TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.

Impact of preexisting coronary artery and peripheral artery disease on outcomes in diabetic patients after kidney transplant.

BACKGROUND: Atherosclerotic cardiovascular disease is highly prevalent in patients with end-stage kidney disease (ESKD). Kidney transplant (KT) improves patient survival and cardiovascular outcomes. The impact of preexisting coronary artery disease (CAD) and peripheral artery disease (PAD) on posttransplant outcomes remains unclear. METHODS: This is a retrospective study utilizing the United States Renal Data System. Adult diabetic dialysis patients who underwent first KT between 2006 and 2017 were included. The study population was divided into four cohorts based on presence of CAD/PAD: (1) polyvascular disease (CAD + PAD); (2) CAD without PAD; (3) PAD without CAD; (4) no CAD or PAD (reference cohort). The primary outcome was 3-year all-cause mortality. Secondary outcomes were incidence of posttransplant myocardial infarction (MI), cerebrovascular accidents (CVA), and graft failure. RESULTS: The study population included 19,329 patients with 64.4% men, mean age 55.4 years, and median dialysis duration of 2.8 years. Atherosclerotic cardiovascular disease was present in 28% of patients. The median follow up was 3 years. All-cause mortality and incidence of posttransplant MI were higher with CAD and highest in patients with polyvascular disease. The cohort with polyvascular disease had twofold higher all-cause mortality (16.7%, adjusted hazard ratio (aHR) 1.5, p < 0.0001) and a fourfold higher incidence of MI (12.7%, aHR 3.3, p < 0.0001) compared to the reference cohort (8.0% and 3.1%, respectively). There was a higher incidence of posttransplant CVA in the cohort with PAD (3.4%, aHR 1.5, p = 0.01) compared to the reference cohort (2.0%). The cohorts had no difference in graft failure rates. CONCLUSIONS: Preexisting CAD and/or PAD result in worse posttransplant survival and cardiovascular outcomes in patients with diabetes mellitus and ESKD without a reduction in graft survival.

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Prevalence, trends, and outcomes of cardiovascular diseases in pregnant patients in the USA: 2010-19.

AIMS: Contemporary data on the prevalence, trends, and outcomes of cardiovascular diseases (CVDs) in pregnant patients are limited. This study aimed to analyse the prevalence, trends, and outcomes of CVD and their subtypes in hospitalized pregnant patients in the USA. METHODS AND RESULTS: This retrospective population-based cohort study used the Nationwide Readmission Database to identify all hospitalized pregnant patients from 1 January 2010, to 31 December 2019. Data analyses were conducted from January to February 2022. Pregnancy-associated hospitalizations were identified. The main outcomes were the prevalence and trend of CVD in pregnant patients. 39 212 104 hospitalized pregnant patients were identified: 4 409 924 with CVD (11.3%) and 34 802 180 without CVD (88.8%). The annual age-adjusted CVD prevalence increased from 9.2% in 2010 to 14.8% in 2019 (P < 0.001). Hypertensive disorder of pregnancy (1069/10 000) was the most common, and aortic dissection (0.1/10 000) was the least common CVD. The trends of all CVD subtypes increased; however, the trend of valvular heart disease decreased. Age-adjusted in-hospital all-cause mortality was 8.2/10 000 in CVD, but its trend decreased from 8.1/10 000 in 2010 to 6.5/10 000 in 2019 (P < 0.001). CVD was associated with 15.51 times higher odds of in-hospital all-cause mortality compared with non-CVD patients [odds ratio (OR): 15.51, 95% confidence interval (CI)13.22-18.20, P < 0.001]. CVD was associated with higher 6-week postpartum readmission (OR: 1.97, 95% CI: 1.95-1.99), myocardial infarction (OR: 3.04, 95% CI: 2.57-3.59), and stroke (OR: 2.66, 95% CI: 2.41-2.94)(P < 0.001 for all). CONCLUSION: There is an increasing age-adjusted trend in overall CVD and its subtypes among pregnant patients in the USA from 2010 to 2019. Pregnant patients with CVD had higher odds of in-hospital mortality than those without CVD. However, in-hospital all-cause mortality among patients with and without CVD has decreased over the past 10 years. CVD was associated with higher 6-week postpartum all-cause readmission, myocardial infarction, and stroke rates.

