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Background: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. Methods: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. Results: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2–2.6). Median time from baseline CT to study drug was 62.5 (55–80) minutes, and from study drug to early post-dose CT was 19 (14.5–30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (−0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8–8.3) in the placebo arm ( P =0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (−2.6 to 8.3) in the rFVIIa arm and 0.7 mL (−1.6 to 2.1) in the placebo arm ( P =0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71–1.43]; P =0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994–1.003]; P =0.50; Table 3). Conclusions: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01359202.

Problem Statement: Radiation therapy (RT) for breast cancer (BC) can induce skin and soft tissue fibrosis, raises concerns over cardiac and pulmonary injury, is associated with higher rates of lymphedema and shoulder dysfunction with regional nodal irradiation, and significantly increases complication rates in women undergoing implant-based reconstruction due to radiation toxicity. Although these toxicities are not generally associated with higher mortality, in general, they can represent significant setbacks with respect to quality of life. These toxicities dissuade some patients from breast conservation leading to unnecessary mastectomy and can lead patients to omit reconstruction after mastectomy or choose more extensive autologous breast reconstruction. Women with implant-based reconstruction and radiotherapy have known higher rates of reconstruction failure. Purpose: Ultra-high dose rate radiation (FLASH) has been shown to induce less normal tissue toxicity, therefore if tumor control of FLASH-RT would be comparable to conventional radiotherapy (CONV) then it has the potential to lower morbidity associated with radiotherapy for breast cancer and allow overall improved outcomes. At first, we aimed to determine the effectiveness of FLASH-RT compared to CONV in eradicating small breast tumors in an orthotopic BC model using single-fraction 20 or 30Gy RT to compare effectiveness of FLASH-RT vs CONV. Methods: Radiation sensitive, syngeneic mammary tumor cell line Py117, that efficiently forms non-metastatic orthotopic tumors in C57BL/6 mice, were injected (106 cells) into the left 4th mammary fat pad. 30mm3 tumors or a range of greater volumes (200-800mm3) were irradiated with single-fraction 20 or 30Gy with a 2x2cm radiation field (~17MeV beams), exposing only 5mm of the surrounding tissue. FLASH RT was delivered with 2Gy per pulse at dose rate ~200Gy/s compared to CONV dose rate of 0.13Gy/s Results: Single-fraction 20Gy suppressed 30mm3 tumor growth until ~day 15 post-RT then regrew for both FLASH and CONV, while 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy. Larger tumors irradiated with 30Gy regressed until ~day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth suppression or tumor eradication between FLASH and CONV in any cohort. Conclusion: In this murine model of breast cancer, FLASH is as effective as CONV in controlling tumor growth. Future studies will extend the evaluation of the tumor control using clinically relevant fractionated dose schedules to be followed by comparisons of tumor control in xenograft models. Additional studies will assess normal tissue toxicity of FLASH vs CONV in murine models of implant-based breast reconstruction. We have established collaborations to understand differences in molecular pathways activated by FLASH vs CONV in tumor and normal tissue to explain the observed experimental differences in normal tissue, tumor, and cancer stem cells. Citation Format: Frederick Dirbas, Stavros Melemenidis, Bill Loo, Kathleen Horst, Edward E. Graves, Suparna Dutt, Vignesh Viswanathan, Brianna Lau, Amy Yu. FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-02.

The 2022 update of theCanadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7thedition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acuteischemicvascular event. Notable changes in the 7thedition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention,1the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7thedition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available atwww.strokebestpractices.ca.

The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O2) and hypoxic conditions (≤2% O2) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O2) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), usingS. aureusandS. pyogenesCas9 “bait” DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to “prey” DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1×102-5×106Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DNA damage activated APA event occurs in the first intron ofCDKN1A, inducing an alternate last exon (ALE)-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform and is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53 transcriptional activation. RNA binding protein (RBP) HuR and the transcriptional repressor CTCF regulate SPUD levels. SPUD induction increases p21 protein, but not CDKN1A full-length levels, affecting p21 functions in cell-cycle, CDK2 expression, and cell viability. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD can change their association with CDKN1A full-length in a DDR-dependent manner. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cellcycle.

