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Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS. [ABSTRACT FROM AUTHOR]

PurposePrevious studies indicate that there is an axial gradient of collagen lamellar branching and anastomosing leading to regional differences in corneal tissue stiffness that may control corneal shape. To further test this hypothesis we have measured the axial material stiffness and quantified the collagen lamellar complexity in ectatic and mechanically weakened keratoconus corneas (KC).MethodsAcoustic radiation force elastic microscopy (ARFEM) was used to probe the axial mechanical properties of the cone region of three donor KC buttons. 3 Dimensional second harmonic generation microscopy (3D-SHG) was used to qualitatively evaluate lamellar organization in 3 kC buttons and quantitatively measure lamellar branching point density (BPD) in a separate KC button that had been treated with epikeratophakia (Epi-KP).ResultsThe mean elastic modulus for the KC corneas was 1.67 ± 0.44 kPa anteriorly and 0.970 ± 0.30 kPa posteriorly, substantially below that previously measured for normal human cornea. 3D-SHG of KC buttons showed a simplified collagen lamellar structure lacking noticeable angled lamellae in the region of the cone. BPD in the anterior, posterior, central and paracentral regions of the KC cornea were significantly lower than in the overlying Epi-KP lenticule. Additionally, BPD in the cone region was significantly lower than the adjacent paracentral region in the KC button.ConclusionsThe KC cornea exhibits an axial gradient of mechanical stiffness and a BPD that appears substantially lower in the cone region compared to normal cornea. The findings reinforce the hypothesis that collagen architecture may control corneal mechanical stiffness and hence corneal shape.

The integration of risk assessment into clinical breast screening holds promise in decreasing breast cancer morbidity and mortality and increasing health care efficiency. Currently, clinical recommendations regarding risk counseling, screening, and chemoprevention are being made based on a woman’s personal risk. One of the criteria that can be used to categorize a woman as “increased risk” is her projected 5-year risk for invasive breast cancer as determined by one of various risk models which are heavily based on family history. We hypothesized that the frequency of screening mammography patients at our medical institution who would be considered at “increased risk” would be different according to different risk models and according to race/ethnicity, thus impacting the volume of patients who are targeted for risk-reducing intervention. Risk scores were calculated for 307 White, Hispanic, and Asian screening mammography patients according to the Gail, BCSC, and Tyrer-Cuzick models. Scores were compared within and between race/ethnicities, according to the different models, individually and in combination. As expected, White women had higher risk scores than Hispanic and Asian women according to all models tested (p

PurposeAlthough corneal curvature plays an important role in determining the refractive power of the vertebrate eye, the mechanisms controlling corneal shape remain largely unknown. To address this question, we performed a comparative study of vertebrate corneal structure to identify potential evolutionarily based changes that correlate with the development of a corneal refractive lens.MethodsNonlinear optical (NLO) imaging of second-harmonic-generated (SHG) signals was used to image collagen and three-dimensionally reconstruct the lamellar organization in corneas from different vertebrate clades.ResultsSecond-harmonic-generated images taken normal to the corneal surface showed that corneal collagen in all nonmammalian vertebrates was organized into sheets (fish and amphibians) or ribbons (reptiles and birds) extending from limbus to limbus that were oriented nearly orthogonal (ranging from 77.7°-88.2°) to their neighbors. The slight angular offset (2°-13°) created a rotational pattern that continued throughout the full thickness in fish and amphibians and to the very posterior layers in reptiles and birds. Interactions between lamellae were limited to "sutural" fibers in cartilaginous fish, and occasional lamellar branching in fish and amphibians. There was a marked increase in lamellar branching in higher vertebrates, such that birds ≫ reptiles > amphibians > fish. By contrast, mammalian corneas showed a nearly random collagen fiber organization with no orthogonal, chiral pattern.ConclusionsOur data indicate that nonmammalian vertebrate corneas share a common orthogonal collagen structural organization that shows increased lamellar branching in higher vertebrate species. Importantly, mammalian corneas showed a different structural organization, suggesting a divergent evolutionary background.

