Partnerships to Care for Our Patients and Communities During COVID-19.

The Coronavirus disease 2019 (COVID-19) pandemic forced not only rapid changes in how clinical care and educational programs are delivered but also challenged academic medical centers (AMCs) like never before. The pandemic made clear the need to have coordinated action based on shared data and shared resources to meet the needs of patients, learners, and communities. Family medicine departments across the country have been key partners in AMCs' responses. The Duke Department of Family Medicine and Community Health (FMCH) was involved in many aspects of Duke University's and Health System's responses, including leadership contributions in delivering employee health and student health services. The pandemic also surfaced the biological and social interactions that reveal underlying socioeconomic inequalities, for which family medicine has advocated since its inception. Key to success was the department's ability to integrate "horizontally" with the broader community, thereby accelerating the institution's response to the pandemic.

Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses.

The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze-fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.

Biodegradable Gold Nanoclusters with Improved Excretion Due to pH-Triggered Hydrophobic-to-Hydrophilic Transition.

Gold is a highly useful nanomaterial for many clinical applications, but its poor biodegradability can impair long-term physiological clearance. Large gold nanoparticles (∼10-200 nm), such as those required for long blood circulation times and appreciable tumor localization, often exhibit little to no dissolution and excretion. This can be improved by incorporating small gold particles within a larger entity, but elimination may still be protracted due to incomplete dispersion of gold. The present study describes a novel gold nanoparticle formulation capable of environmentally triggered decomposition. Ultrasmall gold nanoparticles are coated with thiolated dextran, and hydrophobic acetal groups are installed through direct covalent modification of the dextran. This hydrophobic exterior allows gold to be densely packed within ∼150 nm polymeric micelles. Upon exposure to an acidic environment, the acetal groups are cleaved and the gold nanoparticles become highly water-soluble, leading to destabilization of the micelle. Within 24 h, the ultrasmall water-soluble gold particles are released from the micelle and readily dispersed. Micelle degradation and gold nanoparticle dispersion was imaged in cultured macrophages, and micelle-treated mice displayed progressive physiological clearance of gold, with >85% elimination from the liver over three months. These particles present a novel nanomaterial formulation and address a critical unresolved barrier for clinical translation of gold nanoparticles.

Indocyanine Green-Coated Gold Nanoclusters for Photoacoustic Imaging and Photothermal Therapy.

Traditional oncology treatment modalities are often associated with a poor therapeutic index. This has driven the development of new targeted treatment modalities, including several based on the conversion of optical light into heat energy (photothermal therapy, PTT) and sound waves (photoacoustic imaging, PA) that can be applied locally. These approaches are especially effective when combined with photoactive nanoparticles that preferentially accumulate in tissues of interest and thereby further increase spatiotemporal resolution. In this study, two clinically-used materials that have proven effective in both PTT and PA - indocyanine green and gold nanoparticles - were combined into a single nanoformulation. These particles, "ICG-AuNP clusters", incorporated high concentrations of both moieties without the need for additional stabilizing or solubilizing reagents. The clusters demonstrated high theranostic efficacy both in vitro and in vivo, compared with ICG alone. Specifically, in an orthotopic mouse model of triple-negative breast cancer, ICG-AuNP clusters could be injected intravenously, imaged in the tumor by PA, and then combined with near-infrared laser irradiation to successfully thermally ablate tumors and prolong animal survival. Altogether, this novel nanomaterial demonstrates excellent therapeutic potential for integrated treatment and imaging.

PirB regulates asymmetries in hippocampal circuitry.

Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of ε2 subunits, we previously found that ß2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB), an MHCI receptor. As in ß2-microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry.

Lyme disease: case report of persistent Lyme disease from Pulaski County, Virginia.

A 50-year-old woman from Pulaski, Virginia, presented to a local clinic with headaches, fever, generalized joint pain, excessive thirst and fluid intake, and a progressing rash on her back. On physical examination, she had a large circular red rash on her back with a bull's-eye appearance, 16 × 18 cm in diameter. Serologic tests confirmed a diagnosis of Lyme disease. The patient could recall a walk through the woods 3 weeks prior, although she never noticed a tick on her body. Following a prolonged course of antibiotics, this case report presents a patient with ongoing symptoms consistent with post-treatment Lyme disease.

Quantum critical behavior of the cluster glass phase.

In disordered itinerant magnets with arbitrary symmetry of the order parameter, the conventional quantum critical point between the ordered phase and the paramagnetic Fermi liquid (PMFL) is destroyed due to the formation of an intervening cluster glass (CG) phase. In this Letter, we discuss the quantum critical behavior at the CG-PMFL transition for systems with continuous symmetry. We show that fluctuations due to quantum Griffiths anomalies induce a first-order transition from the PMFL at T = 0, while at higher temperatures a conventional continuous transition is restored. This behavior is a generic consequence of enhanced non-Ohmic dissipation caused by a broad distribution of energy scales within any quantum Griffiths phase in itinerant systems.