Multi-nuclear sodium, diffusion, and perfusion MRI in human gliomas.

PURPOSE: There is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas. METHODS: Twenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI. RESULTS: Both relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs. CONCLUSION: Sodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment.

Urologic morbidity associated with placenta accreta spectrum surgeries: single-center experience with a multidisciplinary team.

BACKGROUND: Hysterectomy for placenta accreta spectrum may be associated with urologic morbidity, including intentional or unintentional cystostomy, ureteral injury, and bladder fistula. Although previous retrospective studies have shown an association between placenta accreta spectrum and urologic morbidities, there is still a paucity of literature addressing these urologic complications. OBJECTIVE: We sought to report a systematic description of such morbidity and associated factors. STUDY DESIGN: This was a retrospective study of all histology-proven placenta accreta spectrum deliveries in an academic center between 2011 and 2020. Urologic morbidity was defined as the presence of at least one of the following: cystotomy, ureteral injury, or bladder fistula. Variables were reported as median (interquartile range) or number (percentage). Analyses were made using appropriate parametric and nonparametric tests. Multinomial regression analysis was performed to assess the association of adverse urologic events with the depth of placental invasion. RESULTS: In this study, 58 of 292 patients (19.9%) experienced urologic morbidity. Patients with urologic morbidity had a higher rate of placenta percreta (compared with placenta accreta and placenta increta) than those without such injuries. Preoperative ureteral stents were placed in 54 patients (93.1%) with and 146 patients (62.4%) without urologic injury (P=.003). After adjusting for confounding variables, multinomial regression analysis revealed that the odds of having adverse urologic events was 6.5 times higher in patients with placenta percreta than in patients with placenta accreta. CONCLUSION: Greater depth of invasion in placenta accreta spectrum was associated with more frequent and severe adverse urologic events. Whether stent placement confers any protective benefit requires further investigation.

A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury.

Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.

The vagus nerve somatosensory evoked potential in the intact brain: state-of-evidence and some representative vignettes.

OBJECTIVE: Scalp-recorded evoked potentials elicited by applying afferent electrical stimulation at the tragus region of the human external ear have shown inconsistent results. We aim to disentangle discrepant findings and interpretations, and put forward novel physiological explanations on the origin of the vagus nerve somatosensory evoked potentials (VSEP). METHODS: We systematically search and critically appraise in PubMed, Web of Science, and Scielo databases the scientific reports publishing VSEP findings elicited by afferent electrical stimulation at the tragus region from individuals without brain disorders. Eligible studies published from January 2000 to April 2020 were extracted. The following information was identified from each article: number of participants; age; gender; stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters and neurobiological variables was also extracted. Representative vignettes with novel scalp responses induced by stimulating the tragus were also included to add support to our conclusions. RESULTS: 140 healthy participants were identified from six selected reports. Mean age ranged from 24.3 to 61.5 years. Stimulating and recording aspects were miscellaneous among studies. Scalp responses marked as the VSEP were recorded in 76% of participants, and showed high variability, low validity and poor reproducibility. Age correlated with response latencies. There were not gender differences in scalp response parameters. Cardiovascular function was unaltered by tragus stimulation. Vignettes showed that the VSEP was scalp muscle responses. CONCLUSION: VSEP did not fulfil evoked potential guidelines. VSEP corresponded to volume conduction propagating from muscles surrounding scalp recording sites.

Radiotherapy versus combination radiotherapy-bevacizumab for the treatment of recurrent high-grade glioma: a systematic review.