Abstract: The USPSTF recommends that women who are at increased risk for breast cancer and at low risk for adverse medication effects should be offered risk-reducing medications, such as tamoxifen or raloxifene, by their clinicians. The NCCN also recommends risk counseling for women with a 5-year risk of ≥1.7% as calculated by the NCI-developed Breast Cancer Risk Assessment Tool (BCRAT, based on the Gail model) or other risk model. The integration of risk assessment into clinical breast screening holds promise in reducing breast cancer risk for many women; however, the criteria that contribute to elevated risk status are different according to different risk models. The University of California, Irvine (UCI) Athena Breast Health Network has integrated a computerized risk assessment largely based on the BCRAT into the screening mammography process at UCI mammography centers. Women identified to be at elevated risk are provided with personalized risk counseling by a Breast Health Specialist. In recent years, breast density has been increasingly recognized as a risk factor for breast cancer; however, it is not part of the BCRAT. In this pilot analysis, we sought to determine if incorporating breast density into the risk assessment program would affect the % of women in our cohort who have a 5-year risk of ≥1.7%. We hypothesized that an increased % of Asian women would reach this threshold since breast density is known to be higher in Asians. We used the BCSC model, which includes density as a variable, to calculate risk scores for a subset of our screening population (n=309), age-matched for three race/ethnic groups, and compared them to their scores according to the BCRAT. Our results showed that while Asians did exhibit significantly higher breast density (30.3% had BIRADS breast density classification 4, extremely dense) than White and Hispanic women (8.7% and 5.6%, respectively), their BCRAT and BCSC scores were significantly lower than in White women but higher than in Hispanic women, with 14.1% of Asians having a BCSC score ≥1.7% compared to 43.7% of Whites and 10.3% in Hispanics, and 17.2% of Asians having a BCRAT score of ≥1.7% compared to 34.0% of Whites and 6.5% of Hispanics. Interestingly, when differences were explored between BCRAT and BCSC scores within the same sub-group of women, the scores were not statistically different among White or Hispanic women but were approaching statistical significance in Asian women. Contrary to our hypothesis, in Asian women, BCSC-calculated risk was actually lower than according to the BCRAT. These findings suggest that, despite higher breast density, Asian women still exhibit lower breast cancer risk scores than White women; thus, a smaller proportion of Asian women in our cohort will be recommended for high risk counseling and chemoprevention. Citation Format: Hannah Lui Park, Stephanie M. Tran, Jennifer Lee, Deborah Goodman, Argyrios Ziogas, Richard Kelly, Kathryn M. Larsen, Andrea Alvarez, Chris Tannous, Julie Strope, Wendy Lynch, Hoda Anton-Culver. A pilot study comparing breast cancer risk scores using models with and without breast density among women of different race/ethnicities undergoing breast screening in the University of California, Irvine Athena Breast Health Network cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3243. doi:10.1158/1538-7445.AM2014-3243

OBJECTIVES: To assess the effectiveness of a proactive provider intervention in prompting prior authorization (PA) submissions or provider response prior to PA expiration for medically complex Medicaid patients. STUDY DESIGN: Pre-post outreach study with data from pharmacy claims and provider outreach. METHODS: The intervention and historical comparison (control) groups included expired PAs from December 2019 to February 2020 and from December 2018 to February 2019, respectively. Provider outreach, including telephonic and fax attempts, was conducted over a 2-week period prior to PA expiration. Outcomes were classified as positive or negative based on provider conversation coupled with the result (eg, PA submission) for the intervention group and based solely on pharmacy claims for the control group. The primary end point was the percentage of positive outcomes between the groups, analyzed via χ² test. The time from PA expiration to the new PA submission was evaluated via t test. RESULTS: A total of 342 outreach attempts were conducted for 270 PAs representing 193 unique patients. Outreach was more likely to result in positive outcomes in the intervention group vs no outreach in the control group (87% vs 25%; P < .00001). On average, PAs were submitted 3.5 days prior to expiration in the intervention group vs 13.0 days after expiration in the control group (t = --7.50; P < .00001). CONCLUSIONS: Proactive outreach resulted in a greater percentage of PA submissions and a significantly reduced time to PA submission. These findings provide important information for payers in guiding clinical programs to enhance continuity of care among at-risk populations. [ABSTRACT FROM AUTHOR]

Mice deficient in the transcription factor pleomorphic adenoma gene 1 (PLAG1) exhibit reproductive issues that are characterized, in part, by decreased progressive sperm motility in the male. However, the underlying cause of this impairment is unknown. As epididymal transit is critical for sperm maturation and motility, the morphology of the epididymis of Plag1-deficient mice was investigated and the spatial expression patterns of PLAG1 protein and mRNA were identified. Using X-gal staining and in situ hybridization, PLAG1 was shown to be widely expressed in both the epithelium and stroma in all regions of the mouse epididymis. Interestingly, the X-gal staining pattern was markedly different in the cauda, where it could be suggestive of PLAG1 secretion into the epididymal lumen. At all ages investigated, the morphology of epididymides from Plag1 knockout (KO) mice was aberrant; the tubule failed to elongate and coil, particularly in the corpus and cauda, and the cauda was malformed, lacking its usual bulbous shape. Moreover, the epididymides from Plag1 KO mice were significantly reduced in size relative to body weight. In 20% of Plag1-deficient mice, the left testicle and epididymis were lacking. The impaired morphogenesis of the epididymal tubule is likely to be a major contributing factor to the fertility problems observed in male Plag1-deficient mice. These results also establish PLAG1 as an important regulator of male reproduction, not only through its involvement in testicular sperm production, but also via its role in the development and function of the epididymis. [ABSTRACT FROM AUTHOR]