Person:

Young, Grace

Abstract The importance of 1,5‐anhydroglucitol (1,5‐AG) as an intermediate biomarker for diabetic pregnancy is multi‐fold: (1) it serves as a reliable indicator of moderate‐level glycemic control, especially during early gestation; (2) it has been associated with increased risk of diabetes, independent of HbA1c and fasting glucose; and (3) it is an independent risk factor for the development of eclampsia during pregnancy. However, the clinical use of this biomarker during pregnancy has been underutilized due to physiological changes in glomerular filtration rate, plasma volume, and other hemodynamic parameters which have been hypothesized to bias gestational serum 1,5‐AG concentrations. Here, we develop an in‐silico model of gestational 1,5‐AG by combining pre‐existing physiological data in the literature with a two‐compartment mathematical model, building off of a previous kinetic model described by Stickle and Turk (1997) Am. J. Physiol., 273, E821. Our model quantitatively characterizes how renal and hemodynamic factors impact measured 1,5‐AG during normal pregnancy and during pregnancy with gestational diabetes and diabetes mellitus. During both normal and diabetic pregnancy, we find that a simple two‐compartment model of 1,5‐AG kinetics, with all parameters but reabsorption fraction adjusted for time in pregnancy, efficiently models 1,5‐AG kinetics throughout the first two trimesters. Allowing reabsorption fraction to decrease after 25 weeks permits parameters closer to expected physiological values during the last trimester. Our quantitative model of 1,5‐AG confirms the involvement of hypothesized renal and hemodynamic mechanisms during pregnancy, clarifying the expected trends in 1,5‐AG to aid clinical interpretation. Further research and data may elucidate biological changes during the third trimester that account for the drop in 1,5‐AG concentrations, and clarify physiological differences between diabetes subtypes during pregnancy.

Melanoma is the most lethal of skin cancers, in part because of its proclivity for rapid and distant metastasis. It is also potentially the most neurotropic cancer in terms of probability of CNS metastasis from the primary lesion. Despite surgical resection and radiotherapy, prognosis remains guarded for patients with brain metastases. Over the past five years, a new domain of personalized therapy has emerged for advanced melanoma patients with the introduction of BRAF and other MAP kinase pathway inhibitors, immunotherapy, and combinatory therapeutic strategies. By targeting critical cellular signaling pathways and unleashing the adaptive immune response against tumor antigens, a subset of melanoma patients have demonstrated remarkable responses to these treatments. Over time, acquired resistance to these modalities inexorably develops, providing new challenges to overcome. We review the rapidly evolving terrain for intracranial melanoma treatment, address likely and potential mechanisms of resistance, as well as evaluate promising future therapeutic approaches currently under clinical investigation.

ABSTRACT Background:: Longitudinal clinical experiences are a common component of undergraduate medical curricula, yet these programs have not been systematically characterized in US medical schools. Objective:: Our study sought to identify and characterize longitudinal clinical programs (LCPs) in US medical schools and measure associations between programs’ structures and goals. Design:: Using a mixed-methods approach, we conducted a secondary analysis of data from publicly available websites. We conducted a systematic keyword search of the websites of 137 LCME-accredited US medical schools to identify LCPs. We included programs with student–patient interactions of at least six months. We categorized programs using qualitative thematic analysis and compared associations between program structures and goals. Results:: We identified 98 LCPs in 69 schools. Half (52.0%) of LCPs occurred during the core clinical year. Program structures included ‘clinic attachments’ (50.0%), ‘longitudinal integrated clerkships’ (26.5%), and ‘patient attachments’ (20.4%). We identified goals in 89 programs, including ‘exposing students to specific topics, patient demographics, or practice settings’ (78.7%); ‘clinical or professional skill development’ (65.2%); and ‘understanding the patient experience’ (19.1%). Patient attachments were associated with ‘exposure to specific patient demographics’ (P = .04) and ‘understanding the patient experience’ (P = .03). Pre-clinical programs were associated with clinical skills development (P = .01). Conclusions:: Our study identifies the scope and nature of LCPs in US medical schools. Understanding connections between educational structures and goals may guide program design and research investigations of educational processes and outcomes.