PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but its role in PAH is unsettled. Here, we report that: (1) PAI-1 is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared to controls; (2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with up-regulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and (3) pharmacological inhibition of uPA in human PAH PASMCs suppresses pro-proliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that down-regulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent up-regulation of mTOR and TGF-b signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.

Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

The medical humanities at United States medical schools: a mixed method analysis of publicly assessable information on 31 schools.

INTRODUCTION: There have been increasing efforts to integrate the arts and humanities into medical education, particularly during undergraduate medical education (UME). Previous studies, however, have focused on courses and curricular programming without rigorous characterization of the associated paracurricular environment or infrastructure enabling or facilitating these offerings. METHODS: To assess opportunities for students to engage the arts and humanities during their medical education as well as the institutional resources to support those opportunities, we developed the Humanities and Arts Programming Scale (HARPS): an 18-point scale involving eight sub-domains (Infrastructure, Curricular Opportunities, Extracurricular Engagement, Opportunities for Immersion, Faculty Engagement, Staff Support, Student Groups, and Scholarship). This scale was used to evaluate the top-31 ranked United States medical schools as determined by US News and World Report's (USWNR) Medical School Research Rankings using information derived from public-facing, online information. RESULTS: Mean cumulative HARPS score was 11.26, with a median score of 12, a standard deviation of 4.32 and a score range of 3-17. Neither USWNR ranking nor private/public institution status were associated with the cumulative score (p = 0.121, p = 0.739). 52% of institutions surveyed had a humanities-focused center/division with more than 70% of the schools having significant (> 5) faculty engaged in the medical humanities. 65% of schools offered 10 or more paracurricular medical humanities events annually, while 68% of the institutions had more than 5 medical humanities student organizations. While elective, non-credit courses are available, only 3 schools required instruction in the arts and humanities, and comprehensive immersive experiences in the medical humanities were present in only 29% of the schools. CONCLUSIONS: Although there is a significant presence of the medical humanities in UME, there is a need for integration of the arts and humanities into required UME curricula and into immersive pathways for engaging the medical humanities.

Diversity, Equity, and Inclusion: Moving from Performance to Transformation Through the Arts and Humanities.

Effective engagement on issues of diversity, equity, and inclusion (DEI) requires activities that promote deep introspection and group conversations that serve to complement and build upon formal DEI presentations. The arts and humanities by their nature allow for intentional and sustained reflection and have the potential to be transformative of thinking. We therefore propose that the next phase of institutional pro-equity/anti-racism efforts includes arts- and humanities-based initiatives to facilitate reflection and that serve to complement and build upon formal DEI didactic presentations, implicit bias workshops, and anti-racism training.

A Systematic Review and Meta-analysis of Depression, Anxiety, and Sleep Disorders in US Adults with Food Insecurity.

INTRODUCTION: A large number of peer-reviewed studies, with various methodologies and populations, have addressed the effects of food insecurity (FIS) on mental health conditions such as depression, anxiety, and sleep disorders. There are currently, however, no published systematic assessments or meta-analyses of this literature. METHODS: A systematic search of the literature was conducted in PubMed, PsycInfo, Embase, Scopus, and Web of Science. Cross-sectional studies assessing the association between food insecurity and depression, anxiety, or sleep disorders were identified. For each of the three health outcomes, we extracted (or calculated when possible) the following effect sizes: odds ratio (OR), Hedges' g, Pearson correlation coefficients r, or bivariate coefficients. Then, for each mental health-outcome/effect-size pair, the available studies were combined using the random effect model. Heterogeneity, publication bias, and subgroup dependence, for each meta-analysis, were also assessed. RESULTS: Fifty-seven studies provided cross-sectional data on the relationship between FIS and depression (n = 169,433), 13 on anxiety and psychological distress (n = 91,957), and 8 studies provided data on sleep disorders (n = 85,788). Meta-analysis showed that FIS is associated with an increased risk of testing positive for depression OR = 2.74 [95% CI 2.52-2.97, n = 135,500, Q(df = 41) = 69, I2 = 40%], anxiety OR = 2.41 [95% CI 1.81-3.22, n = 51,541, Q(df = 3) = 8, I2 = 63%], and sleep disorders OR = 1.80 [95% CI 1.51-2.15, n = 84,800, Q(df = 5) = 13, I2 = 62%]. The highest risks were found for depression and anxiety which had statistically similar values. The results were robust to covariates and population groups. DISCUSSION: This systematic review and meta-analysis demonstrates a strong association between FIS and depression, anxiety, and sleep disorders, for which more longitudinal studies addressing effect sizes are warranted to further study causation.

