The Patient-Physician Relationship: Medical Students' Perceptions in a Novel Course.

The patient-physician relationship, especially in the case of severely ill patients, is often fraught with anxiety, grief, and guilt in the physician who may come to feel that he or she has failed the patient and thereby becomes a "second victim." This notion was first explored in a 1973 publication (Artiss and Levine N Engl J Med 288(23):1210-4, 1973) that described a novel interactive seminar series for oncology fellows that had been designed to address and possibly remedy the frequent disquiet experienced by young physicians in this setting. Fifty years later, the medical student co-authors of this Perspective enrolled in an elective course that comprised a similar series of interactive seminars, now addressing the contemporary patient-physician relationship. The earlier paper was employed as a historical background, and the framework of the course then broadened such that the students considered the current environmental changes in medical practice (social, cultural, financial, legal, policy) that may be linked to the character of individual patient-physician relationships. This essay reports on the students' perception of such relationships, and on the environmental elements that may be helpful or harmful to the well-being of both patients and physicians.

Causal feature selection using a knowledge graph combining structured knowledge from the biomedical literature and ontologies: A use case studying depression as a risk factor for Alzheimer's disease.

BACKGROUND: Causal feature selection is essential for estimating effects from observational data. Identifying confounders is a crucial step in this process. Traditionally, researchers employ content-matter expertise and literature review to identify confounders. Uncontrolled confounding from unidentified confounders threatens validity, conditioning on intermediate variables (mediators) weakens estimates, and conditioning on common effects (colliders) induces bias. Additionally, without special treatment, erroneous conditioning on variables combining roles introduces bias. However, the vast literature is growing exponentially, making it infeasible to assimilate this knowledge. To address these challenges, we introduce a novel knowledge graph (KG) application enabling causal feature selection by combining computable literature-derived knowledge with biomedical ontologies. We present a use case of our approach specifying a causal model for estimating the total causal effect of depression on the risk of developing Alzheimer's disease (AD) from observational data. METHODS: We extracted computable knowledge from a literature corpus using three machine reading systems and inferred missing knowledge using logical closure operations. Using a KG framework, we mapped the output to target terminologies and combined it with ontology-grounded resources. We translated epidemiological definitions of confounder, collider, and mediator into queries for searching the KG and summarized the roles played by the identified variables. We compared the results with output from a complementary method and published observational studies and examined a selection of confounding and combined role variables in-depth. RESULTS: Our search identified 128 confounders, including 58 phenotypes, 47 drugs, 35 genes, 23 collider, and 16 mediator phenotypes. However, only 31 of the 58 confounder phenotypes were found to behave exclusively as confounders, while the remaining 27 phenotypes played other roles. Obstructive sleep apnea emerged as a potential novel confounder for depression and AD. Anemia exemplified a variable playing combined roles. CONCLUSION: Our findings suggest combining machine reading and KG could augment human expertise for causal feature selection. However, the complexity of causal feature selection for depression with AD highlights the need for standardized field-specific databases of causal variables. Further work is needed to optimize KG search and transform the output for human consumption.

Retention, mobility, and successful transition to independence of health sciences postdocs.

