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Background: Two out of three family caregivers are female. However, current trends show that men are more likely to undertake caregiving duties, yet female caregivers report a higher burden. This paper analyzed data from long-term family caregivers to determine whether, under similar circumstances, gender differences in caregiving persist. We examined whether the observed gender gap affects caregivers' satisfaction with their health and quality of life., Methods: We analyze cross-sectional data from family caregivers of persons with spinal cord injury (SCI) in Switzerland. The data provides comprehensive information about the time and type of weekly tasks family caregivers undertake. To determine differences in caregiving related to gender, we balanced the characteristics of the caregiver and the cared-for person using a propensity score kernel matching. With the balanced sample, we estimated how the observed differences in caregiving varied across cohorts using a Poisson regression., Results: Under similar circumstances, male and female caregivers invest similar time in caregiving. This result holds for 21 caregiving tasks, except for household chores, where women spent, on average, four more hours per week than male caregivers. Despite these differences, female caregivers report a quality of life and satisfaction with their health that is similar to that of male caregivers., Conclusion: Gender differences in caregiving narrow over time, except for household chores, where female caregivers continue to spend significantly more hours than male caregivers. Measures designed for family caregivers must consider these gender differences, as the support needs of female caregivers can differ greatly from those of male caregivers., (© 2024. The Author(s).)

Background: Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features., Methods: We retrospectively investigated 44 adults (age 17-48 years) with a histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identify the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival)., Results: We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent gross total or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients., Conclusions: Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.

The primary aim of this systematic analysis is to highlight opportunities to improve the environmental impact of advanced therapy medicinal products (ATMP) manufacturing. We have compared the Greenhouse Gas (GHG) emissions expressed in CO2eq of a classic clean room open system (AinB) Cell Factory versus a comparable closed system equipped with isolators (AinD). We have therefore outlined a theoretical situation to simulate the use of a closed system with an equivalent production output to that obtained in the Cell Factory (CF) of the Regina Margherita Children's Hospital. Open and closed systems for ATMPs have been compared as regards energy requirements, ecological footprints, and costs by analyzing a hypothetic cell production cycle of 21 days. The results demonstrate energy saving and a reduction of 52% in GHG emissions using closed systems per process cycle. Moreover, a reduction in production costs in an isolator setting is also evident. This study shows that the closed system solution has evident advantages compared with the open one.

The introduction of new therapeutics requires validation of Good Manufacturing Practice (GMP)-grade manufacturing including suitable quality controls. This is challenging for Advanced Therapy Medicinal Products (ATMP) with personalized batches. We have developed a person-alized, cell-based gene therapy to treat age-related macular degeneration and established a vali-dation strategy of the GMP-grade manufacture for the ATMP; manufacturing and quality control were challenging due to a low cell number, batch-to-batch variability and short production duration. Instead of patient iris pigment epithelial cells, human donor tissue was used to produce the transfected cell product ("tIPE"). We implemented an extended validation of 104 tIPE productions. Procedure, operators and devices have been validated and qualified by determining cell number, viability, extracellular DNA, sterility, duration, temperature and volume. Transfected autologous cells were transplanted to rabbits verifying feasibility of the treatment. A container has been engineered to ensure a safe transport from the production to the surgery site. Criteria for successful validation and qualification were based on tIPE's Critical Quality Attributes and Process Parameters, its manufacture and release criteria. The validated process and qualified operators are essential to bring the ATMP into clinic and offer a general strategy for the transfer to other manufacture centers and personalized ATMPs.

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R-RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof-of-concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α-overexpressing breast cancer, thereby suggesting a novel strategy for anti-breast cancer therapy., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: To identify the coping strategies used by family caregivers of persons with spinal cord injury (SCI) in Switzerland in order to develop tailored support programs., Materials and Methods: Purposive sample of >18 years participants, speaking an official Swiss language fluently, being family caregivers of persons with SCI for at least 4 years, and perceiving either a high or low burden in relation to caregiving. Data were collected through face-to-face semi-structured interviews ( N  = 22). Thematic analysis was performed., Results: Four main coping strategies were identified: reappraisal, active acceptance, setting limits to the caregiver role, and seeking support. These strategies can be used one at a time or combined, and at different times of a caregiver pathway. Our analysis highlighted that caregivers need skills to implement these strategies (e.g., self-evaluation skills)., Conclusions: Caregivers of persons with SCI develop cognitive coping strategies to make sense of the situation and establish a "new normal" and problem-focused coping strategies to deal with their new tasks and role. These strategies do not seem to be typical only of SCI caregivers. Hence, interventions that worked for caregivers in other fields could be adapted. Rehabilitation centers should systematically integrate programs targeted to caregivers into their offerings.IMPLICATIONS FOR REHABILITATIONHealthcare systems need to develop educational and support measures for both persons with a health condition and their caregivers.Caregivers should become long-term partners in rehabilitation and a regular and structured needs assessment should be offered.Interventions that worked for caregivers in other fields can be adapted to support also caregivers in SCI.Educational and support programs dedicated to caregivers should teach not only how to perform caregiving tasks but also how to balance between responding to the care recipient's needs and their own needs.

Inflectional values, such as singular and plural, sustain agreement relations between constituents in sentences, allowing sentence parsing and prediction in online processing. Ideally, these processes would be facilitated by a consistent and transparent correspondence between the inflectional values and their form: for example, the value of plural should always be expressed by the same ending, and that ending should only express plural. Experimental research reports higher processing costs in the presence of a non-transparent relation between forms and values. While this effect was found in several languages, and typological research shows that consistency is far from common in morphological paradigms, it is still somewhat difficult to precisely quantify the transparency degree of the inflected forms. Furthermore, to date, no accounts have quantified the transparency in inflection with regard to the declensional classes and the extent to which it is expressed across different parts of speech, depending on whether these act as controllers of the agreement (e.g., nouns) or as targets (e.g., adjectives). We present a case study on Italian, a language that marks gender and number features in nouns and adjectives. This work provides measures of the distribution of forms in the noun and adjective inflection in Italian, and quantifies the degree of form-value transparency with respect to inflectional endings and declensional classes. In order to obtain these measures, we built Flex It, a dedicated large-scale database of inflectional morphology of Italian, and made it available, in order to sustain further theoretical and empirical research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pescuma, Zanini, Crepaldi and Franzon.)

In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative "smart" therapies in medulloblastomas.

Introduction  The newborn hearing screening (NHS) is the most effective strategy for detecting newborns and infants suspected to have hearing loss. Objective  To verify possible associations between the route of delivery and the results of the NHS conducted at 3 independent times (24, 36, and 36 hours with a facilitator auricular maneuver [FAM]) in the lives of full-term newborns. Methods  A descriptive, observational, prospective study performed with a sample of 462 newborns, with a gestational age ≥ 37 weeks, without risk indicators of hearing loss. The NHS was conducted as a routine element of the facilities, two times: at 24 and 36 hours of life. In the presence of a "failure" in the last test, a new one was immediately performed, following the FAM. Statistic analyses were carried out on the program SPSS version 21.0 (IBM Inc., Armonk, NY, USA). Results  Of the 462 newborns assessed, 304 (65.80%) were born by vaginal delivery. There was a statistical significance of "pass" in the NHS for the 24-hour evaluation ( p  ≤ 0.001 for a vaginal delivery and p  = 0.002 for a cesarean delivery), with the prevalence of the "pass" index being higher when the baby's lifespan was greater. A statistically significant difference was not observed when the NHS results were compared by taking into account the babies' routes of delivery and the different times of life. Conclusion  These findings show that full-term babies who were born by cesarean did not show more "failure" in the NHS results, contradicting the hypothesis of the study. Furthermore, to reduce the false-negative rates, regardless of the route of delivery, this assessment should be conducted after the first 24 hours of the newborns' life., Competing Interests: Conflict of Interests The authors declare that there is no conflict of interests., (Fundação Otorrinolaringologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Purpose: To explore medical doctors' views on what are barriers in providing rehabilitation services for persons with SCI in Mongolia., Methods: A qualitative study with semi-structured interviews was conducted with 12 medical doctors. Participants were purposely sampled. The World Health Organization (WHO)'s report International Perspectives on Spinal Cord Injury was chosen as a guide to structure the interviews. The study used inductive thematic analysis., Results: Five barriers in the provision of rehabilitation services were identified: low awareness and limited knowledge regarding SCI and rehabilitation issues, inadequate rehabilitation policies, deficiencies in infrastructure, deficiencies in equipment and medication, and a shortage of well-prepared rehabilitation workforce., Conclusions: Based on WHO recommendations "Rehabilitation in health systems", this study provides suggestions on how to strengthen rehabilitation services in Mongolia to better respond to the needs of the SCI population. Our findings highlight that a core issue is the lack of awareness among policymakers regarding rehabilitation and its benefits at the micro, meso and macro levels of the health system. Actions are needed at the level of health policies to ensure, for instance, adequate financing and access to the services. Also, synergies between the Ministries of Education and Health can improve the training of the workforce.Implications for rehabilitationEvidence that rehabilitation services contribute to improving health outcomes and cost-effectiveness could raise awareness among Mongolian policymakers and inform their decisions on funding schemes.Health policies in Mongolia should be reformed to remove barriers in the provision of rehabilitation services for persons with complex and chronic health conditions.Rehabilitation services need to be included into the Mongolian health insurance scheme in order to improve the quality and accessibility of rehabilitation services.Synergies between the Ministry of Education and the Ministry of Health in Mongolia are needed to develop training standards for rehabilitation professionals.

The overload of health information has been a major challenge during the COVID-19 pandemic. Public health authorities play a primary role in managing this information. However, individuals have to apply critical health literacy to evaluate it. The objective of this paper is to identify targets for strengthening critical health literacy by focusing on the field of argumentation theory. This paper is based on the textual analysis of instances of health information through the lens of argumentation theory. The results show that critical health literacy benefits from: (1) understanding the concept of argument and the supporting reasons, (2) identifying the main argument schemes, and (3) the knowledge and use of the main critical questions to check the soundness of arguments. This study operationalizes the main aspects of critical health literacy. It calls for specific educational and training initiatives in the field. Moreover, it argues in favor of broadening the current educational curricula to empower individuals to engage in informed and quality decision making. Strengthening individuals' critical health literacy involves interventions to empower in argument evaluation. For this purpose, argumentation theory has analytical and normative frameworks that can be adapted within a lay-audience education concept.

Study Design: Qualitative exploratory study., Objectives: To explore the lived experience of SCI caregivers, with a focus on the challenges of their role., Setting: Caregivers of people with SCI living in the community in Switzerland., Methods: Data were collected through semi-structured interviews. Thematic analysis was performed., Results: The sample included 22 participants (16 women, 15 life partners) with a mean age of 61 years who had been caregivers for an average of 18 years. Caregiving in SCI seemed to be characterized by two phases. The first phase was relatively short and was central to becoming a caregiver; it was marked by challenges related to adjusting to the role of caregiver (e.g., dealing with shock, feeling unprepared). The second phase is lifelong and is characterized by a number of recurrent challenges related to balancing caregiving and personal life (e.g., having to prioritize caregiving over personal wishes, negotiating tasks and workload). Challenges related to lacking appropriate housing, facing financial uncertainty and dealing with bureaucracy were noted during both phases. Caregivers had to deal with these challenges to stay in step with life changes and newly emerging needs., Conclusions: Informal caregivers have a major role in supporting people with SCI. But their needs are not static. Any strategy to empower them has to adapt to an evolving role characterized by multiple tasks and challenges. A functional relationship between caregivers and care recipients is based on the recognition of their individualities and the different phases of adaptation, which is also an enriching process.

Study Design: Observational study using data from the second community survey of the Swiss Spinal Cord Injury Cohort Study (Survey 2017)., Objectives: To examine information seeking of individuals with spinal cord injury (SCI) in Switzerland and its association with personal characteristics, quality of life, satisfaction with health, and healthcare services utilization., Setting: Community., Methods: Descriptive statistics were used to describe information needs, information sources, and health literacy of the participants. Linear, logistic, and Poisson regression analyses were used to assess the association of information-related variables with personal characteristics, quality of life, satisfaction with health, and healthcare services utilization., Results: One quarter of the 1294 study participants (24.6%) reported having information needs. Most frequently mentioned were needs for medical information about SCI, complications and comorbidities (30.5%), and information on living with SCI (28.6%). The most often used sources of information were healthcare professionals (72.3%), the Internet (43.2%), and other people living with SCI (40.8%). Almost half of the participants (41.4%) were only somewhat or not at all confident in their ability to find information. Having information needs was associated with suboptimal outcomes., Conclusions: This study confirms the importance of information for individuals living with SCI. By providing evidence on topics to be addressed and modalities of information delivery, our findings can help institutions in developing information to support individuals living with SCI in their daily activities. Information should cover all aspects of living with SCI, be relevant to and understandable for people of all backgrounds, and be made available online and offline.

Communicating an unfavourable prognosis while maintaining patient hope represents a critical challenge for healthcare professionals (HPs). Duty requires respect for the right to patient autonomy while at the same time not doing harm by causing hopelessness and demoralisation. In some cases, the need for therapeutic privilege is discussed. The primary objectives of this study were to explore HPs' perceptions of hope in the prognosis communication and investigate how they interpret and operationalise key ethical principles. Sixteen qualitative semistructured interviews with HPs from different positions and experience, including doctors and nurses in four different departments (intensive care, oncology, palliative care, rehabilitation), were conducted in the Ticino Cantonal Hospital, Switzerland. The interviews were recorded, transcribed verbatim and analysed using thematic analysis. HPs defined prognosis and patient hope as interdependent concepts related to future perspectives for subjective quality of life. Two main factors allow HPs to maximise the benefits and minimise the harm of their communication: respecting the patient's timing and sharing the patient's wishes. Time is required to reframe needs and expectations. Furthermore, communication needs to be shared by HPs, patients and their relatives to build common awareness and promote a person-centred approach to prognosis. In this process, interprofessional collaboration is key: doctors and nurses are complementary and can together guarantee that patients and relatives receive information in the most appropriate form when they need it. Organisational aspects and the HPs' emotional difficulties, particularly in coping with their own despair, are barriers to effective communication that need further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine the information seeking behavior and health literacy of caregivers of individuals living with spinal cord injury in Switzerland and their impact on the caregiving experience., Methods: Nationwide survey of family caregivers of people with spinal cord injury (N = 717). Caregivers aged 18+ who assisted with activities of daily living were included. Self-reported information seeking behavior, including topics, preferred sources, and health literacy were assessed and analyzed., Results: Health professionals were the most trusted source of information. Among information-seekers, higher health literacy levels were shown to be associated with lower subjective caregiver burden and, in turn, with higher caregivers' satisfaction with own health., Conclusion: Caregivers use information on different topics and coming from different sources. In order for information to improve the caregiving experience, however, caregivers need health literacy skills to make sense of it., Practice Implications: Building health literacy is a promising approach to support caregivers in their activities, reduce their subjective burden, and even to improve their health. Interventions should consider involving health professionals, as the most trusted source of information, and address both health-related and more practical issues., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application., (© 2020 Wiley Periodicals LLC.)

