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Prone position ventilation (PPV) is resource-intensive, yet the optimal strategy for PPV in intubated patients with COVID-19 is unclear.Does a prolonged (24 or more hours) PPV strategy improve mortality in intubated COVID-19 patients compared to intermittent (∼16 hours with daily supination) PPV?Multicenter, retrospective cohort study of consecutively admitted intubated COVID-19 patients treated with PPV between March 11 - May 31, 2020. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 90-day all-cause mortality and prone-related complications. Inverse probability treatment weights (IPTW) were used to control for potential treatment selection bias.Of the COVID-19 patients who received PPV, 157 underwent prolonged and 110 underwent intermittent PPV. Patients undergoing prolonged PPV had reduced 30-day (adjusted hazard ratio [aHR] 0.475, 95% CI 0.336-0.670, P value0.001) and 90-day (aHR 0.638, 95% CI 0.461-0.883, P value = 0.006) mortality compared to intermittent PPV. In patients with PAmong intubated COVID-19 patients who received PPV, prolonged PPV was associated with reduced mortality. Prolonged PPV was associated with fewer pronation and supination events and a small increase in rates of facial edema. These findings suggest that prolonged PPV is a safe, effective strategy for mortality reduction in intubated COVID-19 patients.

Background Stimulant use has increased across the US, with concomitant opioid and methamphetamine use doubling between 2011 and 2017. Shifting patterns of polysubstance use have led to rising psychostimulant-involved deaths. While it is known that individuals who use methamphetamine require greater access to treatment, there is still little known about methamphetamine use and treatment among individuals who are already engaged in outpatient substance use treatment. Objectives To characterize care-engaged individuals who use methamphetamine to guide harm reduction and treatment strategies. Methods Retrospective cohort study of individuals at a large academic medical center in Massachusetts with ≥ 2 positive methamphetamine oral fluid toxicology tests between August 2019 and January 2020. We performed descriptive analysis of sociodemographic, medical, and drug use characteristics and a comparative analysis of injection methamphetamine use versus other routes of use. Results Included were 71 individuals [56 male (80%), 66 non-Hispanic white (94%), median age 36 (IQR 30–42)]. Nearly all had opioid (94%) and stimulant use disorder (92%). Most had (93%) or were (83%) being treated with medications for opioid use disorder, but few received pharmacologic treatment for methamphetamine use disorder (24%). None received contingency management treatment. People who inject methamphetamine (68%) were more likely to have a history of overdose (91% vs. 70%; p = 0.02), have HCV (94% vs. 52%; p Conclusions Individuals in our study had high prevalence of polysubstance use, particularly concomitant methamphetamine and opioid use. Individuals who were well connected to substance use treatment for their opioid use were still likely to be undertreated for their methamphetamine use disorder and would benefit from greater access to contingency management treatment, harm reduction resources, and resources to address adverse social determinants of health.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand–receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development. Lung samples collected soon after death from COVID-19 are used to provide a single-cell atlas of SARS-CoV-2 infection and the ensuing molecular changes.

Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients.Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years).Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model.In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

Introduction: Advanced-stage pulmonary arterial hypertension (asPAH) is characterized by endothelial dysfunction and fibrotic remodeling of pulmonary arterioles that promotes irreversible right heart failure. Thus, identifying mechanisms that regulate vascular fibrosis in early PAH (esPAH) may have translational importance. Hypothesis: We hypothesized that profibrotic molecular pathways differentiate esPAH from asPAH. Methods: To test this hypothesis, male Sprague-Dawley rats were administered one dose of monocrotaline (60 mg/kg; day 0) to induce inflammatory PAH. Cardiac catheterization and pulmonary artery endothelial cell (PAEC) transcriptomic analyses were performed on days 15 and 21 for esPAH and asPAH, respectively. Results: The esPAH profile included: right ventricular-pulmonary arterial (RV-PA) uncoupling (1.13 ± 0.05 vs. 0.90 ± 0.06, RV end-systolic elastance/PA elastance, P=0.02, N=6) and increased indexed pulmonary vascular resistance (50 ± 8 vs. 213 ± 29 mmHg*min*g -1 *mL -1 , Pin silico . Pulmonary endothelial expression of Csk protein by immunofluorescence correlated with vascular collagen by picrosirius red stain (r=+0.87, P=0.006, N=4). To validate these findings in vitro , human PAECs (HPAEC) were treated with an inflammatory stimulus of lipopolysaccaride (0.03 mg/mL) + interferon-γ (50 ng/mL) + interleukin-1β (50 ng/mL), or vehicle control (V). Compared to V-control, inflammation increased Csk protein and mRNA expression by 2.3- and 2.0-fold, respectively (P-4 , N=4) vs. V-treated cells. Overexpression of Csk by adenovirus transfection attenuated inflammation-mediated hydroxyproline accumulation by 84% (P=1.3x10 -5 , N=3). Conclusions: These data suggest that impaired Csk may underlie HPAEC fibrosis in esPAH, which, in turn, may have potential therapeutic implications for the prevention of fibrotic vascular remodeling and PAH progression.