INTRODUCTION: Obtaining a tenure track faculty position (TTFP) after postdoctoral appointment (PDA) completion is considered an indicator of successful transition to independence (TTI). Whether cross-institutional mobility (CIM)-moving to a different institution from that of the PDA-contributes to TTI is unclear, as data evaluating retention and mobility is lacking. We tested the hypothesis that, for postdocs (PDs) at R1 institutions, CIM is a significant predictor of successful TTI defined as TTFP-status 3 years post-PDA. MATERIALS AND METHODS: Using University of Pittsburgh data for health sciences PDs we tested the association of CIM at PDA completion (moved to a different institution (CIM = 1) or retained at Pitt (CIM = 0)) with TTFP-status 3 years post-PDA (TTFP, non-TTFP, or left faculty position) using multinomial logistic regression models. RESULTS: Among all 622 Pitt PDs, 3-year retention in a faculty position at Pitt was 21%, while 14% had a faculty position outside of Pitt. Among the analytic sample of PDs with an academic career outcome during the study period (N = 238; 50% women, 8% underrepresented minorities (URM)), at baseline PDA completion 39% moved to a different institution (CIM = 1), and 61% remained at Pitt (CIM = 0) in any job type. Those with CIM = 1 had greater odds of having a TTFP at follow-up than those with CIM = 0 [adjusted OR (95% CI): 4.4 (2.1, 9.2)]. DISCUSSION: One fifth of Pitt PDs were retained by Pitt as faculty. While Pitt PDs were equally likely to get a faculty position whether they were retained at Pitt or left, those who left had greater odds of obtaining a TTFP. Future work with longer follow-up times, expanded markers of TTI, and samples from other R1 institutions is needed to better understand the reason for these results. This knowledge can lead to better support for the next generation of PDs as they successfully transition to faculty.

Evaluation of two longitudinal faculty leadership training programs: behavioral change and institutional impact.

PURPOSE: Building leadership skills among faculty in academic medicine is essential, yet professional development programs focused on leadership are not always attentive to the needs of faculty on diverse career pathways or at differing career stages-nor are they often rigorously assessed. Evaluations commonly focus on participant satisfaction and short-term learning but not behavior change and institutional impact, which are difficult to assess but arguably more meaningful. Given the substantial time and money invested in these programs, more rigorous evaluation is critical. DESIGN/METHODOLOGY/APPROACH: The authors evaluated an intensive, shared leadership-focused training program for early-career and mid-career faculty, offered by the University of Pittsburgh's School of Medicine over the course of a year. They administered a pre/post-program assessment of confidence in key skill areas, and conducted semi-structured interviews with 21 participants between 1-4 years after program completion. FINDINGS: Participants in both programs showed statistically significant improvement (p < 0.001) on every item measured in the pre/post-test. Analysis of the interviews revealed indications of substantial behavior change as well as institutional impact. The evaluation also suggested particular benefits for female professionals. ORIGINALITY/VALUE: The authors conducted a long-term assessment of leadership training focused on career pathway and career stage and found that it (a) prompted both positive behavioral change and institutional impact and (b) suggested benefits for female faculty in particular, which could potentially help to eliminate gender-based disparities in leadership in academic medical centers.

Impact of A Required, Longitudinal Scholarly Project in Medical School: A Content Analysis of Medical Students' Reflections.

INTRODUCTION: Medical schools increasingly require students to complete scholarly projects. Scholarly project programs that are required and longitudinal require considerable resources to implement. It is necessary to understand medical students' perspectives on the impact of such programs. Students at the University of Pittsburgh School of Medicine participate in a required, longitudinal research program (LRP) throughout all years of medical school training. Authors studied students' perceptions of this program. METHODS: Fourth-year medical students submit a written report in which they reflect on their experience with the LRP. Qualitative analysis of students' written reflections was performed on 120 reports submitted 2012-2017. Content analysis was performed using an inductive approach in which investigators coded information and searched for emerging themes. RESULTS: Four themes were identified. First, students described engaging in many steps of the research process, with many participating in projects from conception to completion. Second, students reported the LRP provided opportunities for leadership and independence, and many found this to be meaningful. Third, students developed appreciation for the difficulty of the research process through challenges encountered and practiced problem solving. Fourth, students acquired skills useful across multiple career paths, including critical appraisal of scientific literature, teamwork, and communication. DISCUSSION: Through participation in a required, longitudinal research program, medical students reported gaining valuable skills in leadership, problem solving, critical thinking, and communication. Students found that the longitudinal nature of the program enabled meaningful research experiences. These educational impacts may be worth the effort of implementing and maintaining longitudinal research experiences for medical students. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01319-6.

cGAS suppresses genomic instability as a decelerator of replication forks.

