Safety and efficacy of SARS-CoV-2 vaccination in patients with immune thrombocytopenia:A two-centre review

Multiple studies have reported immune thrombocytopenia (ITP) relapse following SARS-CoV-2 vaccination, however baseline ITP relapse rate and antibody response to vaccination are not known. Patients with ITP who received at least one of the first three SARS-CoV-2 vaccination doses were included in the study. One hundred and twenty-four patients met the inclusion criteria. Relapse rate was 4.2% following a first vaccine dose, 9.1% after a second and 2.9% after a third; baseline relapse rate was 7.6%. Ninety-four per cent of patients who received three vaccine doses developed a clinical antibody response. SARS-CoV-2 vaccination appears to be safe and effective in patients with ITP.</p

Thrombosis, major bleeding, and survival in COVID-19 supported by VV- ECMO in the first vs second wave- multicentre observational study in the UK

BACKGROUND: Bleeding and thrombosis are major complications of veno-venous extracorporeal membrane (VV-ECMO). OBJECTIVES: To assess thrombosis, major bleeding (MB) and 180-day in patients supported by VV-ECMO between first (1st March-31st May 2020) and second (1st June 2020-30th June 2021) waves of the COVID-19 pandemic. PATIENTS/METHODS: Observational study of 309 consecutive patients (≥18years) with severe COVID-19 supported by VV-ECMO in four nationally commissioned ECMO centres, UK. RESULTS: Median age was 48 (19-75)years and 70.6% were male. Probabilities of survival, thrombosis, and MB at 180 days in the overall cohort were 62.5% (193/309), 39.8%(123/309) and 30%(93/309). In multivariate analysis, age >55 years (HR 2.29 [1.33-3.93],p=0.003) and elevated creatinine (HR 1.91 [1.19-3.08],p=0.008) were associated with increased mortality. Corrected for duration of VV-ECMO support, arterial thrombosis alone (HR 3.0 [95% CI1.5-5.9], P= 0.002) or circuit thrombosis alone (HR 3.9 [95% 2.4-6.3], P<0.001), but not venous thrombosis, increased mortality. MB during ECMO had 3-fold risk (95% CI 2.6-5.8, P<0.001) of mortality. The first wave cohort had more males (76.7% vs 64%, p=0.014), higher 180-day survival (71.1% vs 53.3% p=0.003), more venous thrombosis alone (46.4% vs 29.2%, p=0.02) and lower circuit thrombosis (9.2% vs 28.1%, p<0.001). The second wave cohort received more steroids (121/150 [80.6%] vs 86/159 [54.1%], p<0.0001) and Tocilizumab (20/150 [13.3%] vs 4/159 [2.5%] p=0.005). CONCLUSIONS: MB and thrombosis are frequent complications in patients on VV-ECMO and significantly increase mortality. Arterial thrombosis alone or circuit thrombosis alone increased mortality whilst venous thrombosis alone had no effect. MB during ECMO support increased mortality 3.9-fold

Not Just Efficiency: Insolvency Law in the EU and Its Political Dimension

Certain insolvency law rules, like creditors’ priorities and set-off rights, have a distributive impact on creditors. Distributional rules reflect the hierarchies of values and interests in each jurisdiction and, as a result, have high political relevance and pose an obstacle to reforming the EU Insolvency Regulation. This paper will show the difficulty of reform by addressing two alternative options to regulate cross-border insolvencies in the European Union. The first one is the ‘choice model’, under which companies can select the insolvency law they prefer. Although such a model would allow distressed firms to select the most efficient insolvency law, it would also displace Member States’ power to protect local constituencies. The choice model therefore produces negative externalities and raises legitimacy concerns. The opposite solution is full harmonisation of insolvency law at EU level, including distributional rules. Full harmonisation would have the advantage of internalising all externalities produced by cross-border insolvencies. However, the EU legislative process, which is still based on negotiations between states, is not apt to decide on distributive insolvency rules; additionally, if harmonisation includes such rules, it will indirectly modify national social security strategies and equilibria. This debate shows that the choice regarding power allocation over bankruptcies in the EU depends on the progress of European integration and is mainly a matter of political legitimacy, not only of efficiency

A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. Methods We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Results Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95 % CI = 0.96–0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Conclusions Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome

Evidence for B cell exhaustion in chronic graft-versus-host disease

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21− B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21− B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively; p < 0.01). Compared with naïve (CD27−CD21+) and classical memory (CD27+CD21+) B cells, CD19+CD21− B cells in cGvHD were CD10 negative, CD27 negative and CD20hi, and exhibited features of exhaustion, including increased expression of multiple inhibitory receptors such as FCRL4, CD22, CD85J, and altered expression of chemokine and adhesion molecules such as CD11c, CXCR3, CCR7, and CD62L. Moreover, CD21− B cells in cGvHD patients were functionally exhausted and displayed poor proliferative response and calcium mobilization in response to B-cell receptor triggering and CD40 ligation. Finally, the frequencies of circulating CD21− B cells correlated with cGvHD severity in patients after HSCT. Our study further characterizes B cells in chronic cGVHD and supports the use of CD21−CD27−CD10− B cell frequencies as a biomarker of disease severity

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Understanding the biological and clinical impact ofcopy number aberrations (CNA)for the development of precision therapies in cancer remains anunmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNAconferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although severalgenes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MMpatient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapystrategies in multiple myeloma and other types of cancer

Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover