Interactive computational and experimental approaches improve the sensitivity of periplasmic binding protein-based nicotine biosensors for measurements in biofluids.

We developed fluorescent protein sensors for nicotine with improved sensitivity. For iNicSnFR12 at pH 7.4, the proportionality constant for ∆F/F0vs [nicotine] (δ-slope, 2.7 µM-1) is 6.1-fold higher than the previously reported iNicSnFR3a. The activated state of iNicSnFR12 has a fluorescence quantum yield of at least 0.6. We measured similar dose-response relations for the nicotine-induced absorbance increase and fluorescence increase, suggesting that the absorbance increase leads to the fluorescence increase via the previously described nicotine-induced conformational change, the 'candle snuffer' mechanism. Molecular dynamics (MD) simulations identified a binding pose for nicotine, previously indeterminate from experimental data. MD simulations also showed that Helix 4 of the periplasmic binding protein (PBP) domain appears tilted in iNicSnFR12 relative to iNicSnFR3a, likely altering allosteric network(s) that link the ligand binding site to the fluorophore. In thermal melt experiments, nicotine stabilized the PBP of the tested iNicSnFR variants. iNicSnFR12 resolved nicotine in diluted mouse and human serum at 100 nM, the peak [nicotine] that occurs during smoking or vaping, and possibly at the decreasing levels during intervals between sessions. NicSnFR12 was also partially activated by unidentified endogenous ligand(s) in biofluids. Improved iNicSnFR12 variants could become the molecular sensors in continuous nicotine monitors for animal and human biofluids.

Interactive computational and experimental approaches improve the sensitivity of periplasmic binding protein-based nicotine biosensors for measurements in biofluids.

We developed fluorescent protein sensors for nicotine with improved sensitivity. For iNicSnFR12 at pH 7.4, the proportionality constant for ΔF/F0 vs [nicotine] (δ-slope, 2.7 µM-1) is 6.1-fold higher than the previously reported iNicSnFR3a. The activated state of iNicSnFR12 has a fluorescence quantum yield of at least 0.6. We measured similar dose-response relations for the nicotine-induced absorbance increase and fluorescence increase, suggesting that the absorbance increase leads to the fluorescence increase via the previously described nicotine-induced conformational change, the "candle snuffer" mechanism. Molecular dynamics (MD) simulations identified a binding pose for nicotine, previously indeterminate from experimental data. MD simulations also showed that Helix 4 of the periplasmic binding protein (PBP) domain appears tilted in iNicSnFR12 relative to iNicSnFR3a, likely altering allosteric network(s) that link the ligand binding site to the fluorophore. In thermal melt experiments, nicotine stabilized the PBP of the tested iNicSnFR variants. iNicSnFR12 resolved nicotine in diluted mouse and human serum at 100 nM, the peak [nicotine] that occurs during smoking or vaping, and possibly at the decreasing levels during intervals between sessions. NicSnFR12 was also partially activated by unidentified endogenous ligand(s) in biofluids. Improved iNicSnFR12 variants could become the molecular sensors in continuous nicotine monitors for animal and human biofluids.

Effect of a Workshop to Break the Bias Habit for Internal Medicine Faculty: A Multisite Cluster Randomized Controlled Study.

PURPOSE: Recognition that cultural stereotypes can unintentionally perpetuate inequities throughout academic medicine has led to calls for "implicit bias training" without strong evidence to support these recommendations and some evidence of potential harm. The authors sought to determine the effectiveness of a single 3-hour workshop in helping department of medicine faculty overcome implicit stereotype-based bias and in improving the climate in the working environment. METHOD: A multisite cluster randomized controlled study (October 2017 to April 2021) with clustering at the level of divisions within departments and participant-level analysis of survey responses involved 8,657 faculty in 204 divisions in 19 departments of medicine: 4,424 in the intervention group (1,526 attended a workshop) and 4,233 in the control group. Online surveys at baseline (3,764/8,657 = 43.48% response rate) and 3 months after the workshop (2,962/7,715 = 38.39% response rate) assessed bias awareness, bias-reducing intentional behavioral change, and perceptions of division climate. RESULTS: At 3 months, faculty in the intervention vs control divisions showed greater increases in awareness of personal bias vulnerability ( b = 0.190 [95% CI, 0.031 to 0.349], P = .02), bias reduction self-efficacy ( b = 0.097 [95% CI, 0.010 to 0.184], P = .03), and taking action to reduce bias ( b = 0.113 [95% CI, 0.007 to 0.219], P = .04). The workshop had no effect on climate or burnout, but slightly increased perceptions of respectful division meetings ( b = 0.072 [95% CI, 0.0003 to 0.143], P = .049). CONCLUSIONS: Results of this study should give confidence to those designing prodiversity interventions for faculty in academic medical centers that a single workshop which promotes awareness of stereotype-based implicit bias, explains and labels common bias concepts, and provides evidence-based strategies for participants to practice appears to have no harms and may have significant benefits in empowering faculty to break the bias habit.