The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyperproliferation, and genomic instability. While the majority of cGAS is cytoplasmic, a fraction of cGAS associates with chromatin. cGAS interacts with replication fork proteins in a DNA binding-dependent manner, suggesting that cGAS encounters replication forks in DNA. Independent of cGAMP and STING, cGAS slows replication forks by binding to DNA in the nucleus. In the absence of cGAS, replication forks are accelerated, but fork stability is compromised. Consequently, cGAS-deficient cells are exposed to replication stress and become increasingly sensitive to radiation and chemotherapy. Thus, by acting as a decelerator of DNA replication forks, cGAS controls replication dynamics and suppresses replication-associated DNA damage, suggesting that cGAS is an attractive target for exploiting the genomic instability of cancer cells.

m5C modification of mRNA serves a DNA damage code to promote homologous recombination.

Recruitment of DNA repair proteins to DNA damage sites is a critical step for DNA repair. Post-translational modifications of proteins at DNA damage sites serve as DNA damage codes to recruit specific DNA repair factors. Here, we show that mRNA is locally modified by m5C at sites of DNA damage. The RNA methyltransferase TRDMT1 is recruited to DNA damage sites to promote m5C induction. Loss of TRDMT1 compromises homologous recombination (HR) and increases cellular sensitivity to DNA double-strand breaks (DSBs). In the absence of TRDMT1, RAD51 and RAD52 fail to localize to sites of reactive oxygen species (ROS)-induced DNA damage. In vitro, RAD52 displays an increased affinity for DNA:RNA hybrids containing m5C-modified RNA. Loss of TRDMT1 in cancer cells confers sensitivity to PARP inhibitors in vitro and in vivo. These results reveal an unexpected TRDMT1-m5C axis that promotes HR, suggesting that post-transcriptional modifications of RNA can also serve as DNA damage codes to regulate DNA repair.

The Highly Structured Physician Scientist Training Program (PSTP) for Medical Students at the University of Pittsburgh.

The University of Pittsburgh School of Medicine Physician Scientist Training Program (PSTP) is a 5-year medical student training program designed to prepare the next generation of MD-only physician-scientists engaging in preclinical research. This article provides an overview of the program, including the novel longitudinal structure and competency goals, which facilitate success and persistence in a laboratory-based physician-scientist career. The authors present data on 81 medical students accepted to the program from academic year 2007-2008 through 2018-2019. Extrinsic outcomes, such as publications, grant funding, and residency matching, indicate that PSTP trainees have actively generated research deliverables. A majority of eligible PSTP trainees have earned Howard Hughes Medical Institute Medical Research Fellow funding. PSTP students have produced a mean of 1.6 first-authored publications (median, 1.0) and a mean of 5.1 total publications (median, 4.0) while in medical school and have authored 0.9 publications per year as residents/fellows, excluding internship. Nearly 60% of PSTP students (26/46) have matched to top-10 National Institutes of Health-funded residency programs in their specialty (based on Blue Ridge Institute rankings). PSTP alumni are twice as likely as their classmates to match into research-heavy departments and to publish first-authored papers. Results of a 2018 program evaluation survey indicate that intrinsic outcomes, such as confidence in research skills, significantly correlate with extrinsic outcomes. The program continues to evolve to maximize both scientific agency and career navigation skills in participants. This medical student PSTP model has potential to expand the pool of physician-scientist researchers in preclinical research beyond the capacity of dedicated MD-PhD and postgraduate training programs.

Molecular Biology Information Service: an innovative medical library-based bioinformatics support service for biomedical researchers.

