Meet the Tutors: Student Expectations, Tutor Perspectives, and Some Recommendations for Sharing Information about Tutors Online

This article presents findings from an IRB-approved study about tutors’ online information on writing center websites, scheduling systems, and social media. The study used surveys to investigate students’ responses to tutors’ online information and focus groups to investigate tutors’ rationale for the information they shared. While many researchers have studied how writing centers are presented online, little research considers how tutors are represented. The authors argue that such representation merits attention, as tutor profiles can affect students’ comfort with the writing center staff and their microdecisions about who to see and how to interact with them (Salem, 2016). The authors share advice for making decisions about how tutors are presented online and for using the process of creating meet the staff and similar pages to study and improve their centers

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.United States. Dept. of Defense (Grant W81-XWH-13-1-0323)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells’ antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate–putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations — germline deletion of MCHR1 and conditional ablation of MCH neurons — induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length

MALDI imaging mass spectrometry differentiates basal cell carcinoma from trichoblastoma and trichoepithelioma: A proof of principle study

BACKGROUND: Basal cell carcinoma (BCC) comprises a large portion of dermatopathology specimens; however, benign mimics such as trichoblastoma/trichoepithelioma (TB/TE) place accurate diagnosis at risk and consequently lead to inappropriate clinical management and overuse of healthcare resources. This study aims to address the challenges of traditional histopathological evaluation by utilizing matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). METHODS AND FINDINGS: Formalin-fixed paraffin-embedded BCC and TB/TE tissue blocks were taken from archival tissue. A cohort of 69 BCC and TB/TE specimens were identified, each having three concordant diagnoses given by Dermatopathologists after a blinded analysis. H&amp;E stained sections of each specimen were imaged for pathological analysis and uploaded to a digital annotation software with the following classifications: BCC, TB, TE, BCC stroma, TB stroma, and TE stroma. Mass spectra were collected from unstained serial sections guided by the areas annotated by the Dermatopathologists on the H&amp;E stained serial sections. Before informatics, the data from the cohort were divided randomly into a training set (n = 55) and a validation set (n = 14). Prediction models were developed using a support vector machine (SVM) classification model from the training set data. The platform predicted BCC and TB/TE in model 2 (tumor nests alone) with a sensitivity of 98.9% (95% CI 98.3-99.4%) and specificity of 88.4% (95% CI 78.4-94.5%) at the spectral level in the validation set. Model 1 (stroma alone) had a sensitivity of 46.1% (95% CI 43.0-49.1%) and specificity of 99.2% (95% CI 97.1-99.9%). A combined model 3 (tumor nests and stroma) had a sensitivity of 90.26% (95% CI 89.1%-91.3%) and a specificity of 97.1% (95% CI 94.6% to 98.7%). The limitations of this study included a small sample set, which included easily identifiable cases obtained from a single tissue source. CONCLUSIONS: Our study proves that BCC and TB/TE exhibit different proteomic profiles that one can use to enable accurate differential diagnosis. While our findings are not yet validated for clinical use, this merits further research to support IMS as an ancillary diagnostic tool for adequately and efficiently identifying the most common cutaneous malignancy in the United States. We recommend that future studies obtain a more extensive set of histologically challenging cases from multiple institutions and adequate clinical follow-up to confirm diagnostic accuracy

Implementing Provider‐based Sampling for the National Children's Study: Opportunities and Challenges

Background:  The National Children's Study (NCS) was established as a national probability sample of births to prospectively study children's health starting from in utero to age 21. The primary sampling unit was 105 study locations (typically a county). The secondary sampling unit was the geographic unit (segment), but this was subsequently perceived to be an inefficient strategy. Methods and Results:  This paper proposes that second‐stage sampling using prenatal care providers is an efficient and cost‐effective method for deriving a national probability sample of births in the US. It offers a rationale for provider‐based sampling and discusses a number of strategies for assembling a sampling frame of providers. Also presented are special challenges to provider‐based sampling pregnancies, including optimising key sample parameters, retaining geographic diversity, determining the types of providers to include in the sample frame, recruiting women who do not receive prenatal care, and using community engagement to enrol women. There will also be substantial operational challenges to sampling provider groups. Conclusion:  We argue that probability sampling is mandatory to capture the full variation in exposure and outcomes expected in a national cohort study, to provide valid and generalisable risk estimates, and to accurately estimate policy (such as screening) benefits from associations reported in the NCS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94504/1/ppe12005.pd

Dopamine D2-like receptor stimulation blocks negative feedback in visual and spatial reversal learning in the rat: behavioural and computational evidence

Abstract: Rationale: Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson’s disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. Objectives: We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. Methods: Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on “probe trials”, during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. Results: D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. Conclusions: D2R stimulation impairs reversal learning by blocking the impact of negative feedback

Pathology of Chronic Mycoplasma ovipneumoniae Carriers in a Declining Bighorn Sheep (\u3cem\u3eOvis canadensis\u3c/em\u3e) Population

Bighorn sheep (Ovis canadensis) across North America commonly experience populationlimiting epizootics of respiratory disease. Although many cases of bighorn sheep pneumonia are polymicrobial, Mycoplasma ovipneumoniae is most frequently associated with all-age mortality events followed by years of low recruitment. Chronic carriage of M. ovipneumoniae by adult females serves as a source of exposure of naïve juveniles; relatively few ewes may be responsible for maintenance of infection within a herd. Test-and-remove strategies focused on removal of adult females with evidence of persistent or intermittent shedding (hereafter chronic carriers) may reduce prevalence and mitigate mortality. Postmortem confirmation of pneumonia in chronic carriers has been inadequately reported and the pathology has not been thoroughly characterized, limiting our understanding of important processes shaping the epidemiology of pneumonia in bighorn sheep. Here we document postmortem findings and characterize the lesions of seven ewes removed from a declining bighorn sheep population in Wyoming, USA, following at least two antemortem detections of M. ovipneumoniae within a 14-mo period. We confirmed that 6/7 (85.7%) had variable degrees of chronic pneumonia. Mycoplasma ovipneumoniae was detected in the lung of 4/7 (57.1%) animals postmortem. Four (57.1%) had paranasal sinus masses, all of which were classified as inflammatory, hyperplastic lesions. Pasteurella multocida was detected in all seven (100%) animals, while Trueperella pyogenes was detected in 5/7 (71.4%). Our findings indicate that not all chronic carriers have pneumonia, nor do all have detectable M. ovipneumoniae in the lung. Further, paranasal sinus masses are a common but inconsistent finding, and whether sinus lesions predispose to persistence or result from chronic carriage remains unclear. Our findings indicate that disease is variable in chronic M. ovipneumoniae carriers, underscoring the need for further efforts to characterize pathologic processes and underlying mechanisms in this system to inform management

Estimating prevalence of overweight and obesity at the neighborhood level: the value of maternal height and weight data available on birth certificate records

<p>Abstract</p> <p>Objective</p> <p>To determine the value of maternal height and weight data on birth certificate records when estimating prevalence of overweight and obese adults at the neighborhood level.</p> <p>Research Design and Methods</p> <p>Regression analysis was used to determine how much variation in the percentage of the adult population with a body mass index (BMI) of ≥ 25 (based on survey data) could be accounted for by the percentage of mothers with BMI ≥ 25 (based on birth certificate data) -- alone and in combination with other sociodemographic characteristics of census tracts.</p> <p>Results</p> <p>Alone, the percentage of mothers with BMI ≥ 25 explained more than half (R²= .52) of the variation in the percentage of all residents in census tracts with BMI ≥ 25; in combination with several measures of the sociodemographic characteristics of the census tracts, 75% ( R²= 75.2) of the variation is explained.</p> <p>Conclusions</p> <p>Maternal height and weight data available from birth certificate records may be useful for identifying neighborhoods with relatively high or low prevalence of adult residents who are overweight or obese. This is especially true if used in combination with readily available census data.</p

Cardiovascular comorbidities among public health clinic patients with diabetes: the Urban Diabetics Study

BACKGROUND: We sought to determine the frequency and distribution of cardiovascular comorbidities in a large cohort of low-income patients with diabetes who had received primary care for diabetes at municipal health clinics. METHODS: Outpatient data from the Philadelphia Health Care Centers was linked with hospital discharge data from all Pennsylvania hospitals and death certificates. RESULTS: Among 10,095 primary care patients with diabetes, with a mean observation period of 4.6 years (2.8 after diabetes diagnosis), 2,693 (14.3%) were diagnosed with heart disease, including 270 (1.4%) with myocardial infarction and 912 (4.8%) with congestive heart failure. Cerebrovascular disease was diagnosed in 588 patients (3.1%). Over 77% of diabetic patients were diagnosed with hypertension. Incidence rates of new complications ranged from 0.6 per 100 person years for myocardial infarction to 26.5 per 100 person years for hypertension. Non-Hispanic whites had higher rates of myocardial infarction, and Hispanics and Asians had fewer comorbid conditions than African Americans and non-Hispanic whites. CONCLUSION: Cardiovascular comorbidities were common both before and after diabetes diagnosis in this low-income cohort, but not substantially different from mixed-income managed care populations, perhaps as a consequence of access to primary care and pharmacy services