BACKGROUND: High-grade gliomas (HGG) comprise the most common primary adult brain cancers and universally recur. Combination of re-irradiation therapy (reRT) and bevacizumab (BVZ) therapy for recurrent HGG is common, but its reported efficacy is mixed. OBJECTIVE: To assess clinical outcomes after reRT ± BVZ in recurrent HGG patients receiving stereotactic radiosurgery (SRS), hypofractionated radiosurgery (HFSRT), or fully fractionated radiotherapy (FFRT). METHODS: We performed a systematic review of PubMed, Web of Science, Scopus, Embase, and Cochrane databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified studies reporting outcomes for patients with recurrent HGG treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality (SRS, HFSRT, and FFRT). Outcome variables were overall survival (OS), progression-free survival (PFS), and radiation necrosis (RN). RESULTS: Data on 1399 patients was analyzed, with 954 patients receiving reRT alone and 445 patients receiving reRT + BVZ. All patients initially underwent standard-of-care therapy for their primary HGG. In a multivariate analysis that adjusted for median patient age, WHO grade, RT dosing, reRT fractionation regimen, time between primary and re-irradiation, and re-irradiation target volume, BVZ therapy was associated with significantly improved OS (2.51, 95% CI [0.11, 4.92] months, P = .041) but no significant improvement in PFS (1.40, 95% CI [- 0.36, 3.18] months, P = .099). Patients receiving BVZ also had significantly lower rates of RN (2.2% vs 6.5%, P < .001). CONCLUSIONS: Combination of reRT + BVZ may improve OS and reduce RN rates in recurrent HGG, but further controlled studies are needed to confirm these effects.

Online interprofessional education related to chronic illness for health professionals: a scoping review.

This scoping review focuses on identifying the quantity and quality of research evidence available with regard to online interprofessional education related to chronic disease management. Recent advances have seen the emergence of information communication technology and digital health solutions that may improve monitoring of and self-management of chronic disease. With the growing chronic disease burden globally, and the advancement of information communication technology, digital health solutions may improve chronic disease monitoring and self-management. However, health professionals are slow to utilize this technology in chronic disease management. Online education has the potential to enhance utilization of digital health solutions across interprofessional healthcare teams. This scoping review focuses on online interprofessional education and eLearning strategies used to promote engagement and achievement of learning outcomes between health care professionals in chronic disease management. A systematic search of the literature yielded 3112 papers; 15 studies were included in the review following an independent screening process. The review found very limited research for online interprofessional education related to chronic disease so it is not feasible to comment or draw conclusions in relation to its impact on interprofessional learning, student engagement in education or its impact in practice, services or health outcomes. Research methodology and online eLearning strategies varied across studies, highlighting the need for further rigorous studies that include consistency in online interprofessional education strategies, evaluations and study methods.

Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state.

INTRODUCTION: Conflicting results have been reported in the association between glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) glioblastoma subjects. METHODS: Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival. RESULTS: Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that glioblastoma stem cells exhibit increased DNA repair capacity, glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that glioblastoma stem cells are more aggressive and refractory to therapy, patients with glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01). CONCLUSION: An unbiased analysis of TCIA suggests that glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.

Identification of epithelial membrane protein 2 (EMP2) as a molecular marker and correlate for angiogenesis in meningioma.

PURPOSE: Although intracranial meningiomas are the most common primary brain tumor in adults, treatment options are few and have traditionally been limited to surgical resection and radiotherapy. Additional targeted therapies and biomarkers are needed, especially as complete surgical resection is frequently not feasible in many patients. METHODS: Non-pathologic brain tissue from 3 patients undergoing routine autopsies and tumor specimens from 16 patients requiring surgical resection for meningioma were collected. EMP2 protein expression was evaluated by immunohistochemistry and western blot analysis. EMP2 mRNA expression was also investigated using surgical specimens and validated by analysis of several independent NCBI GEO databases. RESULTS: EMP2 mRNA expression levels were found to be higher in meningioma relative to non-pathologic meninges (P = 0.0013) and brain (P = 0.0011). Concordantly, strong EMP2 protein expression was demonstrated in 100% of meningioma specimens from all 16 patients, with no observable protein expression in normal brain tissue samples from 3 subjects (P < 0.001). EMP2 expression was confirmed by western blot analysis in five samples, with EMP2 protein intensity positively correlating with histologic staining score (R2 = 0.780; P = 0.047). No association was found between EMP2 mRNA or protein levels and WHO grade or markers of proliferation. However, EMP2 expression was positively associated with an angiomatous pattern on histologic evaluation (P = 0.0597), VEGF-A mRNA expression (P < 0.001), and clinical markers of tumor vascularity such as operative blood loss (P = 0.037). CONCLUSIONS: EMP2 is not found in normal brain tissue, yet has shown consistently high mRNA and protein expression in meningiomas, and may serve as a useful molecular marker for these tumors.

Phase-Contrast MRI: Physics, Techniques, and Clinical Applications.

With phase-contrast imaging, the MRI signal is used to visualize and quantify velocity. This imaging modality relies on phase data, which are intrinsic to all MRI signals. With use of bipolar gradients, degrees of phase shift are encoded and in turn correlated directly with the velocity of protons. The acquisition of diagnostic-quality images requires selection of the correct imaging plane to ensure accurate measurement and selection of the encoding velocity and thus prevent aliasing and achieve the highest signal-to-noise ratio. Multiple applications of phase-contrast imaging are actively used in clinical practice. One of the most common clinical uses is in cardiac valvular flow imaging, at which the data are used to assess the severity of valvular disease and quantify the shunt fraction. In neurologic imaging, phase-contrast imaging can be used to measure the flow of cerebrospinal fluid. This measurement can aid in the diagnosis and direct management of normal pressure hydrocephalus or be used to evaluate the severity of stenosis, such as that in Chiari I malformations. At vascular analysis, phase-contrast imaging can be used to visualize arterial and venous flow, and this application is used most commonly in the brain. Three-dimensional imaging can yield highly detailed flow data in a technique referred to as four-dimensional flow. A more recently identified application is in MR elastography. Shear waves created by using an impulse device can be velocity encoded, and this velocity is directly proportional to the stiffness of the organ, or the shear modulus. This imaging modality is most commonly used in the liver for evaluation of cirrhosis and steatosis, although research on the assessment of other organs is being performed. Phase-contrast imaging is an important tool in the arsenal of MRI examinations and has many applications. Proper use of phase-contrast imaging requires an understanding of the many practical and technical factors and unique physics principles underlying the technique.©RSNA, 2020.

Multimodality Imaging of Dementia: Clinical Importance and Role of Integrated Anatomic and Molecular Imaging.

Neurodegenerative diseases are a devastating group of disorders that can be difficult to accurately diagnose. Although these disorders are difficult to manage owing to relatively limited treatment options, an early and correct diagnosis can help with managing symptoms and coping with the later stages of these disease processes. Both anatomic structural imaging and physiologic molecular imaging have evolved to a state in which these neurodegenerative processes can be identified relatively early with high accuracy. To determine the underlying disease, the radiologist should understand the different distributions and pathophysiologic processes involved. High-spatial-resolution MRI allows detection of subtle morphologic changes, as well as potential complications and alternate diagnoses, while molecular imaging allows visualization of altered function or abnormal increased or decreased concentration of disease-specific markers. These methodologies are complementary. Appropriate workup and interpretation of diagnostic studies require an integrated, multimodality, multidisciplinary approach. This article reviews the protocols and findings at MRI and nuclear medicine imaging, including with the use of flurodeoxyglucose, amyloid tracers, and dopaminergic transporter imaging (ioflupane). The pathophysiology of some of the major neurodegenerative processes and their clinical presentations are also reviewed; this information is critical to understand how these imaging modalities work, and it aids in the integration of clinical data to help synthesize a final diagnosis. Radiologists and nuclear medicine physicians aiming to include the evaluation of neurodegenerative diseases in their practice should be aware of and familiar with the multiple imaging modalities available and how using these modalities is essential in the multidisciplinary management of patients with neurodegenerative diseases.©RSNA, 2020.

