AbstractPopulation screening is a long-established tool for effectively identifying disease risk when existing approaches are inadequate for optimizing care. DNA-based population screening (DNAPS) in adult populations has the power to identify individuals at an increased genetic risk of cancer, heart disease, and other health conditions, thus allowing for evidence-based interventions to reduce associated morbidity and mortality. One example of the type of risk identified in such screening is BRCA1- and BRCA2-associated cancer risk, where current risk-identification strategies have been shown to miss greater than 70% of at-risk individuals. Since the first DNA-based screening pilot in adults was initiated in 2008, a growing number of other large-scale projects carrying out DNAPS in adults have followed, and, in aggregate, these projects are engaging millions of people around the world. There are features of DNAPS that make this population screening approach distinct from other population health screens, such as the scale of the datasets that will be created and stored for each participant. This review focuses on an examination of DNAPS in the context of other population health screens, the state of the evidence for this screening approach, and gaps to be addressed to optimize implementation of this population screening approach.

Changes in clinical practice drive interest in relevant education. Most clinicians, including primary care providers, have not been routinely expected to (i) order genomic tests, (ii) explain results, or (iii) initiate clinical management. As genomic screening expands for common diseases, education must deliver just-in-time, practical guidance to prepare all clinicians for genomic risk assessment and management.

Limber pine (LP; Pinus flexilis) and whitebark pine (WBP; Pinus albicaulis) are classified as endangered in Canada due to rapid declines caused by the introduced pathogen causing white pine blister rust (WPBR; Cronartium ribicola), mountain pine beetle, and other stressors. A long-term monitoring study from 2003 to 2019 on 102 LP and 232 WBP permanent plots found that LP mortality decreased with increasing latitude and spring solar radiation, while WBP mortality was highest at low latitudes and elevations in areas with higher moisture and longer growing degree days. WPBR incidence in LP was associated with lower latitudes, high spring precipitation, cool/wet summers, and low solar radiation, while WBP disease incidence drivers were similar, plus increasing tree diameter and slope. Annually, mature LP and WBP mortality from all causes increased 0.4% and 0.5%, respectively, while disease incidence in live trees increased 0.6% and 0.5%. Regeneration density increased 1.3% annually on average for WBP and 2.5% for LP. Disease incidence and mortality rates have slowed compared to prior assessments, likely due to a recruitment deficit of healthy trees and some natural selection for blister rust resistance. The results support customizing landscape restoration strategies based on each species' unique biology and local climatic factors that influence mortality and infection.

Clinical interest in polygenic (PRS) and integrated (PRS plus clinical factors) risk scores (IRS) is growing, yet little data exist on how healthcare providers navigate returning these results to patients. The eMERGE IV study implemented a genome-informed risk assessment for 11 common complex conditions, incorporating PRS, IRS, and monogenic findings, offering an opportunity to examine providers' experiences disclosing these results. We used a cross-sectional survey with closed- and open-ended questions to assess result disclosure experiences. All study providers involved in disclosing high-risk results were invited to participate. Of 21 respondents, 86% were female and the mean age was 35 years. Most were genetic counselors (76%), followed by pharmacists (10%), research coordinators (10%), and a nurse/nurse practitioner (5%). Confidence in disclosing high-risk results was highest for monogenic (92% extremely/very confident), followed by PRS (78%) and IRS (69%). Most rated disclosures as slightly/moderately complex (77% monogenic, 89% PRS, 69% IRS). Breast cancer (69%) and obesity (39%) were rated as the most challenging conditions to disclose. Key considerations when delivering PRS/IRS included clarifying clinical meaning, clear communication of risk, and acknowledging limitations. Challenges involved ensuring patient understanding, confusion over care recommendations, and PRS complexity. Concerns reflected both personal and perceived patient views, including PRS validity, interpretation of relative risk, and healthcare impact. Study findings provide early insights into result disclosure practices for different types of genomic risk and conditions, which can inform training, resources, and clinical integration of these emerging genomic tools.

