Bilateral Lung Transplantation in a Patient with Humoral Immune Deficiency: A Case Report with Review of the Literature

Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs

The Products of the Herpes Simplex Virus Type 1 Immediate-Early U(S)1/U(S)1.5 Genes Downregulate Levels of S-Phase-Specific Cyclins and Facilitate Virus Replication in S-Phase Vero Cells

Herpes simplex virus type 1 ICP22(−)/U(S)1.5(−) mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express γ(2) late proteins. Although the function of ICP22/U(S)1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/U(S)1.5. For this purpose, we first isolated and characterized an ICP22(−)/U(S)1.5(−) mutant virus, 22/n199. Like other ICP22(−)/U(S)1.5(−) mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient γ(2) late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/U(S)1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U(S)1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly

xDelia: D18-2.4.2 Learning Intervention Package - Development and Evaluation (Year 3)

The core purpose of xDelia is to develop learning approaches to improve the financial decision making of private investors who trade frequently using a trading platform. This group has significant economic importance in the EU, and is sufficiently well understood to be a viable target of learning interventions. Much financial training has, to date, focused primarily on imparting propositional knowledge and increasing people’s understanding. However, investors may have appropriate knowledge, but despite this go on to be ruled by their attitudes, habits, or emotional states. Emotions mediate both rapid expert situation recognition and the application of expert intuition but also important persistent biases in decision-making such as framing effects and the disposition effect in particular. There is an increasing body of evidence that effective emotion regulation can reduce maladaptive biases mediated via emotions whilst still allowing the application of expert intuition. Investigating this, the project has developed new, technologically supported approaches to training; and the project has developed support for non-formal and informal learning in real-world trading settings to tackle the challenges faced by investors when they make financial decisions. This document sets out the nature and scope of the final xDelia learning pathway, its pedagogical underpinnings and constituent elements. A summary of major functionalities are described and learning applications. This document focuses on the evolution of the learning pathway in Year 3 of the xDelia Project and presents the final form of the learning pathway we have designed and its constituent elements. To be maximally useful to those wishing either to deploy the approaches and tools we have developed or to carry out further research and development, we also include a summary account of our evaluation of our learning approach1 and (in the appendices) documentation for each of the learning elements

xDelia: emotion-centred financial decision making and learning (final report)

Competence in financial matters has become part and parcel of everyday life, both at the work place and in our daily lives. Traditional learning cannot deliver the necessary skills, and more innovative solutions are needed. Serious games, wearable sensors, and a focus on emotions lie at the heart of this project’s novel, technology-supported approach to expertise and competence-building in financial decision making. xDelia is a 3-year pan-European project building on the knowledge, skills, and competences of seven partner organisations from a variety of research disciplines and from business. The principal objective of xDelia is to develop technology-enhanced learning approaches that help improve the financial decision making of investors who trade frequently using an electronic trading platform. We focus on emotions, and how they affect maladaptive decision biases and trading performance. Our earlier field work with traders has shown that the development of emotion regulation skills is a key facet of trader expertise. For that reason we consider expert traders our benchmark for adaptive behaviour rather than normative rationality. Our goal is to provide investors with the tools and techniques to develop greater self-awareness of internal states, increase their ability to reflect critically on emotion-informed choices, develop emotion management skills, and support the transfer of these skills to the real-world practice setting of financial trading. This report provides a comprehensive overview of what xDelia is about and what we have achieved over the life of the project. In the sections that follow, we explain the decision problems investors are faced with in a fast paced environment and the limitations of traditional approaches to reduce cognitive errors; introduce an alternative, technology-enhanced learning approach of diagnosis and feedback, skill development, and transfer; describe the learning intervention comprising twelve autonomous learning elements that we have developed; and present evidence from thirty-five studies we have conducted on learning effects and stakeholder acceptance. Much of this document is based on the thirty or so project deliverables, which offer far more detailed and definite discussion on the various aspects that we could only sketch out here. We have provided references to these deliverables throughout the document. The remainder of this report is divided into five sections: The xDelia project – summarises what xDelia tries to achieve, the learning intervention we have developed and the instruments we have used in the process, how the work unfolded over the three years, and how we evaluated our work and the project output. The concept and purpose of the learning intervention – describes the challenge of reducing and overcoming financial decision biases, and the alternative approach we have developed, the investor target group, and the pedagogy underpinning our learning intervention. The xDelia learning pathway – describes the pedagogical framework and the three stage learning approach of diagnosis and feedback, skill development, and learning transfer. Elements of the learning pathway – briefly describes the purpose and key features of each of the learning elements within the learning intervention. Evidence-based design and evaluation – presents an overview of the evaluation of the learning elements and of the user experience. For further details about xDelia, project publications and deliverables, and contacts, please visit the project web site at www.xdelia.org

ICP22 Is Required for Wild-Type Composition and Infectivity of Herpes Simplex Virus Type 1 Virions

The immediate-early regulatory protein ICP22 is required for efficient replication of herpes simplex virus type 1 in some cell types (permissive) but not in others (restrictive). In mice infected via the ocular route, the pathogenesis of an ICP22(−) virus, 22/n199, was altered relative to that of wild-type virus. Specifically, tear film titers of 22/n199-infected mice were significantly reduced at 3 h postinfection relative to those of mice infected with wild-type virus. Further, 22/n199 virus titers were below the level of detection in trigeminal ganglia (TG) during the first 9 days postinfection. On day 30 postinfection, TG from 22/n199-infected mice contained reduced viral genome loads and exhibited reduced expression of latency-associated transcripts and reduced reactivation efficiency relative to TG from wild-type virus-infected mice. Notably, the first detectable alteration in the pathogenesis of 22/n199 in these tests occurred in the eye prior to the onset of nascent virus production. Thus, ICP22(−) virions appeared to be degraded, cleared, or adsorbed more rapidly than wild-type virions, implying potential differences in the composition of the two virion types. Analysis of the protein composition of purified extracellular virions indicated that ICP22 is not a virion component and that 22/n199 virions sediment at a reduced density relative to wild-type virions. Although similar to wild-type virions morphologically, 22/n199 virions contain reduced amounts of two γ(2) late proteins, U(S)11 and gC, and increased amounts of two immediate-early proteins, ICP0 and ICP4, as well as protein species not detected in wild-type virions. Although ICP22(−) viruses replicate to near-wild-type levels in permissive cells, the virions produced in these cells are biochemically and physically different from wild-type virions. These virion-specific differences in ICP22(−) viruses add a new level of complexity to the functional analysis of this immediate-early viral regulatory protein

Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis

Background: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. Objectives: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. Methods: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. Results: Among patients taking nintedanib ( n  = 107) or pirfenidone ( n  = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p  = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p  = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. Conclusion: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. Registration: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT0431678

Preemptive antiviral therapy in lung transplantation from hepatitis C donors results in a rapid and sustained virologic responseCentral MessagePerspective

Objective: The study objective was to assess the safety and efficacy of a preemptive direct-acting antiviral therapy in lung transplants from hepatitis C virus donors to uninfected recipients. Methods: This study is a prospective, open-label, nonrandomized, pilot trial. Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Recipients of nucleic acid test positive lungs were compared with recipients of lungs from nucleic acid test negative donors. Primary end points were Kaplan–Meier survival and sustained virologic response. Secondary outcomes included primary graft dysfunction, rejection, and infection. Results: Fifty-nine lung transplantations were included: 16 nucleic acid test positive and 43 nucleic acid test negative. Twelve nucleic acid test positive recipients (75%) developed hepatitis C virus viremia. Median time to clearance was 7 days. All nucleic acid test positive patients had undetectable hepatitis C virus RNA by week 3, and all alive patients (n = 15) remained negative during follow-up with 100% sustained virologic response at 12 months. One nucleic acid test positive patient died of primary graft dysfunction and multiorgan failure. Three of 43 nucleic acid test negative patients (7%) had hepatitis C virus antibody positive donors. None of them developed hepatitis C virus viremia. One-year survival was 94% for nucleic acid test positive recipients and 91% for nucleic acid test negative recipients. There was no difference in primary graft dysfunction, rejection, or infection. One-year survival for nucleic acid test positive recipients was similar to a historical cohort of the Scientific Registry of Transplant Recipients (89%). Conclusions: Recipients of hepatitis C virus nucleic acid test positive lungs have similar survival as recipients of nucleic acid test negative lungs. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission

sj-docx-1-tar-10.1177_17534666231165912 – Supplemental material for Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis

Supplemental material, sj-docx-1-tar-10.1177_17534666231165912 for Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis by Todd L. Astor, Hilary J. Goldberg, Laurie D. Snyder, Andrew Courtwright, Ramsey Hachem, Tahuanty Pena, Lorenzo Zaffiri, Gerard J. Criner, Marie M. Budev, Tany Thaniyavarn, Thomas B. Leonard, Shaun Bender, Aliaa Barakat, Janis L. Breeze and Peter LaCamera in Therapeutic Advances in Respiratory Disease</p

Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation

<div><p>Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.</p></div