Criteria positive and criteria negative anaphylaxis, with a focus on undifferentiated somatoform idiopathic anaphylaxis: A review and case series.

Background: Undifferentiated somatoform (US) idiopathic anaphylaxis (IA) is considered a psychogenic disorder characterized by a lack of observable physical findings and poor response to treatment. Although failure to diagnose true anaphylaxis can have disastrous consequences, identification of US-IA is crucial to limit unnecessary expenses and use of health care resources. Objective: To better define the presentation and understand the potential relationship between US-IA and underlying psychiatric comorbidities. Methods: We retrospectively reviewed 110 visits by 107 patients to our institution for evaluation and management of anaphylaxis over a 1-year period. The patients were classified as having either criteria positive (CP) or criteria negative (CN) anaphylaxis based on whether they met Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium criteria for the clinical diagnosis of anaphylaxis. Patient characteristics, including objective and subjective signs and symptoms, and the presence of psychiatric diagnoses were collected and analyzed. Statistical significance was assessed by using the Fisher exact test. A literature review of US-IA and other psychogenic forms of anaphylaxis was performed. Results: Patients with CP anaphylaxis were more likely to present with hypotension, wheezing, urticaria, and vomiting than were patients with CN anaphylaxis. The patients with CN anaphylaxis were more likely to present with subjective symptoms of sensory throat tightness or swelling compared with patients with CP anaphylaxis. No significant difference was detected in the prevalence of psychiatric conditions between the two groups. Conclusion: Patients who met previously established diagnostic criteria for anaphylaxis were more likely to present with objective physical findings than those who did not meet criteria for true anaphylaxis. CN patients who presented for treatment of anaphylaxis were more likely to present with subjective symptoms. Formal diagnostic criteria should be used by clinicians when evaluating patients with suspected anaphylaxis.

Physician Preceptor Satisfaction and Productivity Across Curricula: A Comparison Between Longitudinal Integrated Clerkships And Traditional Block Rotations.

Phenomenon: Physicians are under intense pressure to improve clinical productivity. High clinical load, limited availability, and decreased clinical efficiency are well-documented barriers to precepting medical students and threaten clinical productivity. In an era of increasing medical student enrollment, these barriers have already led to a decreased availability of clinical teachers and training sites across the United States. Improved preceptor satisfaction could have a great impact on recruitment and retention of medical student preceptors and is likely linked to changes in productivity. Curriculum structure could impact both preceptor productivity and satisfaction. Comparing productivity and satisfaction of physician preceptors teaching in longitudinal integrated clerkships (LICs) to those teaching in traditional block rotations (TBRs), or in both settings (LIC-TBR), could lead to a better understanding of the impact of curriculum structure on preceptor productivity and satisfaction. Approach: Data were collected through a quantitative cross-sectional survey of outpatient physician preceptors in North Carolina in 2017. Preceptor satisfaction and student influence on productivity-related aspects of practice were analyzed with bivariate chi-square statistics and multivariate logistic regression. Findings: Analyses included 338 physician preceptors: 79 LIC (23%), 50 LIC-TBR (15%), and 209 TBR preceptors (62%). LIC preceptors were more likely to indicate being "very satisfied" with precepting than either their LIC-TBR or TBR counterparts. There were no differences in perceived productivity-related aspects of practice across the different curricula, such as patient flow, income, or physician working hours. Logistic regressions controlling for potential confounding variables suggested that those teaching in LICs were almost 3 times more likely to be "very satisfied" relative to those teaching in LIC-TBR and TBR settings and that the negative influence of students on patient flow and physician working hours had an adverse effect on preceptor satisfaction. Insights: Preceptor satisfaction was high overall, though satisfaction was significantly higher among preceptors who teach in LICs. The perceived impact of students on clinical productivity was stable across the different curricula. In an era of increasing need for physician preceptors, the higher satisfaction of those who teach in LICs should be considered in curricular design and for preceptor recruitment and retention.