Background Infections due to Pseudomonas aeruginosa displaying difficult-to-treat resistance (DTR-PA) necessitate the use of sub-efficacious and/or toxic “reserve” antibiotics and are associated with considerable morbidity and mortality. Ceftazidime-avibactam (CAZ-AVY) and ceftolozane-tazobactam (CEF-TAZO) are novel ß-lactam/ß-lactamase inhibitors (BLBLI) that tend to retain in vitro activity against DTR-PA. However, little is known about their in vivo effectiveness compared to reserve agents. Methods Inpatients aged ≥ 18 years with ≥1 blood, urine, respiratory, or body fluid culture growing DTR-PA who received targeted therapy with either CAZ-AVY, CEF-TAZO, or Best-Available Therapy (BAT) were identified in the Premier Healthcare Database. Primary outcome was in-hospital mortality or discharge to hospice and secondary outcome was length of hospital stay (LOS) for survivors. The primary outcome was compared for CAZ-AVY vs CEF-TAZO and novel agents (CAZ-AVY or CEF-TAZO) vs BAT using overlap weighting and binomial regression with downstream adjustment controlling for patient and treatment characteristics. The secondary outcomes were compared using overlap weighting and poisson regression with downstream adjustment controlling for patient and treatment characteristics. Results Between 2016 and 2020, 1,552 patients with DTR-PA infections were identified at 105 hospitals, of which 202 (13.0%) were treated with CAZ-AVY, 906 (58.4%) with CEF-TAZO, and 444 (28.6%) with BAT. Patient characteristics were similar among treatment groups (Table 1, Table 2). Overall crude mortality was 15.5%. The adjusted risk of mortality was lower in patients treated with CAZ-AVI (12.5%, 95% CI 7.9–17.1) vs CEF-TAZO (18.8%, 95% CI 15.9–21.8) for a risk difference of 6.3% (95% 1.1–11.5, p = 0.02). The novel agents were not associated with a reduced mortality risk when collectively compared to BAT (risk difference -1.1%, 95% CI -5.4; 3.2%). LOS favoured novel agents and were comparable for CAZ-AVY and CEF-TAZO. Conclusion In this real-world observational study of patients with DTR-PA infections, the novel ß-lactam/ß-lactamase inhibitors were comparably effective against BAT, though the use of CAZ-AVY was associated with a reduced mortality compared to CEF-TAZO. Disclosures All Authors: No reported disclosures.

To shed new light on the place of Christianity in seventeenth-century Chinese society and the debates and conflicts between Christians and Buddhists, this paper reflects on Christians' critiques of Buddhist dogma and praxis as well as rejoinders from the Buddhists. It will focus on the sustained debates, roughly between 1590 and 1690, with regard to the relative ‘merits and defects’ as represented in polemical texts. Several treatises serve as the essential link of the continuous debates, eliciting back-and-forth elaboration and rebuttals from both sides. Through an analysis of the polemical discourse, I argue that the Buddhist–Christian case offers an instance of what René Girard termed ‘mimetic rivalry’. The conflict entails internal rivalry resulting not only from different religious perspectives but also from social, cultural and economic ones. Seeking interconnectedness between traditions by creative imagination and analogy may offer a way out of ignorance and enmity in dealing with interreligious relationship. 1

1)ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a common cause of liver disease worldwide, and is characterized by the accumulation of fat in the liver. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a leading cause of liver transplantation. Fibrosis is the histologic feature most associated with liver-related morbidity and mortality in patients with NASH, and treatment options remain limited. In previous studies, we discovered that acid ceramidase (aCDase) is a potent antifibrotic target using human hepatic stellate cells (HSCs) and models of hepatic fibrogenesis. Using two dietary mouse models, we demonstrate that depletion of aCDase in HSC reduces fibrosis without worsening metabolic features of NASH, including steatosis, inflammation, and insulin resistance. Consistently, pharmacologic inhibition of aCDase ameliorates fibrosis but does not alter metabolic parameters. The findings suggest that targeting aCDase is a viable therapeutic option to reduce fibrosis in patients with NASH.

