Abstract
The verification of ASICs through simulation is critical to ensure their successful operation in particle physics detectors and to minimize the number of long and expensive production cycles ...required. Three radiation-tolerant ASICs (HCC, AMAC, and ABC) will perform the front-end readout, monitoring, and control of the ITk Strip charged-particle tracker for the ATLAS detector at the HL-LHC. The Python-based cocotb verification framework is used to design sophisticated tests with contributions from ASIC verification non-experts and students. The verification program includes interactions between multiple ASICs, realistic data flows, operational stress tests, and a focus on mitigation of disruptive Single Event Effects due to radiation.
Abstract
For the high-luminosity phase of the LHC, which begins operation in 2029, the current ATLAS inner detector will be replaced by a new tracker, the ITk. The ITk consists of two subdetectors, ...one using pixels and the second using silicon-strips, the ITk Strip detector. The HCC and AMAC chip are radiation-tolerant ASICs that contribute to the front-end readout, monitoring and control of the ITk Strip subsystem. Low temperature startups and low internal regulated voltage tests have been performed on HCC and AMAC to guarantee their reliability at edge operation conditions. In addition, to ensure the operation of the HCC and AMAC under a radiation heavy environment, gamma and x-ray irradiation campaigns were conducted. HCC and AMAC successfully operated at harsher conditions than the ones expected during the HL-LHC.
Abstract
The high-luminosity upgrade to the LHC requires a new silicon-strip charged-particle tracking detector for ATLAS. The HCC (Hybrid Controller Chip) is one of three new radiation-tolerant ...ASICs for this silicon-strip detector. As the interface to multiple binary readout ASICs, the HCC is responsible for buffering and forwarding control signals and readout requests to them as well as serializing their readout data into a 640 Mbps output. All HCCs undergo a suite of tests to verify their analog and digital functionality. The yield for the HCC exceeds the 90% target for production.
Abstract
For the high-luminosity upgrade to the LHC, the ATLAS Inner Detector will be replaced by an all-silicon tracker (ITk) consisting of two systems: pixels and strips. HCC and AMAC are ITk Strip ...ASICs vital for performing the system readout, monitoring, and control. To ensure these ASICs will successfully operate in the high-radiation environment of the HL-LHC, they need to be tested for radiation tolerance, and tests have been performed using both heavy ions and protons. The ASIC designs were shown to protect against single event effects due to radiation.
Summary
Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)‐matched ...allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA‐haploidentical HCT recipients who receive post‐transplant cyclophosphamide (PTCy)‐based graft‐versus‐host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin‐based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment‐related mortality hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13–4⋅07; P = 0⋅002 and inferior 2‐year overall survival (HR 1⋅65, 99% CI 1⋅11–2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long‐term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long‐term outcomes in such patients.
Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and ...posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy n = 545: hazard ratio HR, 50.3; SibCy n = 279: HR, 47.7; SibCNI n = 1065: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.
•PTCy increased the risk of CMV infection in seropositive Haplo and Sib HCT recipients relative to Sib HCT with conventional GVHD prophylaxis.•CMV infection was associated with higher chronic GVHD in PTCy recipients, potentially negating the protective effect of PTCy.
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Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and ...mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio rUPCR); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.
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•A consensus panel of transplantation-associated thrombotic microangiopathy (TA-TMA) experts was convened by international hematopoietic cell transplantation societies.•Modified Jodele diagnostic criteria with definitions of cytopenia were agreed upon as standard.•TA-TMA should be stratified using high-risk features associated with death.•Elevated sC5b-9, lactate dehydrogenase, proteinuria, multiorgan dysfunction, and concurrent acute graft-versus-host disease/infection are high-risk features.
Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated ...pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.
Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. ...We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ⩾2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders). All groups displayed short stature by mean height-adjusted Z-score (HAZ) before (-1.29) and after HSCT (HAZ -1.38, P=0.47). After HSCT, younger children with HLH/XLP grew better (HAZ -3.41 vs -1.65, P=0.006), whereas older subjects had decline in growth (HAZ -0.8 vs -1.01, P=0.06). Those with steroid therapy beyond standard GVHD prophylaxis were shorter than those without (P 0.04). After HSCT, older subjects with HLH/XLP became thinner with a mean body mass index (BMI) Z-score of 1.20 vs 0.64, P=0.02, and similar to metabolic/genetic disorders (BMI-Z= 0.59 vs -0.99, P<0.001). BMI increased among younger children in these same groups. Thyroid function was abnormal in 24% (18/76). 25-OH vitamin D levels were insufficient in 73% (49/65), with low bone mineral density in 8 of 19 evaluable subjects. Despite RIC, children and young adults still have significant late endocrine effects. Further research is required to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols.
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