Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

Allogeneic hematopoietic stem cell transplantation as immunotherapy: B lymphocytes versus leukemia

Research described in this thesis focuses on the role of B lymphocytes in graft versus leukemia responses following allogeneic hematopoietic stem cell transplantation (HSCT) as treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) are myeloid malignancies with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is often applied as consolidation therapy, to induce a graft versus leukemia (GvL) immune response. However, this is a high-risk therapy with major complications, excluding many people for this treatment. The aim of this thesis was to study GvL immune-biology, because a better understanding of GvL immune responses will lay the foundation to develop less harmful, more effective therapies. We studied the role of B cells in GvL immune responses in patients with AML and MDS who were treated successfully with an allogeneic HSCT and found new targets for therapy and potent antibodies

Patients' and caregivers' views on conversations and shared decision making in diagnostic testing for Alzheimer's disease: The ABIDE project

Introduction This study aims to assess patients' and caregivers' views on and experiences with (1) decisions about diagnostic testing for Alzheimer's disease (AD) and (2) receiving test results. Methods We conducted separate focus groups with patients from three hospitals who underwent diagnostic testing for AD (N = 11) and their caregivers (N = 11). Audio recordings were transcribed verbatim and analyzed using MaxQDA. Results Patients and caregivers preferred and perceived active involvement in decision making, but the decision to initiate diagnostic testing seems to be made before the clinician-patient encounter. Patients and caregivers indicate that decisions are driven by a strong need to explain the patient's symptoms. They missed information on why different diagnostic tests were used, what the results of these tests were, and to what extent these results were (ab)normal. Discussion The decision-making process around diagnostic testing for AD and the information provision before and after diagnostic testing could be improved

Tumor Specific Glycosylated CD43 Is a Novel and Highly Specific Target for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Proteomic

An AML patient derived monoclonal antibody recognizes a unique CD43 epitope expressed on all myeloid leukemias and shows strong anti-tumor reactivity in vivo

Proteomic

Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice

Proteomic

Melanoma cells can be eliminated by sialylated CD43 x CD3 bispecific T cell engager formats in vitro and in vivo

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3 epsilon. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.Experimental cancer immunology and therap

Alignment of the CMS silicon strip tracker during stand-alone commissioning

The results of the CMS tracker alignment analysis are presented using the data from cosmic tracks, optical survey information, and the laser alignment system at the Tracker Integration Facility at CERN. During several months of operation in the spring and summer of 2007, about five million cosmic track events were collected with a partially active CMS Tracker. This allowed us to perform first alignment of the active silicon modules with the cosmic tracks using three different statistical approaches; validate the survey and laser alignment system performance; and test the stability of Tracker structures under various stresses and temperatures ranging from +15C to -15C. Comparison with simulation shows that the achieved alignment precision in the barrel part of the tracker leads to residual distributions similar to those obtained with a random misalignment of 50 (80) microns in the outer (inner) part of the barrel.Comment: 41 pages, 63 postscript figures, submitted to JINS