Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes.

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

Clinical presentation and natural history of Barth Syndrome: An overview.

Barth Syndrome is a rare X-linked disorder caused by pathogenic variants in the gene TAFAZZIN, which encodes for an enzyme involved in the remodeling of cardiolipin, a phospholipid primarily localized to the inner mitochondrial membrane. Barth Syndrome is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities, among other features. In this review, we will discuss the clinical presentation and natural history of Barth Syndrome, review key features of this disease, and introduce less common clinical associations. Recognition and understanding of the natural history of Barth Syndrome are important for ongoing patient management and developing endpoints for the demonstration of efficacy of new and emerging therapies.

Current approaches to diagnostic testing in von Willebrand Disease.

Von Willebrand Disease (VWD) is considered the most common inherited bleeding disorder. It has multiple subtypes and a primary symptom of mucocutaneous bleeding. Some researchers in this field speculate that inherited disorders of platelet function may be as common but underdiagnosed due to the difficulty of accessing testing. The diagnostic approach for this disease has evolved as new instruments and diagnostic testing have become available. The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing. The three main screening tests used in the diagnosis of VWD include von Willebrand Factor (VWF) antigen, platelet-dependent VWF activity, and factor VIII activity. Improvements in laboratory assays discussed include changes in how traditional assays are performed as well as the addition of new laboratory assays. The role of genetic testing and management of patients with borderline low von Willebrand factor are also discussed.

Vulnerability in Biomedical Research: A Historical Reflection and Practical Implications for HIV Cure-Related Research.

The concept of vulnerability in bioethics was first referenced in 1979, when the Belmont Report highlighted the need for special consideration of certain populations in the application of its general principles of respect for persons, beneficence, and justice in research with human participants. Since then, a body of literature has emerged regarding the content, status, and scope, as well as ethical and practical implications of vulnerability in biomedical research. The social history of HIV treatment development has at various points reflected and actively influenced bioethics' debate on vulnerability. In the late 1980s and early 1990s, people with AIDS activist groups drafted landmark patient empowerment manifestos like The Denver Principles, fighting to have greater involvement in the design and oversight of clinical trials related to HIV treatment, and in doing so, pushed against research ethics protocols created with the intention of protecting vulnerable populations. The determination of appropriate benefit/risk profiles in clinical trials was no longer limited to the purview of clinicians and scientists, but began to include the perspectives of people with HIV (PWH) and affected communities. In contemporary HIV cure-related research, where participants often risk health for no personal clinical benefit, the community's voiced motivations and objectives for participation continue to challenge population-based accounts of vulnerability. While the development of a framework for discussion and the establishment of clear regulatory requirements are necessary to support the practical and ethical conduct of research, they risk distraction from the fundamental value of voluntary participation and potentially overlook the unique history and perspectives of PWH in their participation in the quest toward an HIV cure.

Shades of grey: choice, control and capacity in alcohol-related brain damage.

Liaison psychiatrists have identified that conducting capacity assessments in general hospital patients with alcohol-related brain damage (ARBD) can be challenging. This educational article uses the fictitious case of a man with ARBD, alcohol dependence and significant self-neglect, focusing on assessment of his capacity to decide about moving into a care home on discharge. We provide an overview of clinical, legal and ethical literature relevant to decision-making and capacity assessment in individuals with ARBD, with the aim of guiding clinicians approaching complex capacity assessments.

Temporal and anatomic relationship between superficial and deep vein thromboses in hospitalized children.

BACKGROUND: Recent publications have increasingly demonstrated a link between superficial-vein thrombosis (SVT) and deep-vein thrombosis (DVT) in the adult population and have led to changes in SVT treatment considerations. A similar relationship between SVT and DVT in pediatric populations, however, is not currently well established. OBJECTIVES: We sought to evaluate the temporal and anatomic relationship between SVT and DVT among pediatric inpatients in order to determine to what degree SVT is associated with DVT. METHODS: We first retrospectively reviewed our institution's local prospective hospital-acquired VTE (HA-VTE) registry to identify all children (age 0-21 years, inclusive) admitted to Children's Hospital Colorado for more than 48 h between January 2012 and September 2017 who developed a DVT while hospitalized. We then reviewed each patient's electronic health record for evidence of SVT to identify SVT + DVT cases. Afterwards, we utilized a list of ICD codes to identify all patients during this time frame who developed an SVT and removed patients whom we previously identified as SVT + DVT cases to obtain the number of patients with isolated SVT. RESULTS: Of 59,910 patients admitted during the study period, 438 (0.7%) developed a thrombosis while hospitalized - 197 (0.3%) with isolated SVT, 161 (0.3%) with isolated DVT, and 80 (0.1%) with both SVT + DVT. These 80 SVT + DVT patients represent 33% of the 241 total DVT patients and 29% of the 277 total SVT patients. Of the 12 SVT + DVT patients in whom the SVT was diagnosed before the DVT, the subsequent DVT occurred within a mean of 6.4 (range 1-22) days and at the same anatomic site in 6 (50%). The age breakdown for this cohort was: 0 (0%) 0-1 months, 2 (17%) 1 month-2 years, 3 (25%) 2-12 years, 3 (25%) 12-16 years, and 4 (33%) 16-21 years. CONCLUSIONS: Our results indicate a temporal and anatomic relationship between SVT and DVT in hospitalized children, particularly those with central venous catheters.

Should Neonatologists Give Opinions Withdrawing Life-sustaining Treatment?

An infant has a massive intracranial hemorrhage. She is neurologically devastated and ventilator-dependent. The prognosis for pulmonary or neurologic recovery is bleak. The physicians and parents face a choice: withdraw the ventilator and allow her to die or perform a tracheotomy? The parents cling to hope for recovery. The physician must decide how blunt to be in communicating his own opinions and recommendations. Should the physician try to give just the facts? Or should he also make a recommendation based on his own values? In this article, experts in neonatology, decision-making, and bioethics discuss this situation and the choice that the physician faces.