Background Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. Methods We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. Findings Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. Interpretation Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. Funding The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542–02) from Harvard Catalyst.

Rationale: Data on the molecular mechanisms that regulate platelet–pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet–pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein–protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography–mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet–endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O(2)) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)–dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9–P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet–pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9(−/−) mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9–P-selectin protein–protein interaction is a modifiable target with which to inhibit platelet–pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

Among hospitalized persons under investigation for coronavirus disease 2019 (COVID-19), more repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs) after a negative NAAT were positive from lower than from upper respiratory tract specimens (1.9% vs 1.0%, P = .033). Lower respiratory testing should be prioritized among patients displaying respiratory symptoms with moderate-to-high suspicion for COVID-19 after 1 negative upper respiratory NAAT.

Rationale: Early in the coronavirus disease 2019 (COVID-19) pandemic there was significant practice variation among hospitals regarding the choice and timing of treatments for acute respiratory failure. It is unknown whether this practice variation contributed to outcome differences. Methods: We performed a retrospective study of all adult patients with respiratory failure due to COVID-19 admitted between March 11 and May 31, 2020 to a medical or surgical ICU at three Massachusetts hospitals. Medical charts were manually reviewed by physicians and abstracted into a standardized REDCap database. Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables were performed using R version 4.0.2. Results: Data from 429 patients were analyzed. Among the three institutions, there were significant differences in race, prevalence of hypertension and diabetes mellitus, duration of COVID-19 symptoms on presentation, and days between admission and intubation. Significant differences were observed in presentation acuity by sequential organ failure assessment (SOFA) score but not simplified acute physiology score (SAPS) or PaO2:FiO2 ratios. Hospital A intubated more patients on the day of admission and utilized more inhaled nitric oxide and less immunosuppression (steroids, anti-IL6 agents). Hospital B treated more patients with remdesivir, other experimental antivirals, and early paralysis (within 48 hours of intubation) but less awake prone positioning. Hospital C utilized more non-invasive positive pressure ventilation (NIPPV) and high flow oxygen in lieu of intubation;it also administered more statins and steroids for acute respiratory distress syndrome (ARDS) and used less early proning within 48 hours of intubation. No difference in hydroxychloroquine use was seen across institutions. There were no statistical differences across hospitals in reintubation, ventilator-free days at 28 days, or in-hospital mortality. Transition to comfort measures was more common at hospital C. There was a trend at hospital A toward lower 30-day (A=25.3%, B=32.1%, C=39.4%;p=0.054) and 90-day (A=28.5%, B=36.1%, C=41.4%;p=0.085) mortality. At hospital A there was significantly longer hospital length-of-stay (A=25.0, B=19.0, C=15.0;p=0.004) and ICU length-of-stay (A=18.0, B=15.0, C=12.0;p=0.001). Conclusions: Early in the COVID-19 pandemic in Massachusetts, there were significant differences in patient characteristics and treatments administered across three institutions. One institution demonstrated a trend toward lower 30-day and 90-day mortality despite later presentation from symptom onset, higher admission acuity, and less utilization of remdesivir or steroids. Practice variation across institutions may explain differences in outcomes, independent of baseline characteristics, and should be studied further as it may inform future management of COVID-19.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary embolism (PE), in which the red, platelet-rich thrombus does not resolve but forms into an organized yellow, fibrotic scar-like obstruction in the pulmonary vasculature. Here we review the pathobiology of CTEPH. Our current knowledge has predominantly been informed by studies of human samples and animal models that are inherently limited in their ability to recapitulate all aspects of the disease. These studies have identified alterations in platelet biology and inflammation in the formation of a scar-like thrombus that comprised endothelial cells, myofibroblasts, and immune cells, along with a small vessel pulmonary arterial hypertension-like vasculopathy. The development of CTEPH-specific therapies is currently hindered by a limited knowledge of its pathobiology. The development of new CTEPH medical therapies will require new insights into its pathobiology that bridge the gap from bench to bedside.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection

A Man with a Self-Inflicted Gunshot Wound A 37-year-old man was admitted to the surgical intensive care unit because of a self-inflicted gunshot wound to the face. Management decisions were made.

Rationale: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. Objective: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. Methods and Results: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011–2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P −46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pV o 2 ) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements ( P o 2 and pV o 2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold ( P P =0.0018; 95% CI, 1.5–5.2) increase in hazard for age- and pV o 2 -adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. Conclusions: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pV o 2 that predict hospitalization in patients with exercise intolerance.

