Performance evaluation of a self-administered point-of-care test for anal HPV screening in PrEP users: data from a community-based PrEP service.

OBJECTIVES: In this study, we compared the performance of a self-administered point-of-care test (POCT) for anal human papillomavirus (HPV) screening with laboratory gold-standard test in pre-exposure prophylaxis (PrEP) users and evaluated its feasibility. METHODS: We enrolled PrEP users from a local community-based PrEP service. Each participant self-collected an anal swab to test anal HPV with a PCR POCT capable of detecting 14 high-risk HPV genotypes. Anonymous questionnaires on self-sampling feasibility were completed. Participants were then referred to local clinics to undergo standard viral genotyping. Concordance between POCT and gold-standard test was measured with absolute agreement and Cohen's kappa. Receiver operating characteristic (ROC) curves were used to calculate POCT sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: 179 subjects got a valid POCT result, most of them men (98.3%) and men who have sex with men (90.4%). 68.2% tested positive for at least one high-risk HPV genotype on POCT. 150 feasibility questionnaires were collected: 92.7% of compilers found the self-swab easy to perform. For 178 subjects, a gold-standard test valid result was also available: 77% tested positive for at least one high-risk HPV genotype. The median time elapsed between the two tests was 9.8 months, due to COVID-19-related service interruptions. Agreement between POCT and gold-standard test was 79.3% (Cohen's kappa=0.49). POCT showed a sensitivity of 81.0%, a specificity of 73.8%, a PPV of 91.0% and an NPV of 54.4%. CONCLUSIONS: POCT showed a moderate agreement with gold-standard test and a discrete sensitivity and specificity, suggesting that it could be a useful and feasible additional tool for HPV screening, especially in low-resource and community-based settings.

How to HEEAL: A Patient and Peer-Centric Simulation Curriculum for Medical Error Disclosure.

Introduction: Medical errors are an unfortunate certainty with emotional and psychological consequences for patients and health care providers. No standardized medical curriculum on how to disclose medical errors to patients or peers exists. The novel HEEAL (honesty/empathy/education/apology-awareness/lessen chance for future errors) curriculum addresses this gap in medical education through a multimodality workshop. Methods: This 6-hour, two-part curriculum incorporated didactic and standardized patient (SP) simulation education with rapid cycle deliberate practice (RCDP). The morning focused on provider-patient error disclosure; the afternoon applied the same principles to provider-provider (peer) discussion. Summative simulations with SPs evaluated learners' skill baseline and improvement. Formative simulations run by expert simulation educators used RCDP to provide real-time feedback and opportunities for adjustment. Medical knowledge was measured through pre- and postintervention multiple-choice questions. Learners' confidence and attitude towards medical errors disclosure were surveyed pre- and postintervention with assistance of the Barriers to Error Disclosure Assessment tool, revised with the addition of several questions related to provider-provider disclosure. Results: Fourteen medical students participated in this pilot curriculum. Statistical significance was demonstrated in medical knowledge (p = .01), peer-disclosure skills (p = .001), and confidence in medical error disclosure (p < .001). Although there was improvement in patient-disclosure skills, this did not reach statistical significance (p = .05). Discussion: This curriculum addresses the need for designated training in medical error disclosure. Learners gained knowledge, skills, and confidence in medical error disclosure. We recommend this curriculum for medical students preparing for transition to residency.

Do we Still Need Eligibility Criteria to Recommend PrEP? Impact of National Prescribing Requirements on Retention in Care and Sexually Transmitted Infections Acquisition.

