Faculty Bibliography

BACKGROUND:To address financial barriers that limit access to genomic profiling and precision medicine, philanthropy supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system (CNS) tumors. METHODS:Tumor DNA or CSF-derived circulating tumor DNA (CSF ctDNA) was analyzed using the MSK-IMPACT assay, supplemented by targeted RNA panel sequencing in select cases. Results were returned to the patients/families and treating oncologists. RESULTS:63 patients from 11 countries had successful MSK-IMPACT testing. The results provided clinically relevant new diagnostic or prognostic information in 41% and 38% of solid and CNS tumor patients, respectively. Potentially therapeutically actionable alterations were identified in 44% of pediatric solid tumor and 21% of pediatric CSF ctDNA samples, respectively. Four patients subsequently received molecularly guided therapy, resulting in partial responses in two and prolonged stable disease in one. Serial tumor and CSF sampling identified resistance mutations in two patients, informing additional molecular targeted therapy recommendations. CONCLUSIONS:The Make-an-IMPACT program provided global access to state-of-the-art tumor and CSF genomic profiling across a diverse cohort of pediatric cancer patients, providing clinically relevant and actionable diagnostic, prognostic and therapeutic information reported in real time to patients and local physicians.

IMPORTANCE/UNASSIGNED:The rise in chatbot health advice (CHA) studies is accompanied by heterogeneity in reporting standards, impacting their interpretability. OBJECTIVE/UNASSIGNED:To provide reporting recommendations for studies evaluating the performance of generative artificial intelligence (AI)-driven chatbots when summarizing clinical evidence and providing health advice. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:CHART was developed in several phases after performing a comprehensive systematic review to identify variation in the conduct, reporting, and methodology in CHA studies. Findings from the review were used to develop a draft checklist that was revised through an international, multidisciplinary modified asynchronous Delphi consensus process of 531 stakeholders, 3 synchronous panel consensus meetings of 48 stakeholders, and subsequent pilot testing of the checklist. RESULTS/UNASSIGNED:CHART includes 12 items and 39 subitems to promote transparent and comprehensive reporting of CHA studies. These include title (subitem 1a), abstract or summary (subitem 1b), background (subitems 2ab), model identifiers (subitem 3ab), model details (subitems 4abc), prompt engineering (subitems 5ab), query strategy (subitems 6abcd), performance evaluation (subitems 7ab), sample size (subitem 8), data analysis (subitem 9a), results (subitems 10abc), discussion (subitems 11abc), disclosures (subitem 12a), funding (subitem 12b), ethics (subitem 12c), protocol (subitem 12d), and data availability (subitem 12e). CONCLUSIONS AND RELEVANCE/UNASSIGNED:The CHART checklist and corresponding methodological diagram were designed to support key stakeholders including clinicians, researchers, editors, peer reviewers, and readers in reporting, understanding, and interpreting the findings of CHA studies.

This article looks at the current state of aneurysm risk modeling, exploring the limitations of linear measurement. It reviews articles using Food and Drug Administration (FDA)-approved artificial intelligence-driven volumetric measurement tools both for evaluating potential aneurysm growth in patients being managed conservatively as well as in assessing morphologic change prerupture and postrupture. The challenges of defining the aneurysm boundary are explored, and a novel definition of aneurysm/parent artery interface is proposed.

Imaging follow-up is an established component of intracranial aneurysm management that allows ongoing assessment of rupture risk and timely intervention to maintain protection from bleeding. Yet the frequency, duration, and imaging modality for follow-up vary widely. This review outlines contemporary imaging techniques and practice for follow-up of treated and untreated aneurysms, highlighting existing knowledge gaps and technical limitations that limit standardization. Updated evidence on the expected evolution and long-term outcome of common treatment strategies is presented to guide accurate reporting of radiological outcome after treatment and considerations regarding follow-up regimen.

OBJECTIVE:This study was undertaken to investigate diagnostic delay in adolescent onset focal epilepsy, including reasons for longer delays and associated morbidities. METHODS:Secondary analysis was done using enrollment data from the Human Epilepsy Project, a multi-institutional cohort including 34 sites in the USA, Canada, Finland, Austria, and Australia (2012-2017). Participants were aged 11-64 years at enrollment and within 4 months of treatment initiation for newly diagnosed focal epilepsy. Participants with seizure onset at age ≤ 21 years were evaluated. Data included seizure diaries documenting onset, frequency, and characteristics of seizures, reasons for diagnostic delays, and prediagnosis morbidities, including injuries, suicidal ideation, and self-injurious behaviors. RESULTS: = 7.04, p = .008). SIGNIFICANCE/CONCLUSIONS:This study highlights significant delays in diagnosing adolescent onset focal epilepsy, especially in cases with nonmotor seizures. These delays, often due to lack of recognition by patients and health care providers, are linked to more frequent seizures, higher injury rates, and increased suicidal ideation and self-injury. Early recognition and diagnosis may mitigate adverse outcomes and improve quality of life for adolescents with epilepsy.

Brain death/death by neurologic criteria (BD/DNC) is accepted as legal death throughout much of the world. The World Brain Death Project and a subsequent review of the literature through 2023 highlighted several medicolegal controversies related to BD/DNC in Canada, the United Kingdom, and the United States but did not discuss medicolegal controversies related to BD/DNC in low- and middle-income countries, such as India. Although the Transplantation of Human Organs Act of 1994 acknowledged BD/DNC as death in India, BD/DNC evaluations are not always completed when BD/DNC is suspected. This has been attributed to lack of awareness/acceptance by medical professionals, lack of public awareness/acceptance of BD/DNC, communication challenges, fear, time limitations, and the inclusion of BD/DNC in organ donation law (but not general law). There has been a gradual rise in the number of donations after BD/DNC (a correlate for the number of BD/DNC determinations) in southern and western states, but the number of donations after BD/DNC has decreased in the southwestern state of Kerala in the setting of recent medicolegal controversies. This article reviews the history of BD/DNC determination in India as a whole, then describes the recent medicolegal controversies related to BD/DNC in the state of Kerala. Finally, these controversies are contextualized relative to the aforementioned controversies in high-income countries. Three key international themes of medicolegal controversies related to BD/DNC are regulation, religion, and resource allocation. The global neurocritical care community must advocate for consistency and accuracy in BD/DNC determination and collaborate with legal and policy experts to develop means to mitigate these challenges through revisions to the law, standardization of practice and policies, education, and communication.

The loss of maternal UBE3A causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel UBE3A^L734S variant that is not present in two neurotypical siblings. The UBE3A^L734S variant was confirmed to be maternally inherited, and the affected individuals exhibited early global developmental delay, ongoing learning difficulties, and autistic features. Their phenotypes were inconsistent with Angelman syndrome. Biochemical characterization showed the UBE3A^L734S variant causes a dramatic increase in the activity of the UBE3A enzyme, suggesting that a gain in UBE3A activity is the driver of neurodevelopmental disease. Our observations document an emerging class of neurodevelopmental disorders caused by gain-of-function mutations in UBE3A.

Although the concept of treating cerebral aneurysms by filling the sac from the inside (endosaccular) started many years ago first with detachable balloons and then coils, the use of a single metallic resheathable device acting as a flow disruptor is a much more recent innovation. The most studied device among these is certainly the WEB, which became part of standard clinical practice for treatment of wide-neck bifurcation aneurysms. This study reviews the most important features of the WEB device with a short summary of the most important literature. A small section at the end reviews also other endosaccular devices.