Background: In pulmonary hypertension subgroups, elevated pulmonary vascular resistance (PVR) of 3·0 Wood units or more is associated with poor prognosis. However, the spectrum of PVR risk in pulmonary hypertension is not known. To address this area of uncertainty, we aimed to analyse the relationship between PVR and adverse clinical outcomes in pulmonary hypertension. Methods: We did a retrospective cohort study of all patients undergoing right heart catheterisation (RHC) in the US Veterans Affairs health-care system (Oct 1, 2007–Sep 30, 2016). Patients were included in the analyses if data from a complete RHC and at least 1 year of follow-up were available. Both inpatients and outpatients were included, but individuals with missing mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure, or cardiac output were excluded. The primary outcome measure was time to all-cause mortality assessed by the Veteran Affairs vital status file. Cox proportional hazards models were used to assess the association between PVR and outcomes, and the mortality hazard ratio was validated in a RHC cohort from Vanderbilt University Medical Center (Sept 24, 1998–June 1, 2016). Findings: The primary cohort (N=40 082; 38 751 [96·7%] male; median age 66·5 years [IQR 61·1–73·5]; median follow-up 1153 days [IQR 570–1971]), included patients with a history of heart failure (23 201 [57·9%]) and chronic obstructive pulmonary disease (13 348 [33·3%]). We focused on patients at risk for pulmonary hypertension based on a mPAP of at least 19 mm Hg (32 725 [81·6%] of 40 082). When modelled as a continuous variable, the all-cause mortality hazard for PVR was increased at around 2·2 Wood units compared with PVR of 1·0 Wood unit. Among patients with a mPAP of at least 19 mm Hg and pulmonary artery wedge pressure of 15 mm Hg or less, the adjusted hazard ratio (HR) for mortality was 1·71 (95% CI 1·59–1·84; p

A 57-year-old man with a history of DVT and pulmonary embolism, transient ischemic attacks, prior 60 pack-year smoking history, and oxygen-dependent COPD presented with insidiously worsening dyspnea associated with new pleuritic chest and back pain.

Transcriptomic analysis of pulmonary microvascular endothelial cells from experimental models offers insight into pulmonary arterial hypertension (PAH) pathobiology. However, culturing may alter the molecular profile of endothelial cells prior to analysis, limiting the translational relevance of results. Here we present a novel and validated method for isolating RNA from pulmonary microvascular endothelial cells (PMVECs) ex vivo that does not require cell culturing. Initially, presumed rat PMVECs were isolated from rat peripheral lung tissue using tissue dissociation and enzymatic digestion, and cells were cultured until confluence to assess endothelial marker expression. Anti-CD31, anti-von Willebrand Factor, and anti-α-smooth muscle actin immunocytochemistry/immunofluorescence signal was detected in presumed rat PMVECs, but also in non-endothelial cell type controls. By contrast, flow cytometry using an anti-CD31 antibody and isolectin 1-B4 (from Griffonia simplicifolia) was highly specific for rat PMVECs. We next developed a strategy in which the addition of an immunomagnetic selection step for CD31+ cells permitted culture-free isolation of rat PMVECs ex vivo for RNA isolation and transcriptomic analysis using fluorescence-activated cell sorting. Heterogeneity in the validity and reproducibility of results using commercial antibodies against endothelial surface markers corresponded to a substantial burden on laboratory time, labor, and scientific budget. We demonstrate a novel protocol for the culture-free isolation and transcriptomic analysis of rat PMVECs with translational relevance to PAH. In doing so, we highlight wide variability in the quality of commonly used biological reagents, which emphasizes the importance of investigator-initiated validation of commercial biomaterials.

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). Here, we developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2–5), and increased NKX2–5 binding to COL3A1. Upregulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap, and, thus, was not contingent on TGF-β-signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent post-translational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

Background Residency training is charged with improving resident teaching skills. Utilizing simulation in teacher training has unique advantages such as providing a controlled learning environment and opportunities for deliberate practice. Objective We assessed the impact of a simulation-based resident-as-teacher (RaT) program. Design A RaT program was embedded in an existing 8-case simulation curriculum for 52 internal medicine (IM) interns. Residents participated in a workshop, then served as facilitators in the curriculum and received feedback from faculty. Methods Residents' teaching and feed back skills were measured using a pre- and post-program self-assessment and post-session and post-curriculum evaluations by intern learners. Setting/participants Forty-one second- and third-year residents participated in the study August 2013 to October 2013 at a single center. Results Pre- and post-program teaching skills were assessed for 34 of 41 resident facilitators (83%) participating in 3.9 sessions on average. Partaking in the program led to improvements in resident facilitators' self-reported teaching and feedback skills across all domains. The most significant improvement was in teaching in a simulated environment (2.81 to 4.16, P Conclusions Our simulation-based RaT program offered a unique opportunity for deliberate practice of teaching skills in a controlled environment and led to improvements in resident facilitators' teaching and feed back skills. The simulation curriculum, facilitated by residents, was well received by the intern learners. Our program design may serve as a model for the development of simulation curricula and RaT programs within IM residencies.

