Estradiol regulates responsiveness of the dorsal premammillary nucleus of the hypothalamus and affects fear‐ and anxiety‐like behaviors in female rats

Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E₂) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole‐cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E₂. Our results show that E₂ increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E₂ as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E₂ persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E₂ treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α‐ and β‐adrenoreceptors. In summary, our results implicate E₂ in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E₂ may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders.     

Optimization of retinotopy constrained source estimation constrained by prior

Studying how the timing and amplitude of visual evoked responses (VERs) vary between visual areas is important for understanding visual processing but is complicated by difficulties in reliably estimating VERs in individual visual areas using noninvasive brain measurements. Retinotopy constrained source estimation (RCSE) addresses this challenge by using multiple, retinotopically mapped stimulus locations to simultaneously constrain estimates of VERs in visual areas V1, V2, and V3, taking advantage of the spatial precision of fMRI retinotopy and the temporal resolution of magnetoencephalography (MEG) or electroencephalography (EEG). Nonlinear optimization of dipole locations, guided by a group‐constrained RCSE solution as a prior, improved the robustness of RCSE. This approach facilitated the analysis of differences in timing and amplitude of VERs between V1, V2, and V3, elicited by stimuli with varying luminance contrast in a sample of eight adult humans. The V1 peak response was 37% larger than that of V2 and 74% larger than that of V3, and also ～10–20 ms earlier. Normalized contrast response functions were nearly identical for the three areas. Results without dipole optimization, or with other nonlinear methods not constrained by prior estimates were similar but suffered from greater between‐subject variability. The increased reliability of estimates offered by this approach may be particularly valuable when using a smaller number of stimulus locations, enabling a greater variety of stimulus and task manipulations. Hum Brain Mapp 35:1815–1833, 2014. © 2013 Wiley Periodicals, Inc.     

Sensitivity analysis for a partially missing binary outcome in a two‐arm randomized clinical trial

Although recent guidelines for dealing with missing data emphasize the need for sensitivity analyses, and such analyses have a long history in statistics, universal recommendations for conducting and displaying these analyses are scarce. We propose graphical displays that help formalize and visualize the results of sensitivity analyses, building upon the idea of ‘tipping‐point’ analysis for randomized experiments with a binary outcome and a dichotomous treatment. The resulting ‘enhanced tipping‐point displays’ are convenient summaries of conclusions obtained from making different modeling assumptions about missingness mechanisms. The primary goal of the displays is to make formal sensitivity analysesmore comprehensible to practitioners, thereby helping them assess the robustness of the experiment's conclusions to plausible missingness mechanisms. We also present a recent example of these enhanced displays in amedical device clinical trial that helped lead to FDA approval. Copyright © 2014 John Wiley & Sons, Ltd.     

Is Religiosity Positively Associated With School Connectedness: Evidence From High School Students in Atlantic Canada?

School connectedness (SC) is associated with decreased student risk behavior and better health and social outcomes. While a considerable body of research has examined the factors associated with SC, there is limited evidence about the particular role of religiosity in shaping levels of SC. Employing data reported by junior and senior high school students from Atlantic Canada, this study examines whether religiosity is positively associated with SC and whether such associations differ by gender. We tested the association between SC and religiosity using a random intercept multilevel logistic regression. The between-school variability in SC was first determined by our estimating a null or empty model; three different model specifications that included covariates were estimated: in Model 1 we adjusted for gender, age, academic performance, parental education, and living arrangement; in Model 2 for sensation seeking and subjective social status in addition to Model 1 variables; and in Model 3 we added substance use to the analysis. Our multilevel regression analyses showed that religiosity was protectively associated with lower SC across the three model specifications when both genders were examined together. In gender-stratified analyses we found similar protective associations of religiosity, with lower SC for both males and females in all three models. Given the overwhelming positive impact of SC on a range of health, social and school outcomes, it is important to understand the role of religiosity, among other factors, that may be modified to enhance student’s connectedness to school.     

Usefulness of translatability assessment: results from a retrospective study

Purpose

The purpose of the study is to evaluate the extent to which a retrospectively conducted translatability assessment (TA) could identify the items previously singled out during the validation study as having poor content validity or poor measurement performance. This study was performed with the intent of supporting evidence of the usefulness of TA early in the PRO development process. The Weight module of the Youth Quality-of-Life Instrument (YQOL-W) was used for this appraisal of translatability.

Methods

Two linguists, blinded to the design and results of content validation and psychometric analyses, conducted a TA on the 32-item version of the YQOL-W taken into cross-sectional validation for item reduction. TA results were categorized into (1) issues relating to target culture (cross-cultural issues) and (2) issues relating to the structure of the original questionnaire (structural issues). Items for possible revision or deletion were identified. We compared the results of the TA with the content validity and psychometric results and decisions to eliminate items after cross-sectional validation.

Results

Content validation identified seven of the 32 items to be dropped, and psychometric analyses including the 25 remaining items highlighted an additional four to be eliminated, yielding a final instrument with 21 items. Out of these 11 dropped items, TA had identified nine as problematic (82 %) and the developer was advised to drop five of them (45.4 %). In addition, TA results highlighted the need to change the original formulation of eight items for semantic reasons and identified two instances where alternative wording should be used for translation purposes without any change to the original formulation.

Conclusion

Our study showed that translatability assessment confirmed problematic issues in items previously identified as having poor content validity or poor measurement performance. In general, a translatability assessment offers the possibility for the identification of alternative formulations for translation purposes, modifications of original formulations to optimize subsequent translations efforts, and the early detection and discussion of irrelevant or inappropriate items.     

Validation of the Osteoporosis-Specific Morisky Medication Adherence Scale in long-term users of bisphosphonates

Purpose

To examine the psychometric properties and validity of the 8-item Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS-8) in postmenopausal women prescribed bisphosphonates (BPs) for at least 15 months.

Methods

A random sample of women aged ≥55 years with osteoporosis prescribed daily or weekly BPs was identified. Pharmacy fill data were extracted to calculate the medication possession ratio (MPR). Eligible women were stratified by low (<0.50), medium (0.50–0.79), or high (≥0.80) MPR, with the a priori goal of recruiting 133 participants in each group. OS-MMAS-8 scores can range from 0 to 8 and were categorized as low (<6), medium (6 to <8), and high (8) adherence. Internal consistency reliability (Cronbach’s alpha), test–retest reliability [intraclass correlation coefficients (ICCs)] and convergent validity (correlating OS-MMAS-8 with MPR and other self-reported measures) were assessed.

Results

A total of 400 women out of 449 respondents reported that they were still taking their BPs at the time of the survey and completed OS-MMAS-8. Overall, 38.5, 34.3, and 27.3 % of participants had low, medium, and high OS-MMAS-8 scores, respectively. The mean (SD) MPRs according to OS-MMAS-8 scores (<6, 6 to <8 and 8) were 56.9 (22.6), 69.0 (24.9), and 76.7 (26.4), respectively. The correlation between OS-MMAS-8 and MPR was 0.36; p < 0.0001. Cronbach’s alpha was 0.74, and the ICC was 0.83 (95 % CI 0.76–0.88).

Conclusions

OS-MMAS-8 has acceptable psychometric properties for assessing medication adherence in postmenopausal women prescribed therapy for osteoporosis. Additional studies are needed to investigate the psychometric properties of OS-MMAS-8 in other settings and populations.     

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm

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Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate

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Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented?

There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual-allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL-33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.