Defending Racial and Ethnic Diversity in Undergraduate and Medical School Admission Policies.

This Viewpoint argues that reversing or restricting the use of race and ethnicity in academic admission policies could also threaten the diversity of medical schools, both directly by restricting race consciousness in medical school admission practices and indirectly by reducing the overall number of minoritized undergraduate students attending US colleges and universities who could apply to medical school.

NEU1 sialidase regulates the sialylation state of CD31 and disrupts CD31-driven capillary-like tube formation in human lung microvascular endothelia.

The highly sialylated vascular endothelial surface undergoes changes in sialylation upon adopting the migratory/angiogenic phenotype. We recently established endothelial cell (EC) expression of NEU1 sialidase (Cross, A. S., Hyun, S. W., Miranda-Ribera, A., Feng, C., Liu, A., Nguyen, C., Zhang, L., Luzina, I. G., Atamas, S. P., Twaddell, W. S., Guang, W., Lillehoj, E. P., Puché, A. C., Huang, W., Wang, L. X., Passaniti, A., and Goldblum, S. E. (2012) NEU1 and NEU3 sialidase activity expressed in human lung microvascular endothelia. NEU1 restrains endothelial cell migration whereas NEU3 does not. J. Biol. Chem. 287, 15966-15980). We asked whether NEU1 might regulate EC capillary-like tube formation on a Matrigel substrate. In human pulmonary microvascular ECs (HPMECs), prior silencing of NEU1 did not alter tube formation. Infection of HPMECs with increasing multiplicities of infection of an adenovirus encoding for catalytically active WT NEU1 dose-dependently impaired tube formation, whereas overexpression of either a catalytically dead NEU1 mutant, NEU1-G68V, or another human sialidase, NEU3, did not. NEU1 overexpression also diminished EC adhesion to the Matrigel substrate and restrained EC migration in a wounding assay. In HPMECs, the adhesion molecule, CD31, also known as platelet endothelial cell adhesion molecule-1, was sialylated via α2,6-linkages, as shown by Sambucus nigra agglutinin lectin blotting. NEU1 overexpression increased CD31 binding to Arachis hypogaea or peanut agglutinin lectin, indicating CD31 desialylation. In the postconfluent state, when CD31 ectodomains are homophilically engaged, NEU1 was recruited to and desialylated CD31. In postconfluent ECs, CD31 was desialylated compared with subconfluent cells, and prior NEU1 silencing completely protected against CD31 desialylation. Prior CD31 silencing and the use of CD31-null ECs each abrogated the NEU1 inhibitory effect on EC tube formation. Sialyltransferase 6 GAL-I overexpression increased α2,6-linked CD31 sialylation and dose-dependently counteracted NEU1-mediated inhibition of EC tube formation. These combined data indicate that catalytically active NEU1 inhibits in vitro angiogenesis through desialylation of its substrate, CD31.

A 15-Year Analysis of Supply and Demand for Hematology and Oncology Training in the United States.