Study Design: Qualitative exploratory study., Objectives: Pressure injuries (PIs) are a major secondary condition occurring after spinal cord injuries (SCI). Optimization of outpatient and community care may be a promising approach to better support community-dwelling individuals with SCI in preventing PIs. The aim of this study was to examine the experiences of individuals with SCI, family caregivers and health professionals (HPs) in using or providing outpatient and community services for early treatment and prevention of PIs in SCI., Setting: Switzerland., Methods: Semi-structured interviews with a sample of Swiss residents community-dwelling individuals with SCI (n = 20), family caregivers (n = 5) and HPs (n = 22) were analysed using thematic analysis., Results: General practitioners (GPs), home care providers, SCI-specialized outpatient clinics and an SCI-specialized nursing service are involved in the prevention and early treatment of PIs. Our findings show that the needs of individuals with SCI are not fully met: outpatient and community care is often fragmented, mono-professional and non-specialized, while persons with SCI and HPs prefer coordinated, inter-professional and specialized services for preventing and treating PIs. Our findings also highlight the challenges faced by HPs in providing care to individuals with SCI in the community., Conclusions: Although there seems to be a gap in service provision, there is the potential for improvement by better integrating the different providers in a network and structuring their collaborations. Concrete suggestions are: systematizing knowledge transfer to home care providers and GPs; redefining the role of involved HPs and individuals with SCI and reinforcing the role of the SCI-specialized nursing service.

Context : Environmental factors play a key role in the lives of individuals with a spinal cord injury (SCI). This study identifies environmental barriers and their impacts on daily lives as perceived by individuals living with SCI in Mongolia. Design: A qualitative study with semi-structured interviews was conducted. A topic guide for the interviews was structured around the components of the International Classification of Functioning, Disability, and Health. Setting: Urban and rural areas of Mongolia. Participants: A purposive sample of 16 persons with traumatic SCI. Interventions: Not applicable. Outcome Measures: Not applicable. Results: Seven categories of environmental barriers were mentioned, such as poor access to the physical environment, absence of wheelchair-friendly transportation, negative societal attitudes, inadequate health and rehabilitation services, lack of access to assistive devices and medicines, limited financial resources for healthcare, and inaccurate categorization of disabilities in laws. These barriers were claimed to have an impact on physical and psychological health, limit activities, and restrict participation in almost all areas of life. Conclusion: This study contributes to the identification of targets for interventions aimed at improving the lived experience of persons with SCI in a low-resource context. The findings reveal that while the Mongolian government already has laws and policies in place to improve access to the physical environment, transportation, assistive devices and employment, much more has to be done in terms of enforcement. Specialized SCI care and rehabilitation services are highly demanded in Mongolia.

Myocarditis can lead to autoimmune disease, dilated cardiomyopathy, and heart failure, which is modeled in the mouse by cardiac myosin immunization (experimental autoimmune myocarditis [EAM]). Signal transducer and activator of transcription 3 (STAT3) systemic inhibition exerts both preventive and therapeutic effects in EAM, and STAT3 constitutive activation elicits immune-mediated myocarditis dependent on complement C3 and correlating with activation of the STAT3-interleukin 6 (IL-6) axis in the liver. Thus, liver-specific STAT3 inhibition may represent a therapeutic option, allowing to bypass the heart toxicity, predicted by systemic STAT3 inhibition. We therefore decided to explore the effectiveness of silencing liver Stat3 and C3 in preventing EAM onset and/or the recovery of cardiac functions. We first show that complement C3 and C5 genetic depletion significantly prevents the onset of spontaneous myocarditis, supporting the complement cascade as a viable target. In order to interfere with complement production and STAT3 activity specifically in the liver, we took advantage of liver-specific Stat3 or C3 small interfering (si)RNA nanoparticles, demonstrating that both siRNAs can significantly prevent myocarditis onset and improve the recovery of heart functions in EAM. Our data demonstrate that liver-specific Stat3/C3 siRNAs may represent a therapeutic option for autoimmune myocarditis and suggest that complement levels and activation might be predictive of progression to dilated cardiomyopathy., (© 2020 The Author(s).)