Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma.

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P ¼ 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. ©2017 AACR

A Survey to Guide the Emerging Role of Allied Health Teams in a Regional Tertiary Hospital Emergency Department

ABSTRACT Purpose: A multidisciplinary allied health team has worked in The Townsville Hospital Emergency Department for seven years. Patients are referred to the allied health team by medical and nursing staff with the aim of reducing patient admission and improving patient outcomes. However, the type and number of referrals received by the allied health team suggest there is a lack of detailed interdisciplinary knowledge by the referrers. Therefore, the Emergency Department Allied Health Team surveyed other emergency department health professionals to ascertain their knowledge of allied health roles. The results will be used to develop education sessions to fill gaps in knowledge. Methods: A cross-sectional survey consisting of 22 true/false statements and demographic questions was developed by the Emergency Department Allied Health Team. Questions described some of the common triggers for referral to physiotherapy, occupational therapy, social work, and pharmacy staff in the emergency department at the Townsville Hospital. The survey was distributed opportunistically to nursing, medical and physician assistant staff at handover or education sessions. Descriptive statistics were used to describe the data and comparisons used chi squared tests. Results: The response rate for the survey was 63% (n=154), including 52 doctors (65%), 95 (59%) nursing staff, 3 physician assistants (100%), and 4 who did not state their discipline. Preferred responses were low for questions about occupational therapy’s ability to do home visits up to four weeks post emergency department discharge (37.7%), physiotherapists’ necessity to perform mobility assessments (24.7%), identifying APINCH acronym as mnemonic for high risk drugs (35.7%) and the correct application of “close the gap” prescriptions (27.9%). Staff with more experience and prescribers were more likely to give the preferred response. Conclusions: Some gaps exist in doctors’, nurses’, and physician assistants’ knowledge of the roles of allied health in an emergency department. The knowledge gap decreases as staff experience in emergency departments increases. Therefore, for the allied health team in our emergency department to work at full scope of practice, these knowledge gaps need to be addressed. Our challenge now is to provide sustainable education on the role of allied health in a busy emergency department full of shift working and rotating staff being pulled by a myriad of contrasting priorities

LAB/NTAL Facilitates Fungal/PAMP-induced IL-12 and IFN-γ Production by Repressing β-Catenin Activation in Dendritic Cells.

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted inLat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/−mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance

From Veteran to Student: Using Structural Equation Modeling to Examine the Impact of School Environment on Education and Psychosocial Outcomes

Post-9/11 veterans are increasingly entering higher education. As a result of their time in service, they may bring both strengths and challenges to the academic setting. The campus environment has been suggested to be an important factor in the support of Post-9/11 student veterans. Progress has been made in providing veteran-specific supports on campus, but this population also experiences stigmatization from others on campus. Using structural equation modeling (SEM), this dissertation study sought to explore veterans\u27 perceptions of veteran-friendliness and stigmatization on campus and the effects on educational and psychosocial outcomes. Results indicated that while many student veterans are educationally successful, many also struggle with posttraumatic stress disorder (PTSD) symptoms, and perceive low amounts of veteran-friendliness and considerable amounts of stigmatization. Results of the SEM analysis suggest that their experiences of stigmatization on campus and PTSD negatively affect their quality of life and beliefs about treatment seeking. Veteran-friendliness, by contrast, may buffer negative effects of stigmatization on the quality of life. Implications of this study for policy and social work include the need to use GI Bill funding to support veteran specific services on campus. In addition to support specifically for student veterans, findings from this study highlight the additional need of educating others on campus in order to address cultural concerns

Temperature variability and multiple environmental stressors: how will tadpole performance change with our climate?

This project seeks to analyze how predicted changes in climate and its interactions with other environmental factors will influence tadpole growth and development. Our first study examined how the frequency and magnitude of temperature variability affect wood frog and gray tree frog tadpole performance. We found that performance responses to repeatedly fluctuating treatments did not differ significantly from constant temperatures held at the same mean for wood frog tadpoles. However, elevated mean temperatures of 26 degrees Celsius caused tadpoles to metamorphose early, suggesting a potential developmental threshold. We found that gray tree frog performance was affected by fluctuating temperature treatments, with a small mass and reduced development time following an extreme temperature fluctuation late in development and increased development time under a biweekly temperature fluctuation pattern. Our second study was concerned with determining how elevated temperatures, road salts, interspecific competition, and the interactions between these factors affected the survival, growth, and development of wood frog and spring peeper tadpoles. Ultimately we found that performance responses were influenced by elevated temperatures, road salts, and interspecific competition and by synergistic interactions between the factors. Additionally, both species responded similarly to the aforementioned stressors, with the exception of mass at metamorphosis. We suggest further examination of temperature variability and the consideration of synergistic interactions when mitigating the threat of climate change to amphibian populations in the future

Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy

© 2015 . Introduction: Depression and memory dysfunction significantly impact the quality of life of patients with epilepsy. Current therapies for these cognitive and psychiatric comorbidities are limited. We explored the efficacy and safety of transcranial direct current stimulation (TDCS) for treating depression and memory dysfunction in patients with temporal lobe epilepsy (TLE). Methods: Thirty-seven (37) adults with well-controlled TLE were enrolled in a double-blinded, sham-controlled, randomized, parallel-group study of 5 days of fixed-dose (2. mA, 20 min) TDCS. Subjects were randomized to receive either real or sham TDCS, both delivered over the left dorsolateral prefrontal cortex. Patients received neuropsychological testing and a 20-minute scalp EEG at baseline immediately after the TDCS course and at 2- and 4-week follow-up. Results: There was improvement in depression scores immediately after real TDCS, but not sham TDCS, as measured by changes in the Beck Depression Inventory (BDI change: - 1.68 vs. 1.27, p. \u3c. 0.05) and NDDI-E (- 0.83 vs. 0.9091, p. = 0.05). There was no difference between the groups at the 2- or 4-week follow-up. There was no effect on delayed or working memory performance. Transcranial direct current stimulation was well-tolerated and did not increase seizure frequency or interictal discharge frequency. Transcranial direct current stimulation induced an increase in delta frequency band power over the frontal region and delta, alpha, and theta band power in the occipital region after real stimulation compared to sham stimulation, although the difference did not reach statistical significance. Discussion: This study provides evidence for the use of TDCS as a safe and well-tolerated nonpharmacologic approach to improving depressive symptoms in patients with well-controlled TLE. However, there were no changes in memory function immediately following or persisting after a stimulation course. Further studies may determine optimal stimulation parameters for maximal mood benefit

Quantifying Spatial Patterns of Hyporheic Exchange in a Floodplain Meander System via High-Resolution Hydrogeologic, Geochemical and Geophysical Observations

The spatial and temporal patterns of hyporheic exchange impact riverine ecosystems through regulation of stream temperature and water chemistry. In gravel-bedded meandering streams, these patterns are tied to the hydraulic architecture of the floodplain aquifer, which is a product of the geomorphic history of the channel. In this study, we investigate the connection between floodplain stratigraphy and hyporheic exchange in an intensively instrumented reach of the East Fork Jemez River located in the Valles Caldera National Preserve. We employ a suite of hydrogeologic, geochemical, and geophysical methods to document the stratigraphy of the floodplain meander system and quantify groundwater fluxes to the stream channel. We map the floodplain aquifer and characterize subsurface hydraulic properties of the floodplain using a dense network of piezometers across a 340 m long, 2 m wide reach that includes four meanders. Grain size analysis, slug tests, and low-field borehole nuclear magnetic resonance (NMR) measurements were conducted in a subset of augerholes and reveal distinct gravel- and clay-rich units. Slug test hydraulic conductivities varied from 1x10-8 to 1x10-4 m/s, while NMR-derived estimates of hydraulic conductivity ranged from 1x10-11 to 1x10-8 m/s. Slug test and NMR-derived hydraulic conductivity estimates showed general correspondence, with the largest deviation occurring in gravel-rich layers. NMR logging, which provides information about the saturated pore size, revealed variability in the extent to which gravel layers included fine particles. Our observations suggest large variability in the extent to which gravel-rich layers are accompanied by fine particles. Electrical resistivity surveys and borehole NMR across a single meander provided evidence for continuous clay (conductive) layers across meander bends. However, geochemical analyses of groundwater in the network of wells indicate large variability in chemical composition (major cation and anion) and dissolved oxygen, over small spatial scales. Our multi-method mapping of a floodplain meander system demonstrates the utility of high resolution spatial characterization to constraining hyporheic fluxes

Severe Monkeypox in Hospitalized Patients - United States, August 10-October 10, 2022.

As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States.§ Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox¶ during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy†† in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox.§§ Engaging all persons with HIV in sustained care remains a critical public health priority