PURPOSE: There is a paucity of research on the supply of the hematology and oncology workforce despite projected shortages in the United States Over the past 15 years of the hematology and oncology match (HOM), we hypothesized that there would be more growth in the number of training positions relative to applicants, higher match rates for US allopathic graduates relative to non-US allopathic graduates, and fewer applicants matching at their top fellowship choices. METHODS: This was a national, retrospective cohort study of all applicants in the HOM (2009-2023). Match rates and applicant-to-training position ratios were calculated and compared over time with Pearson tests. RESULTS: Growth in the number of annual training positions (426-708; 66% increase) exceeded growth in the number of interested applicants (706-945; 34% increase; P < .001). Annual applicant-to-training position ratios decreased from 1.7 to 1.3 (r = -0.813; P < .001). Match rates increased over the study period for both US allopathic graduates (79%-88%; r = 0.761; P = .001) and non-US allopathic graduates (45%-63%; r = 0.801; P < .001). During each year, match rates for US allopathic graduates exceeded those for non-US allopathic graduates (P < .001). From 2018 to 2023, US allopathic graduates (83%) had higher match rates than US osteopathic graduates (60%) and international medical graduates (50%; P < .001). The percentage of applicants that matched at one of their top three fellowship choices increased from 53% to 60% (r = 0.480; P = .070). Fewer available annual training positions went unfilled over the study period (3%-0.3%; r = - 0.870; P < .001). CONCLUSION: Match rates have increased in the HOM but remain competitive especially for non-US allopathic graduates. Future investigation is needed to understand disparities in match outcomes by additional applicant and fellowship program characteristics. Ongoing surveillance of HOM outcomes remains critical given the projected shortages in the US hematology and oncology workforce.

Psychological and emotional experiences of participants in a medical school, early assurance admissions program targeting students from groups underrepresented in medicine.

BACKGROUND: There are growing number of pathway programs, with an early assurance of admission, that target undergraduate students from groups underrepresented in medicine (URiM) to enable their competitiveness for and matriculation to medical school, including the Penn Access Summer Scholars (PASS) program. The psychological and emotional experiences of students in these programs, however, have not been previously described. METHODS: Students from the summer 2021 cohort of the PASS program were interviewed using a structured set of questions that explored four specific areas: (i) the application process; (ii) the benefits and value of being in the PASS program; (iii) the emotional and psychological challenges and stresses of being in the PASS program; (iv) feelings and emotions about not taking the MCAT or having to interview at multiple schools. The transcribed, de-identified interviews were then subjected to a qualitative analysis. RESULTS: Students in PASS reported that the program was valuable to them in that it reduced the stress of the pre-medical process; relieved worry and anxiety surrounding the MCAT; enabled development of supportive relationships and provided meaningful exposures to the medical profession and biomedical research. Despite this, students reported feelings of imposterism, guilt, and fear of disappointing, along with varying degrees of regret over not taking the MCAT and not interviewing at more than one medical school. CONCLUSIONS: URiM and other marginalized students participating in early assurance admissions programs likely enter medical school with a range of positive and negative emotions as a result of their participation in these programs. These data can be used to inform the development of programing and other initiatives that further support the transition and success of these students in medical school.

Medical Students' Reflections on Their Experiences in a Trauma Chaplain Shadowing Program.

The importance of spirituality in patient care is well recognized and efforts to develop educational opportunities to improve medical students' competency in spirituality and health are ongoing. In this regard, shadowing of healthcare chaplains has emerged as an experiential approach for providing exposure to and instruction in issues of spirituality in the patient experience and in patient care. Recently published data suggest that a 6-8 hour experience of shadowing a trauma chaplain is effective at introducing first-year medical students to healthcare chaplaincy, difficult spiritual conversations with patients and families, and interprofessional collaboration. As a follow-up to these data, this study provides a qualitative analysis of student reflections written immediately after their shadowing experience with the goal of further characterizing the educational impact of trauma chaplain shadowing. Qualitative analysis of 90 anonymous, student reflections indicated that trauma chaplain shadowing was an experience that provided insights about nature of chaplaincy, enabled opportunities to closely observe the relational skills of chaplains, allowed students to bear witness to suffering, fostered growth toward a professional identity, and facilitated recognition of shortcomings in medical education and clinical medicine. These data therefore provide further evidence of the value of chaplain shadowing in not only enhancing students' understanding of various dimensions of spirituality and medicine but also in promoting their development of a strong physician identity.

