, and decision tree machine learning techniques to identify individual (e.g., sex) and institutional (e.g., academic caliber) factors that accurately classify previous concussion diagnosis status (all diagnosed vs 1+ undiagnosed) among Concussion Assessment, Research, and Education Consortium participants with concussion histories ( n = 7714). Across all classifiers, the factors examined enable >50% classification between previous diagnosed and undiagnosed concussion histories. However, across 20-fold cross validation, ROC-AUC accuracy averaged between 56% and 65% using all factors. Similar performance is achieved considering individual risk factors alone. By contrast, classifications with institutional risk factors typically did not distinguish between those with all concussions diagnosed versus 1+ undiagnosed; average performances using only institutional risk factors were almost always <58%, including confidence intervals for many groups <50%. Participants with more extensive concussion histories were more commonly classified as having one or more of those previous concussions undiagnosed. Although the current study provides preliminary evidence about factors to help classify concussion diagnosis status, more work is needed given the tested models' accuracy. Future work should include a broader set of theoretically indicated factors, at levels ranging from individual behavioral determinants to features of the setting in which the individual was injured.

Association between Body Mass Index and Risk of Gastric Cancer by Anatomic and Histologic Subtypes in Over 500,000 East and Southeast Asian Cohort Participants.

This study was performed to investigate the association between body mass index (BMI) and gastric cancer in East and Southeast Asia where most of gastric cancer is non-cardia gastric cancer. On the basis of 8,997 gastric cancer cases among the Asia Cohort Consortium participants from China, Japan, Korea, and Singapore (N = 538,835), we assessed gastric cancer risk according to BMI by calculating hazard ratios (HR) and 95% confidence intervals (CI) using the Cox proportional hazard regression model. A U-shaped associations between BMI and gastric cancer risk were observed. Gastric cancer risks in underweight group (&lt;18.5 kg/m2) and in obesity group (≥27.5 kg/m2) were higher than reference BMI group (23-24.9 kg/m2; HR, 1.15; 95% CI, 1.05-1.25 for underweight; HR, 1.12; 95% CI, 1.03-1.22 for obesity, respectively). The associations of underweight and obesity with gastric cancer risk were consistent in the analyses for non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer. No significant association of underweight and obesity with the risk of cardia gastric cancer, diffuse-type gastric cancer, and early-onset gastric cancer was observed. In addition, we found that the U-shaped association between BMI and gastric cancer risk remained in nonsmokers, while only underweight was related to increased gastric cancer risk in smokers. BMI has a U-shaped association with gastric cancer risk in East and Southeast Asian population, especially for the non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer. Future studies with consideration of anatomic location and histology of gastric cancer are needed to establish the association of underweight as well as obesity with gastric cancer risk.

Arizona Space Grant Consortium Participation and Contribution During the 2017 Solar Eclipse

Students from the Arizona/NASA Space Grant Consortium attended the Montana State University (MSU) Solar Eclipse Workshop in July 2016, where the MSU-designed ground station and payloads were assembled. The team returned with the systems, making modifications and conducting tests leading up to the eclipse in the following areas: ground station tracking and payload improvements, including expanded video capability. With the initial aid of Louisiana State University (LSU), the team upgraded the tracking system to use both Automated Packet Reporting System (APRS) beacons and MSU’s Iridium tracking system. This update improved the accuracy of determining the location of the balloon and payloads. The hardware improvements for the ground station included the addition of mobile HughesNet satellite internet service. Payload improvements included using medium-gain antennas, next generation Ubiquiti modems, and Raspberry Pi 3 computers. In addition, a 360 degree video camera payload was developed. The systems were tested over six balloon flights. During the solar eclipse, the team was in Glendo, WY, and flew the following payloads on two balloons: Digital Video Payload (DVP), Digital Image Payload (DIP), 360 Video Payload, Arizona State University (ASU) Scientific Payload, flight termination payload, and tracking payloads. Each of these payloads functioned correctly with the exception of DVP, possibly due to damage at launch, which meant the team was unable to live stream video during the eclipse. Instead, the team streamed an image slideshow to a NASA website during the eclipse with still images downlinked from the DIP. However, videos from both the DVP and 360 Video Payload were recovered after the flight and later processed. Overall the mission was successful in collecting video, images, and data of the eclipse from the high-altitude perspective.

Coronary artery calcium scores indicating secondary prevention level risk: Findings from the CAC consortium and FOURIER trial