Italian guidelines recommend HIV pre-exposure prophylaxis (PrEP) only upon satisfying strict eligibility criteria. The objective of this study is to evaluate if PrEP candidates attending a community-based service comply with these criteria and whether these prescribing conditions affect retention in care and sexually transmitted infections (STIs) acquisition. A retrospective analysis was performed on PrEP candidates evaluated from January 2019 to June 2022. Data were collected from self-administered questionnaires and clinical files. The population was divided in subjects with 0/1 (0/1 C) and ≥ 2 (≥ 2 C) criteria. Descriptive statistics and non-parametric tests were employed to describe study population. Incidence of PrEP discontinuation and of STIs was estimated per 100 persons-year of follow up (PYFU), and incidence rate ratio (IRR) was calculated. Univariate and multivariable Cox regression analyses were used to evaluate the association strength between PrEP drop out and other variables. The analyses enrolled 659 individuals: 422 individuals were included in 0/1 C, 237 in ≥ 2 C group, respectively. Inconsistent condom use was the most reported prescribing criteria (399 individuals, 60.6%), followed by a previous STI (186 individuals, 28.2%). 0/1 C exhibited lower STIs incidence. PrEP discontinuation was 29% in 0/1 C and 38% in ≥ 2 C (p = 0.031). Cox model revealed that inconsistent condom use was the only prescribing criteria associated to PrEP persistence. The majority of PrEP candidate did not comply with prescribing conditions. Eligibility criteria failed to identify individuals with better retention in care. Our results suggest that Italian guidelines should be updated removing barriers to prescription.

Front-Line Health Care Workers' COVID-19 Infection Contamination Risks: A Human Factors and Risk Analysis Study of Personal Protective Equipment.

Infectious risks escalate with complex donning and doffing personal protective equipment (PPE) protocols. Recent studies suggest that PPE donning and doffing behaviors that deviate from protocol during PPE reuse compounded the risks of health care worker (HCW) self-contamination. This study quantified the occurrence of behaviors associated with known risks in PPE use and reuse. We conducted a prospective study of emergency department HCWs and video-recorded PPE donning and doffing 5 times in simulated patient encounters. Trained coders recorded HCW behaviors according to an evidence-based guide. All 28 participants deviated from the Centers for Disease Control and Prevention (CDC) sanctioned donning and doffing protocol order, and most were documented to have (92.85%) self-contaminated at least once during each simulated clinical encounter. Behaviors that compounded self-contamination due to PPE reuse were also observed. Wide variation in PPE donning and doffing behaviors was found among front-line, experienced HCWs. Future work is needed to determine which deviations put HCWs at increased risk for accidental self-contamination and what changes are needed to the CDC protocol for protecting HCW from infections.

MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation.

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.

Detection of Asymptomatic Mpox Carriers among High-Ri Men Who Have Sex with Men: A Prospective Analysis.

Mpox is traditionally considered a zoonotic disease with endemic circulation in Africa, but the 2022-2023 outbreak reached an unprecedented high number of cases in non-endemic countries, so that it was declared a public health emergency of international concern. The reasons for this extensive global spread, characterized by sexual transmission amongst men who have sex with men (MSM), have not been fully clarified. The existence of asymptomatic carriers with viable viral shedding might be an explanation and is under-debated after retrospective studies suggested that infection without symptoms might have a prevalence of 6.5%. We aimed to prospectively assess the presence of mpox infection in asymptomatic high-risk MSM using HIV pre-exposure prophylaxis and living with HIV. We selected individuals with no signs of active infection nor suggestive symptoms in the previous 21 days. Eligible individuals collected oral and anal swabs to undergo point-of-care testing for mpox and completed a 21-days follow-up. Seventy-two individuals were enrolled, and none tested positive for mpox infection nor developed symptoms during follow-up. We selected a high-risk population with a significant history of sexual exposure, but we failed to detect any asymptomatic infection. This observation might have important consequences in terms of contact management and epidemic control.

Closing the gender gap in medicine: the impact of a simulation-based confidence and negotiation course for women in graduate medical education.

