Exploring regulatory flexibility to create novel incentives to optimize drug discovery.

Efforts by governments, firms, and patients to deliver pioneering drugs for critical health needs face a challenge of diminishing efficiency in developing those medicines. While multi-sectoral collaborations involving firms, researchers, patients, and policymakers are widely recognized as crucial for countering this decline, existing incentives to engage in drug development predominantly target drug manufacturers and thereby do little to stimulate collaborative innovation. In this mini review, we consider the unexplored potential within pharmaceutical regulations to create novel incentives to encourage a diverse set of actors from the public and private spheres to engage in the kind of collaborative knowledge exchange requisite for fostering enhanced innovation in early drug development.

Examining trauma, anxiety, and depression as predictors of dropout from residential treatment for substance use disorders.

Substance use disorders (SUDs) are highly prevalent and have deleterious effects on one's health and well-being. Inpatient treatment for SUDs reduces patient relapse, which subsequently ameliorates these negative effects on the individual and society. Additionally, those who complete treatment are less likely to relapse compared to those who do not complete treatment. Thus, maintaining patient engagement in treatment and reducing the rates of those leaving against medical advice (AMA) is particularly important. Examining the factors and comorbidities that may contribute to treatment dropout has the potential to identify at-risk patients in need of additional individualized intervention. The current study aimed to examine comorbid anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms as predictors of dropout AMA in a residential substance use treatment population. Results showed that patients with social anxiety were more likely to leave treatment AMA, while those with PTSD were more likely to complete treatment. Findings suggest that PTSD-specific treatment, as offered in this facility, may help with patient retention, while group focused therapy may be distressing to those with social anxiety. Clinical implications of this research may include incorporating evidence-based practice for social anxiety early during inpatient treatment to reduce anxiety such that patients may better engage with SUDs treatment.

Intimate Partner Violence Perpetration Among Sexual Minority Young Adults: Associations With Alcohol Use, PTSD Symptoms, Internalized Homophobia, and Heterosexist Discrimination.

Lesbian, gay, bisexual, queer, and other sexual minority (LGBQ+) young adults report similar or higher rates of intimate partner violence (IPV) perpetration than their heterosexual peers. Elevated IPV risk among LGBQ+ young adults may be attributable to experiencing heterosexist discrimination and internalized homophobia. In addition, LGBQ+ people report disproportionate posttraumatic stress disorder (PTSD) symptoms, alcohol use, and IPV perpetration in dating relationships. Thus, this study explored which combinations of IPV risk factors (i.e., experiencing heterosexist discrimination, internalized homophobia, PTSD symptoms, alcohol use) related to forms of IPV perpetration, inclusive of psychological, physical, and sexual forms, in a sample of 342 LGBQ+ young adults. Internalized homophobia was related to psychological IPV perpetration at high and medium levels of PTSD symptoms and only high levels of alcohol use. PTSD symptoms and alcohol use interacted to predict psychological IPV perpetration; and PTSD symptoms related to increased psychological IPV perpetration at high and medium, but not low, alcohol use levels. Alcohol use was positively related to physical IPV perpetration. No other risk factors or interactions were significantly related to physical or sexual IPV perpetration. Results were consistent with prior findings that linked internalized homophobia, alcohol use, and PTSD symptoms to IPV perpetration and highlight the interacting nature of these IPV perpetration risk factors. Comprehensive IPV interventions with LGBQ+ young adults should evaluate the impact of simultaneously targeting these multiple IPV risk factors considering their interacting contributions to IPV perpetration risk. More research is needed to examine the temporal relations between minority stress, PTSD symptoms, alcohol use, and IPV perpetration.

An Integrative Model of Youth Anxiety: Cognitive-Affective Processes and Parenting in Developmental Context.

