Philadelphia Towards Racial and Environmental Equity (Philly TREEs): how a medical school can advance health equity through urban forestry in Philadelphia, PA, USA.

Inequity in access to urban greenspaces might contribute to health disparities in the USA via multiple pathways. Academic medical centres can promote health equity in their surrounding communities by partnering with community organisations to improve greenspace access in urban environments. Academic medical centres are also uniquely positioned to advance health-equity leadership among the next generation of doctors through medical-education initiatives; of particular importance is that medical professionals are involved in advocating for the expansion of greenspace access due to its direct relationship with human health and wellness. Furthermore, by focusing educational, research, and service endeavours on addressing the most important health issues within their communities, institutions could allocate some of their resources towards community greening as a form of preventive health investment. This Personal View describes our medical-student-led pilot project Philadelphia Towards Racial and Environmental Equity (Philly TREEs) at the Perelman School of Medicine (University of Pennsylvania, Philadelphia, PA, USA), which aims to improve tree equity and community wellness in Philadelphia. We highlight this project to show how academic medical institutions can help cities to achieve urban tree-canopy goals in an equitable way through community partnership and address disparities in the environment and in health.

Reversible Cerebral Vasoconstriction Syndrome Exacerbation After Calcitonin Gene-Related Peptide Inhibitor Administration.

Background: Reversible cerebral vasoconstriction syndrome (RCVS) is a non-inflammatory vasculopathy. While most patients have good clinical outcomes, RCVS can be associated with severe brain injury from ischemic stroke, subarachnoid, and intracerebral hemorrhage. Purpose: A number of vasoactive medications have been implicated in RCVS, including triptans, amphetamines, antidepressants, and decongestants. Given the role of CGRP in modulating cerebral vasodilation, the possibility of CGRP inhibitors contributing to RCVS has been raised. Research Design: Case report at the University of Pennsylvania. Study Sample: Patient at the University of Pennsylvania. Results: We report a patient with RCVS in which severe exacerbation resulting in multifocal ischemic stroke occurred following administration of the calcitonin gene-related peptide (CGRP) inhibitor fremanezumab. Conclusions: It is unclear whether fremanezumab played a role in this patient's case, but CGRP-inhibitor use should be considered as a potential precipiating factor.

State of current management of the heightened risk for atherosclerotic cardiovascular events in an established cohort of patients with lupus erythematosus.

OBJECTIVE: Patients with lupus erythematosus (LE) are at heightened risk for clinical events, chiefly heart attacks and strokes, from atherosclerotic cardiovascular disease (ASCVD). We recently proposed new guidelines to assess and manage ASCVD event risk specifically in LE. Here, we examined current cardiovascular management in light of these new recommendations. METHODS: We studied our entire UPenn Longitudinal Lupus Cohort of patients with cutaneous LE, without (CLE-only) or with (CLE+SLE) concurrent systemic LE, for whom we had full access to medical records (n=370, LE-ASCVD Study Cohort). RESULTS: Of our LE-ASCVD Study Cohort, 336 out of 370 (90.8%) had a designated primary-care physician. By the new guidelines, the most recent low-density lipoprotein (LDL) levels were above-goal for 249 out of 370 (67.3%). Two-hundred sixty-six (71.9%) had hypertension, which was undertreated or untreated in 198 out of 266 (74.4%). Of current smokers, 51 out of 63 (81.0%) had no documented smoking cessation counselling or referrals. Diabetes and triglyceridaemia were generally well managed. Of the cohort, 278 qualified for two widely used online estimators of ASCVD event risk in primary prevention: the ACC-ASCVD Risk Estimator Plus and QRisk3. We also stratified these 278 patients into our recently defined categories of ASCVD event risk in LE. These three methods for estimating ASCVD event risk showed clinically meaningful discordance for 169 out of 278 (60.8%). The documented rate of ASCVD events in the first 10 years after enrolment was 13.5% (95% CI 8.9%, 17.9%), similar between CLE-only and CLE+SLE, indicating an at-risk population despite the preponderance of women and an average age at enrolment of only 47 years. CONCLUSION: Patients with CLE-only or CLE+SLE are undertreated compared with the new guidelines and, accordingly, they experience a significant burden of ASCVD events. Moreover, it is unclear how to accurately assess their future ASCVD event risk, except that it is substantial. Efforts are underway to improve ASCVD event risk estimation and guideline implementation in patients with lupus.

