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Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as “high-risk” (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or “low-risk” (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somatic mutations detected at 6 months after IST predicted high-risk evolution.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is caused by inactivating somatic mutations in the UBA1 gene. Here, we characterize the immunological landscape of VEXAS syndrome by performing multi-omics single-cell RNA analysis, cytokine multiplex assays, and in vitro functional assays on patients’ peripheral blood. Our data reveals a broad immune system activation with upregulation of multiple inflammatory response pathways and proinflammatory cytokines. Unexpectedly, we find that monocytes have dysfunctional features irrespective of UBA1 mutation status, exhibiting impaired efferocytosis and blunted cytokine production in vitro. In contrast, UBA1 -mutated NK cells show an upregulation of the inflammation pathways and enhanced cytotoxicity. Within the lymphocyte subsets, predominantly UBA1 wild-type, we identify clonal expansion of effector memory CD8 + T cells and skewed B cell differentiation with loss of transitional B cells and expansion of plasmablasts. Thus, our analysis indicates that VEXAS syndrome is characterized by profound alterations in both adaptive and innate immune systems, accounting for the complex pathophysiology of the disease, and provides a basis to understand the marked clinical heterogeneity and variable disease course. VEXAS syndrome is a clinically heterogeneous inflammatory condition caused by mutations in the UBA1 gene. Here, by single cell transcriptomics on peripheral blood cells from VEXAS patients, the authors reveal innate and adaptive immune dysregulations irrespective of UBA1 mutations, including the presence of functionally impaired monocytes and clonal expansion of UBA1 wild-type effector memory B cells and plasmablasts.

Severe immune aplastic anemia is a fatal disease due to the destruction of marrow hematopoietic cells by cytotoxic lymphocytes, serving as a paradigm for marrow failure syndromes and autoimmune diseases. To better understand its pathophysiology, we apply advanced single cell methodologies, including mass cytometry, single-cell RNA, and TCR/BCR sequencing, to patient samples from a clinical trial of immunosuppression and growth factor stimulation. We observe opposing changes in the abundance of myeloid cells and T cells, with T cell clonal expansion dominated by effector memory cells. Therapy reduces and suppresses cytotoxic T cells, but new T cell clones emerge hindering robust hematopoietic recovery. Enhanced cell-cell interactions including between hematopoietic cells and immune cells, in particular evolving IFNG and IFNGR, are noted in patients and are suppressed post-therapy. Hematologic recovery occurs with increases in the progenitor rather than stem cells. Genetic predispositions linked to immune activation genes enhances cytotoxic T cell activity and crosstalk with target cells. The transcriptional phenotype of immune cells associated with severe aplastic anaemia (SAA) may change post immunotherapy. Here the authors analyse single cell transcriptomics of hematopoietic and immune cells from SAA patients and assess how these phenotypes change after treatment showing alterations in myeloid cells and TCR clonal abundance correlate with robustness of hematopoietic response.

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance. The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. Here the authors demonstrate that hematopoietic stem cells with short telomeres induced by mutations affecting telomerase complex genes undergo differentiation towards megakaryopoiesis through the activation of the IFI16-mediated interferon response.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a newly diagnosed syndrome comprising severe systemic inflammatory and hematological manifestations including myelodysplastic syndrome and plasma cell dyscrasia. Since its discovery four years ago, several groups have identified pleomorphic clinical phenotypes, but few effective medical therapies exist which include Janus Kinase (JAK) inhibitors, interleukin inhibitors (IL-1 and IL-6), and hypomethylating agents. Prospective trials are lacking at this time and most patients remain corticosteroid dependent. VEXAS has a high morbidity from frequent life threatening inflammatory symptoms and risk of progression to hematological malignancies and has an overall survival of 50% at 10 years. Allogeneic stem cell transplant (allo-HCT) is a curative option for this disease caused by somatic mutations in the UBA1 gene. Here we outline the role of allo-HCT in treating patients with VEXAS syndrome, highlighting the outcomes from several single-institution studies and case reports. Prospective trials will be required to precisely define the role of allo-HCT in the management of VEXAS syndrome.

Abstract Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67–533.70]) or NTM (HR, 29.09 [95% CI, 9.51–88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29–114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30–2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective. Patients with VEXAS syndrome are at increased risk for opportunistic infections, including Pneumocystis jirovecii (PJP), which are associated with increased mortality risk. Prophylaxis against PJP and herpes zoster may substantially lower infection rates of these organisms in patients with VEXAS.

The discovery of the genetic cause of an inflammatory disorder shows that, in winnowing down candidate variants obtained by DNA sequencing screens, geneticists have been (so to speak) throwing the baby out with the bath water.

Loneliness is a significant public health issue. The COVID-19 pandemic has resulted in lockdown measures limiting social contact. The UK public are worried about the impact of these measures on mental health outcomes. Understanding the prevalence and predictors of loneliness at this time is a priority issue for research. The study employed a cross-sectional online survey design. Baseline data collected between March 23rd and April 24th 2020 from UK adults in the COVID-19 Psychological Wellbeing Study were analysed (N = 1964, 18-87 years, M = 37.11, SD = 12.86, 70% female). Logistic regression analysis examined the influence of sociodemographic, social, health and COVID-19 specific factors on loneliness. The prevalence of loneliness was 27% (530/1964). Risk factors for loneliness were younger age group (OR: 4.67-5.31), being separated or divorced (OR: 2.29), scores meeting clinical criteria for depression (OR: 1.74), greater emotion regulation difficulties (OR: 1.04), and poor quality sleep due to the COVID-19 crisis (OR: 1.30). Higher levels of social support (OR: 0.92), being married/co-habiting (OR: 0.35) and living with a greater number of adults (OR: 0.87) were protective factors. Rates of loneliness during the initial phase of lockdown were high. Risk factors were not specific to the COVID-19 crisis. Findings suggest that supportive interventions to reduce loneliness should prioritise younger people and those with mental health symptoms. Improving emotion regulation and sleep quality, and increasing social support may be optimal initial targets to reduce the impact of COVID-19 regulations on mental health outcomes.

The COVID-19 pandemic has necessitated physical distancing which is expected to continue in some form for the foreseeable future. Physical distancing policies have increased reliance on digital forms of social connection and there are widespread concerns about social isolation and mental health in this context. This qualitative study sought to understand how loneliness was experienced during physical distancing in the initial national UK COVID-19 lockdown. Eight individuals who reported feeling lonely during the initial lockdown were interviewed in May 2020. Interviews were analysed using reflexive thematic analysis. Four main themes were identified: (1) Loss of in-person interaction causing loneliness, (2) Constrained freedom, (3) Challenging emotions, and (4) Coping with loneliness. The loss of in-person interaction contributed to feelings of loneliness and digital interaction was viewed as an insufficient alternative. Social freedom could be constrained by distancing policies and by social contacts, contributing to strained personal relationships and feelings of frustration as part of loneliness. Fluctuations in mood and difficult emotions were experienced alongside loneliness, and distraction and seeking reconnection were commonly reported methods of coping, although they were less accessible. These findings indicate that physical distancing measures can impact loneliness due to the limitations they impose on in-person social contact and the perceived insufficiency of digital contact as a substitute.