Aspergillosis is a major cause of morbidity and mortality in penguins, with triazole antifungal drugs being commonly used for prophylaxis and treatment. This report describes 15 cases of fatal hemolysis associated with liquid itraconazole and voriconazole formulations administered to African penguins (Spheniscus demersus) from four institutions. All penguins underwent stressful events (e.g. relocation, induced molt) and were administered commercial liquid itraconazole formulations or compounded voriconazole liquid suspension. Observed clinical signs in affected penguins prior to death included hyporexia, weight loss, lethargy, dyspnea, red-tinged droppings, and obtunded mentation. Intra- and extravascular hemolysis and hemoglobinuric nephrosis were the primary pathologic manifestations on postmortem examination. The concentration-dependent hemolytic potentials of itraconazole, voriconazole, and commercial and compounded vehicle suspensions were evaluated in vitro by exposing chicken whole blood as a surrogate for penguin blood. Hemoglobin content in blood plasma was then measured by spectrophotometry. Neither itraconazole nor voriconazole alone induced hemolysis in vitro. The vehicle ingredients sorbitol and hydromellose induced hemolysis, but not at predicted plasma levels in chicken erythrocytes, suggesting neither the azole antifungals nor their major vehicles alone were likely to contribute to hemolysis in vivo in these penguins. Potential mechanisms of toxicosis include generation of an unmeasured reactive metabolite causing hemolysis, preexisting erythrocyte fragility, or species-specific differences in hemolytic thresholds that were not assessed in the chicken erythrocyte model. More research is needed on the potential for toxicosis of azole antifungal drugs and carrier molecules in this and other avian species.

ObjectivesPremature peripheral artery disease (PAD), defined by lower extremity revascularization (LER) at age ≤ 50 years, is associated with poor major adverse limb events. The early onset of disease is thought to be influenced by genetic factors that regulate homeostasis of the vascular wall and coagulation. The aim of this study is to investigate the effect of anticoagulation as an adjunct to antiplatelet therapy on the outcomes of LER in patients with premature PAD.MethodsThere were 8,804 patients with premature PAD on pre- and post-operative antiplatelet therapy only and 1,236 patients on pre- and post-operative anticoagulation plus antiplatelet therapy in the Vascular Quality Initiative (VQI) peripheral vascular intervention, infra-, and suprainguinal files. Propensity score matching (2:1) was performed between patients with premature PAD who were on antiplatelet therapy and those on anticoagulation plus antiplatelet therapy. Perioperative and one-year outcomes were analyzed including reintervention, major amputation, and mortality.ResultsPatients on anticoagulation were more likely to have coronary artery disease (48.7% vs 41.2%, P<.001), congestive heart failure (20.2% vs 13.1%, P<.001), and have undergone prior LER (73.9% vs 49.2%, P<.001) compared to patients on antiplatelet therapy only. They were also less likely to be independently ambulatory (74.2% vs 81.8%, P<.001) and be on a statin medication (66.8% vs 74.3%, P<.001) compared to patients on antiplatelet therapy only. Patients on anticoagulation were also less likely to be treated for claudication (38.1% vs 48.6%, P<.001), and less likely to be treated with an endovascular procedure (64.8% vs 73.8%, P<.001). After matching for baseline characteristics, there were 1,256 patients on antiplatelet therapy only and 628 patients on anticoagulation. Patients on anticoagulation were more likely to require a return to the operating room (3.7% vs 1.6%, P<.001) and had higher perioperatively mortality (1.1% vs 0.3%, P=.032), but major amputation was not significantly different (1.8% vs 1.6%, P=.798) compared to patients on antiplatelet therapy alone. At one-year, amputation-free survival was higher in patients on antiplatelets only compared to patients on anticoagulation and antiplatelet medications (87.5% vs 80.9%, log-rank P=.001).ConclusionAnticoagulation in addition to antiplatelet therapy in patients with premature PAD undergoing lower extremity revascularization is associated with increased reintervention and mortality at one year.

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Objective Development of clinical phenotypes from electronic health records (EHRs) can be resource intensive. Several phenotype libraries have been created to facilitate reuse of definitions. However, these platforms vary in target audience and utility. We describe the development of the Centralized Interactive Phenomics Resource (CIPHER) knowledgebase, a comprehensive public-facing phenotype library, which aims to facilitate clinical and health services research.Materials and Methods The platform was designed to collect and catalog EHR-based computable phenotype algorithms from any healthcare system, scale metadata management, facilitate phenotype discovery, and allow for integration of tools and user workflows. Phenomics experts were engaged in the development and testing of the site.Results The knowledgebase stores phenotype metadata using the CIPHER standard, and definitions are accessible through complex searching. Phenotypes are contributed to the knowledgebase via webform, allowing metadata validation. Data visualization tools linking to the knowledgebase enhance user interaction with content and accelerate phenotype development.Discussion The CIPHER knowledgebase was developed in the largest healthcare system in the United States and piloted with external partners. The design of the CIPHER website supports a variety of front-end tools and features to facilitate phenotype development and reuse. Health data users are encouraged to contribute their algorithms to the knowledgebase for wider dissemination to the research community, and to use the platform as a springboard for phenotyping.Conclusion CIPHER is a public resource for all health data users available at https://phenomics.va.ornl.gov/ which facilitates phenotype reuse, development, and dissemination of phenotyping knowledge.

Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors’ employers or affiliated institutions.Requests for permissions must be directed to the American College of Medical Genetics and Genomics, as rights holder. Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors’ employers or affiliated institutions. Requests for permissions must be directed to the American College of Medical Genetics and Genomics, as rights holder.

Soil disturbance amelioration affected tree survival, growth, health, mineral soil chemistry, and their covariation on five Long-Term Soil Productivity (LTSP) sites in southeastern British Columbia. The two most different LTSP treatments (baseline disturbance of no compaction / all organic matter left, versus most severe of heavy compaction / forest floor removed) were compared to five amelioration treatments: rehabilitation of most severe LTSP treatment (soil tillage with or without incorporation of removed forest floor [Rehab + FF]), root disease (Armillaria ostoyae (Romagn.) Herink) amelioration treatments (stump removal or biological with Hypholoma fasiculare), and enhancement of soil organic matter (tilling extra forest floor into mineral soil). Treatment significantly (p < 0.05) affected 10-year mineral soil carbon, nitrogen, sulfur, mineralizable nitrogen, and potassium, which were lower on forest floor removal treatments and higher on forest floor addition treatments (27 to 97% of baseline versus 78 to 183% of baseline, respectively). Western white pine (Pinus monticola Dougl. ex D.Don) 15-year productivity (m3/ha) was significantly affected by treatment (Rehab + FF yielding a 10 fold increase in productivity versus the poorly growing baseline treatment), with treatment also significant when total disease was a covariate and for average and total volume when mineral soil Ca:Al ratio was a marginally significant (p < 0.1) covariate, and for survival when the incidence of total disease or white pine blister rust (Cronartium ribicola) were significant covariates; or with mineral soil C:N ratio as a significant covariate. The incidence of blister rust and total disease were significantly influenced by treatment when C:N was a significant covariate. For 20-year lodgepole pine (Pinus contorta Dougl. Ex Loud) there were no direct relationships apparent, but western gall rust (Endocronartium harknessii) had treatment significant when total sulfur was a significant covariate. Fifteen- and twenty-year Douglas-fir (Pseudotsuga menziesii var. glauca [Beissn.] Franco) had no significant relationships. Results demonstrate that restoring or adding extra organic matter (forest floor) into mineral soil increased soil carbon and related nutrients and can increase above ground carbon (forest productivity). Conversely, removing forest floor lowered mineral soil carbon and generally lowered tree volume. Varied effects due to growth limiting factors like frost and competing vegetation affected results on a few plots. Recommendations include leaving or enhancing organic matter onsite for soil carbon, nutrients, forest health and site productivity. Further analysis with the larger LTSP dataset and ongoing monitoring is encouraged to determine if the results persist in the long-term and to better understand the significant covariate relationships.