The aim of this study was to evaluate the feasibility and preliminary outcomes of immersive integrated experiential and didactic courses in strengthening competency-based global health learning in dental education. To address global inequities in oral health and student interest in global health, the Harvard School of Dental Medicine introduced two global health courses in 2017-18. The first was a didactic course in the core predoctoral curriculum, and the second, in collaboration with the Inter-American Center for Global Health, was a five-day elective experiential learning course in rural Costa Rica. The experiential course was an extension of the didactic course. All 33 second-year dental students completed the didactic course, and three of those students completed the experiential course. A pre-post survey and a six-month follow-up survey on self-reported knowledge based on course learning objectives were administered. The experiential course students also completed journals and interviews for qualitative analysis. Thirty-two students completed the pre-post didactic course surveys, for a response rate of 94%. There was a 100% response rate on the pre-post didactic surveys by those students who participated in the experiential learning course. While the experiential learning group scored similarly to the class average before the didactic course, they had higher scores than the class averages both immediately after and at the six-month follow-up. All three students reported that the experiential learning course was "extremely effective" in building on what they learned in the didactic course. Qualitative analysis of the journals and interviews suggested enhanced learning from the combination of didactic and experiential methods. These preliminary results support the Global Health Learning Helix Model, a theoretical competency-based teaching model for ethical student global health engagement to better prepare the future generation in tackling oral health disparities both locally and worldwide.

Early clinical exposure (ECE), defined as any interaction with patients prior to the portion of the curriculum when den- tal students spend most of their time at school as a primary provider, is a growing trend in curriculum reform across U.S. dental schools in the 21st century. The aims of this study were to characterize the types of ECE implementation in U.S. dental schools and determine if ECE correlated with earlier clinical competency assessments. In September 2018, the academic deans of all 66 U.S. dental schools were invited to respond to an eight-item electronic survey about ECE at their schools. Representatives of 40 schools submitted complete responses, for a response rate of 60.6%. Among the respondents, 85% reported their schools started their principal clinical experience (PCE), the portion of the curriculum when students spend most of their time as the primary provider for patients, during the last quarter of Year 2 or the first quarter of Year 3. Respondents at all 40 schools reported offering some form of ECE as part of the formal curriculum, with shadowing and performing dental prophylaxis the most commonly of- fered types. No statistically significant associations were found between specific types of ECE and related Commission on Dental Accreditation (CODA) clinical standards for both formative and summative assessments. Although U.S. dental schools have been incorporating more ECE into their curricula over the past decade, these findings suggest that it has not led to earlier clinical competency assessments.

With an increasing number of patients seeking gender-affirming hormone therapy (GAHT), the clinical impact of testosterone treatments on headache needs to be determined. Our case report looks at the potential effect of testosterone on migraine among transgender patients. We present two transmasculine patients who used masculinising hormone therapy with testosterone. Both patients described their headache as moderate-to-severe pain with features that fulfilled the criteria for chronic migraine without aura. Following GAHT, one patient improved in both frequency and intensity of headache symptoms while the other noted improvement in headache intensity alone. Our report postulates that testosterone therapy may have a positive impact on headaches in individuals participating in GAHT, highlighting the need for further research on the role of testosterone therapy on headache in transmasculine individuals.