Predictors of cardiovascular implantable electronic device dependence at long-term follow-up after alcohol septal ablation in hypertrophic cardiomyopathy patients.

BACKGROUND: The most common complication of alcohol septal ablation (ASA) is transient periprocedural high-grade AV block (HGAVB). To date, no long-term follow-up of cardiovascular implantable electronic device (CIED) utilization after ASA has been reported. We hypothesized that CIED dependence on long-term follow-up can be predicted by ECG or procedural characteristics. METHODS: We analyzed all patients with HCM who underwent ASA from December 1998 to December 2019 and received their first CIED within 30 days after ASA for HGAVB. All follow-up interrogations were reviewed. CIED dependence was defined as ventricular pacing of ≥ 5%. RESULTS: A total of 138 patients with HCM underwent ASA. Of these, 35 had a prior device and were excluded. Of the remaining 103 patients, 25 patients received a CIED for HGAVB within 30 days after ASA. Average follow-up duration was 10.1 years. On long-term follow-up, 16 patients (64%) were found to be CIED-dependent. Baseline characteristics, including pre- and post-ASA ECG, were not significantly different between dependent and non-dependent patients. The only predictor for CIED dependence was > 1 ml of alcohol injected (OR 6.0, p = 0.031). CONCLUSIONS: CIED implantation after ASA is common. Almost two thirds of patients who received a CIED for post-procedural HGAVB were CIED-dependent on long-term follow-up. CIED dependence can be predicted by the amount of injected alcohol > 1 ml.

Age Associations with Dry Eye Clinical Signs and Symptoms in the Dry Eye Assessment and Management (DREAM) Study.

Purpose: To evaluate how increasing age is associated with dry eye disease (DED) signs and symptoms in the Dry Eye Assessment and Management (DREAM) study. This study was undertaken to better understand how DED signs and symptoms differ across decades of life with goals to help assess detection and treatment of DED. Design: Secondary analysis of the DREAM study. Subjects: One hundred twenty, 140, 185, and 90 participants aged < 50, 50 to 59, 60 to 69, and ≥ 70 years, respectively. Methods: We performed a secondary analysis of data from the DREAM study, a multicenter randomized clinical trial, to evaluate the effect of omega-3 fatty acid supplementation for the treatment of DED. At baseline, 6 months, and 12 months follow-up, participants underwent an assessment of DED symptoms and signs using Ocular Surface Disease Index, Brief Pain Inventory, tear break-up time (TBUT) (in seconds), Schirmer test with anesthesia (mm/5 minutes), conjunctival staining, corneal staining, meibomian gland dysfunction evaluation, and tear osmolarity (mOsm/l). Multivariable generalized linear regression models were used to compare DED symptoms and signs across the 4 age groups among all participants and by sex. Main Outcome Measures: Scores of DED symptoms, individual signs, and composite scores of DED signs. Results: Among 535 patients with DED, increasing age was significantly associated with worse TBUT (P = 0.01), corneal staining (P < 0.001), a composite severity score of DED signs (P = 0.007), and tear osmolarity (P = 0.001). Similar significant differences were found across 4 age groups of 334 women in TBUT, corneal staining score, composite severity score of DED signs, and tear osmolarity (all P < 0.05) but not in men. Conclusion: We found that corneal staining, TBUT, tear osmolarity, and a composite severity score of DED signs were significantly more severe with increasing age in women but not in men; worsening symptoms did not increase with increasing age. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Sex-related differences and hormonal effects in the Dry Eye Assessment and Management (DREAM) study.