Can integrating the Memory Support Intervention into cognitive therapy improve depression outcome? A randomized controlled trial.

We investigated if improving a patient's memory for the content of their treatment, via the Memory Support Intervention, improves illness course and functional outcomes. The platform for investigating this question was major depressive disorder (MDD) and cognitive therapy (CT). Adults diagnosed with MDD (N = 178) were randomly allocated to CT + Memory Support (n = 91) or CT-as-usual (n = 87). Both treatments were comprised of 20-26, 50-min sessions over 16 weeks. Blind assessments were conducted before and immediately following treatment (post-treatment) and 6 months later (6FU). Patient memory for treatment, assessed with a free recall task, was higher in CT + Memory Support for past session recall at post-treatment. Both treatment arms were associated with reductions in depressive symptoms and functional impairment except: CT + Memory Support exhibited lower depression severity at 6FU (b = -3.09, p = 0.050, d = -0.27), and greater reduction in unhealthy days from baseline to 6FU (b = -4.21, p = 0.010, d = -1.07), compared to CT-as-usual. While differences in illness course and functional outcomes between the two treatment arms were limited, it is possible that future analyses of the type of memory supports and longer follow-up may yield more encouraging outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01790919. Registered October 6, 2016.

Structural insights into binding of therapeutic channel blockers in NMDA receptors.

Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects.

Engaging faculty in a workshop intervention on overcoming the influence of implicit bias.

INTRODUCTION: To study the effectiveness of any educational intervention for faculty requires first that they attend the training. Using attendance as a measure of faculty engagement, this study examined factors associated with the percentage of faculty in divisions of departments of medicine who attended a workshop as part of a multisite study. METHODS: Between October 2018 and March 2020, 1675 of 4767 faculty in 120 divisions of 14 departments of medicine attended a 3-hour in-person workshop as part of the Bias Reduction in Internal Medicine (BRIM) initiative. This paper describes the workshop development and study design. The number of faculty per division ranged from 5 to 296. Attendance rates varied from 2.7% to 90.1%. Taking a quality improvement approach, the study team brainstormed factors potentially related to variations in workshop attendance, constructed several division- and institution-level variables, and assessed the significance of factors on workshop attendance with hierarchical linear models. RESULTS: The following were positively associated with workshop attendance rate: the division head attended the workshop, the BRIM principal investigator gave Medical Grand Rounds, and the percentage of local workshop presenters who completed training. Workshop attendance rates fell when departments identified more than five on-site study leaders. CONCLUSIONS: Factors associated with higher workshop attendance may have increased the perceived status and value of attending the workshop, leading faculty to choose the workshop over other competing demands. For future investigators studying educational interventions that require participation of faculty in clinical departments at multiple sites, this work offers several valuable lessons.

A randomized controlled trial of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) to improve serious mental illness outcomes in a community setting.

OBJECTIVE: To determine if the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) improves functional impairment, psychiatric symptoms, and sleep and circadian functioning. METHOD: Adults diagnosed with serious mental illness (SMI) and sleep and circadian dysfunction (N = 121) were randomly allocated to TranS-C plus usual care (TranS-C + UC; n = 61; 8 individual weekly sessions) or 6 months of Usual Care followed by Delayed Treatment with TranS-C (UC-DT; n = 60). Schizophrenia (45%) and anxiety disorders (47%) were common. Blind assessments were conducted pre-treatment, post-treatment, and 6 months later (6FU). The latter two were the post-randomization points of interest. The location was Alameda County Behavioral Health Care Services (ACBHCS), a Community Mental Health Center (CMHC) in California. RESULTS: For the primary outcomes, relative to UC-DT, TranS-C + UC was associated with reduction in functional impairment (b = -3.18, p = 0.025, d = -0.58), general psychiatric symptoms (b = -5.88, p = 0.001, d = -0.64), sleep disturbance (b = -5.55, p < .0001, d = -0.96), and sleep-related impairment (b = -9.14, p < .0001, d = -0.81) from pre-treatment to post-treatment. These effects were maintained to 6-month follow-up (6FU; d = -0.42 to -0.82), except functional impairment (d = -0.37). For the secondary outcomes, relative to UC-DT, TranS-C + UC was associated with improvement in sleep efficiency and on the Sleep Health Composite score from pre-treatment to 6FU. TranS-C + UC was also associated with reduced total wake time and wake time variability from pre-treatment to post-treatment, as well as reduced hallucinations and delusions, bedtime variability, and actigraphy measured waking activity count variability from pre-treatment to 6FU. CONCLUSIONS: A novel transdiagnostic treatment, delivered within a CMHC setting, improves selected measures of functioning, symptoms of comorbid disorders, and sleep and circadian outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Improving Department Climate Through Bias Literacy: One College's Experience.