Biomedical researchers are increasingly reliant on obtaining bioinformatics training in order to conduct their research. Here we present a model that academic institutions may follow to provide such training for their researchers, based on the Molecular Biology Information Service (MBIS) of the Health Sciences Library System, University of Pittsburgh (Pitt). The MBIS runs a four-facet service with the following goals: (1) identify, procure and implement commercially licensed bioinformatics software, (2) teach hands-on workshops using bioinformatics tools to solve research questions, (3) provide in-person and email consultations on software/databases and (4) maintain a web portal providing overall guidance on the access and use of bioinformatics resources and MBIS-created webtools. This paper describes these facets of MBIS activities from 2006 to 2018, including outcomes from a survey measuring attitudes of Pitt researchers about MBIS service and performance.

Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status.

Background: Recent studies investigating longevity have revealed very few convincing genetic associations with increased lifespan. This is, in part, due to the complexity of biological aging, as well as the limited power of genome-wide association studies, which assay common single nucleotide polymorphisms (SNPs) and require several thousand subjects to achieve statistical significance. To overcome such barriers, we performed comprehensive DNA sequencing of a panel of 20 genes previously associated with phenotypic aging in a cohort of 200 individuals, half of whom were clinically defined by an "early aging" phenotype, and half of whom were clinically defined by a "late aging" phenotype based on age (65-75 years) and the ability to walk up a flight of stairs or walk for 15 min without resting. A validation cohort of 511 late agers was used to verify our results. Results: We found early agers were not enriched for more total variants in these 20 aging-related genes than late agers. Using machine learning methods, we identified the most predictive model of aging status, both in our discovery and validation cohorts, to be a random forest model incorporating damaging exon variants [Combined Annotation-Dependent Depletion (CADD) > 15]. The most heavily weighted variants in the model were within poly(ADP-ribose) polymerase 1 (PARP1) and excision repair cross complementation group 5 (ERCC5), both of which are involved in a canonical aging pathway, DNA damage repair. Conclusion: Overall, this study implemented a framework to apply machine learning to identify sequencing variants associated with complex phenotypes such as aging. While the small sample size making up our cohort inhibits our ability to make definitive conclusions about the ability of these genes to accurately predict aging, this study offers a unique method for exploring polygenic associations with complex phenotypes.

ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB.

Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB in turn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSB displays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced R loops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51 axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.

Scholarly Research Projects Benefit Medical Students' Research Productivity and Residency Choice: Outcomes From the University of Pittsburgh School of Medicine.

PURPOSE: Many medical schools require scholarly research projects. However, outcomes data from these initiatives are scarce. The authors studied the impact of the Scholarly Research Project (SRP), a four-year longitudinal requirement for all students at the University of Pittsburgh School of Medicine (UPSOM), on research productivity and residency match. METHOD: The authors conducted a longitudinal study of non-dual-degree UPSOM graduates in 2006 (n = 121, non-SRP participants) versus 2008 (n = 118), 2010 (n = 106), and 2012 (n = 132), all SRP participants. The authors used PubMed for publication data, National Resident Matching Program for residency match results, and Blue Ridge Institute for Medical Research for National Institutes of Health funding rank for residency-affiliated academic institutions. RESULTS: Research productivity of students increased for those completing the SRP, measured as a greater proportion of students with publications (27.3% in 2006 vs. 45.8% in 2008, 55.7% in 2010, and 54.5% in 2012; P < .001) and first-authorship (9.9% in 2006 vs. 26.3% in 2008, 33.0% in 2010, and 35.6% in 2012; P < .001). Across years, there was a significantly greater proportion of students with peer-reviewed publications matched in higher-ranked residency programs (57.0% with publications in the top 10%, 52.7% in the top 10%-25%, 32.4% in the top 25%-50%, 41.2% in the bottom 50%, and 45.2% in unranked programs; P = .018). CONCLUSIONS: Longitudinal research experiences for medical students may be one effective tool in fostering student publications and interest in extending training in a research-focused medical center.

SIRT6 facilitates directional telomere movement upon oxidative damage.