BACKGROUND/AIMS: To compare dry eye disease (DED) signs and symptoms between men and women, as well as between premenopausal and postmenopausal women, in the Dry Eye Assessment and Management (DREAM) study. METHODS: 434 women and 101 men self-reported prior medical history and underwent a standardised DED assessment using the Ocular Surface Disease Index, Brief Pain Inventory, Tear Break-Up Time (TBUT)(s), Schirmer's test 2 (mm/5 min), National Eye Institute-graded lissamine conjunctival staining, corneal staining, meibomian gland dysfunction evaluation and tear osmolarity (mOsms/L) at baseline, 6 months and 12 months. Multivariable linear regression models were used to compare these scores. RESULTS: Women experienced significantly worse DED signs than men with lower Schirmer's test scores (9.27 vs 12.16; p<0.001), higher corneal staining scores (3.59 vs 2.70; p=0.006) and worse composite DED sign scores (0.52 vs 0.40; p<0.001). Postmenopausal women experienced significantly worse DED signs than premenopausal women with higher corneal staining scores (3.74 vs 2.58, p<0.001), higher conjunctival staining scores (2.80 vs 2.22, p<0.001), higher tear osmolarity (304 vs 299, p=0.004), lower TBUT (3.37 vs 3.93, p=0.047), worse meibomian gland dysfunction (3.05 vs 2.62, p=0.04) and worse composite DED sign scores (0.54 vs 0.42, p<0.001). There were no significant differences in DED symptoms between sex and between premenopausal and postmenopausal women (all p≥0.08). CONCLUSION: In the DREAM study, women experienced more severe DED signs than men. Further, postmenopausal women presented with more severe DED signs than premenopausal women. Elucidating these differences may improve DED diagnosis and provide future direction in understanding sex-related differences in DED. TRIAL REGISTRATION NUMBER: NCT02128763.

Risk and protective factors for heavy episodic drinking among college students: Influence of mental health service use.

Objective: This study was designed to assess the relationship between mental health service utilization and heavy episodic drinking (HED) after controlling for demographic and student-level variables. Participants: A national sample of college undergraduate respondents to the 2017-2018 Healthy Minds Study survey (n = 67,427). Methods: Hierarchical logistic regression entering all variables on a single step. Subsequent logistic regression was used to assess interactions between mental health service variables and select demographic and student level variables. Results: Twenty-two demographic and student-level variables were associated with current HED (9 protective and 11 risk factors). Current mental health therapy was associated with a lower risk of current HED while mental health medication use in the past 12 months (but not currently) was associated with a higher risk of HED. Conclusions: Findings provide guidance to college/university community professionals given the responsibility of designing and implementing programs for mitigation of alcohol misuse on their campus.

Sex-Specific Differences in Ventricular Remodeling and Response After Cardiac Resynchronization Therapy.

In this study, we investigated the baseline characteristics and "trajectories" of clinical response in men and women after cardiac resynchronization therapy (CRT) implantation. Although women enjoy improved echocardiographic response after CRT compared with men, the kinetics of this response and its relation to functional performance and outcomes are less clear. We identified 592 patients who underwent CRT implantation at our center between 2004 and 2017 and were serially followed in a multidisciplinary clinic. Longitudinal linear mixed effects regression for cardiac response was specified, including interaction terms between time after CRT and sex , and Cox regression models were used to assess differences in all-cause mortality by gender after CRT. Women in our cohort were younger than men, had less frequent ischemic etiology of heart failure (24% vs 60% in men), a shorter QRS (151 vs 161 ms) and more frequent left bundle branch block (77% vs 52%) at baseline. Women had a greater improvement in left ventricular ejection fraction that was evident starting at approximately 1-month after CRT. We did not observe effect modification by gender in New York Heart Association class or 6-minute walk distance after CRT. Although women had improved mortality after CRT, after adjustment for potential confounders, gender was not associated with mortality after CRT. In conclusion, women were more likely to have CRT implantation for left bundle branch block and exhibited improved echocardiographic but not functional response within the first year after CRT. Clinical outcomes after CRT were not associated with gender in adjusted analysis.