Many institutions of higher education are investing in "implicit bias training" as a mechanism to improve diversity and inclusion on their campuses. In this study, we describe an effort to implement this training in the form of a 3-hour workshop delivered to faculty members in the College of Engineering at the University of Wisconsin-Madison. Evaluation form data collected immediately post-workshop, and in-person interviews and survey data collected 6-12 months post-workshop, were used to measure the effectiveness of the intervention. These data show that faculty awareness of implicit bias in their workplace environments increased significantly, although individual motivation and self-efficacy to act without bias, and self-reported bias-reduction actions, did not increase. At the same time, we found evidence of improved department climates and bias-reduction actions at the department level, which increase our confidence that the workshops were having a positive impact. Importantly, women and faculty of color in the College did not report increases in negative behavior after the workshop, and reported that their departments were engaging in explicit discussions of potential biases in departmental processes more often. These findings support the continued implementation of the "Breaking the Bias Habit®" workshops along with measurement of their success.

Open trial of the Parent Behavior Change Intervention (PBC-I): Study protocol.

OBJECTIVE: Parents have profound impacts on adolescents' health behaviors. Yet parents receive minimal training in the elements of conversations that optimally inspire their children toward engaging in healthy behaviors. The current study examines a novel interpersonal target: parent-adolescent conversations about adolescent health behavior change. Derived from advances in the science of behavior change, the Parent Behavior Change Intervention (PBC-I) contains conversational elements (e.g., behavior change techniques, positive communication strategies) hypothesized to reduce parent-adolescent coercion and conflict and facilitate upward spirals of healthy behavior change in adolescents. METHOD/DESIGN: The first phase of the study involves the development of the PBC-I in a small case series (N = 12 dyads). The second phase involves an open trial of the PBC-I (N = 36 dyads). Adolescents will receive six 50-min sessions of the Transdiagnostic Sleep and Circadian Intervention to improve sleep while their parents receive six50-min sessions of the PBC-I. Parent-adolescent dyads will be assessed before and after the intervention. The primary analysis will examine whether postintervention use of behavior change techniques and positive communication strategies by parents is higher than preintervention use and whether increased use by parents predicts more positive conversational behaviors, less parent-adolescent conflict, higher adolescent motivation for change, and improved adolescent sleep. DISCUSSION: This research provides an initial test of the hypothesis that improving the parent-adolescent conversation will improve adolescent sleep health behavior. While sleep-related health behaviors are the focus of this study, the research is designed to be relevant to a broad range of health behavior change in young people. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Promises and Pitfalls of Diversity Statements: Proceed With Caution.

As part of their efforts to increase the diversity of their workforce and student body, medical schools, academic medical centers, and individual departments are increasingly crafting public statements about their value for and commitment to diversity. For these statements to effectively enhance diversity, however, care must be taken, as research shows that some diversity-related messages can backfire. To avoid the pitfalls and realize the promise of diversity statements, this article presents recommendations based on experimental studies that investigate the impact of diversity messages. These studies suggest that diversity statements be aspirational, emphasize autonomy, and express a value for difference. Aspirational statements avoid creating the impression that equity has been achieved, thus preventing the "illusion of fairness" and the "paradox of meritocracy," wherein espousing egalitarian values and the existence of a meritocracy can increase biased outcomes and workplace disparities. Statements that emphasize autonomy avoid the backlash that can occur when organizational members feel coerced into adopting prodiversity actions. Statements that emphasize the value of human differences convey a multicultural message that has shown positive outcomes compared with "colorblind" statements that acknowledge our common humanity. Although there are no studies specific to academic medicine, current research on a variety of organizations, including some studies from the health care industry, suggests that relying on these recommendations to craft a diversity statement may help contribute to academic medical centers' larger efforts to promote diversity and inclusion and may help them avoid some deleterious effects.

The effect of an intervention to break the gender bias habit for faculty at one institution: a cluster randomized, controlled trial.

PURPOSE: Despite sincere commitment to egalitarian, meritocratic principles, subtle gender bias persists, constraining women's opportunities for academic advancement. The authors implemented a pair-matched, single-blind, cluster randomized, controlled study of a gender-bias-habit-changing intervention at a large public university. METHOD: Participants were faculty in 92 departments or divisions at the University of Wisconsin-Madison. Between September 2010 and March 2012, experimental departments were offered a gender-bias-habit-changing intervention as a 2.5-hour workshop. Surveys measured gender bias awareness; motivation, self-efficacy, and outcome expectations to reduce bias; and gender equity action. A timed word categorization task measured implicit gender/leadership bias. Faculty completed a work-life survey before and after all experimental departments received the intervention. Control departments were offered workshops after data were collected. RESULTS: Linear mixed-effects models showed significantly greater changes post intervention for faculty in experimental versus control departments on several outcome measures, including self-efficacy to engage in gender-equity-promoting behaviors (P = .013). When ≥ 25% of a department's faculty attended the workshop (26 of 46 departments), significant increases in self-reported action to promote gender equity occurred at three months (P = .007). Post intervention, faculty in experimental departments expressed greater perceptions of fit (P = .024), valuing of their research (P = .019), and comfort in raising personal and professional conflicts (P = .025). CONCLUSIONS: An intervention that facilitates intentional behavioral change can help faculty break the gender bias habit and change department climate in ways that should support the career advancement of women in academic medicine, science, and engineering.

Promoting Institutional Change Through Bias Literacy.

The National Science Foundation and others conclude that institutional transformation is required to ensure equal opportunities for the participation and advancement of men and women in academic science, technology, engineering, mathematics, and medicine (STEMM). Such transformation requires changing the habitual attitudes and behaviors of faculty. Approaching implicit bias as a remediable habit, we present the theoretical basis and conceptual model underpinning an educational intervention to promote bias literacy among university faculty as a step toward institutional transformation regarding gender equity. We describe the development and implementation of a Bias Literacy Workshop in detail so others can replicate or adapt it to their setting. Of the 220 (167 faculty and 53 nonfaculty) attendees from the initial 17 departments/divisions offered this workshop, all 180 who completed a written evaluation found the workshop at least "somewhat useful" and 74% found it "very useful." Over 68% indicated increased knowledge of the workshop material. Of the 186 participants who wrote a commitment to engage in new activities to promote gender equity, 87% incorporated specific workshop content. Twenty-four participants were interviewed 4-6 months after attending the workshop; 75% of these not only demonstrated increased bias awareness, but described plans to change-or had actually changed-behaviors because of the workshop. Based on our sample of faculty from a Midwestern university, we conclude that at least one third of STEMM faculty who are invited will attend a 2.5-hr Bias Literacy Workshop, that nearly all will find it useful, and that most will complete a written commitment to promoting gender equity. These findings suggest that this educational intervention may effectively promote institutional change regarding gender equity.

Searching for excellence & diversity: increasing the hiring of women faculty at one academic medical center.

One opportunity to realize the diversity goals of academic health centers comes at the time of hiring new faculty. To improve the effectiveness of search committees in increasing the gender diversity of faculty hires, the authors created and implemented a training workshop for faculty search committees designed to improve the hiring process and increase the diversity of faculty hires at the University of Wisconsin-Madison. They describe the workshops, which they presented in the School of Medicine and Public Health between 2004 and 2007, and they compare the subsequent hiring of women faculty in participating and nonparticipating departments and the self-reported experience of new faculty within the hiring process. Attendance at the workshop correlates with improved hiring of women faculty and with a better hiring experience for faculty recruits, especially women. The authors articulate successful elements of workshop implementation for other medical schools seeking to increase gender diversity on their faculties.

NIH Director's Pioneer Awards: could the selection process be biased against women?

One of the first National Institutes of Health (NIH) Roadmap initiatives to be launched was the Director's Pioneer Award. This award was established to "identify and fund investigators of exceptionally creative abilities and diligence, for a sufficient term (five years) to allow them to develop and test far-ranging ideas." Nine excellent scientists were chosen as NIH Pioneers, but the selection of all men is at odds with the percentage of women receiving doctoral degrees for the past three decades, serving as principal investigators on NIH research grants, and achieving recognition as scientific innovators in non-NIH award competitions. The absence of women Pioneers provokes the following question: In the context of extant research on the impact of gender-based assumptions on evaluation of men and women in traditionally male fields, such as science, were there aspects about the process of nomination, evaluation, and selection that inadvertently favored men? We present evidence to suggest that women scientists would be disadvantaged by the following components of the NIH Director's Pioneer Award initiative: (1) time pressure placed on evaluators, (2) absence of face-to-face discussion about applicants, (3) ambiguity of performance criteria, given the novelty of the award, combined with an emphasis on subjective assessment of leadership, potential achievements rather than actual accomplishments, and risk taking, (4) emphasis on self-promotion, (5) weight given to letters of recommendation, and (6) the need for finalists to make a formal, in-person presentation in which the individual and not his or her science was the focus of evaluation. We offer an analysis of this process to encourage the NIH to embark on self-study and to educate all reviewers regarding an evidence-based approach to gender and evaluation.