Background Small observational studies have suggested that statin users have a lower risk of dying with COVID‐19. We tested this hypothesis in a large, population‐based cohort of adults in 2 of Canada’s most populous provinces: Ontario and Alberta. Methods and Results We examined reverse transcriptase–polymerase chain reaction swab positivity rates for SARS‐CoV‐2 in adults using statins compared with nonusers. In patients with SARS‐CoV‐2 infection, we compared 30‐day risk of all‐cause emergency department visit, hospitalization, intensive care unit admission, or death in statin users versus nonusers, adjusting for baseline differences in demographics, clinical comorbidities, and prior health care use, as well as propensity for statin use. Between January and June 2020, 2.4% of 226 142 tested individuals aged 18 to 65 years, 2.7% of 88 387 people aged 66 to 75 years, and 4.1% of 154 950 people older than 75 years had a positive reverse transcriptase–polymerase chain reaction swab for SARS‐CoV‐2. Compared with 353 878 nonusers, the 115 871 statin users were more likely to test positive for SARS‐CoV‐2 (3.6% versus 2.8%, P Conclusions Compared with statin nonusers, patients taking statins exhibit the same risk of testing positive for SARS‐CoV‐2 and those younger than 75 years exhibit similar outcomes within 30 days of a positive test. Patients older than 75 years with a positive SARS‐CoV‐2 test and who were taking statins had more emergency department visits and hospitalizations, but exhibited lower 30‐day all‐cause mortality risk.

Background The transfer of patients between hospitals (inter-hospital transfer, or IHT) is a common occurrence for patients, but guidelines to ensure safe and effective IHTs are lacking. Poor IHTs result in higher rates of mortality, longer lengths of stay, and higher hospitalization costs compared to admissions from the emergency department. Nurses are often the first point of contact for IHT patients and can provide valuable insights on key challenges to IHT processes. Objective To characterize the experiences of inpatient floor-level bedside nurses caring for IHT patients and identify care coordination challenges and solutions. Design/Participants/Approach Qualitative study using semi-structured focus groups and interviews conducted from October 2019 to July 2020 with 21 inpatient floor-level nurses caring for adult medicine patients at an academic hospital. Nurses were recruited using a purposive convenience sampling approach. A combined inductive and deductive coding approach guided by thematic analysis was used for data analysis. Key Results Results from this study are mapped to the Agency for Healthcare Research and Quality Care Coordination Measurement Framework domains of communication, assessing needs and goals, and negotiating accountability. The following key themes characterize nurses’ experiences with IHT related to these domains: (1) challenges with information exchange and team communication during IHT, (2) environmental and information preparation needed to anticipate transfers, and (3) determining responsibility and care plans after the IHT patient has arrived at the accepting facility. Conclusions Nurses described the absence of standardized processes to coordinate care before or at the time of patient arrival. Challenges to communication and coordination during IHTs negatively impacted patient care and nursing professional satisfaction. To streamline care for IHT patients and reduce nursing stress, future IHT interventions should include standardized handoff reports, timely identification and easy access to admitting clinicians, and timely clinician evaluation and orders. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07276-5.

Background & Aims Although colonoscopies for dysplasia surveillance are standard of care in patients with long-standing ulcerative colitis (UC), there is a paucity of data on the yield of surveillance colonoscopies in those older than 75 years of age. Methods We conducted a multicenter retrospective cohort study including patients with UC who underwent ≥1 colonoscopy at age ≥75 years. The primary outcome was diagnosis of dysplasia (visible or random) and colorectal cancer. Multivariable regression adjusted for relevant confounders examined the predictors of polypoid or non-polypoid dysplasia or colorectal cancer. Results The primary cohort included 211 patients with UC who underwent 635 colonoscopies after age ≥75 years. A total of 83 patients (39.3%) patients had dysplasia or cancer detected. Among colonoscopies, 123 (19.4%) identified visible dysplasia, 23 (3.6%) had random dysplasia (1 high-grade dysplasia found in each group, respectively), and 5 (0.8%) had colon cancer. In multivariable analysis, prior adenoma or colon cancer below age 75 tears (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07–3.96), flat dysplasia before 75 years (OR, 2.78; 95% CI, 1.05–7.44), and older age (80-84 years (OR, 2.29; 95% CI, 1.20–4.38), ≥85 years (OR, 3.54; 95% CI, 1.27–9.82) were associated with detection of dysplasia or cancer. Only 1 patient was noted to have a procedure-related complication. Conclusions Patients with long-standing UC without prior dysplasia may have a low yield on continued endoscopic surveillance at age ≥75 years. A targeted approach to surveillance may be appropriate in older individuals with UC.

12102 Backgroun1d: Timely identification of palliative care needs have the ability to reduce hospitalizations and improve QOL. The Supportive & Palliative Care Indicators Tool (SPICT) is used to identify patients with advanced stage medical conditions who may need special care planning. The Rothman Index (RI) detects patients at high risk of acutely decompensating in the inpatient setting and has been validated to assess 24-hour mortality risk. We used SPICT and RI in cancer patients admitted to the hospital and evaluated their roles in recognizing early palliative care needs and 6-month mortality. Methods: Advanced/metastatic cancer patients admitted to our institution from Jan 1, 2019 to June 30, 2019 were retrospectively reviewed. Patient demographics, length of hospital stay (LOS), comorbidities, palliative/hospice care referrals, vital status, initial RI score, and computed SPICT scores were obtained. Worse clinical indicators were defined as SPICT positive if it met > 2 clinical indicators or RI < 60. Univariate and bivariate analyses were performed. Results: A total of 227 patients were included, mean age 68, 34% Caucasians, 63% Blacks, 59% female, median comorbidities of 3, with majority having lung and GI malignancies. A total of 137 (60%) were SPICT +, 47 (21%) had RI < 60, and 38 (17%) concurrent SPICT + and RI < 60. SPICT + patients were more likely to have longer hospital stay, change in code status, more palliative/hospice referrals, and increased mortality. Those with RI < 60 had similar results (Table). SPICT + patients are more likely to have RI < 60 (p = 0.0013). Conclusions: SPICT and RI are valuable tools in predicting 6-month mortality and palliative/hospice care referrals. These can also be utilized to initiate early palliative and goals of care discussions in patients with advanced cancer. [Table: see text]

Background The Coronavirus Disease 2019 (COVID-19) caused unprecedented challenges within medical centers, revealing inequities embedded in the medical community and exposing fragile social support systems. While faculty and staff faced extraordinary demands in workplace duties, personal responsibilities also increased. The goal of this study was to understand the impact of the COVID-19 pandemic on personal and professional activities of faculty and staff in order to illuminate current challenges and explore solutions. Methods Qualitative, semi-structured group interviews involved faculty and staff at four affiliate sites within the Department of Medicine at the University of Colorado, School of Medicine. Focus groups addressed the impact of COVID-19 on (1) Changes to roles and responsibilities at work and at home, (2) Resources utilized to manage these changes and, (3) Potential strategies for how the Department could assist faculty and staff. Thematic analysis was conducted using an inductive method at the semantic level to form themes and subthemes. Results Qualitative analysis of focus group transcripts revealed themes of: (1) Challenges and disparities experienced during the pandemic, (2) Disproportionate impact on women personally and professionally, (3) Institutional factors that contributed to wellness and burnout, and (4) Solutions and strategies to support faculty and staff. Within each of these themes were multiple subthemes including increased professional and personal demands, concern for personal safety, a sense of internal guilt, financial uncertainty, missed professional opportunities, and a negative impact on mentoring. Solutions were offered and included an emphasis on addressing preexisting inequities, the importance of community, and workplace flexibility. Conclusions The COVID-19 pandemic created burdens for already challenged faculty and staff in both their personal and professional lives. Swift action and advocacy by academic institutions is needed to support the lives and careers of our colleagues now and in the future.