The development of phenotypes using electronic health records is a resource-intensive process. Therefore, the cataloging of phenotype algorithm metadata for reuse is critical to accelerate clinical research. The Department of Veterans Affairs (VA) has developed a standard for phenotype metadata collection which is currently used in the VA phenomics knowledgebase library, CIPHER (Centralized Interactive Phenomics Resource), to capture over 5000 phenotypes. The CIPHER standard improves upon existing phenotype library metadata collection by capturing the context of algorithm development, phenotyping method used, and approach to validation. While the standard was iteratively developed with VA phenomics experts, it is applicable to the capture of phenotypes across healthcare systems. We describe the framework of the CIPHER standard for phenotype metadata collection, the rationale for its development, and its current application to the largest healthcare system in the United States.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Aim The Yale Generations Project (YGP) is a precision health cohort initiative that began enrollment in New Haven Connecticut USA in July 2019. In March 2020, after nine months of operation, pandemic restrictions prompted abrupt changes to staff availability as well as changes to the project’s recruitment, consenting, and sample acquisition. This manuscript describes the successful addition of remote recruitment, consenting, and DNA sampling to YGP workflows during the initial 27-months of pandemic restrictions ending June 30, 2022. Methods The initial YGP protocol established face-to-face workflow for recruiting, consenting and peripheral blood collection. A telemedicine consent protocol was initiated in April of 2020, and a remote saliva collection was established in October of 2020. De-identified data was extracted from YGP dataset and reported here. Results At the completion of YGP’s initial 36 months (9-months pre-pandemic and 27-months pandemic) YGP enrolled N=4949 volunteers. There were N=1,950 (216.7 per month) volunteers consented pre-pandemic and N=2,999 (111.1 per month) during pandemic. The peak consenting month was February 2020 with N=428. DNA sample acquisition peaked in the pre-pandemic month of February 2020 with N=291 peripheral blood draws, and in the pandemic period the peak DNA acquisition month was November 2020 with N=176 (N=68 peripheral blood draws and N=108 saliva samples). Conclusion The YGP successfully transitioned from pre-pandemic recruiting, consenting and sample acquisition model that was exclusively face-to-face, to pandemic model that was predominantly remote. The added value of remote recruiting, consenting, and sampling has led to plans for an optimized hybrid model post-pandemic. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No external support or sponsorship ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Yale Institutional Review Board (IRB) approved the protocol and the consent for Yale Generations Project (study HIC#2000024015). All patients were consented via the IRB approved process. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.

Whitebark pine (Pinus albicaulis Engelm.) is an ecologically important subalpine and treeline forest tree of the western U.S. and Canada. It is categorized as endangered by the IUCN and by Canada under the Species at Risk Act and was recently proposed for listing in the U.S. as threatened under the Endangered Species Act. Whitebark pine populations are declining nearly rangewide primarily from the spread and intensification of Cronartium ribicola J.C. Fisch., the exotic, invasive pathogen that causes white pine blister rust (WPBR); recent, large-scale outbreaks of mountain pine beetles (MPB) (Dendroctonus ponderosae Hopkins); altered fire regimes; and, multiple impacts from climate change. For more than two decades, researchers and managers within the U.S. Forest Service and Canadian forestry agencies have been developing restoration and conservation tools and techniques to help mitigate these threats. Four conservation and restoration principles for whitebark pine were previously emphasized: (1) conserve genetic diversity, (2) promote WPBR resistance, (3) protect seed sources, and (4) deploy restoration treatments, while mitigating for climate change. These principles are served by ten additional management or conservation actions that form the basis of a restoration and adaptive management plan but apply primarily to regions with moderate to high levels of WPBR and MPB outbreaks. Where the pathogen and MPB are absent or present at low levels, managers can implement proactive management to build resilience to prevent the future loss of ecological function. Here, we review the key management actions currently used for whitebark pine conservation and restoration in the U.S. and Canada, which include gene conservation, increasing natural genetic resistance to C. ribicola, cone collections, growing and planting seedlings or directly sowing seeds, protecting seed sources, prescribed fire and silvicultural thinning to reduce competition in late seral communities, proactive intervention, stand health surveys and monitoring, and monitoring the impacts of restoration for adaptive management. This review is the outcome of an experts' workshop held in association with the development of the National Whitebark Pine Restoration Plan (NWPRP), a collaborative U.S. multi- agency and tribal effort initiated in 2017 in consultation with the U.S. Forest Service and facilitated by the non-profit organizations, the Whitebark Pine Ecosystem Foundation and American Forests.

Over the past decade, the secondary analysis of existing DNA datasets for clinical resulting has become an established practice. However, this established practice is typically limited to only one category of secondary genomic findings, the identification of "disease risk". Diagnostic resulting has been left out of secondary genomic findings. In medical practice, diagnostic resulting is triggered when a test is ordered for a patient based on a recognizable clinical indication for evaluation; most genetic and genomic testing is carried out in support of diagnostic evaluations. The secondary analysis of existing DNA data has the potential to cost less and have more rapid turnaround times for diagnostic results compared to current DNA diagnostic approaches that typically generate a new dataset with every test ordered. Worldwide, innovative health systems could position themselves to deliver valid secondary genomic finding results in both the established category of disease risk results, as well as a new category of diagnostic results. To support the ongoing delivery of both categories of secondary findings, health systems will need comprehensive genomic datasets for patients and secure workflows that allow for repeated access to that data for on-demand secondary analysis.

Background: There is an incomplete understanding of why some women develop breast cancer 20-25 years earlier than the majority of women. Only 30-40% of women with high risk family history are found to have known cancer predisposing mutations. This phenomenon is referred to as “missing heredity”. We hypothesize that women with high-risk cancer family history but no known high penetrance cancer predisposing mutations who develop breast cancer at a young age have a higher deleterious load of germline high functional impact (gHFI) single nucleotide variants in cancer relevant genes. Methods: 94 women diagnosed with breast cancer age <50 with high risk cancer family history who tested negative for germline cancer predisposing mutations were identified at Yale Cancer Prevention Clinic (YCPC). 149 controls, healthy Caucasian individuals age > 65 with no cancer family history were identified from Yale Generations project. Whole-exome sequencing (WES) was performed on peripheral blood from 94 cases, 149 controls, and 42 matched tumors. WES data was analyzed from 1,112 female breast cancer cases with first-degree breast cancer family history and 50,887 healthy women without breast cancer family history from UKBiobank. Rare gHFI variants were defined as nonsynonymous variants predicted as deleterious in MetaSVM, or loss-of-function in gnormAD, or pathogenic in ClinVar database with mutation frequency <0.01. Hallmark genes were 1,558 genes involved in 21 cancer pathways and 83 cancer predisposition genes (CPGs). 468 somatic cancer genes were used. Rare gHFI in cases vs controls were compared using SNP-set (Sequence) Kernel Association Test (SKAT). Somatic mutations in YCPC vs 652 ER+ breast cancer TCGA cases were compared using 13/468 cancer genes mutated >5% of cases using Fisher’s exact test. FDRs were calculated using Benjamini & Hochberg. Results: The majority of YCPC patients were Caucasian (78.7%), median age (43.5), with invasive ductal carcinoma (85.1%), ER+PR+HER2- (67.0%). YCPC patients had a higher average burden of rare gHFI variants in cancer hallmark genes (excluding CPGs) compared to controls (p=0.0075, adjusted for race), but did not show a higher germline burden in CPGs. Similarly, UKBiobank breast cancer patients with a family history had a higher germline variant burden in hallmark genes (excluding CPGs) compared to controls (p=0.0368). The main pathways affected by gHFI in the YCPC cohort were adaptive immunity (p=1.61 x 10-8) and extracellular matrix (p=0.0034). Thirty six (87.8%) YCPC matched tumors carried somatic mutations in known cancer related genes. Compared to TCGA, YCPC samples had fewer TP53 mutations (5% vs 17%, FDR = 0.27), but more mutations in CHEK2, GNAQ, APC, and SDHA (FDR<0.028). Conclusions: Our cohort of young women with breast cancer and high risk family history with no known germline high penetrance cancer gene mutations showed a higher burden of germline high functional impact variants in hallmark cancer genes. This higher germline variant burden suggests that the totality of gHFI variants in cancer related genes could explain why these women develop breast cancer at a younger age. CohortRace (%)AgeCases (N)Control (N)GenesetAverage Case BurdenAverage Case BurdenSKAT testYaleCaucasian (78.7)439414983 CPGs0.27660.30200.56921508 Hallmark4.23404.18790.0075UK BiobankBritish (100)5611125088783 CPGs0.37410.28064.19x10-51508 Hallmark3.36423.33990.0368 Citation Format: Mariya Rozenblit, Tao Qing, Yixuan Ye, Hongyu Zhao, Erin Hofstatter, Vinit Singh, Emily Reisenbichler, Michael Murray, Lajos Pusztai. Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-01.

Background It is unclear how many of genes contribute to the biology of cancer. We hypothesize that genes that interact with core cancer gene (CCG) in a protein-protein interaction network (PPI) may have functional importance. Methods We categorized genes into 1- (n=6791), 2- (n=7724), 3- (n=1587), and >3-steps (n=362) removed from the nearest CCG in the STRING PPI and demonstrate that the cancer-biology related functional contribution of the genes in these different neighborhood categories decreases as their distance from the CCGs increases. Results Genes closer to cancer genes manifest greater connectedness in the network, show greater importance in maintaining cell viability in a broad range of cancer cells in vitro, are also under greater negative germline selection pressure in the healthy populations, and have higher somatic mutation frequency and cancer effect. Conclusions Approximately 70% of human genes are 1 or 2 steps removed from cancer genes in protein network and show functional importance in cancer-biology. These results suggest that the universe of cancer-relevant genes extends to thousands of genes that can contribute functional effects when dysregulated.

Parasitism of cephalopods is common, including infection with Aggregata spp., Ichthyobodo spp., dicyemids, cestodes of the orders Tetraphyllidea and Trypanorhynchidea, and various crustaceans. Cestodiasis in octopuses is reported, although a full histologic description of lesions has not been previously described. Cestodiasis was identified in 10 octopuses of 4 different species, which included 4 common octopuses ( Octopus vulgaris), 3 Caribbean reef octopuses ( Octopus briareus), 2 two-spot octopuses ( Octopus bimaculoides), and 1 giant Pacific octopus ( Enteroctopus dofleini). Larval cestodes were present in the cecum ( n = 5), intestines ( n = 4), digestive gland ( n = 3), chitinous alimentary tract ( n = 2), renal appendage ( n = 1), and salivary duct ( n = 1). In 5 cases, larval cestodes invaded tissue and were associated with hemocytic inflammation and tracts of necrotic tissue in the intestines ( n = 3), digestive gland ( n = 3), and/or renal appendage ( n = 1). When present in the chitinous alimentary tract (esophagus, stomach) or cecum, larval cestodes were in the central lumen and not associated with lesions. One adult cestode was identified in the mantle cavity and was not associated with lesions. Other common concurrent parasitic infections included enteric Aggregata spp. infection, branchial Rickettsia-like organism infection, enteric nematodiasis, and an arthropod-associated branchitis.

BACKGROUND:Premature peripheral artery disease (PAD), defined as ≤ 50 years of age, is associated with poor outcomes following lower extremity revascularization (LER). However, the specific characteristics and outcomes of this group of patients compared to those at the common age undergoing revascularization have not been examined. The aim of this study is to compare patients with early versus late onset premature PAD undergoing LER focusing on major adverse limb events (MALEs). METHODS:All LER procedures (open and endovascular) in the Vascular Quality Initiative (VQI) were reviewed. A histogram of patient age at the time of initial LER (no prior LER) was used to define the common age, which included all patients within one standard deviation of the mean. Characteristics and outcomes of patients with premature PAD were compared to patients treated at the common age of presentation undergoing LER. RESULTS:A histogram of all patients undergoing LER was used to define 60 to 80 years as the common age. Patients with premature PAD were more likely to be female, African American, and Hispanic compared to patients at the common age. Patients with premature PAD were also more likely to have insulin-dependent diabetes, be current smokers, on dialysis, and be treated for claudication. Patients with premature PAD were less likely to have Transatlantic Intersociety Consensus (TASC II) C or D disease and were less likely to be on antiplatelets and statins. These differences were more pronounced in patients with chronic limb-threatening ischemia (CLTI). Cox proportional hazards regression demonstrated that premature PAD was independently associated with major adverse limb events (MALEs) at 1-year for patients with claudication (HR:1.7, 95% CI:1.4-2.0) and CLTI (HR:1.3, 95% CI:1.2-1.5) compared to patients 60 to 80 years of age. CONCLUSIONS:Patients with premature PAD have significant differences in characteristics compared to patients treated at the common age. Vascular providers should emphasize medical therapy prior to LER given the lower rates of medical optimization and worse 1-year MALEs in patients with premature PAD.