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

How I conduct the family meeting to discuss the limitation of life-sustaining interventions: a recipe for success.

The meeting with the family of a hospitalized patient dying with advanced cancer or hematologic disease in which the limitation of life-sustaining interventions is discussed can be a challenge, particularly for junior physicians. A successful conclusion to this discussion involves an outcome in which the family, without coercion or manipulation, comes to accept that the appropriate care has been provided to their loved one, while the caregivers are enabled to provide care that is goal-directed and patient-centered. This type of result can be achieved through an approach in which patient-focused recommendations are offered in the context of diligent efforts to establish and sustain trust, thoughtful preparation, and respectful discussions with the family.

Case writing as a vehicle for promoting cultural competency: a retrospective, descriptive qualitative analysis.

BACKGROUND: A variety of approaches are available that provide cultural competency education for practicing physicians. There is, however, still a need for additional, innovative approaches that address continuing education and professional improvement regarding cultural competency for physicians after their training. OBJECTIVE: To assess the potential impact on established clinicians of writing an extended case narrative on cultural competency. METHODS: We conducted structured interviews of physician contributors (n = 14) to a book of cases on cultural competency. Authors were invited to contribute to the book based on their experiences as established clinicians, and previous expertise in cultural competency research or education was not required. Because of this, the editors employed a process in which they worked with contributors in a one-on-one manner to develop their case(s). RESULTS: The participants were experienced physicians (all > 10 years since medical school graduation), most of whom were white (64%) and affiliated with an academic medical center (86%). The majority of the contributors (1) reported that writing their case(s) increased their awareness of, and sensitivity to, issues of cultural competency; (2) indicated that the writing of their case(s) changed their approach to patient care and/ or their education of medical students or graduate medical trainees; and (3) would recommend case writing as a vehicle for promoting cultural sensitivity and awareness. CONCLUSIONS: Although preliminary, these data suggest that the cultural awareness, sensitivity, and competence of established physicians might be enhanced by a process in which clinicians are facilitated in the writing of cases that address issues of culture that are pertinent to their practice and patient experiences.

Match Outcomes for Cardiovascular Disease Fellowship Training: 2010 to 2021.

Background This study elucidates recent trends in application and match rates in the Cardiovascular Disease Fellowship Match. We hypothesized that (1) match rates have increased with time; (2) match rates are highest for US allopathic graduates; and (3) most candidates match at 1 of their top 3 ranked fellowship choices. Methods and Results This was a retrospective cohort study of all applicants in the Cardiovascular Disease Fellowship Match from 2010 to 2021 (n=14 674). Chi-square tests were used to compare trends over time and match rates by applicant archetype (US allopathic graduates and non-US allopathic graduates). The annual number of applicants increased from 1184 to 1575 (33% increase) while training positions increased 718 to 1045 (46% increase) over the study period. The percentage of applicants that matched increased from 61% in 2010 to 66% in 2021 (P=0.090). The average match rate was 70% over the study period. During each year, US allopathic graduates had higher match rates than non-US allopathic graduates (P<0.001), but this disparity narrowed with time (83% versus 41% in 2010 and 83% versus 54% in 2021). Most applicants matched at 1 of their top 3 choices (first, 37%; second, 12%; third, 7%). Applicants matching at 1 of their top 3 choices decreased from 51% in 2010 to 48% in 2021 (P=0.704). Conclusions The Cardiovascular Disease Fellowship Match has remained equally competitive over the past decade. US allopathic graduates have an advantage over non-US allopathic graduates. Most applicants match at 1 of their top 3 ranked fellowship choices.

Food insecurity, type 2 diabetes, and hyperglycaemia: A systematic review and meta-analysis.