BACKGROUND: Currently, 75-80% of the medical workforce worldwide consists of women. Yet, women comprise 21% of full professors and less than 20% of department chairs and medical school deans. Identified causes of gender disparities are multifactorial including work-life responsibilities, gender discrimination, sexual harassment, bias, lack of confidence, gender differences in negotiation and leadership emergence, and lack of mentorship, networking, and/or sponsorship. A promising intervention for the advancement of women faculty is the implementation of Career Development Programs (CDPs). Women physician CDP participants were shown to be promoted in rank at the same rate as men by year five, and more likely to remain in academics after eight years compared to both men and women counterparts. The objective of this pilot study is to investigate the effectiveness of a novel, simulation-based, single-day CDP curriculum for upper-level women physician trainees to teach communication skills identified as contributing to medicine's gender advancement gap. METHODS: This was a pilot, pre/post study performed in a simulation center implementing a curriculum developed to educate women physicians on 5 identified communication skills recognized to potentially reduce the gender gap. Pre- and post-intervention assessments included confidence surveys, cognitive questionnaires, and performance action checklists for five workplace scenarios. Assessment data were analyzed using scored medians and descriptive statistics, applying Wilcoxon test estimation to compare pre- versus post-curriculum intervention scores, with p < 0.05 considered statistically significant. RESULTS: Eleven residents and fellows participated in the curriculum. Confidence, knowledge, and performance improved significantly after completion of the program. Pre-confidence: 28 (19.0-31.0); Post-confidence: 41 (35.0-47.0); p < 0.0001. Pre-knowledge: 9.0 (6.0-11.00); Post knowledge: 13.0 (11.0-15.0); p < 0.0001. Pre-performance: 35.0 (16.0-52.0); Post-performance: 46.0 (37-53.00); p < 0.0001. CONCLUSION: Overall, this study demonstrated the successful creation of a novel, condensed CDP curriculum based on 5 identified communication skills needed for women physician trainees. The post-curriculum assessment demonstrated improved confidence, knowledge, and performance. Ideally, all women medical trainees would have access to convenient, accessible, and affordable courses teaching these crucial communication skills to prepare them for careers in medicine to strive to reduce the gender gap.

HIV-Indicator Condition Guided Testing in a Hospital Setting.

Late diagnosis is still a major issue in HIV infection management, leading to important consequences for both patients and community. In this perspective, HIV screening targeted on some clinical conditions (HIV indicator conditions-HIVICs) emerged as a useful strategy, also involving patients not considered at high behavioral risk. We organized an in-hospital HIVICs guided screening campaign named ICEBERG in Milan, Italy, between 2019 and 2021. Among the 520 subjects enrolled, mainly presenting with viral hepatitis or mononucleosis-like syndrome, 20 resulted HIV positive (3.8% prevalence). A significant proportion of them had multiple conditions and advanced immunosuppression, with 40% being AIDS-presenters. As adherence to the screening campaign was modest for non-ID specialists, educational interventions to raise clinicians' sensitivity are urgently needed. HIV-ICs guided testing was confirmed as a useful tool, but a combined approach with other screening strategies seems to be essential for early HIV diagnosis.

Neurotoxic Effect of Doxorubicin Treatment on Cardiac Sympathetic Neurons.

Doxorubicin (DOXO) remains amongst the most commonly used anti-cancer agents for the treatment of solid tumors, lymphomas, and leukemias. However, its clinical use is hampered by cardiotoxicity, characterized by heart failure and arrhythmias, which may require chemotherapy interruption, with devastating consequences on patient survival and quality of life. Although the adverse cardiac effects of DOXO are consolidated, the underlying mechanisms are still incompletely understood. It was previously shown that DOXO leads to proteotoxic cardiomyocyte (CM) death and myocardial fibrosis, both mechanisms leading to mechanical and electrical dysfunction. While several works focused on CMs as the culprits of DOXO-induced arrhythmias and heart failure, recent studies suggest that DOXO may also affect cardiac sympathetic neurons (cSNs), which would thus represent additional cells targeted in DOXO-cardiotoxicity. Confocal immunofluorescence and morphometric analyses revealed alterations in SN innervation density and topology in hearts from DOXO-treated mice, which was consistent with the reduced cardiotropic effect of adrenergic neurons in vivo. Ex vivo analyses suggested that DOXO-induced denervation may be linked to reduced neurotrophic input, which we have shown to rely on nerve growth factor, released from innervated CMs. Notably, similar alterations were observed in explanted hearts from DOXO-treated patients. Our data demonstrate that chemotherapy cardiotoxicity includes alterations in cardiac innervation, unveiling a previously unrecognized effect of DOXO on cardiac autonomic regulation, which is involved in both cardiac physiology and pathology, including heart failure and arrhythmias.

Development of a simulation technical competence curriculum for medical simulation fellows.

BACKGROUND AND NEEDS: Medical educators with simulation fellowship training have a unique skill set. Simulation fellowship graduates have the ability to handle basic and common troubleshooting issues with simulation software, hardware, and equipment setup. Outside of formal training programs such as this, simulation skills are inconsistently taught and organically learned. This is important to address because there are high expectations of medical educators who complete simulation fellowships. To fill the gap, we offer one way of teaching and assessing simulation technical skills within a fellowship curriculum and reflect on lessons learned throughout the process. This report describes the instructional designs, implementation, and program evaluation of an educational intervention: a simulation technology curriculum for simulation fellows. CURRICULUM DESIGN: The current iteration of the simulation technical skill curriculum was introduced in 2018 and took approximately 8 months to develop under the guidance of expert simulation technology specialists, simulation fellowship-trained faculty, and simulation center administrators. Kern's six steps to curriculum development was used as the guiding conceptual framework. The curriculum was categorized into four domains, which emerged from the outcome of a qualitative needs assessment. Instructional sessions occurred on 5 days spanning a 2-week block. The final session concluded with summative testing. PROGRAM EVALUATION: Fellows were administered summative objective structured exams at three stations. The performance was rated by instructors using station-specific checklists. Scores approached 100% accuracy/completion for all stations. CONCLUSIONS: The development of an evidence-based educational intervention, a simulation technical skill curriculum, was highly regarded by participants and demonstrated effective training of the simulation fellows. This curriculum serves as a template for other simulationists to implement formal training in simulation technical skills.

Gamma-Delta T-Cell Phenotype and Function in DAA-Treated HIV-HCV Co-Infected and HCV-Mono-Infected Subjects.

HIV-HCV co-infected subjects are at risk of liver fibrosis which may be linked to immune imbalances. Direct-acting antivirals (DAAs) represent the mainstay of HCV treatment in co-infected individuals, yet their effects on immune cell populations playing a role in fibrogenesis is unknown. We assessed γδ T-cell phenotype and function, Treg and Th17 frequencies, as well as γ-globulins and B-cell activation in 47 HIV-HCV co-infected and 35 HCV mono-infected individuals prior to and following DAA treatment (SVR12). Γδ T-cell activation decreased in both groups yet persisted at higher levels in the HIV-HCV co-infected subjects. No differences were registered in terms of γδT-cell function. Of note, the Vδ2/Th17 ratio, inversely linked to liver damage, increased significantly in the two groups upon treatment, yet a negative correlation between the Vδ2/Th17 ratio and liver function enzymes was found in the co-infected subjects alone. B-cell activation and γ-globulin levels decreased in both settings, yet B-cell activation remained higher in the HIV-HCV co-infected individuals. In HIV-HCV co-infected and HCV mono-infected participants, the effect of DAA was limited to γδ T- and B-cell activation as well as γ-globulin concentrations and the Vδ2/Th17 ratio, with no changes in γδ T-cell function and Treg frequencies. Importantly, γδ T- and B-cell activation remained at higher levels in the co-infected individuals than in those with HCV mono-infection alone. The persistence of such alterations within these cell subsets may be associated with the risk of hepatic and extrahepatic complications.

Nerve growth factor transfer from cardiomyocytes to innervating sympathetic neurons activates TrkA receptors at the neuro-cardiac junction.

Sympathetic neurons densely innervate the myocardium with non-random topology and establish structured contacts (i.e. neuro-cardiac junctions, NCJ) with cardiomyocytes, allowing synaptic intercellular communication. Establishment of heart innervation is regulated by molecular mediators released by myocardial cells. The mechanisms underlying maintenance of cardiac innervation in the fully developed heart, are, however, less clear. Notably, several cardiac diseases, primarily affecting cardiomyocytes, are associated with sympathetic denervation, supporting the hypothesis that retrograde 'cardiomyocyte-to-sympathetic neuron' communication is essential for heart cellular homeostasis. We aimed to determine whether cardiomyocytes provide nerve growth factor (NGF) to sympathetic neurons, and the role of the NCJ in supporting such retrograde neurotrophic signalling. Immunofluorescence on murine and human heart slices shows that NGF and its receptor, tropomyosin-receptor-kinase-A, accumulate, respectively, in the pre- and post-junctional sides of the NCJ. Confocal immunofluorescence, scanning ion conductance microscopy and molecular analyses, in co-cultures, demonstrate that cardiomyocytes feed NGF to sympathetic neurons, and that this mechanism requires a stable intercellular contact at the NCJ. Consistently, cardiac fibroblasts, devoid of NCJ, are unable to sustain SN viability. ELISA assay and competition binding experiments suggest that this depends on the NCJ being an insulated microenvironment, characterized by high [NGF]. In further support, real-time imaging of tropomyosin-receptor-kinase-A vesicle movements demonstrate that efficiency of neurotrophic signalling parallels the maturation of such structured intercellular contacts. Altogether, our results demonstrate the mechanisms which link sympathetic neuron survival to neurotrophin release by directly innervated cardiomyocytes, conceptualizing sympathetic neurons as cardiomyocyte-driven heart drivers. KEY POINTS: CMs are the cell source of nerve growth factor (NGF), required to sustain innervating cardiac SNs; NCJ is the place of the intimate liaison, between SNs and CMs, allowing on the one hand neurons to peremptorily control CM activity, and on the other, CMs to adequately sustain the contacting, ever-changing, neuronal actuators; alterations in NCJ integrity may compromise the efficiency of 'CM-to-SN' signalling, thus representing a potentially novel mechanism of sympathetic denervation in cardiac diseases.

Real World Estimate of Vaccination Protection in Individuals Hospitalized for COVID-19.

Whether vaccination confers a protective effect against progression after hospital admission for COVID-19 remains to be elucidated. Observational study including all the patients admitted to San Paolo Hospital in Milan for COVID-19 in 2021. Previous vaccination was categorized as: none, one dose, full vaccination (two or three doses >14 days before symptoms onset). Data were collected at hospital admission, including demographic and clinical variables, age-unadjusted Charlson Comorbidity index (CCI). The highest intensity of ventilation during hospitalization was registered. The endpoints were in-hospital death (primary) and mechanical ventilation/death (secondary). Survival analysis was conducted by means of Kaplan-Meier curves and Cox regression models. Effect measure modification by age was formally tested. We included 956 patients: 151 (16%) fully vaccinated (18 also third dose), 62 (7%) one dose vaccinated, 743 (78%) unvaccinated. People fully vaccinated were older and suffering from more comorbidities than unvaccinated. By 28 days, the risk of death was of 35.9% (95%CI: 30.1−41.7) in unvaccinated, 41.5% (24.5−58.5) in one dose and 28.4% (18.2−38.5) in fully vaccinated (p = 0.63). After controlling for age, ethnicity, CCI and month of admission, fully vaccinated participants showed a risk reduction of 50% for both in-hospital death, AHR 0.50 (95%CI: 0.30−0.84) and for mechanical ventilation or death, AHR 0.49 (95%CI: 0.35−0.69) compared to unvaccinated, regardless of age (interaction p > 0.56). Fully vaccinated individuals in whom vaccine failed to keep them out of hospital, appeared to be protected against critical disease or death when compared to non-vaccinated. These data support universal COVID-19 vaccination.

Novel Optics-Based Approaches for Cardiac Electrophysiology: A Review.

Optical techniques for recording and manipulating cellular electrophysiology have advanced rapidly in just a few decades. These developments allow for the analysis of cardiac cellular dynamics at multiple scales while largely overcoming the drawbacks associated with the use of electrodes. The recent advent of optogenetics opens up new possibilities for regional and tissue-level electrophysiological control and hold promise for future novel clinical applications. This article, which emerged from the international NOTICE workshop in 2018, reviews the state-of-the-art optical techniques used for cardiac electrophysiological research and the underlying biophysics. The design and performance of optical reporters and optogenetic actuators are reviewed along with limitations of current probes. The physics of light interaction with cardiac tissue is detailed and associated challenges with the use of optical sensors and actuators are presented. Case studies include the use of fluorescence recovery after photobleaching and super-resolution microscopy to explore the micro-structure of cardiac cells and a review of two photon and light sheet technologies applied to cardiac tissue. The emergence of cardiac optogenetics is reviewed and the current work exploring the potential clinical use of optogenetics is also described. Approaches which combine optogenetic manipulation and optical voltage measurement are discussed, in terms of platforms that allow real-time manipulation of whole heart electrophysiology in open and closed-loop systems to study optimal ways to terminate spiral arrhythmias. The design and operation of optics-based approaches that allow high-throughput cardiac electrophysiological assays is presented. Finally, emerging techniques of photo-acoustic imaging and stress sensors are described along with strategies for future development and establishment of these techniques in mainstream electrophysiological research.

Declining Mortality Rate of Hospitalised Patients in the Second Wave of the COVID-19 Epidemics in Italy: Risk Factors and the Age-Specific Patterns.