Multiple theoretical frameworks have been proposed to provide a more comprehensive picture of the risk factors that influence anxiety-related developmental trajectories. Nonetheless, there remains a need for an integrative model that outlines: (1) which risk factors may be most pertinent at different points in development, and (2) how parenting may maintain, exacerbate, or attenuate an affective style that is characterized by high negative emotional reactivity to unfamiliar, uncertain, and threatening situations. A developmentally informed, integrative model has the potential to guide treatment development and delivery, which is critical to reducing the public health burden associated with these disorders. This paper outlines a model integrating research on many well-established risk mechanisms for anxiety disorders, focusing on (1) the developmental progression from emotional reactivity constructs early in life to those involving higher-level cognitive processes later in youth, and (2) potential pathways by which parenting may impact the stability of youth's cognitive-affective responses to threat-relevant information across development.

Sexual Narcissism and Hypersexuality Relate to Sexual Coercion in Hookups among U.S. University Students.

Sexual violence remains a prevalent issue on college campuses. Sexual coercion, a form of sexual violence, is frequently employed within casual sexual encounters (i.e., hookups). The present study investigated hypersexuality and sexual narcissism as unique predictors of sexual coercion and examined whether there were gender differences in these associations. Participants (N = 793, ages 18-25) were undergraduate students at a large southeastern university who have: (1) engaged in sexual activity within the past six months and (2) had at least one prior hookup experience. Respondents completed surveys online assessing levels of sexual narcissism, hypersexuality, and sexual coercion perpetration in hookups. Participants primarily identified as female (71.7%), White (84.2%), and heterosexual (86.6%), with an average of 9.77 sexual engagements per month. Bivariate correlations and independent samples t-tests were conducted to examine associations between and gender differences across study variables, respectively. We assessed the factor structure of study variables using confirmatory factor analysis and tested hypotheses using structural equation modeling. Compared to women, men scored higher on sexual exploitation and all hypersexuality subscales. After establishing good-fitting measurement models, we found that both sexual narcissism and hypersexuality predicted increased sexual coercion perpetration and that gender did not moderate these associations. Study findings demonstrated that sexual narcissism and hypersexuality are risk factors for sexual coercion perpetration in hookups across gender. Although associations were consistent across gender, men may report higher levels of sexual coercion perpetration risk factors. Future researchers could focus on gender differences in the etiology of sexual coercion risk factors.

Eating Competence Among Caregivers of Toddlers: Associations With Caregiver and Child Overweight/Obesity.

OBJECTIVE: To examine the association between caregiver eating competence and child overweight/obesity and caregiver obesity. DESIGN: Longitudinal cohort. SETTING: A large US children's hospital. PARTICIPANTS: Caregiver-child dyads (n = 288 with complete data at 2 time points) were sampled in 2017-2019 from those who received care at Nationwide Children's Hospital. MAIN OUTCOME MEASURE(S): Child overweight/obesity at 24 months of age (body mass index [BMI]) z-score >2 per World Health Organization standards and caregiver weight status (underweight/healthy [BMI < 25 kg/m2], overweight [BMI ≥ 25 and < 30 kg/m2], or obese [BMI ≥ 30 kg/m2]). ANALYSIS: Log-binomial models examined the relationship between caregiver eating competence (ecSatter Inventory) at 18 months and child overweight/obesity at 24 months of age. Proportional odds models investigated the relationship between caregivers' eating competence and weight status. RESULTS: Eating competent caregivers had more than twice the odds (odds ratio, 2.11; 95% confidence interval, 1.30-3.42) of having a lower BMI category and had lower average BMI than noneating competent caregivers. Child overweight/obesity at 24 months did not differ by caregiver eating competence. CONCLUSIONS AND IMPLICATIONS: Although child overweight/obesity did not vary by caregiver eating competence, caregiver eating competence was related to their weight status. Longer-term studies are needed to clarify the role of caregiver eating competence as children develop. Promoting caregivers' eating competence may translate into healthier behaviors and skills for caregivers and their children long term.

Inhibition of androgenic pathway impairs encoding of cerebellar-dependent motor learning in male rats.