High-fidelity medical simulation has gained widespread use in medical education because it allows learners an opportunity to actively engage in experiential learning and deliberate practice in a safe learning environment. This resource is a six-case simulation curriculum that focuses on decision-making training in critical care clinical scenarios, designed for medical interns at the end of the first year of training. To our knowledge, this is the first such curriculum implemented within an internal medicine training program. The materials enclosed include individual case protocols and teaching handouts for each of the six cases, as well as a guide for the implementation of the curriculum. The critical care curriculum was implemented based on our experiences and lessons learned with the general medicine curriculum at our institution. The case protocols include information necessary for facilitators to conduct the simulation sessions including learning objectives, a description of the case narrative and progression, an instructor guide, and appendices including laboratory data, radiographic images, and electrocardiograms. The teaching notes, which are one-to-two page documents paired with each of the cases, review the most vital diagnostic and management principles to be learned from the case. While they were created as an independent study resource for the learners (to be distributed after each session), they can also serve as an additional preparation tool for the case facilitators prior to the sessions. The curriculum is delivered through three 1-hour sessions, covering two cases per session. We find that the learning is maximized when two-to-three intern learners work through the cases on one high-fidelity manikin. The cases are designed to be facilitated by two individuals, one acting as the manikin operator and the other as the nurse. Each scenario runs for approximately 15 minutes, followed by a 15-minute debriefing. Debriefings are conducted by one or two facilitators using a learner-centered model of debriefing.

Residency training is charged with improving resident teaching skills. Utilizing simulation in teacher training has unique advantages such as providing a controlled learning environment and opportunities for deliberate practice.We assessed the impact of a simulation-based resident-as-teacher (RaT) program.A RaT program was embedded in an existing 8-case simulation curriculum for 52 internal medicine (IM) interns. Residents participated in a workshop, then served as facilitators in the curriculum and received feedback from faculty.Residents' teaching and feed back skills were measured using a pre- and post-program self-assessment and post-session and post-curriculum evaluations by intern learners.Forty-one second- and third-year residents participated in the study August 2013 to October 2013 at a single center.Pre- and post-program teaching skills were assessed for 34 of 41 resident facilitators (83%) participating in 3.9 sessions on average. Partaking in the program led to improvements in resident facilitators' self-reported teaching and feedback skills across all domains. The most significant improvement was in teaching in a simulated environment (2.81 to 4.16, P0.001). Interns rated the curriculum highly (81% "excellent," 19% "good") and reported that resident facilitators frequently utilized debriefing techniques covered in the RaT program.Our simulation-based RaT program offered a unique opportunity for deliberate practice of teaching skills in a controlled environment and led to improvements in resident facilitators' teaching and feed back skills. The simulation curriculum, facilitated by residents, was well received by the intern learners. Our program design may serve as a model for the development of simulation curricula and RaT programs within IM residencies.

Glypican-3 (Gpc3) is a heparan sulfate proteoglycan (HSPG) expressed widely during vertebrate development. Loss-of-function mutations cause Simpson–Golabi–Behmel syndrome (SGBS), a rare and complex congenital overgrowth syndrome with a number of associated developmental abnormalities including congenital heart disease. We found that Gpc3-deficient mice display a high incidence of congenital cardiac malformations like ventricular septal defects, common atrioventricular canal and double outlet right ventricle. In addition we observed coronary artery fistulas, which have not been previously reported in SGBS. Coronary artery fistulas are noteworthy because little is known about the molecular basis of this abnormality. Formation of the coronary vascular plexus in Gpc3-deficient embryos was delayed compared to wild-type, and consistent with GPC3 functioning as a co-receptor for fibroblast growth factor-9 (FGF9), we found a reduction in Sonic Hedgehog (Shh) mRNA expression and signaling in embryonic mutant hearts. Interestingly, we found an asymmetric reduction in SHH signaling in cardiac myocytes, as compared with perivascular cells, resulting in excessive coronary artery formation in the Gpc3-deficient animals. We hypothesize that the excessive development of coronary arteries over veins enables the formation of coronary artery fistulas. This work has broad significance to understanding the genetic basis of coronary development and potentially to molecular mechanisms relevant to revascularization following ischemic injury to the heart.