Background: The Coronavirus Disease 2019 (COVID-19) caused unprecedented challenges within medical centers, revealing inequities embedded in the medical community and exposing fragile social support systems. While faculty and staff faced extraordinary demands in workplace duties, personal responsibilities also increased. The goal of this study was to understand the impact of the COVID-19 pandemic on personal and professional activities of faculty and staff in order to illuminate current challenges and explore solutions. Methods:This is a multi-methods, prospective, observational study of faculty and staff within the Department of Medicine at the University of Colorado, School of Medicine, comprised of four separate sites. Participants received a preliminary department-wide survey followed by an invitation to participate in focus groups addressing: (1) the impact on personal and professional activities, on (2) career advancement and promotion, and (3) potential strategies to assist faculty and staff. Qualitative analysis was performed for thematic content of the focus groups.Results: One hundred and fifty-one faculty and staff responded to the initial survey (11%), 28 faculty and staff participated in focus groups. Prior to the pandemic, male respondents spent 20.5 hours (+/- 18.2) on home responsibilities while women spent 28.8 hours (+/-17.9), and since, time spent on these responsibilities rose to 32.4 hours (+/- 18.4) and 49.6 hours (+/-29.0), respectively. Qualitative analysis of focus group transcripts revealed thematic domains: (1) changing domestic responsibilities, (2) changing workplace expectations, (3) the untenable nature of a return to “normal,” (4) an opportunity to address pre-existing inequities and (5) internal conflict and guilt. Solutions were offered and included an emphasis on the importance of community.Conclusions: The COVID-19 pandemic created burdens for already challenged faculty and staff in both their personal and professional lives, and for women in particular. Swift action and advocacy by academic institutions is needed to support the lives and careers of our colleagues.

Endoscopic remission is a recognized therapeutic endpoint in inflammatory bowel disease (IBD; Crohn's disease (CD), ulcerative colitis (UC)). The impact of persistent histologic activity on long-term outcomes is less clear and limited by small studies.We performed a systematic search of PubMed and Embase to identify eligible studies examining the association between histologic activity and relapse in patients with CD or UC in endoscopic remission. Studies were pooled together using random effects meta-analysis per the DerSimonian and Laird inverse variance method. The impact of different histologic scales, cut-offs, and individual features were examined.Our meta-analysis included 28 studies contributing 2,806 patients (2677 UC; 129 CD). In UC, histologically active disease was associated with an overall increased risk of relapse (OR, 2.41; 95% CI, 1.91-3.04), with a similar effect noted in the subgroup with endoscopic Mayo endoscopic score of 0 vs 0 or 1. More rigorous Geboes cut-offs demonstrated numerically stronger impact on relapse rates-Geboes3.1 (OR, 2.40; 95% CI, 1.57-3.65), Geboes2.1 (OR, 3.91; 95% CI, 2.21-6.91) and Geboes 0 (OR, 7.40; 95% CI, 2.00-18.27). Among individual histologic features, basal plasmacytosis (OR, 1.94), neutrophilic infiltrations (OR, 2.30), mucin depletion (OR, 2.05), and crypt architectural irregularities (OR, 2.22) predicted relapse. There was no association between histologic activity and relapse in CD.In patients with UC in endoscopic remission, persistent histologic activity is associated with higher rates of relapse. Greater degree of normalization may have a stronger impact.

Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid, ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein, β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most downregulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.

BACKGROUND: Since 2017, women have made up over 50% of medical school matriculants; however, only 16% of department chairs are women—a number that has remained stagnant and demonstrates the underrepresentation of women in leadership positions in medicine. OBJECTIVE: To better understand the challenges women face in leadership positions and to inform how best to advance women leaders in Hospital Medicine. DESIGN, SETTING, AND PARTICIPANTS: Using hermeneutical phenomenological methods, we performed semi-structured qualitative interviews of ten female division heads from hospital medicine groups in the USA, transcribed verbatim, and coded for thematic saturation using Atlas.ti software. MEASUREMENTS: Qualitative themes and subthemes. KEY RESULTS: Ten women hospitalist leaders were interviewed from September through November 2019. Participants identified four key challenges in their leadership journeys: lack of support to pursue leadership training, bullying, a sense of sacrifice in order to achieve balance, and the need for internal and external validation. Participants also suggested key interventions in order to support women leaders in the future: recommending a platform to share experiences, combat bullying, advocate for themselves, and bolster each other in sponsorship and mentorship roles. Finally, participants identified how they have unique strengths as women in leadership, and are transforming the culture of medicine with a focus on diversity and flexibility. CONCLUSION: Women in leadership positions face unique challenges, but also have a unique perspective as to how to support the next generation of leaders.

Key Points Question Is implementation of a novel high-sensitivity cardiac troponin T protocol in patients with chest pain associated with less resource use and within acceptable safety parameters? Findings This cohort study of 31 543 emergency department encounters found that implementation of the protocol was associated with a shorter length of stay in the emergency department and a higher proportion of patients discharged. There was no difference in the rate of 30-day hospitalization for myocardial infarction or death. Meaning This or similar protocols that rapidly rule out myocardial infarction have the potential to reduce emergency department overcrowding and improve health care quality., This cohort study of patients at a large US safety net hospital examines the safety of and resource use associated with a new protocol for excluding myocardial infarction from diagnosis of patients with chest pains through the use of high-sensitivity troponin., Importance High-sensitivity cardiac troponin T (hs-cTnT) protocols for the evaluation of chest pain in the emergency department (ED) may reduce unnecessary resource use and overcrowding. Objective To determine whether the implementation of a novel hs-cTnT protocol, which incorporated troponin values drawn at 0, 1, and 3 hours after ED presentation and the modified HEART score (history, electrocardiogram, age, risk factors), was associated with improvements in resource use while maintaining safety. Design, Setting, and Participants This retrospective cohort study from Parkland Health and Hospital System, a large safety net hospital in Dallas, Texas, included data on 31 543 unique ED encounters in which patients underwent electrocardiographic and troponin testing from January 1, 2017, to October 16, 2018. The hs-cTnT protocol was implemented in December 2017. Main Outcomes and Measures Resource use outcomes included trends in ED dwell time, troponin to disposition decision time (the difference between the first troponin draw time and the time an order was placed for inpatient admission, admission to observation, or discharge), and final patient disposition. Safety outcomes included readmission for myocardial infarction and death. Results In 31 543 encounters, mean (SD) patient age was 54 (14.4) years and 14 675 patients (48%) were female. Department dwell time decreased by a mean of −1.09 (95% CI, −2.81 to 0.64) minutes per month in the preintervention period. The decline was steeper after the intervention (−4.69 [95% CI, −9.05 to −0.33] minutes per month) (P for interaction = .007). The troponin to disposition time was increasing in the preintervention period by 1.72 (95% CI, 1.08 to 2.36) minutes per month; postintervention, the mean difference increased more slowly (0.37 [95% CI, −1.25 to 1.99 minutes per month; P value for interaction = .007]). The proportion of patients discharged from the ED increased after the intervention (48% vs 54%, P

BACKGROUND Unnecessary hospitalizations may pose the risk of iatrogenic complications, suboptimal patient experience, and increased cost. Administrative data lack granularity to understand the proportion and causes of hospitalizations preventable through optimizing care continuum (HPOCC). We aim to identify the incidence and causes of HPOCC through clinician-adjudicated chart review. METHODS A retrospective review was performed for inpatient admissions from the emergency department (ED) over 1 week. Each admission was reviewed by a clinician to determine whether it is an HPOCC defined as not requiring inpatient care with the assumption of idealized outpatient care and social support. RESULTS Of the 515 patients admitted from the ED, 31 (6.0%) patients were judged to have had an HPOCC. Causes of HPOCC include urgent diagnostics (9, 29.0%), unnecessary transfer from a long-term facility (7, 23.0%), needing IV therapy (5, 16.0%), benign incidental finding (5, 16.0%), diagnostic uncertainty in complex chronic illness (3, 10.0%), and lack of access to care for disposition (2, 6.0%). CONCLUSION Hospitalizations preventable through optimizing care continuum account for about 1 in every 15 hospitalizations in an urban academic medical center. The need for urgent diagnostics accounts for a plurality of HPOCC and could be an important target for quality improvement.

