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Abstract Background Current research on the transmission of trauma and eating disorders across generations is limited. However, quantitative studies suggest that the influence of parents’ and grandparents’ eating disorders and their prior exposure to trauma are associated with the development of eating disorders in future generations. Qualitative research exploring personal accounts of the impact of transgenerational trauma on the development of eating disorders has been largely unexplored. The aim of the current qualitative study was to explore the meaning that participants ascribed to their eating disorders in the context of transgenerational trauma across three generations. Methods Six adult female participants who had received a diagnosis of anorexia nervosa and/or bulimia nervosa completed multiple unstructured interviews, informed by a psychoanalytical methodology. Results Four themes were developed from the material that emerged from the interviews: (1) The toll of undigested emotions (2), A need for safety (3), “It’s not just me” – making connections with the past, and (4) “Last link” in the chain? Conclusions The themes were discussed in respect of previous literature, with a particular emphasis on Gerson’s concept of the dead third, which emphasises an unconscious compulsion to repeat unprocessed transgenerational traumas. Clinical implications of the research underscores the importance of a holistic approach to the treatment of eating disorders, recognising both individual and familial traumas within the family system. Moreover, the research demonstrates the significant impact that mental health clinicians can have in eating disorder treatment by fostering a supportive, safe and trusting therapeutic relationship.

Abstract Pulsed Field Ablation (PFA) is a new ablation method being rapidly adopted for treatment of atrial fibrillation, which shows advantages in safety and efficiency over radiofrequency and cryo-ablation. In this study, we used an in vivo swine model (10 healthy and 5 with chronic myocardial infarct) for ventricular PFA, collecting intracardiac electrograms, electro-anatomical maps, native T1-weighted and late gadolinium enhancement MRI, gross pathology, and histology. We used 1000–1500 V pulses, with 1–16 pulse trains to vary PFA dose. Lesions were assessed at 24 h, 7 days, and 6 weeks in healthy and at 48 h in infarcted ventricles. Comparisons of lesion sizes using a numerical model enabled us to determine lethal electric field thresholds for cardiac tissue and its dependence on the number of pulse trains. Similar thresholds were found in normal and infarcted hearts. Numerical modeling and temperature-sensitive MRI confirmed the nonthermal nature of PFA, with less than 2% of a lesion’s volume at the highest dose used being attributed to thermal damage. Longitudinal cardiac MRI and histology provide a comprehensive description of lesion maturation. Lesions shrink between 24 h and 7 days post-ablation and then remain stable out to 6 weeks post-ablation. Periprocedural electrograms analysis yields good correlation with lesion durability and size.

Abstract Background Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8+ T-lymphocyte and a decreased CD3+ T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8+ T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors. Graphical Abstract

Abstract Background Despite a strong evidence base and policy recommendation supporting the implementation of psychoeducation interventions within the mental health system, equitable access for many service users and family members has not been achieved. To enhance translation, developing an evidence-base around the factors that influence implementation of interventions is critical. Methods The aim of the study was to explore the factors influencing implementation of a group cofacilitated recovery focused psychoeducation intervention. The study design was explorative qualitative descriptive, involving the collection of data through individual and focus group interviews with key stakeholders (n = 75) involved with the implementation within 14 mental health sites in the Republic of Ireland. The Consolidation Framework for Implementation Research (CFIR) was used as a conceptual framework to guide data collection and analysis. Results Key enablers and barriers were identified across all CFIR domains of the framework with some factors (depending on context) being both an enabler and a barrier. Important factors in the outer setting domain included structural stability within national systems and the peer payment system, while the extent of a recovery-oriented culture, leadership, implementation readiness, and buy-in were influential factors in the inner setting. The characteristics of the intervention in terms of design, evidence-base and adaptability also shaped the intervention’s implementation as did the knowledge, beliefs and self-efficacy of facilitators. In terms of processes, implementation was influenced by the degree of engagement of key individuals who championed and supported the programme. The results highlight that while some of the barriers were specific to the programme, many reflected systemic and structural challenges within health services more generally. Conclusion Findings from this study provide an enhanced understanding of the different layers of determinants to implementation of an intervention. Overcoming challenges will involve positive and ongoing engagement and collaboration across the full range of stakeholders that are active within each domain, including policy and operational levels. The quality of leadership at each domain level is of crucial importance to successful implementation.

Summary: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation. : In this article, Laflamme and colleagues show that the transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) partially remuscularizes the scar of infarcted and appropriately immunosuppressed pigs. hESC-CM recipients exhibited frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. These graft-related tachyarrhythmias were found to be due to focal mechanisms rather than macro-reentry. Keywords: human embryonic stem cell-derived cardiomyocytes, pluripotent stem cells, myocardial infarction, ventricular tachyarrhythmias, electroanatomical mapping, MRI

A critical chemotherapeutic complication is cardiotoxicity, often leading, in time, to heart failure. In this work, we developed a novel animal protocol using magnetic resonance (MR) imaging and electrophysiology (EP) tests, designed to detect subtle structural and functional changes associated with myocardial damage in sub-chronic phases post-chemotherapy. A weekly dose of doxorubicin (DOX) was injected in four juvenile swine throughout a four-week plan, using an intravenous approach that mimics the treatment in cancer patients. We performed cardiac MR imaging as follows: in all four pigs pre-DOX; at 1 and 5 weeks post-DOX in a group of two pigs; and, at 1 and 9 weeks post-DOX in the other two pigs, using Cine imaging to assess ejection fraction (EF) and late gadolinium enhancement to quantify collagen density in the left ventricle. Additionally, X-ray-guided voltage mapping and arrhythmia tests were conducted in the group at 9 weeks post-DOX and in a healthy pig. Tissue samples were collected for histology. The results showed that EF decreased from ~46% pre-DOX to ~34% within the first 9 weeks post-DOX. This decline in LV function was explained by a gradual increase in collagen density, especially noticeable at week 9 post-DOX as derived from MRI analysis. Furthermore, ventricular fibrillation was induced via rapid pacing at 9 weeks post-DOX, most likely caused by fibrotic patches identified in voltage maps, as confirmed by MRI and collagen-sensitive histological stains. Overall, our novel preclinical protocol was able to reveal key signs of potentially-irreversible tissue changes, along with electrical remodeling and arrhythmia risk in the early months following DOX therapy. Future work will include more datasets to statistically power the study, and will use the protocol to test cardioprotective strategies.

Abstract Background Following acute myocardial infarction (AMI), microvascular integrity and function may be compromised as a result of microvascular obstruction (MVO) and vasodilator dysfunction. It has been observed that both infarcted and remote myocardial territories may exhibit impaired myocardial blood flow (MBF) patterns associated with an abnormal vasodilator response. Arterial spin labeled (ASL) CMR is a novel non-contrast technique that can quantitatively measure MBF. This study investigates the feasibility of ASL-CMR to assess MVO and vasodilator response in swine. Methods Thirty-one swine were included in this study. Resting ASL-CMR was performed on 24 healthy swine (baseline group). A subset of 13 swine from the baseline group underwent stress ASL-CMR to assess vasodilator response. Fifteen swine were subjected to a 90-min left anterior descending (LAD) coronary artery occlusion followed by reperfusion. Resting ASL-CMR was performed post-AMI at 1–2 days (N = 9, of which 6 were from the baseline group), 1–2 weeks (N = 8, of which 4 were from the day 1–2 group), and 4 weeks (N = 4, of which 2 were from the week 1–2 group). Resting first-pass CMR and late gadolinium enhancement (LGE) were performed post-AMI for reference. Results At rest, regional MBF and physiological noise measured from ASL-CMR were 1.08 ± 0.62 and 0.15 ± 0.10 ml/g/min, respectively. Regional MBF increased to 1.47 ± 0.62 ml/g/min with dipyridamole vasodilation (P 0.60). Conclusions ASL-CMR can assess vasodilator response in healthy swine and detect significant reduction in regional MBF at rest following AMI. ASL-CMR is an alternative to gadolinium-based techniques for assessment of MVO and microvascular integrity within infarcted, as well as salvageable and remote myocardium. This has the potential to provide early indications of adverse remodeling processes post-ischemia.

Abstract Background Radiofrequency (RF) ablation has become a mainstay of treatment for ventricular tachycardia, yet adequate lesion formation remains challenging. This study aims to comprehensively describe the composition and evolution of acute left ventricular (LV) lesions using native-contrast cardiovascular magnetic resonance (CMR) during CMR-guided ablation procedures. Methods RF ablation was performed using an actively-tracked CMR-enabled catheter guided into the LV of 12 healthy swine to create 14 RF ablation lesions. T2 maps were acquired immediately post-ablation to visualize myocardial edema at the ablation sites and T1-weighted inversion recovery prepared balanced steady-state free precession (IR-SSFP) imaging was used to visualize the lesions. These sequences were repeated concurrently to assess the physiological response following ablation for up to approximately 3 h. Multi-contrast late enhancement (MCLE) imaging was performed to confirm the final pattern of ablation, which was then validated using gross pathology and histology. Results Edema at the ablation site was detected in T2 maps acquired as early as 3 min post-ablation. Acute T2-derived edematous regions consistently encompassed the T1-derived lesions, and expanded significantly throughout the 3-h period post-ablation to 1.7 ± 0.2 times their baseline volumes (mean ± SE, estimated using a linear mixed model determined from n = 13 lesions). T1-derived lesions remained approximately stable in volume throughout the same time frame, decreasing to 0.9 ± 0.1 times the baseline volume (mean ± SE, estimated using a linear mixed model, n = 9 lesions). Conclusions Combining native T1- and T2-based imaging showed that distinctive regions of ablation injury are reflected by these contrast mechanisms, and these regions evolve separately throughout the time period of an intervention. An integrated description of the T1-derived lesion and T2-derived edema provides a detailed picture of acute lesion composition that would be most clinically useful during an ablation case.

Abstract Background Myocardial hemorrhage is a frequent complication following reperfusion in acute myocardial infarction and is predictive of adverse outcomes. However, it remains unsettled whether hemorrhage is simply a marker of a severe initial ischemic insult or directly contributes to downstream myocardial damage. Our objective was to evaluate the contribution of hemorrhage towards inflammation, microvascular obstruction and infarct size in a novel porcine model of hemorrhagic myocardial infarction using cardiovascular magnetic resonance (CMR). Methods Myocardial hemorrhage was induced via direct intracoronary injection of collagenase in a novel porcine model of ischemic injury. Animals (N = 27) were subjected to coronary balloon occlusion followed by reperfusion and divided into three groups (N = 9/group): 8 min ischemia with collagenase (+HEM); 45 min infarction with saline (I-HEM); and 45 min infarction with collagenase (I+HEM). Comprehensive CMR was performed on a 3 T scanner at baseline and 24 h post-intervention. Cardiac function was quantified by cine imaging, edema/inflammation by T2 mapping, hemorrhage by T2* mapping and infarct/microvascular obstruction size by gadolinium enhancement. Animals were subsequently sacrificed and explanted hearts underwent histopathological assessment for ischemic damage and inflammation. Results At 24 h, the +HEM group induced only hemorrhage, the I-HEM group resulted in a non-hemorrhagic infarction, and the I+HEM group resulted in infarction and hemorrhage. Notably, the I+HEM group demonstrated greater hemorrhage and edema, larger infarct size and higher incidence of microvascular obstruction. Interestingly, hemorrhage alone (+HEM) also resulted in an observable inflammatory response, similar to that arising from a mild ischemic insult (I-HEM). CMR findings were in good agreement with histological staining patterns. Conclusions Hemorrhage is not simply a bystander, but an active modulator of tissue response, including inflammation and microvascular and myocardial damage beyond the initial ischemic insult. A mechanistic understanding of the pathophysiology of reperfusion hemorrhage will potentially aid better management of high-risk patients who are prone to adverse long-term outcomes.

Abstract Crops expressing Bacillus thuringiensis (Bt)-derived insecticidal protein genes have been commercially available for over 15 years and are providing significant value to growers. However, there remains the need for alternative insecticidal actives due to emerging insect resistance to certain Bt proteins. A screen of bacterial strains led to the discovery of a two-component insecticidal protein named AfIP-1A/1B from an Alcaligenes faecalis strain. This protein shows selectivity against coleopteran insects including western corn rootworm (WCR). Transgenic maize plants expressing AfIP-1A/1B demonstrate strong protection from rootworm injury. Surprisingly, although little sequence similarity exists to known insecticidal proteins, efficacy tests using WCR populations resistant to two different Cry proteins show that AfIP-1A/1B and mCry3A differ in their mode of action while AfIP-1A/1B and the binary Cry34Ab1/Cry35Ab1 protein share a similar mode. These findings are supported by results of competitive binding assays and the similarity of the x-ray structure of AfIP-1A to Cry34Ab1. Our work indicates that insecticidal proteins obtained from a non-Bt bacterial source can be useful for developing genetically modified crops and can function similarly to familiar proteins from Bt.

Various lepidopteran insects are responsible for major crop losses worldwide. Although crop plant varieties developed to express Bacillus thuringiensis (Bt) proteins are effective at controlling damage from key lepidopteran pests, some insect populations have evolved to be insensitive to certain Bt proteins. Here, we report the discovery of a family of homologous proteins, two of which we have designated IPD083Aa and IPD083Cb, which are from Adiantum spp. Both proteins share no known peptide domains, sequence motifs, or signatures with other proteins. Transgenic soybean or corn plants expressing either IPD083Aa or IPD083Cb, respectively, show protection from feeding damage by several key pests under field conditions. The results from comparative studies with major Bt proteins currently deployed in transgenic crops indicate that the IPD083 proteins function by binding to different target sites. These results indicate that IPD083Aa and IPD083Cb can serve as alternatives to traditional Bt-based insect control traits with potential to counter insect resistance to Bt proteins.

Few studies have explored the problem of engagement in relation to group psychoeducation from a multi-site and multi-stakeholder perspective. The aim of the study was to explore the factors influencing service user and family engagement with group psychoeducation programmes. The study design was qualitative descriptive. Data were collected through individual and focus group interviews with key stakeholders (n = 75) involved with the programme within 14 mental health sites in the Republic of Ireland. Enablers and barriers to engagement were identified at participant, provider, programme and organization level. Motivated participants and engaged clinicians, peer co-facilitation and support, and skilled and responsive facilitators were some of the factors which enhanced engagement. Barriers to engagement included readiness among participants, concerns related to stigma and confidentiality, desire to distance oneself from mental health services, a lack of support for programme participation within families, group discomfort, the time and length of the programme, issues with transport, visibility of the programme, and structural supports for clinicians. Findings from the study illustrate the multifaceted nature of engagement as well as provide a greater understanding of the multifactorial influences on engagement. Strategies to enhance engagement should therefore reflect a multipronged approach. At the outset of programme implementation, organizations should address their readiness to engage, conduct local needs assessments to anticipate individuals' needs and plan accordingly in order to maximize engagement, and bolster facilitators' engagement skills through the provision of training and mentoring opportunities.