Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult.

Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

Vascular anatomical considerations and clinical decision making during insertion of the Avalon® Elite Dual Lumen single-site veno-venous ECMO cannula in children weighing less than 20 kg.

The correct selection and placement of a single-site Avalon® Elite Dual Lumen Cannula for veno-venous extracorporeal membrane oxygenation (ECMO) in children weighing less than 20 kg is dependent on both the mechanical characteristics of the catheter, including length and diameter, as well as the unique vascular anatomic considerations of the patient. This manuscript describes the development of a clinical strategy, over a four-year period from 2012-2016, for cannula selection to reduce the risk of migration and malposition in 20 critically ill children weighing less than 20 kg who presented for veno-venous ECMO.

One-way valve malfunction in an extracorporeal membrane oxygenation priming circuit.

Developing technologies have changed both the components and the management style when extracorporeal membrane oxygenation (ECMO) is used to support critically ill cardiac and respiratory patients. The Cardiohelp system is a small, portable extracorporeal system just recently available within the United States. Manufacturing standards and quality processes have made mechanical failure and malfunction of extracorporeal components less common; however, there is still potential for mechanical failure or component malfunction before or during extracorporeal support. This case review describes the malfunction of a Retroguard unidirectional flow valve integrated into the priming setup of a Cardiohelp system during the priming process.

Neonatal extracorporeal membrane oxygenation devices, techniques and team roles: 2011 survey results of the United States' Extracorporeal Life Support Organization centers.

In early 2011, surveys of active Extracorporeal Life Support Organization (ELSO) centers within the United States were conducted by electronic mail regarding neonatal Extracorporeal Membrane Oxygenation (ECMO) equipment and professional staff. Seventy-four of 111 (67%) U.S. centers listed in the ELSO directory as neonatal centers responded to the survey. Of the responding centers, 53% routinely used roller pumps for neonatal ECMO, 15% reported using centrifugal pumps and 32% reported using a combination of both. Of the centers using centrifugal pumps, 51% reported that they do not use a compliance bladder in the circuit. The majority (95%) of roller pump users reported using a compliance bladder and 97% reported using Tygon" S-97-E tubing in the raceway of their ECMO circuits. Silicone membrane oxygenators were reportedly used by 25% of the respondents, 5% reported using micro-porous hollow fiber oxygenators (MPHF), 70% reported using polymethylpentene (PMP) hollow fiber oxygenators and 5% reported using a combination of the different types. Some form of in-line blood monitoring was used by 88% of the responding centers and 63% of responding centers reported using a circuit surface coating. Anticoagulation monitoring via the activated clotting time (ACT) was reported by 100% of the reporting centers. The use of extracorporeal cardiopulmonary resuscitation (ECPR) was reported by 53% of the responding centers with 82% of those centers using a crystalloid primed circuit to initiate ECPR. A cooling protocol was used by 77% of the centers which have an ECPR program. When these data are compared with surveys from 2002 and 2008 it shows that the use of silicone membrane oxygenators continues to decline, the use of centrifugal pumps continues to increase and ECMO personnel continues to be comprised of multidisciplinary groups of dedicated allied health care professionals.

Improving perceptions of empathy in patients undergoing low-yield computerized tomographic imaging in the emergency department.

OBJECTIVE: We assessed emergency department (ED) patient perceptions of how physicians can improve their language to determine patient preferences for 11 phrases to enhance physician empathy toward the goal of reducing low-value advanced imaging. METHODS: Multi-center survey study of low-risk ED patients undergoing computerized tomography (CT) scanning. RESULTS: We enroled 305 participants across nine sites. The statement "I have carefully considered what you told me about what brought you here today" was most frequently rated as important (88%). The statement "I have thought about the cost of your medical care to you today" was least frequently rated as important (59%). Participants preferred statements indicating physicians had considered their "vital signs and physical examination" (86%), "past medical history" (84%), and "what prior research tells me about your condition" (79%). Participants also valued statements conveying risks of testing, including potential kidney injury (78%) and radiation (77%). CONCLUSION: The majority of phrases were identified as important. Participants preferred statements conveying cognitive reassurance, medical knowledge and risks of testing. PRACTICE IMPLICATIONS: Our findings suggest specific phrases have the potential to enhance ED patient perceptions of physician empathy. Further research is needed to determine whether statements to convey empathy affect diagnostic testing rates.

Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.