Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.

Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.

Prognostic communication about lung cancer in the precision oncology era: A multiple-perspective qualitative study.

BACKGROUND: Although most patients with cancer prefer to know their prognosis, prognostic communication between oncologists and patients is often insufficient. Targeted therapies for lung cancer improve survival yet are not curative and produce variable responses. This study sought to describe how oncologists communicate about prognosis with patients receiving targeted therapies for lung cancer. METHODS: This qualitative study included 39 patients with advanced lung cancer with targetable mutations, 14 caregivers, and 10 oncologists. Semistructured interviews with patients and caregivers and focus groups or interviews with oncologists were conducted to explore their experiences with prognostic communication. One oncology follow-up visit was audio-recorded per patient. A framework approach was used to analyze interview transcripts, and a content analysis of patient-oncologist dialogue was conducted. Themes were identified within each source and then integrated across sources to create a multidimensional description of prognostic communication. RESULTS: Six themes in prognostic communication were identified: Patients with targetable mutations develop a distinct identity in the lung cancer community that affects their information-seeking and self-advocacy; oncologists set high expectations for targeted therapy; the uncertain availability of new therapies complicates prognostic discussions; patients and caregivers have variable information preferences; patients raise questions about progression by asking about physical symptoms or scan results; and patients' expectations of targeted therapy influence their medical decision-making. CONCLUSIONS: Optimistic patient-oncologist communication shapes the expectations of patients receiving targeted therapy for lung cancer and affects their decision-making. Further research and clinical guidance are needed to help oncologists to communicate uncertain outcomes effectively.

Knowledge About Risks, Benefits, and Curative Potential of Immunotherapy Among Patients with Advanced Cancer.

BACKGROUND: Immunotherapy is the first-line treatment for melanoma and lung cancer and brings new risks of immune-related adverse events. We aimed to describe patients' knowledge about risks, benefits, and goals of immunotherapy. MATERIALS AND METHODS: We conducted a cross-sectional study of patients with advanced melanoma or non-small cell lung cancer that used a 9-item knowledge survey and questions from the Prognosis and Treatment Perceptions Questionnaire. RESULTS: We surveyed 105 participants (57 with melanoma, 48 with lung cancer) with median age 69 years (range 36-89). Participants' responses revealed knowledge deficits about immunotherapy mechanism of action and lack of awareness about the timing and severity of side effects. One third (34%; 36/105) of participants reported that the primary goal of their treatment is to cure their cancer. CONCLUSION: Given the widespread use of immunotherapy, patients would benefit from educational tools so that they know what to expect regarding side effects and prognosis.

Retinal characteristics in eyes with pathologic myopia among individuals self-identifying as Black.

OBJECTIVE: Investigate retinal characteristics of pathologic myopia (PM) among patients self-identifying as Black. DESIGN: Retrospective cohort single-institution retrospective medical record review. METHODS: Adult patients between January 2005 and December 2014 with International Classification of Diseases (ICD) codes consistent with PM and given 5-year follow-up were evaluated. The Study Group consisted of patients self-identifying as Black, and the Comparison Group consisted of those not self-identifying as Black. Ocular features at study baseline and 5-year follow-up visit were evaluated. RESULTS: Among 428 patients with PM, 60 (14%) self-identified as Black and 18 (30%) had baseline and 5-year follow-up visits. Of the remaining 368 patients, 63 were in the Comparison Group. For the study (n = 18) and Comparison Group (n = 29), median (25th percentile, 75th percentile) baseline visual acuity was 20/40 (20/25, 20/50) and 20/32 (20/25, 20/50) in the better-seeing eye and 20/70 (20/50, 20/1400) and 20/100 (20/50, 20/200), respectively, in the worse-seeing eye. In the eyes that did not have choroidal neovascularization (CNV) in the study and Comparison Group, median study baseline optical coherence tomography central subfield thickness was 196 µm (169, 306 µm) and 225 µm (191, 280 µm), respectively, in the better-seeing eye and 208 µm (181, 260 µm) and 194 µm (171, 248 µm), respectively, in the worse-seeing eye. Baseline prevalence of CNV was 1 Study Group eye (3%) and 20 Comparison Group eyes (34%). By the 5-year visit, zero (0%) and 4 (15%) additional eyes had CNV in the study and Comparison Group, respectively. CONCLUSION: These findings suggest that the prevalence and incidence of CNV may be lower in patients with PM self-identifying as Black when compared with individuals of other races.

Women physicians and the COVID-19 pandemic: gender-based impacts and potential interventions.