Oxidative damage to telomeres leads to telomere attrition and genomic instability, resulting in poor cell viability. Telomere dynamics contribute to the maintenance of telomere integrity; however, whether oxidative damage induces telomere movement and how telomere mobility is regulated remain poorly understood. Here, we show that oxidative damage at telomeres triggers directional telomere movement. The presence of the human Sir2 homolog, Sirtuin 6 (SIRT6) is required for oxidative damage-induced telomeric movement. SIRT6 knock out (KO) cells show neither damage-induced telomere movement nor chromatin decondensation at damaged telomeres; both are observed in wild type (WT) cells. A deacetylation mutant of SIRT6 increases damage-induced telomeric movement in SIRT6 KO cells as well as WT SIRT6. SIRT6 recruits the chromatin-remodeling protein SNF2H to damaged telomeres, which appears to promote chromatin decondensation independent of its deacetylase activity. Together, our results suggest that SIRT6 plays a role in the regulation of telomere movement upon oxidative damage, shedding new light onto the function of SIRT6 in telomere maintenance.

RAD52 is required for RNA-templated recombination repair in post-mitotic neurons.

It has been long assumed that post-mitotic neurons only utilize the error-prone non-homologous end-joining pathway to repair double-strand breaks (DSBs) associated with oxidative damage to DNA, given the inability of non-replicating neuronal DNA to utilize a sister chromatid template in the less error-prone homologous recombination (HR) repair pathway. However, we and others have found recently that active transcription triggers a replication-independent recombinational repair mechanism in G0/G1 phase of the cell cycle. Here we observed that the HR repair protein RAD52 is recruited to sites of DNA DSBs in terminally differentiated, post-mitotic neurons. This recruitment is dependent on the presence of a nascent mRNA generated during active transcription, providing evidence that an RNA-templated HR repair mechanism exists in non-dividing, terminally differentiated neurons. This recruitment of RAD52 in neurons is decreased by transcription inhibition. Importantly, we found that high concentrations of amyloid ß, a toxic protein associated with Alzheimer's disease, inhibits the expression and DNA damage response of RAD52, potentially leading to a defect in the error-free, RNA-templated HR repair mechanism. This study shows a novel RNA-dependent repair mechanism of DSBs in post-mitotic neurons and demonstrates that defects in this pathway may contribute to neuronal genomic instability and consequent neurodegenerative phenotypes such as those seen in Alzheimer's disease.

The oxidative DNA damage response: A review of research undertaken with Tsinghua and Xiangya students at the University of Pittsburgh.

Endogenous stress and exogenous toxicants (chemicals and UV light) alter genetic information either directly or indirectly through the production of reactive oxygen species (ROS), thereby driving genomic instability in cells and promoting tumorigenesis. All living cells try to faithfully preserve and transmit their genomic information from one generation to the next using DNA repair mechanisms to repair oxidative DNA damage to prevent cancer or premature aging. Oxidative DNA damage comprises a mixture of DNA lesions including base damage, DNA single strand breaks (SSBs), and DNA double strand breaks (DSBs). This review summarizes some of the studies on DNA damage response at a defined genome locus that are performed by students from the Tsinghua University School of Medicine and the School of Medicine of Central South University (Xiangya Hospital) at the University of Pittsburgh School of Medicine. A summary of their work highlights the continuous contribution of the students to a particular research program and exemplifies the achievements of this China-U.S. collaborative training program.

Sino-U.S. partnerships in research, education, and patient care: The experience of the University of Pittsburgh and UPMC.

