Acquired aplastic anemia (aAA) is a non-malignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin in 22 patients. We found somatic mutations in sixteen patients (72.7%) with a median disease duration of 1 year; twelve (66.7%) were patients with pediatriconset aAA. Fifty-eight mutations in 51 unique genes were primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with 7 mutations. Only two mutations were in genes recurrently-mutated in MDS. Two patients had oligoclonal loss of HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B(p.N642H), CAMK2G(p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging― immune escape and increased proliferation. Our findings expand conceptual understanding of this non-neoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes, and for designing personalized treatment strategies.

Background: Trust in health care has been shown to influence health care utilization, perceptions of fair treatment, and health outcomes in the general population. The literature on trust in health care in individuals with a history of substance use disorder (SUD) is more limited, primarily examining the patient-provider relationship. Women seeking substance abuse treatment in community-based programs have higher rates of prior trauma and health disparities compared with male counterparts and the general population. With higher rates of prior trauma, this population is theoretically at high risk of decreased interpersonal trust and altered interpersonal relationships. Objective: This study sought to identify factors influencing trust in the health care system for women seeking substance abuse treatment in a community-based residential treatment program. Methods: Six client focus groups ( n = 30), 1 provider focus group ( n = 7), and 2 individual clinical administrator interviews ( n = 2) were conducted between November 2016 and August 2017. Focus groups and interviews were audio recorded and transcribed. Coding and coding reconciliation were conducted by 2 independent coders. Themes were extracted and analyzed from sorted and coded quotes. Results: Six themes emerged. Factors that influence trust in the health care system in this population include (1) prior experiences with diagnosis, treatment, and outcomes; (2) stigma of addiction; (3) payment and reimbursement structure; (4) patient rights and protections; (5) efficiency-driven care; and (6) the health care system's role in causing and/or enabling addiction. Conclusions: These themes demonstrate a general distrust of the health care system by women in this population. Distrust is influenced by a perception of a health care system providing care that is variable in quality, often stigmatizing, unaffordable, efficiency driven, and often influencing individuals’ SUD. This aligns with and extends prior literature around trust of health care in individuals with SUD. Future directions in research include formally assessing the impact of trust on health outcomes such as treatment entry and retention.

Summary The bone marrow failure syndromes (BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays (SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre. SNP-A were correlated with medical histories, haematopathology, cytogenetic and molecular data. To assess clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity (CN-LOH) was significantly more frequent in acquired aplastic anaemia (aAA) than in other BMFS (odds ratio 12.2, p<0.01). Homozygosity by descent was most common in congenital BMFS, frequently unmasking autosomal recessive mutations. Copy number variants (CNVs) were frequently polymorphic, and we identified CNVs enriched in neutropenia and aAA. Our results suggest that acquired CN-LOH is a general phenomenon in aAA that is probably mechanistically and prognostically distinct from typical CN-LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal haematopoiesis at diagnosis and at relapse.

Bone marrow failure syndromes (BMFS) are a diverse group of rare life-threatening blood disorders characterized by inadequate hematopoiesis, clonal evolution, and increased risk of hematologic malignancies. Despite recent advances in the understanding of the molecular pathogenesis of BMFS, the ability to diagnose, risk-stratify, and treat patients with these rare disorders remains limited. In both the acquired and the inherited BMFS, the major contributors to mortality are complications of progressive cytopenias, and, albeit to a lesser extent—transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia. The main predictor of malignant transformation is acquisition of clonal cytogenetic abnormalities. Recently, single nucleotide polymorphism arrays (SNP-A) were proposed as a promising tool for high resolution cytogenetic analysis and surveillance of early clonal changes in BMFS, however, their clinical utility still remains to be established. In 2009, the Comprehensive Bone Marrow Failure Center at the Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania incorporated high-density SNP-A as an adjunct to conventional cytogenetics in evaluation of BMFS patients. Here we present a comprehensive analysis of genetic changes in BMFS using 124 SNP-A from 91 patients, who were referred for evaluation of bone marrow failure. SNP-A genotyping was correlated with medical histories, hematopathology, cytogenetic, and molecular data. To assess the potential role of SNP-A in screening for early clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity (CN-LOH) was significantly more frequent in acquired aplastic anemia (aAA) than in other BMFS (OR 12.240, 95% CI 1.333-573.696, p<0.01). In contrast, acquired copy number alterations (CNAs) were more typical of MDS and unclassified BMFS. Extended tracts of homozygosity were common, frequently unmasking recessive loci in cases of inherited BMFS. Copy number variants (CNVs) were frequently polymorphic, and we identified several CNVs that are enriched in patients with aAA and neutropenia and may serve as disease modifiers. Clinical utilization analysis revealed that SNP-A can be helpful as an adjunct to conventional cytogenetics at the time of initial diagnosis (e.g. to identify regions of acquired CN-LOH and inherited homozygosity, acquired CNAs with a small clone size, and CNVs). Our longitudinal analysis showed that the likelihood of detecting a new acquired abnormality in a follow-up SNP-A was significantly higher in the setting of relapse than in the setting of stable disease (OR 27, 95% CI 1.23 to 808.54, p=0.035). Our results suggest that acquired CN-LOH is a general phenomenon in aAA, likely mechanistically and prognostically distinct from typical CN-LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal hematopoiesis at diagnosis and at relapse. Disclosures: No relevant conflicts of interest to declare.

Background: Women with a history of substance use disorder (SUD) constitute a unique population with gender-specific needs in treatment. Most notable is high rates of prior trauma and the need for a trauma-informed care framework. Given theoretical links between trauma and interpersonal trust, understanding quantitatively how trust may impact outcomes for women in this population requires confirmation of validity of existing psychometric instruments. Objective: This study sought to confirm reliability and construct validity of the Rotter Interpersonal Trust Scale, Wake Forest Trust in Physician Scale, and the Revised Health Care System Distrust Scale (RHCSDS) for use in women with a history of SUD seeking treatment in a community-based setting. Methods: A total of 301 participants were enrolled between August 2017 and March 2018 at an urban, community-based residential substance abuse treatment program in the mid-South. Participants were given an electronic survey containing questions about demographics/clinical characteristics, the Rotter, Wake Forest, and RHCSDS scales, Socially Desirable Response Five-Item Survey (SDRS-5), and the Adverse Childhood Experiences (ACEs) questionnaire. All participants also completed a modified protocol of the “Trust Game.” Statistical analysis was completed for each trust scale in regard to scale means and distribution, internal consistency, interscale correlation, and scale correlation to the ACE score. Results: Results confirm statistically significant ( P < .001) differences in global trust and trust of health care providers compared with general population samples in prior studies. Internal consistency of scales is comparable to reliability testing in prior studies (α > .70 for all scales). Interscale correlation between individual scales is statistically significant, with the strongest relationship between the 2 health care–specific scales ( r = −.740, P < .001). There was a weak, negative correlation between the ACE score and interpersonal trust ( r = −.135, P = .019). Individual scales do not have statistically significant correlation with “Trust Game” scores. Discussion: Findings suggest reliability and construct validity of scales for use in this population.