Calciphylaxis: Part I. Diagnosis and pathology.

Calciphylaxis is an uncommon but devastating disorder characterized by vascular calcification and subsequent cutaneous tissue necrosis. This results in exquisitely painful and slow healing wounds that portend exceptionally high morbidity and mortality. The diagnosis of this condition can be complicated because there are no conclusive serologic, radiographic or visual signs that this disease is manifesting. The differential of tissue necrosis is broad, and identifying calciphylaxis requires an adroit understanding of the risk factors and physical signs that should raise suspicion of this condition. Reviews on this subject are uncommon and lack directed commentary from disease experts on the best diagnostic approach for patients suffering from this disease. The goal of this article is to update practicing dermatologists on the current standard of care for calciphylaxis.

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.

NUAK family kinase 2 is a novel therapeutic target for prostate cancer.

Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC. NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration.

Virtual multidisciplinary care for heart failure patients with cardiac resynchronization therapy devices during the Coronavirus Disease 2019 pandemic.

BACKGROUND: Heart failure (HF) patients with CRT devices are a vulnerable patient population during the Coronavirus Disease 2019 (COVID-19) Pandemic. It is important to develop innovative virtual care models to deliver multidisciplinary care while minimizing the risk of SARS-CoV2 exposure. OBJECTIVE: We aim to provide a description of how HF patients with CRT devices were assessed and managed in our virtual multidisciplinary clinic during the COVID-19 Pandemic. Clinical outcomes between this group of patients seen in virtual clinic and a historical cohort followed by in-person multi-disciplinary clinic prior to the pandemic were compared. METHOD: This is a retrospective cohort study of HF patients with CRT implants who were seen in the virtual multidisciplinary clinic from March 18th, 2020 to May 27th, 2020 (Virtual Visit Group, N = 43). A historical cohort of HF patients with CRT devices seen in the ReACT clinic in person during the same calendar time period in 2019 was used as a control group (In-Person Visit Group, N = 39). Both groups were followed until July 1st of the same calendar year (2020 or 2019) for clinical events. The primary outcome measure was a combined outcome of all-cause mortality and HF- or device-related hospitalizations during follow-up. The secondary outcome measures included patient satisfaction, COVID-19 infection, and other cardiovascular events. RESULTS: In the Virtual-Visit Group, 21 patients (48.8%) had their initial ReACT clinic visit (first visit after CRT implant) as a virtual visit; 22 patients (51.2%) had prior in-person ReACT clinic visits before the first virtual visit. During the virtual visits, 12 patients had either potential cardiac symptoms or significant device interrogation findings that required clinical intervention. In post-virtual clinic patient satisfaction survey, all 22 patients surveyed (100%) reported being very satisfied or satisfied with the overall experience of the virtual clinic, and every patient (100%) said they would like to use telemedicine again. During a median follow-up period of 82 days (interquartile range [IQR] 61-96 days), one patient died from pneumonia of unclear etiology at an outside hospital, without documentation of COVID-19 positivity. No patient was hospitalized for HF- or arrhythmia-related complications. No patient was diagnosed with COVID-19. Compared with the In-Person Visit Group, there was no significant increase in mortality or major cardiovascular events in the Virtual-Visit Group (2.3% versus 5.1%, P = 0.60). CONCLUSIONS AND RELEVANCE: Virtual multidisciplinary care was feasible for HF patients with cardiac resynchronization therapy devices and achieved good patient satisfaction. Virtual care was not associated with short-term increase in adverse events for HF patients with CRT device during the COVID-19 Pandemic. This virtual care model could help promote the adoption of digital health methodology for high-risk patients with multiple cardiac comorbidities.