In 2011, the University of Pittsburgh School of Medicine (UPSOM) and Tsinghua University formed a partnership to further the education of Tsinghua medical students. These students come to UPSOM as visiting research scholars for two years of their eight-year MD curriculum. During this time, the students, who have completed four years at Tsinghua, work full-time in medical school laboratories and research programs of their choice, essentially functioning as graduate students. In their first two months in Pittsburgh, the scholars have a one-week orientation to biomedical research, followed by two-week rotations in four labs selected on the basis of the scholars' scientific interests, after which they choose one of these labs for the remainder of the two years. Selected labs may be in basic science departments, basic science divisions of clinical departments, or specialized centers that focus on approaches like simulation and modeling. The Tsinghua students also have a brief exposure to clinical medicine. UPSOM has also formed a similar partnership with Central South University Xiangya School of Medicine in Changsha, Hunan Province. The Xiangya students come to UPSOM for two years of research training after their sixth year and, thus, unlike the Tsinghua students, have already completed their clinical rotations. UPSOM faculty members have also paved the way for UPMC (University of Pittsburgh Medical Center), UPSOM's clinical partner, to engage with clinical centers in China. Major relationships involving advisory, training, managerial, and/or equity roles exist with Xiangya International Medical Center, KingMED Diagnostics, First Chengmei Medical Industry Group, and Macare Women's Hospital. Both UPSOM and UPMC are actively exploring other clinical and academic opportunities in China.

SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming.

DNA single-strand breaks (SSB) are the most common form of DNA damage, requiring repair processes that to initiate must overcome chromatin barriers. The FACT complex comprised of the SSRP1 and SPT16 proteins is important for maintaining chromatin integrity, with SSRP1 acting as an histone H2A/H2B chaperone in chromatin disassembly during DNA transcription, replication, and repair. In this study, we show that SSRP1, but not SPT16, is critical for cell survival after ionizing radiation or methyl methanesulfonate-induced single-strand DNA damage. SSRP1 is recruited to SSB in a PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanistic rationale to target SSRP1 as a general approach to selectively attack cancer cells. Cancer Res; 77(10); 2674-85. ©2017 AACR.

WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1.

Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain. We showed that in addition to steady state telomere erosion, WRN depleted cells are also sensitive to telomeric damage. WRN responds to site-specific telomeric damage via its RQC domain, interacting at Lysine 1016 and Phenylalanine1037 with the N-terminal acidic domain of the telomere shelterin protein TRF1 and demonstrating a novel mechanism for WRN's role in telomere protection. We also found that tankyrase1-mediated poly-ADP-ribosylation of TRF1 is important for both the interaction between WRN and TRF1 and the damage recruitment of WRN to telomeres. Mutations of potential tankyrase1 ADP-ribosylation sites within the RGCADG motif of TRF1 strongly diminish the interaction with WRN and the damage response of WRN only at telomeres. Taken together, our results reveal a novel mechanism as to how WRN protects telomere integrity from damage and telomere erosion.

Tankyrase1-mediated poly(ADP-ribosyl)ation of TRF1 maintains cell survival after telomeric DNA damage.

Oxidative DNA damage triggers telomere erosion and cellular senescence. However, how repair is initiated at telomeres is largely unknown. Here, we found unlike PARP1-mediated Poly-ADP-Ribosylation (PARylation) at genomic damage sites, PARylation at telomeres is mainly dependent on tankyrase1 (TNKS1). TNKS1 is recruited to damaged telomeres via its interaction with TRF1, which subsequently facilitates the PARylation of TRF1 after damage. TNKS inhibition abolishes the recruitment of the repair proteins XRCC1 and polymerase ß at damaged telomeres, while the PARP1/2 inhibitor only has such an effect at non-telomeric damage sites. The ANK domain of TNKS1 is essential for the telomeric damage response and TRF1 interaction. Mutation of the tankyrase-binding motif (TBM) on TRF1 (13R/18G to AA) disrupts its interaction with TNKS1 concomitant recruitment of TNKS1 and repair proteins after damage. Either TNKS1 inhibition or TBM mutated TRF1 expression markedly sensitizes cells to telomere oxidative damage as well as XRCC1 inhibition. Together, our data reveal a novel role of TNKS1 in facilitating SSBR at damaged telomeres through PARylation of TRF1, thereby protecting genome stability and cell viability.