Aim: These are extraordinary times caused by the first global pandemic in our modern era. Physicians and other frontline healthcare providers face unique challenges, for which they have had little formal preparation. This combination of challenge and deficit leads to significant negative impacts, not only on what medical practices and health care systems can deliver to the public, but also on the individual healthcare providers themselves.Methods: In this essay, we specifically address women physicians, and explore the considerable impact they bear from the COVID-19 pandemic, particularly in the contexts of response to stress, social isolation, work-life integration, and autonomy. Because the language we use is important, we think it necessary to clarify that when we refer to 'women physicians,' we are referring to physicians that self-identify as women, and we acknowledge that not all the references we cite may use the same definition.Results: We offer several potential interventions that turn the challenges women physicians are facing into opportunities to address longstanding inequity. These interventions include tackling barriers to work-life balance, addressing gender and maternal bias, and promoting women physician representation in leadership.Conclusion: The COVID-19 pandemic is likely to become a chronic part of our lives; protecting vulnerable populations, such as women physicians, through thoughtful intervention is paramount.KEY MESSAGESWomen physicians experience considerable adversity during the COVID-19 pandemic, particularly in the contexts of response to stress, social isolation, work-life integration, and autonomy.These challenges create opportunities for interventions to improve equity in medicine during the COVID-19 pandemic and in the long-term, including tackling barriers to work-life balance, addressing gender and maternal bias, and promoting women physician representation in leadership.

Therapeutic Gene Editing in Inherited Retinal Disorders.

Since the development of CRISPR/Cas9 gene editing in 2012, therapeutic editing research has produced several phase 1-2a trials. Here we provide an overview of the mechanisms and applications of various gene-editing technologies including adeno-associated virus vectors, lentiviruses, CRISPR/Cas9 systems, base and prime editing, antisense oligonucleotides, short-hairpin RNAs, Cas13, and adenosine deaminase acting on RNA for the treatment of various inherited retinal diseases (IRDs). We outline the various stages of clinical trials using these technologies and the impacts they have made in advancing the practice of medicine.

The physician gender pay gap in Maryland: current state and future directions.

BACKGROUND: Over the last few decades, more attention has been paid to the physician gender pay gap and more interventions have been attempted. This paper discusses the physician gender pay gap between 2017 and 2021 in Maryland. METHODS: An online cross-sectional survey was distributed to over 10,000 physicians in the Maryland Medical Society, featuring questions regarding employment characteristics, compensation, impact of the COVID-19 pandemic, and educational debt. Using descriptive and regression analyses, we explored cross-sectional associations between gender and employment characteristics. RESULTS: Male physicians reported a significantly higher average 2020 pre-tax income ($333,732 per year) than female physicians ($225,473 per year, p < 0.001), amounting to a nearly 50% difference in raw income, consistent with a previously reported pay gap in 2016. Women physicians earned 31.5% less than their male colleagues in 2020 and were projected to earn 28.7% less in 2021. Female physicians were also more likely to have educational debt (33.6% vs.12.9%, p < 0.001) and also more likely to have a high burden of debt, with 36% owing over $200,000 in education loans, compared to 14.7% of men (p < 0.01). CONCLUSION: The physician gender pay gap in Maryland has remained relatively stable over four years, including the period of the COVID-19 pandemic.

The physician gender pay gap in Maryland has remained stable over four years, including the period of the COVID-19 pandemic.Female physicians earned over 30% less than male physicians in Maryland in 2020.Female physicians are more likely to have educational debt, and when they do, they have a greater magnitude of debt.

Management of uncomplicated rhegmatogenous retinal detachments: a comparison of practice patterns and clinical outcomes in a real-world setting.

OBJECTIVE: To investigate practice patterns and clinical outcomes in the repair of uncomplicated rhegmatogenous retinal detachments (RRD) in a real-world setting over a 10-year period. METHODS: We compared preferences for scleral buckling (SB), pars plana vitrectomy (PPV), PPV/SB, or pneumatic retinopexy (PR) over time, and examined the 1-year single surgery anatomic success (SSAS) and best-corrected visual acuity (BCVA) at a tertiary academic institution from 2008-2018. RESULTS: Eight hundred eight eyes had RRD repair between 2008-2011 (n = 240), 2012-2014 (n = 271), and 2015-2017 (n = 297). Compared to 2008-2011, PPV was preferred over SB in 2012-2014 (OR: 2.93; 95% CI: 1.86-4.63) and 2015-2017 (OR: 5.94; 95% CI: 3.76-9.38), and over PPV/SB in 2012-2014 (OR: 2.74; 95% CI: 1.65-4.56) and 2015-2017 (OR: 3.16; 95% CI: 31.96-5.12). PR was uncommonly utilized (<10%). Younger surgeons (graduating 2010-2017) favored PPV over SB when compared to older surgeons [graduating 1984-2000 (OR: 1.77; 95% CI: 1.18-2.65) and 2001-2009 (OR 1.73; 95% CI: 1.14-2.65)], but similarly selected PPV vs. PPV/SB as their older counterparts (p > 0.05). Compared to PPV, SSAS was higher with SB (OR: 1.53; 95% CI: 1.03-2.26) and PPV/SB (OR: 2.55; 95% CI: 1.56-4.17). One-year BCVA was markedly improved compared to baseline only for eyes that achieved SSAS (p < 0.001). CONCLUSIONS: Over the past 10 years, PPV has become the favored approach to repair uncomplicated RRD and this appears to be driven by younger surgeons' preferences. Given the superior long-term SSAS in SB and PPV/SB as compared to PPV, SB and PPV/SB should be more frequently considered when determining the appropriate repair strategy for uncomplicated RRD.

Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer. SIGNIFICANCE: This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489.

Socioeconomic disadvantage and impact on visual outcomes in patients with viral retinitis and retinal detachment.

While socioeconomic disparities impact clinical care and patient outcomes, their impact on the anatomic and visual outcomes of retinal detachment in patients with viral retinitis is unstudied. This case series included 18 eyes in 18 patients from a single academic institution between January 1, 2008 and December 31, 2018. Patient characteristics including age, sex, race, ethnicity, insurance, immunosuppression, viral retinitis, retinal detachment, retinal detachment repair, visual and anatomic outcomes, missed appointments, and Area Deprivation Index [ADI] were collected. The low-ADI group, indicating less socioeconomic disadvantage, was comprised of twelve patients with national ADIs less than 38, and the high-ADI group of six patients with national ADIs greater than 38. High-ADI patients tended to be younger (average age 38.0 versus 51.3; P = 0.06), of female sex (P = 0.03), and had more missed appointments (median 11.0 vs 0; P = 0.002). A similar number of patients in both the high-ADI and low-ADI groups underwent pars plana vitrectomy alone or pars plana vitrectomy with scleral buckle. Visual acuity was similar in the high-ADI group than in the low-ADI group at baseline, but worse at the final follow-up visit (P = 0.004). Post-operative and final visit ocular hypotony were more common in the high-ADI group (P = 0.02). In our series, socioeconomic disadvantage negatively affects the visual outcomes in patients with viral retinitis associated-retinal detachments. These factors should be considered by ophthalmologists when treating these patients.

Experience and supportive care needs of metastatic lung cancer survivors living with uncertainty: a brief qualitative report.

PURPOSE: Molecularly targeted therapies have revolutionized non-small cell lung cancer (NSCLC) treatment. Many patients with metastatic NSCLC receiving targeted therapy may live several years with incurable cancer. We sought to describe how these metastatic cancer survivors and their caregivers experience uncertainty about the future and identify their unmet supportive care needs. METHODS: We conducted semi-structured interviews with patients with metastatic NSCLC receiving targeted therapy (n = 39) and their caregivers (n = 16). We used a framework approach to code and analyze the qualitative data. RESULTS: Metastatic lung cancer survivors described awareness of their mortality and the possibility that their cancer could progress at any time. Though some found ways to cope, many felt inadequately supported to manage their distress, especially since they were "doing fine medically." Survivors struggled with decisions about working and managing their finances given their uncertain life expectancy and sought trustworthy lung cancer information in plain language. They wished to compare experiences with other patients with their molecular subtype of NSCLC. Participants desired comprehensive cancer care that includes psychosocial support, preparation for the future, and ways to promote their own health, such as through lifestyle changes. CONCLUSIONS: Patients with metastatic NSCLC receiving targeted therapy and their caregivers experience distress related to living with uncertainty and desire more coping support, connection with peers, information, and healthy lifestyle guidance. IMPLICATIONS FOR CANCER SURVIVORS: Patients living with treatable yet incurable cancer and their caregivers are a growing population of cancer survivors. Recognition of their unmet needs may inform the development of tailored support services to help them live well with cancer.

A Qualitative Study of the Barriers and Benefits to Resident Education in Ambulatory Surgical Centers.

OBJECTIVE: As Ambulatory Surgical Centers (ASCs) become more common in academic medical centers, large hospital systems must determine how to shift resident education from inpatient to outpatient surgical centers. This study aims to define stakeholders' views regarding the integration of surgical residents into ASCs. DESIGN: Long-form interviews lasting 30 to 60 minutes were conducted. Interviews were hand-transcribed and analyzed by qualitative analysis to determine benefits of learning in ASCs for residents, challenges that arise from integrating residents, and recommendations to improve resident incorporation. SETTING: Interviews were conducted using a video conferencing platform. PARTICIPANTS: Residency program directors, attending surgeons, graduate medical learners, and a nursing manager were interviewed. Twenty-one total interviews were conducted, representing ten different departments. RESULTS: Stakeholders agreed that residents benefit from being placed in ASCs because the fast, surgical pace allows the residents to engage in more cases. However, different stakeholders highlighted different challenges, all centered around the notion of inter-stakeholder conflict due to conflicting priorities among residents, attending physicians, and administration. Likewise, recommendations differed by stakeholder group-faculty members sought more defined learning objectives and enhanced communication, whereas residents desired that ambulatory surgical time be more structured. CONCLUSIONS: Despite the pressures of rapid case turnover, stakeholders agreed that there are many benefits to resident education in ASCs. Findings related to challenges and recommendations support the need to strengthen communication between stakeholder groups and better plan for resident integration into ASCs.

Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment.

Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK-BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease. SIGNIFICANCE: Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infiltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and/or OLFML3 may represent novel therapeutic targets for GBM.This article is highlighted in the In This Issue feature, p. 327.