Background and aimsCoronary artery calcium (CAC) burden displays a stepwise association with atherosclerotic cardiovascular disease (ASCVD) risk. Among primary prevention patients, we sought to determine the CAC scores equivalent to ASCVD mortality rates observed in the FOURIER trial, a modern secondary prevention cohort. Methods and ResultsFor the main analysis, we included participants from the CAC Consortium ≥50 years old with a 10-year ASCVD risk ≥7.5% (n = 20,207). Poisson regression was used to define the relationship between CAC and annual ASCVD mortality. Equations generated from the regression models were then used to derive CAC scores associated with equivalent annual ASCVD mortality as observed in FOURIER placebo participants from the overall trial and in key trial subgroups. The CAC Consortium participants had a similar age (65.5 versus 62.5 years) and sex (22% versus 24% female) distribution as FOURIER. The annualized ASCVD mortality rate in FOURIER participants (0.766 per 100 person-years) corresponded to a CAC score of 781 (418–1467). A CAC score of 255 (162–394) corresponded to an ASCVD mortality rate equivalent to the lowest risk FOURIER subgroup (presence of myocardial infarction >2 years prior to trial enrollment). No CAC score produced a risk equivalent to high-risk FOURIER subgroups, particularly those with symptomatic peripheral arterial disease and/or multivessel coronary heart disease. ConclusionsPrimary prevention individuals with increased CAC burden may have annualized ASCVD mortality rates equivalent to persons with stable secondary prevention-level risk. These findings argue for a risk continuum between higher risk primary prevention and stable secondary prevention patients, as their ASCVD risks may overlap.

Probabilistic Safety Assessment for internal and external events on nuclear power plants and on mitigation strategies/H2020 European projects NARSIS, R2CA and BESEP

The NARSIS project aimed at improving assessment methodologies to be integrated into “extended Probabilistic Safety Assessment” (PSA) procedures for nuclear plants in case of single, cascade and combined external natural events. An open-access framework tool has been released to build multi-hazard scenarios, and various risk integration approaches (e.g., Bayesian Networks) have been implemented and compared, identifying their advantages and limits for further collaborative research activities. The R2CA project aims at harmonizing the safety analysis methods for best estimate evaluations of the radiological consequences, in case of Design Basis Accidents and Design Extension Conditions without significant fuel melting. It is planned to improve models and upgrade existing simulation tools and calculation chains used in safety studies. Finally, the BESEP project is to support safety margin determination, by developing best practices for safety requirement verification against external hazards, using efficient and integrated set of Safety Engineering practices and PSA. The project is carried out in a benchmark exercise based on case studies previously performed by the consortium participants. All three projects aim to improve nuclear safety within the European research and development framework. The research objectives are achieved by the development and improvement of proven and justified safety assessment methodologies for the verification of stringent safety requirements of nuclear industry.

Assessing causality between osteoarthritis with urate levels and gout: a bidirectional Mendelian randomization study

The bidirectional association between osteoarthritis (OA) and urate levels and gout, though well-documented, is inconclusive. This Mendelian randomization (MR) study aims to examine the bidirectional causality between OA and urate levels as well as gout. We used summary statistics data for serum urate levels from 288,649 CKDGen participants and gout from 69,374 Global Urate Genetics Consortium participants. The summary statistics data for OA were obtained from genome-wide association studies including up to 826,690 participants of mainly European ancestry. MR was performed using established analytical methods including the Wald ratio, inverse variance weighted (IVW), weighted median (WM) and MR-Egger. Genetically determined urate levels [IVW odds ratio (OR)=0.99, 95% confidence interval (CI)=0.96, 1.02, P=0.484] and gout (Wald ratio OR=1.00, 95% CI=0.98, 1.02, P=0.908) were not associated with the risk of total OA. In site-specific OA analyses, there was no causal effect of urate levels on knee, hip, spine, thumb and hand OA, and no evidence was provided that gout increased the risk of OA at any site. In the reverse MR analyses, we found no causal effect of total OA on urate levels (IVW Beta=-0.011, 95% CI=-0.095, 0.074, P=0.807) or gout (IVW OR=1.05, 95% CI=0.66, 1.68, P=0.839). A null effect of site-specific OA was also observed. Our MR study supports no bidirectional causal effect of urate levels and gout on total and site-specific OA.

Modeling the Recommended Age for Initiating Coronary Artery Calcium Testing Among At-Risk Young Adults

BackgroundThere are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis. ObjectivesThe purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile. MethodsWe included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors. ResultsParticipants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors. ConclusionsOur derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.

The Southern California Extracorporeal Membrane Oxygenation Consortium During the Coronavirus Disease 2019 Pandemic.

In March 2020, at the onset of the coronavirus disease 2019 (COVID-19) pandemic in the United States, the Southern California Extracorporeal Membrane Oxygenation (ECMO) Consortium was formed. The consortium included physicians and coordinators from the 4 ECMO centers in San Diego County. Guidelines were created to ensure that ECMO was delivered equitably and in a resource effective manner across the county during the pandemic. A biomedical ethicist reviewed the guidelines to ensure ECMO use would provide maximal community benefit of this limited resource. The San Diego County Health and Human Services Agency further incorporated the guidelines into its plans for the allocation of scarce resources. The consortium held weekly video conferences to review countywide ECMO capacity (including census and staffing), share data, and discuss clinical practices and difficult cases. Equipment exchanges between ECMO centers maximized regional capacity. From March 1 to November 30, 2020, consortium participants placed 97 patients on ECMO. No eligible patients were denied ECMO due to lack of resources or capacity. The Southern California ECMO Consortium may serve as a model for other communities seeking to optimize ECMO resources during the current COVID-19 or future pandemics.