Animal Models of Tinnitus Treatment: Cochlear and Brain Stimulation.

Neuromodulation, via stimulation of a variety of peripheral and central structures, is used to suppress tinnitus. However, investigative limitations in humans due to ethical reasons have made it difficult to decipher the mechanisms underlying treatment-induced tinnitus relief, so a number of animal models have arisen to address these unknowns. This chapter reviews animal models of cochlear and brain stimulation and assesses their modulatory effects on behavioral evidence of tinnitus and its related neural correlates. When a structure is stimulated, localized modulation, often presenting as downregulation of spontaneous neuronal spike firing rate, bursting and neurosynchrony, occurs within the brain area. Through anatomical projections and transmitter pathways, the interventions activate both auditory- and non-auditory structures by taking bottom-up ascending and top-down descending modes to influence their target brain structures. Furthermore, it is the brain oscillations that cochlear or brain stimulation evoke and connect the prefrontal cortex, striatal systems, and other limbic structures to refresh neural networks and relieve auditory, attentive, conscious, as well as emotional reactive aspects of tinnitus. This oscillatory neural network connectivity is achieved via the thalamocorticothalamic circuitry including the lemniscal and non-lemniscal auditory brain structures. Beyond existing technologies, the review also reveals opportunities for developing advanced animal models using new modalities to achieve precision neuromodulation and tinnitus abatement, such as optogenetic cochlear and/or brain stimulation.

Using Provider Incentives and an Opt-Out Strategy in a Successful Quality Initiative to Increase Chlamydia Screening.

BACKGROUND: Chlamydia trachomatis (CT) is a highly prevalent sexually transmitted infection in adolescents that can lead to serious complications. San Francisco has one of the highest rates of CT infections in the United States. At baseline, screening rates at the Children's Health Center were significantly below national and network levels. This project aimed to increase screening rates for female patients age 16-24 from 29.2% to 44% in an 18-month period. METHODS: The organization engaged providers, residents, and nursing staff to understand the root causes and choose the screening approach. The following strategies were used to implement this approach in primary and urgent care: (1) universal urine collection, (2) provider and staff education, and (3) adoption of faculty Maintenance of Certification (MOC) credit and resident physician financial incentives. RESULTS: The annual screening rate for CT in primary care female patients 16-24 years old increased from 29.2% to 61.5% in 18 months, and improved to 71.2% one year after the project. Screening rates for female patients over age 15 seen in the colocated urgent care also increased significantly. The research team found no instances of false positive results and had 4 positive results in high-risk patients who initially reported abstinence. CONCLUSIONS: The intervention design and engagement of stakeholders with incentives was associated with significant and sustainable improvements in the CT screening rate for female adolescent primary care patients. This work shows how universal opt-out screening can be a sustainable and effective method to address common barriers to increasing screening for CT in adolescents.

Integrin αvß8-expressing tumor cells evade host immunity by regulating TGF-ß activation in immune cells.

TGF-ß is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-ß (L-TGF-ß) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-ß. Binding of L-TGF-ß to integrin αvß8 results in activation of TGF-ß. We engineered and used αvß8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect ß8 in human tumors. Inhibition of αvß8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. ß8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-ß, suggesting that tumor cell αvß8 serves as a platform for activating cell-surface L-TGF-ß presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to ß8 inhibition with major increases in chemokine and tumor-eliminating genes. High ß8 expression in tumor cells is seen in 20%-80% of various cancers, which rarely coincides with high PD-L1 expression. These data suggest tumor cell αvß8 is a PD-1/PD-L1-independent immunotherapeutic target.