BACKGROUND: Mortality rate from COVID-19 in Italy is among the world's highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020-January 2021) compared to the first one (February-May 2020); further, we verified whether there were clusters of hospitalised patients who particularly benefitted from reduced mortality rate. METHODS: Data collected related to in-patients' demographics, clinical, laboratory, therapies and outcome. Primary end-point was time to in-hospital death. Factors associated were evaluated by uni- and multivariable analyses. A flow diagram was created to determine the rate of in-hospital death according to individual and disease characteristics. RESULTS: A total of 1561 patients were included. The 14-day cumulative incidence of in-hospital death by competing risk regression was of 24.8% (95% CI: 21.3-28.5) and 15.9% (95% CI: 13.7-18.2) in the first and second wave. We observed that the highest relative reduction of death from first to second wave (more than 47%) occurred mainly in the clusters of patients younger than 70 years. CONCLUSIONS: Progress in care and supporting therapies did affect population over 70 years to a lesser extent. Preventive and vaccination campaigns should focus on individuals whose risk of death from COVID-19 remains high.

Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear. PURPOSE: We hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC. METHODS: For translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects. RESULTS: AC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs. CONCLUSIONS: Independently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling.

Adaptive change in simulation education: Comparison of effectiveness of a communication skill curriculum on death notification using in person methods versus a digital communication platform.

Background: Mandates to social distance and "shelter in place" during the COVID-19 pandemic necessitated the exploration of new academic content delivery methods. Digital communication platforms (DCP; e.g., Zoom) were widely used to facilitate content delivery, yet little is known about DCP's capacity or effectiveness, especially for simulation. Objective: The objective was to compare the experience, outcomes, and resources required to implement a simulation-based communication skill curriculum on death notification to a cohort of learners using in-person versus DCP delivery of the same content. Methods: We used the GRIEV_ING mnemonic to train students in death notification techniques either in person or utilizing a DCP. For all learners, three measures were collected: knowledge, confidence, and performance. Individual learners completed knowledge and confidence assessments pre- and postintervention. All performance assessments were completed by standardized patients (SPs) in real time. Wilcoxon rank-sum test was used to identify differences in individual and between-group performances. Results: Thirty-four learners participated (N = 34), 22 in person and 12 via DCP. There was a statistically significant improvement in both groups for all three measures: knowledge, confidence, and performance. Between-group comparisons revealed a difference in pretest confidence but no differences between groups in knowledge or performance. More preparation and prior planning were required to set up the DCP environment than the in-person event. Conclusions: The in-person and DCP delivery of death notification training were comparable in their ability to improve individual knowledge, confidence, and performance. Additional preparation time, training, and practice with DCPs may be required for SPs, faculty, and learners less familiar with this technology.

Arrhythmogenic Cardiomyopathy Is a Multicellular Disease Affecting Cardiac and Bone Marrow Mesenchymal Stromal Cells.

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disorder at high risk of arrhythmic sudden death in the young and athletes. AC is hallmarked by myocardial replacement with fibro-fatty tissue, favoring life-threatening cardiac arrhythmias and contractile dysfunction. The AC pathogenesis is unclear, and the disease urgently needs mechanism-driven therapies. Current AC research is mainly focused on 'desmosome-carrying' cardiomyocytes, but desmosomal proteins are also expressed by non-myocyte cells, which also harbor AC variants, including mesenchymal stromal cells (MSCs). Consistently, cardiac-MSCs contribute to adipose tissue in human AC hearts. We thus approached AC as a multicellular disorder, hypothesizing that it also affects extra-cardiac bone marrow (BM)-MSCs. Our results show changes in the desmosomal protein profile of both cardiac- and BM- MSCs, from desmoglein-2 (Dsg2)-mutant mice, accompanied with profound alterations in cytoskeletal organization, which are directly caused by AC-linked DSG2 downregulation. In addition, AC BM-MSCs display increased proliferation rate, both in vitro and in vivo, and, by using the principle of the competition homing assay, we demonstrated that mutant circulating BM-MSCs have increased propensity to migrate to the AC heart. Taken altogether, our results indicate that cardiac- and BM- MSCs are additional cell types affected in Dsg2-linked AC, warranting the novel classification of AC as a multicellular and multiorgan disease.