Investigating online interprofessional learning and communication using social network analysis: a study protocol.

Interprofessional education (IPE) via the use of online learning environments (OLEs) can help improve patient outcomes, interprofessional attitudes, and behaviors while providing education at a distance. Studies of interprofessional learning often examine communication and its relation to learning outcomes qualitatively. OLEs allow researchers to examine these communication patterns quantitatively, through social network analysis (SNA), and answer questions regarding the nature of communication between interprofessional learners and how this may impact interprofessional attitudes and behaviors. In this paper, we present a study that aims to track interprofessional communication within a cancer care course using SNA and examine how it relates to professional attitudes and collaboration. Using pre and post-course surveys as well as numerous SNA metrics derived from course discussion board posts, we hope to show how communication between interprofessional learners may mediate outcomes. This work will add to the existing IPE literature by providing an added quantitative layer to a largely qualitative literature and encourage future studies in this area.

Systems thinking: advancing health advocacy training; a perspective from junior family physicians in the Middle East.

Healthcare systems are becoming increasingly complex. Physicians are expected to be agents of change to meet the growing health needs. In the Middle East, young family doctors are subtly creating a space for advocacy. Recognising the need for compulsory advocacy training in undergraduate medical curricula, allows health workers and students a concrete exposure to social determinants of health by carrying out clinical encounters from the hospital setting to outpatient dispensaries in underprivileged areas. At the community level, they organise mobile clinics and engage in collaborative initiatives to provide primary healthcare services to vulnerable populations. To be successful, advocacy practice and training should move towards systems thinking. Family doctors need to engage and collaborate with other stakeholders within the healthcare system and understand the dynamics of the relationships between them. This empowers their role in national health agendas, especially those related to universal health coverage (UHC). Future physicians and all members of primary care teams need to partner with people outside their discipline; the idea of interdisciplinary and interprofessional collaboration should be integrated into their schooling and all forms of vocational training.

Emphysema-associated Autoreactive Antibodies Exacerbate Post-Lung Transplant Ischemia-Reperfusion Injury.

Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.

Increased cochlear radiation dose predicts delayed hearing loss following both stereotactic radiosurgery and fractionated stereotactic radiotherapy for vestibular schwannoma.

PURPOSE: Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) are noninvasive therapies for vestibular schwannomas providing excellent tumor control. However, delayed hearing loss after radiation therapy remains an issue. One potential target to for improving hearing rates is limiting radiation exposure to the cochlea. METHODS: We retrospectively reviewed 100 patients undergoing either SRS with 12 Gy (n = 43) or fSRT with 50 Gy over 28 fractions (n = 57) for vestibular schwannoma. Univariate and multivariate analysis were carried out to identify predictors of hearing loss as measured by the Gardner Robertson scale after radiation therapy. RESULTS: Deterioration of hearing occurred in 30% of patients with SRS and 26% with fSRT. The overall long term (> 2 year) progression rates were 20% for SRS and 16% for fSRT. Patients with a decrease in their Gardner Robertson hearing score and those that loss serviceable hearing had significantly higher average minimal doses to the cochlea in both SRS and fSRT cohorts. ROC analysis showed that a cut off of 5 Gy and 35 Gy, for SRS and fSRT respectively, predicted hearing loss with high sensitivity/specificity. CONCLUSION: Our data suggests the minimal dose of radiation that the cochlear volume is exposed to is a predictor of delayed hearing loss after either SRS or fSRT. A threshold of 5 Gy/35 Gy may lead to improved hearing preservation after radiotherapy. Further prospective multi center studies can further elucidate this mechanism.