Cerebellar-dependent learning is essential for the adaptation of motor and no motor behaviors to changing contexts, and neuroactive steroids-mainly referred to as estrogens-may regulate this process. However, the role of androgens in this process has not been established, although they may affect cerebellar physiology. Thus, this study aims to determine whether the activation of androgenic neural pathways may take part in controlling the vestibuloocular (VOR) and optokinetic reflexes (OKR), which depend on a defined cerebellar circuitry. To answer this question, we acutely blocked the activation of androgen receptors (Ars) using systemic administration of the Ars antagonist flutamide (FLUT; 20 mg/Kg) in peripubertal male rats. Then, we evaluated the FLUT effect on general oculomotor performance in the VOR and OKR as well as VOR adaptive gain increases and decreases. We used a paradigm causing fast VOR adaptation that combined in phase/out phase visuo-vestibular stimulations. We found that FLUT impaired the gain increase and decrease in VOR adaptation. However, FLUT altered neither acute nor overtime basal ocular-motor performance in the VOR or OKR. These findings indicate that the activation of androgenic neural pathways participates in phenomena leading to fast VOR adaptation, probably through the modulation of plasticity mechanisms that underlie adaptation of this reflex. Conversely, androgens may not be essential for neural information processing demands in basal ocular-motor reflexes. Moreover, our results suggest that androgens, possibly testosterone and dihydrotestosterone, could rapidly regulate motor memory encoding in the VOR adaptation, acting at both cerebellar and extracerebellar plasticity sites.

Knowledge of Infant Development and Parent Well-Being: Cross-Sectional Analysis of Toddlers.

OBJECTIVE: Knowledge about child development is associated with parenting and children's outcomes. Parents with less accurate knowledge about developmental milestones may have unrealistic expectations for their child's behavior, which may affect parent well-being. Limited research has examined this topic relative to depression, but other aspects of parent well-being (e.g., parenting stress) are unexplored. METHODS: Cross-sectional analysis of an ongoing prospective cohort study of 300 families in central Ohio enrolled when children were a mean (SD) calendar age of 18.2 (0.7) months. Children of all gestational ages at birth are included, and 37% were born preterm (<37 weeks' gestation.) Primary caregivers (93% mothers) completed the 20-item Knowledge of Infant Development Index (KIDI) and questionnaires for child temperament and 3 aspects of parent well-being (depressive and anxious symptoms, parenting stress, and general health). Covariate-adjusted regression models assessed relationships between the KIDI score and each well-being outcome. We hypothesized that parents with less knowledge would have more symptoms of depression and anxiety, greater parenting stress, and poorer health. Whether associations were stronger for parents of children born preterm or who had high negative affect was explored. RESULTS: Knowledge of Infant Development Index scores were associated with sociodemographic characteristics, child temperament, and gestational age (more knowledge: higher socioeconomic position, less child negative affect, and full-term birth). KIDI scores did not predict any aspect of parent well-being, and there was no evidence that child temperament or preterm birth altered these findings. CONCLUSION: In this sample of parents of toddlers assessed in 2018/19, greater knowledge of infant development was not associated with parent well-being.

Feeding Infants at the Breast or Feeding Expressed Human Milk: Long-Term Cognitive, Executive Function, and Eating Behavior Outcomes at Age 6 Years.

OBJECTIVE: To examine how expressed milk feeding diverges from feeding at the breast in its association with neurodevelopment and behavior. We hypothesized that longer and exclusive feeding at the breast only (ie, no formula, no feeding expressed milk) would be associated with the optimal cognitive developmental, executive function, and eating behaviors and that expressed milk feeding would be associated with less-optimal outcomes. STUDY DESIGN: The Moms2Moms cohort (Ohio, US) reported infant feeding practices at 12 months postpartum and children's global cognitive ability, executive function, and eating behaviors at 6 years. Linear and log-binomial regression models estimated associations with durations of feeding at the breast, expressed milk, human milk (modes combined), and formula. RESULTS: Among 285 participants, each month of exclusive feeding at the breast only was associated with a decreased risk of clinically meaningful executive function (working memory) deficit (adjusted relative risk [RR] 0.78, 95% CI 0.63-0.96) but was unassociated with inhibition (adjusted RR 0.92, 95% CI 0.85-1.01). Feeding expressed milk was not clearly related to executive function outcomes. No associations with global cognitive ability were observed. Weak associations were observed with eating behaviors for some feeding practices. CONCLUSIONS: Feeding at the breast may offer advantages to some aspects of executive function that expressed milk may not. