Somatic Mutations In Aging, Paroxysmal Nocturnal Hemoglobinuria, And Myeloid Neoplasms

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal blood disorder frequently associated with bone marrow failure that in rare instances can progress to leukemia. PNH clones of varying sizes occasionally present even in patients with hematologic malignancies and no known history of classical PNH, particularly in myelodysplastic neoplasms (MDS). Curiously, somatic driver mutations considered to be pathogenic and likely pathogenic in myeloid leukemias can be found in phenotypically normal, elderly individuals, as well as those with clonal disorders such as PNH, clonal hematopoiesis of indeterminate potential (CHIP), and age-related clonal hematopoiesis (ARCH). These mutations may be the critical link between PNH and the development of cancer. We suspect that PNH clones, derived from mutations in PIGA, may reflect a disordered bone marrow prone to additional genetic hits involved in tumorigenesis. It is uncertain, however, whether leukemic cells directly arise from PNH+ progenitors with additional genetic variants or if they are in fact distinct populations. Moreover, the specific driver mutations that underlie both PNH and myeloid neoplasms remains an area of active investigation. Our study aims to characterize the prevalence of myeloid neoplasm-associated somatic mutations in older adults and in patients who develop myeloid malignancies (MN+ patients), stratified by whether they also harbor PNH clones. We retrospectively examined the initial genetic evaluation by next-generation sequencing (NGS) of 197 individuals at Yale-New Haven Hospital and elicited the most common driver mutations and their association with age and PNH clonal presence. We demonstrated that pathogenic and likely pathogenic somatic mutations increased with age (average age of patients with one or more mutations was 69.8 years compared to 58.0 years in those with no mutations of interest, p\u3c 0.0001). Variants in SF3B1 (average age= 74.4 years, p= 0.0015), TP53 (average age= 72.8 years, p= 0.0057), SRSF2 (average age= 72.4 years, p= 0.0024), DNMT3A (average age= 71.9 years, p= 0.0059), TET2 (average age= 70.8 years, p= 0.0032), ASXL1 (average age= 70 years, p= 0.0052), and U2AF1 (average age= 69.7 years, p= 0.0082) were most commonly present in adults who were significantly older than those with no relevant mutations. Those with a diagnosis of a myeloid neoplasm were drastically more likely to harbor driver mutations (81.1% with at least one variant of interest vs. 23.5% among those without a myeloid neoplasm, p\u3c 0.0001), and had a greater number of mutations on average (1.95 vs. 0.38 mutations per patient, p\u3c 0.0001). Interestingly, MN+ patients who had a PNH clone ≥0.01% were significantly more likely to possess a neoplasm-associated mutation than those with no PNH clones (91.9% vs. 60.6%, p= 0.0005), indicating that the presence of PNH clones augments the odds of possessing cancer-related genetic lesions as early as the time of the initial evaluation. Specifically, patients who were both MN+ and PNH+ were more likely than their PNH- counterparts to have one or two pathogenic and likely pathogenic variants (58.1% vs. 27.3%), though they were equally likely to possess three or more mutations (33.9% vs. 33.3%). Furthermore, among all patients in the cohort ≥70 years, PNH presence significantly increased the overall likelihood of discovering relevant gene variants (78.9% vs. 48.7%, ?2 p= 0.0027). Among all patients, PNH clone presence was correlated with mutations in SF3B1 (85.7% of cases with SF3B1 variants had PNH clones compared 56.8% of cases with no mutations had PNH clones, Fisher’s exact test, p= 0.0402), and to a lesser degree, with RUNX1 (83.3% PNH+ cases, p= 0.0686) and DNMT3A (80.0% PNH+ cases, p= 0.0914). Finally, we qualitatively described that mutations in ASXL1, TET2, and SRSF2 tended to occur together; there were also concomitant mutations in TET2 with EZH2 and in SF3B1 with RUNX1. Therefore, we recommend early genetic screening of all elderly patients ≥70 years who present with PNH clones of any size in the peripheral blood as these patients have a higher likelihood of harboring pathogenic and likely pathogenic driver mutations. We demonstrated that certain neoplasm-associated mutations are common in elderly patients, while others correlated with PNH clone presence, and that some variants tend to co-occur. Future studies should address the molecular mechanisms of these lesions in leukemogenesis. The observation that PNH clone presence is significantly correlated with somatic mutations in MN+ disease suggests an important relationship between PNH clones and cancer, either as direct tumor precursor populations or as an incidental consequence of high genetic mutability in a vulnerable bone marrow

A Hero\u27s Journey: Experiences Using A Therapeutic Comicbook In A Children’s Psychiatric Inpatient Unit