AIMS: Food insecurity (FIS) is a major public health issue with possible implications for type 2 diabetes mellitus (T2DM) risk. We conducted a systematic review and meta-analysis to explore the association between FIS and T2DM. METHODS: We performed a systematic search in PubMed, Embase, Scopus, and Web of Science. All cross-sectional, peer-reviewed studies investigating the link between FIS and T2DM were included. Population characteristics, study sizes, covariates, T2DM diagnoses, and diabetes-related clinical measures such as fasting blood glucose (FBG) and HbA1c were extracted from each study. Outcomes were compared between food insecure and food secure individuals. Effect sizes were combined across studies using the random effect model. RESULTS: Forty-nine peer-reviewed studies investigating the link between FIS and T2DM were identified (n = 258,250). Results of meta-analyses showed no association between FIS and clinically determined T2DM either through FBG or HbA1c: OR = 1.22 [95%CI: 0.96, 1.55], Q(df = 5) = 12.5, I2  = 60% and OR = 1.21 [95%CI: 0.95, 1.54], Q(df = 5) = 14; I2  = 71% respectively. Standardized mean difference (SMD) meta-analyses yielded no association between FIS and FBG or HbA1c: g = 0.06 [95%CI: -0.06, 0.17], Q(df = 5) = 15.8, I2  = 68%; g = 0.11 [95% CI: -0.02, 0.25], Q(df = 7) = 26.8, I2  = 74% respectively. For children, no association was found between FIS and HbA1c: g = 0.06 [95%CI: 0.00, 0.17], Q(df = 2) = 5.7, I2  = 65%. CONCLUSIONS: Despite multiple proposed mechanisms linking FIS to T2DM, integration of the available literature suggests FIS is not associated with clinically determined T2DM or increases in FBG or HbA1c among adult patients.

A Systematic Review and Meta-Analysis of Food Insecurity and Dyslipidemia.

PURPOSE: There is considerable interest in the association between food insecurity (FIS) and various cardiovascular risk factors such as dyslipidemia. Although the association between FIS and dyslipidemia has been studied across various methodologies and populations, there is no comprehensive systematic review and meta-analysis of these data. METHODS: A systematic literature search was conducted. Cross-sectional peer-review studies assessing the association between FIS and dyslipidemia were identified. Data extracted included population characteristics, study sizes, covariates explored, and laboratory assessments of dyslipidemia. Effect sizes were extracted or calculated, then synthesized across studies using a random effect model, and the heterogeneity, publication bias, and subgroup dependence for each meta-analysis were assessed. RESULTS: For adults, meta-analysis demonstrated no significantly elevated odds for FIS individuals to have a concomitant abnormal lipid measurement. Covariate-unadjusted analysis of standardized mean differences showed no significant differences in lipid measurements between food-insecure and food-secure individuals. In contrast to quantitative laboratory results, food-insecure patients were more likely to self-report previous diagnoses of dyslipidemia. CONCLUSIONS: Although current data do not suggest an association between FIS and dyslipidemia, more longitudinal studies and studies targeting women, children, the elderly, and patients with chronic diseases such as diabetes are needed to further address this issue.

Drawing for Visual Communication in Medicine: A Novel Pilot Course for Senior Medical Students.

OBJECTIVE: Visual aids such as drawings have been reported to improve patient comprehension, retention, and adherence. We sought to determine the feasibility of teaching live drawing for clinical communication to medical students. DESIGN: We designed a course to teach basic drawing skills and visual communication of health information to senior medical students. Data was gathered from both an intervention and control group via written pre- and post-course surveys. The intervention group also completed a survey six months after the course. SETTING: The course was offered as an elective at the University of Pennsylvania Perelman School of Medicine during February 2020. PARTICIPANTS: The intervention group consisted of 17 enrolled students, while 17 students not taking the course served as a control group. Third year, fourth year, and research year medical students were invited to enroll in the course. RESULTS: The intervention group had significantly greater comfort with visual communication for patient care and increased objective drawing and visual communication scores compared to the control group. Visual abilities not targeted by the curriculum did not change between the intervention and control groups. At 6-months follow-up, course participants reported persistently elevated comfort in visual communication, as well as utilization of visual communication skills in their clinical practice. CONCLUSIONS: These data provide initial evidence of the efficacy of an elective course aimed at developing the skill and confidence to draw for visual communication in medicine as well as support for continued efforts to further develop and disseminate this type of curriculum.