Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. The disease typically presents in young boys and adolescent boys. Allogeneic bone marrow transplantation has been used to halt progression of the disease. However, many patients lack suitable HLA- matched related donors and must rely on unmatched donors for a source of stem cells. The purpose of this study was to evaluate outcomes of unrelated donor umbilical cord blood transplantation after chemotherapy-based myeloablative conditioning and retrospectively determine if baseline studies correlate and help predict outcome. Between November 22, 1996, and November 3, 2005, 12 boys with X-linked ALD who lacked HL- matched related donors were referred to Duke University Medical Center for transplantation. These children were conditioned with myeloablative therapy including busulfan, cyclophosphamide, and antithymocyte globulin before receiving umbilical cord-blood transplants from unrelated donors. Baseline studies of neurophysiologic, neuroimaging, and neurodevelopmental status were performed and patients were subsequently evaluated for survival, engraftment, graft-versus-host disease, and neurodevelopmental outcomes. A substudy evaluated whether baseline neuroimaging and neurophysiologic studies correlated with cognitive and motor function and if these studies were predictive of posttransplantation outcomes. The umbilical cord blood grafts had normal levels of very long chain fatty acids. They delivered a median of 6.98 x 10(7) nucleated cells per kilogram of recipient body weight and were discordant for up to 4 of 6 HLA markers. Neutrophil engraftment occurred at a median of 22.9 days after transplantation. Three patients had grade II-IV acute graft-versus-host disease; 2 had extensive chronic graft-versus-host disease. Cumulative incidence of overall survival of the group at 6 months is 66.7% (95% confidence interval 39.9-93.3%). Median follow-up was 3.3 years (range 12 days to 6.3 years). As previously reported with bone marrow transplantation, symptomatic patients faired poorly with lower survival and rapid deterioration of neurologic function. This study included 3 patients transplanted at a very young age (2.6-3.5 years) before the onset of clinical symptoms who continue to develop at a normal rate for 3-5 years posttransplant. Although baseline Loes scores correlated with cognitive and motor outcome, neurophysiologic studies failed to show statistically significant differences. Transplantation of boys with X-linked ALD using partial HLA-matched umbilical cord blood yields similar results to those previously reported after bone marrow transplantation. Superior outcomes were seen in neurologically asymptomatic boys less than 3.5 years of age at the time of transplantation. Baseline Loes scores were a strong predictor of cognitive and motor outcome.     

A structural characterization of shortcut features for prediction

European Journal of Epidemiology - With the rising use of machine learning for healthcare applications, practitioners are increasingly confronted with the limitations of prediction models that are...     

Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.     

The implications for europe of revised FDA guidelines for clinical trials with anti-infective agents

This article summarizes the current collaborative effort between the US Food und Drug Administration and the Infectious Diseases Society of America for the purpose of generating new General and Disease/Organism Specific Guidelines for the evaluation of anti-infective agents. Examples of proposed changes from draft documents are presented. The final documents may assist European colleagues in their efforts to establish a standardized new drug registration process by 1992. An area of mutual interest is the acceptability of safety and efficacy data from international clinical trials. In the interest of human and financial economies, both US and European Guidelines need to clarify the conditions, or criteria, for the conduct of valid off-shore clinical trials.     

A sequential chart for the audit-based evaluation of screening mammogram interpretation

RATIONALE AND OBJECTIVES: Auditing has received much attention recently as a method for radiologists to use to evaluate their interpretation of screening mammograms. U.S. Food and Drug Administration regulations require that some sort of audit be in place before a mammography screening facility can receive accreditation. Auditing presents a unique opportunity to monitor accuracy continually and identify problems early. Audit data present unique challenges, however, and appropriate methods must be used to control the risk of errors. MATERIALS AND METHODS: This article introduces a simple method for the task of deciding if a radiologist yields an acceptable positive predictive value based on audit. The method is based on "sequential" decision-making techniques that have found wide application in quality control problems. These techniques are developed for diagnostic radiology and embodied in an easy-to-use decision-making chart. RESULTS: Several examples, based on audit data from actual mammography facilities, provide insights into the use of these charts and the influence of (a) the selection of standards, (b) the selection of error risks, and (c) radiologist variability. The examples also serve to demonstrate another important property of this method--that is, it specifies the minimum amount of data that has to be collected before any decision can reliably be made. CONCLUSION: The chart presented in this article provides a method by which audit data can be used objectively to evaluate the accuracy of screening mammogram interpretation. The method controls the risk of either falsely accepting an unqualified radiologist or falsely rejecting a qualified radiologist. It should be a useful tool to radiologists who must evaluate their own practices.     

Strategies for improving power in diagnostic radiology research.

Research studies in diagnostic radiology often compare the diagnostic abilities of two imaging techniques. The "power" of such studies is the probability that they will detect a difference in abilities of a certain amount when, indeed, such a difference does exist. This article outlines several strategies that can be used to assess and improve the power of radiologic diagnostic studies. These strategies include selection of cases and controls, matching, use of one-tailed tests, selection of significance level, and choice of sample size.