Citations

Abstract More Americans die every year of lung cancer than any other cancer. While the environmental risks for lung cancer are well understood, the genetic risk factors for this disease are not, even though it has been shown that lung cancer risk aggregates in families. Segregation analyses have confirmed the likelihood of rare, highly penetrant variants affecting lung cancer. Family studies offer a unique opportunity to identify such rare risk variants. We have previously identified a genome-wide significant risk locus for lung cancer using multipoint linkage analysis in highly aggregated lung cancer families. In this study, we performed targeted sequencing on this 6q23-6q27 region on 75 individuals from the 9 most strongly linked families. Parametric two-point linkage analysis using an autosomal dominant model with 10% penetrance for carriers and a 1% phenocopy rate and disease allele frequency of 1% was performed for each family. While we did not find any genome-wide significant results in any of the individual families, we did observe several interesting potential rare risk variants. First, we observed that the significant signal previously observed on 6q is recapitulated in these data but the location of the peak LOD is highly heterogeneous across families and it is likely that each family has a different risk gene. While most of the highest LOD scores were in noncoding variants, we did observe exonic variants with the highest LOD scores in two families (44 and 42). Both variants were rare, with a minor allele frequency (MAF) of approximately 1% and were in LPA and GPR126 respectively. Both these genes have been implicated somatically in lung cancer, however this is the first time that they have been implicated in the germline. While the other families have their highest LOD scores in noncoding variants, some of these genes are also good potential candidate genes including PARK2 (family 30), GRM1 (family 47), and PDE10A (family 102). All three genes have been implicated in lung cancer in some capacity, and this is the first time that GRM1 and PDE10A have been implicated as germline mutations. Again, all these variants are rare (MAF ⇐ 0.01) in the general population, which makes sense for a potential highly penetrant risk variant. In this study, we have elucidated that a previously identified risk locus on 6q25 is heterogeneous in the nine most strongly linked families, with different families appearing to be carrying different risk variants. Many of the top variants in each family are rare variants that are in good potential causal genes that have been identified for the first time here as germline risk variants for lung cancer. Further functional annotation is underway for these variants and some additional linkage analyses using other penetrance matrices may also be performed. Citation Format: Anthony M. Musolf, Claire L. Simpson, Bilal A. Moiz, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Highly aggregated lung cancer families reveal a heterogeneous cause for a previous linkage signal on 6q [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 37.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Understanding temporal dynamics of COVID-19 symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVID pos ; n = 2,317) versus COVID-19-negative (COVID neg ; n = 74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVID pos over COVID neg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVID pos patients during the week prior to PCR testing, in addition to anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.

Background. Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility. Methods. Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement. Results. The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or <72 hours of appropriate antimicrobial therapy in case of ongoing sepsis were considered reasons to delay LT. A simple assessment of the number of organs failing was considered the most appropriate way to decide whether LT should be delayed or denied, with respiratory, circulatory and metabolic failures having the most influence in this decision. The thresholds of severity of organ failures contraindicating LT for which a consensus was achieved were a Pa o 2 /FiO2 ratio<150 mm Hg, a norepinephrine dose >1 μg/kg per minute and a serum lactate level >9 mmol/L. Conclusions. Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented.

Opioid use disorder (OUD) is a cause of significant morbidity and mortality in the United States. Although efforts are being made to limit access to prescription opioids, the use of heroin and synthetic opioids as well as death due to opioid overdose has increased. Medication-assisted treatment (MAT) is the pairing of psychosocial intervention with a Food and Drug Administration (FDA)–approved medication (methadone, buprenorphine plus naltrexone) to treat OUD. MAT has resulted in reductions in overdose deaths, criminal activity, and infectious disease transmission. Access to MAT in rural areas is limited by shortages of addiction medicine-trained providers, lack of access to comprehensive addiction programs, transportation, and cost-related issues. Rural physicians express concern about lack of mentorship and drug diversion as reasons to avoid MAT. The prescribing of MAT with buprenorphine requires a Drug Enforcement Agency (DEA) waiver that can easily be obtained by Family Medicine providers. MAT can be incorporated into the outpatient practice, where patient follow-up rates and number needed to treat to effect change are similar to that of other chronic medical conditions. We describe a case of opioid overdose and a suggested protocol for the induction of MAT with buprenorphine/naloxone (Suboxone) for OUD in a rural family medicine outpatient practice. Treatment access is facilitated by utilizing the protocol, allowing office staff work to the extent allowed by their licensure, promoting teamwork and minimizing physician time commitment. We conclude that improved access to MAT can be accomplished in a rural family medicine outpatient clinic by staff that support and mentor one another through use of a MAT protocol.