Background Inflammatory bowel disease (IBD) frequently affects women during their reproductive years. Although the impact of pregnancy in patients with established IBD has been widely studied, the characteristics and outcomes of patients who develop a new diagnosis of IBD during pregnancy or the postpartum year (“pregnancy-onset”) is not well characterized. Methods We identified all patients with pregnancy-onset IBD between 2006 and 2018 at 2 major academic referral centers. Patient and disease characteristics were abstracted and compared to those of control patients with IBD not diagnosed during pregnancy or postpartum. Diagnostic and therapeutic interventions were noted, as were long-term outcomes including disease treatment course, hospitalizations, and surgery. Results We identified 50 patients with pregnancy-onset IBD and 100 control patients matched for year of diagnosis. The mean age of diagnosis and duration of follow-up was similar among both patients and control patients (aged 30.4 vs 28.5 years). Among patients with pregnancy-onset disease, 30% noted symptom onset in the first trimester, 22% in the second, 24% in the third, and 24% in the postpartum year. Patients with pregnancy-onset IBD were more likely to be diagnosed with ulcerative colitis compared with control patients (76% vs 56%; P = 0.02). On multivariable analysis, pregnancy onset-disease had a 4-fold increase in the risk of hospitalization (28% vs 13%; adjusted odds ratio 4.18; 95% confidence interval, 1.26-13.91). This increased risk persisted even after excluding any index hospitalizations during pregnancy. Conclusions Patients with pregnancy-onset IBD more commonly develop ulcerative colitis and have a higher risk of disease-related hospitalizations.

Background The postpartum period is marked by physiological and psychological stresses that may impact activity in inflammatory bowel disease. The predictors and outcomes of disease activity during this period have not been well characterized. Methods We performed a retrospective review of inflammatory bowel disease patients who underwent successful pregnancy and live birth at 2 referral institutions. Data on patient and disease factors including disease activity before and during pregnancy were abstracted from the medical records. We noted whether therapy was dose-reduced or stopped during pregnancy at each trimester and after delivery. Multivariable logistic regression of independent predictors of postpartum flare was performed, adjusting for relevant covariates. Results We identified a total of 206 eligible women (mean age, 33.2 years). Of these, 97 (47%) had a diagnosis of Crohn’s disease, whereas the remainder had ulcerative colitis. Nearly half the women delivered vaginally (53%), and the rest delivered by Caesarean section (47%). In the entire cohort, 65 (31.6%) experienced a postpartum flare within the year after delivery. In multivariable analysis, development of a postpartum flare was predicted by disease activity during the third trimester (odds ratio [OR], 6.27; 95% confidence interval [CI], 2.81–17.27), therapy de-escalation during pregnancy (OR, 3.00; 95% CI, 1.03–8.68), and therapy de-escalation after pregnancy (OR, 4.43; 95% CI, 1.55–12.65). Postpartum disease flare was not related to disease type, duration of disease, or mode of childbirth. Conclusions One-third of women with inflammatory bowel disease may experience disease flare during the postpartum year. Continued optimization of therapy before, during, and after pregnancy is essential to prevent this morbidity.

We describe the validation and implementation of the new 5th generation high sensitivity Troponin T assay (Roche Diagnostics®). In addition to the assay improved sensitivity, the numerical values, reporting units, reference intervals, and critical limits are markedly different. We describe the use of clinical correlation as the basis for implementation and validation of the fifth-generation hs-TnT assay at a large teaching county hospital.