Children’s mental health care has been on the decline since the start of the century. The COVID-19 pandemic further unearthed this significant worsening of mental health in children with heightened levels of anxiety, depression, loneliness, anger, and fatigue leading to an increase in the number of emergency room visits and inpatient hospitalizations. Art and narrative-based interventions are known to improve patient outcomes and are a crucial component of pediatric inpatient psychiatric care. We discuss the process of adoption of a novel therapeutic comic book that was developed for children admitted to the hospital in a psychiatric inpatient unit at Yale-New Haven Hospital. A Hero’s Journey, a 38-page zine, is a short booklet that was created to demystify the experience of hospitalization, provide scaffolding for skill-building, and promote interaction and socialization. The zine was administered to patients and subsequently, 19 interviews were done with healthcare providers. Using qualitative research methods, a thematic analysis was performed. Three main domains were identified. The main domains of themes were: 1) Implementing or rolling-out of the zine: what worked and what did not work during the process of rollout; 2) Optimizing: the zine was appropriate in length and content for the patient population at hand; 3) Anticipating: the zine has potential areas for growth and development. The zine is a wonderful resource. Yet its implementation faced many challenges including staffing shortages and time constraints. Some ways to overcome these are having a champion for the zine, educating each user on the content, using individual pages of the zine instead of the whole booklet, and exploring avenues for personalization

Austria: Heta Asset Resolution Restructuring, 2015

Hypo Alpe Adria (HAA) was Austria’s sixth-largest bank by assets at the time of the Global Financial Crisis (GFC) of 2007–2009. HAA pursued a growth strategy in southeastern Europe in the years preceding the GFC—emboldened by a liability guarantee from the Austrian state of Carinthia—which proved troublesome for HAA’s loan portfolio and led to large write-downs in autumn 2008. From December 2008 to April 2014, Austria provided EUR 5.8 billion in total capital injections—during which time the government nationalized HAA. Per European Commission (EC) authorization of State Aid, Austria had to submit a restructuring plan, which the EC approved in September 2013. The restructuring plan called for three parts: (1) the sale of HAA’s Austrian subsidiary, (2) the sale of HAA’s southeastern European network, and (3) the creation of an asset management vehicle, Heta Asset Resolution AG (Heta), to liquidate what remained. Heta faced ongoing challenges. In March 2015, the Financial Market Authority (FMA) issued a resolution decree for Heta after an asset quality review revealed a capital shortfall. The FMA imposed a temporary moratorium on Heta’s liabilities until May 2016 to provide an opportunity to value assets and deploy the bail-in tool under the Bank Recovery and Resolution Directive. Heta’s creditors challenged the use of bail-in, given Carinthia’s guarantee. In September 2016, Carinthia offered creditors zero-coupon bonds, resulting in a 10% haircut for senior creditors and a 55% haircut for junior creditors in 2016; however, over the following year, most creditors accepted a government offer to buy back their zero-coupon bonds with an additional 5% haircut. Because asset sales went better than expected, the FMA declared that the resolution of Heta was complete on December 21, 2021, two years ahead of schedule. Legacy senior creditors received additional compensation. The Austrian federal government had EUR 6.5 billion in net losses with regard to the recapitalization of HAA and later resolution of Heta; the Carinthian state also lost EUR 1.2 billion from its guarantee. The bail-in cost legacy creditors about EUR 2.1 billion

YPFS Lessons Learned Oral History Project: An Interview with Ádám Banai

The Yale Program on Financial Stability (YPFS) interviewed Ádám Banai regarding his time as an analyst and director of the National Bank of Hungary (Magyar Nemzeti Bank, or MNB) during the Global Financial Crisis (GFC) and in the subsequent era to date

Technology and the Global Economy

Interpreting individual heterogeneity in terms of probability theory has proved powerful in connecting behaviour at the individual and aggregate levels. Returning to Ricardo\u27s focus on comparative efficiency as a basis for international trade, much recent quantitative equilibrium modeling of the global economy builds on particular probabilistic assumptions about technology. We review these assumptions and how they deliver a unified framework underlying a wide range of static and dynamic equilibrium models

Trade and Domestic Distortions: The Case of Informality

We examine the effects of international trade in the presence of a set of domestic distortions giving rise to informality, a prevalent phenomenon in developing countries. In our quantitative model, the informal sector arises from burdensome taxes and regulations that are imperfectly enforced by the government. Consequently, smaller, less productive firms face fewer distortions than larger, more productive ones, potentially leading to substantial misallocation. We show that in settings with a large informal sector, the gains from trade are significantly amplified, as reductions in trade barriers imply a reallocation of resources from initially less distorted to more distorted firms. We confirm findings from earlier reduced-form studies that the informal sector mitigates the impact of negative labor demand shocks on unemployment. Nonetheless, the informal sector can exacerbate the adverse welfare effects of economic downturns, amplifying misallocation. Last, our research sheds light on the relationship between trade openness and cross-firm wage inequality