Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.     

Rosai dorfman disease — an unusual presentation: A case report

Rosai Dorfman Disease (Sinus Histiocytosis with massive lymphadenopathy) is a rare self-limiting histiocytic disorder of unknown etiology usually presenting with cervical lymphadenopathy and haematological abnormalities. Extra-nodal presentation is rare . This ease is such a rare presentation of Rosai Dorfman Disease.     

Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: transition rate to clinically definite multiple sclerosis

OBJECTIVE: To determine the long-term risk of developing clinically definite multiple sclerosis (CDMS) in patients with acute partial transverse myelitis (APTM) and normal cerebral magnetic resonance imaging (MRI) scans. METHODS: We retrospectively studied 30 consecutive patients with clinical evidence of APTM. Patients with symmetric severe acute transverse myelitis were considered to have complete transverse myelitis and were excluded. All patients underwent spinal and cerebral MRIs, 13 underwent cerebrospinal fluid analysis and 11 patients underwent evoked potential studies. Various other studies were performed to assess for connective tissue disease and causes of APTM other than demyelinating disease. RESULTS: After an average follow-up of 61 months, all laboratory and clinical evidence, including relapse history, indicated that three patients developed lesions on cerebral MRI and could be classified as CDMS by either Poser criteria (two patients) or MacDonald criteria (one patient). Relapses limited to the spinal cord seen clinically were seen in 14/30 (46.6%) patients. Oligoclonal bands were seen in 8/13 (62%) patients; one patient transitioned to CDMS. Unifocal lesions of the cord were seen in 19/30 (63%) patients, multifocal lesions were seen in 8/30 (27%) and 3/30 (10%) had negative MRIs. The three patients who converted to CDMS did so within five years of the onset of myelitis. CONCLUSION: APTM with normal cerebral MRI had a low rate of conversion to CDMS in this long-term study. To date, there have been only a few follow-up studies that have addressed this issue.     

“I may be essential but someone has to look after my kids”: women physicians and COVID-19

ObjectivesThis paper analyzes results from focus groups held with women physicians in British Columbia which explored questions around how gender norms and roles influenced their experiences during COVID-19.MethodsFour virtual focus groups were organized between July and September 2020. Participants (n = 27) were voluntarily recruited. Data were analyzed using applied thematic analysis.ResultsIn addition to the COVID-19-related changes experienced across the profession, women physicians faced distinct challenges related to an increase in unpaid care responsibilities, and often felt excluded from, and occasionally dismissed by, leadership. Women leaders often felt their contributions were unrecognized and undervalued. Participants drew strength from other women leaders, peer networks, and professional support, but these strategies were limited by unpaid care and emotional labour demands, which were identified as increasing risk of burnout.DiscussionEven though women physicians hold a degree of relative privilege, unpaid care work and gender norms contribute to distinct secondary effects of COVID-19. Women physicians link these to pre-pandemic assumptions (within families and communities) that women would absorb care deficits at their own cost. Health system leadership continues to reflect a masculine normative experience wherein the personal and professional are separated, and which devalues the emotional labour often associated with feminine leadership. The strategies participants employed to address negative impacts, while demonstrating resourcefulness and peer support, reflect individualistic responses to social-structural challenges. There is a need for greater recognition of women’s contributions at home and work, increased representation in decision-making, and practical supports such as childcare and counselling.     

Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis

Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.     

Right Medication,Right Dose,Right Patient,Right Time,and Right Route: How Do We Select the Right Patient-Controlled Analgesia (PCA) Device?

Patient safety related to medication infusion devices has received considerable attention recently. Critical adverse patient outcomes have resulted from misprogrammed delivery devices, inherent flaws in device design, and human error. A key strategy to improving patient safety is the development of an interdisciplinary team in product selection and the inclusion of registered nurses in the process. Such a process would include salient elements of each professional viewpoint and consider product impact on practice. No formal product selection guidelines exist which consider patient safety. This article outlines the process undertaken at University Health Network in the selection of its most recent patient-controlled analgesia device. Various available products were excluded from the selection process based on the interdisciplinary review.     

Ethical and scientific issues surrounding solid organ transplantation in HIV-positive patients: Absence of evidence is not evidence of absence.

End-stage liver disease is emerging as a leading cause of death among HIV-positive patients. Historically, an HIV diagnosis was a contraindication for a liver transplant; however, because of the efficacy of highly active antiretroviral therapy (HAART), HIV-positive patients have one-year, two-year, and three-year post-transplantation survival rates similar to that of HIV-negative patients. Based on this evidence, HIV-positive patients are now considered eligible for transplantation. However, newly emerging guidelines include the stipulation that HIV-positive patients must be on HAART to be placed on a waiting list for transplantation. The purpose of the present paper is to evaluate the scientific and ethical probity of requiring HIV-positive patients to be on HAART as a condition for being on a liver transplant waiting list. It is argued that the emphasis should be placed on the probability of post-transplantation HAART tolerance, and that concerns about pretransplantation HAART tolerance are of secondary importance.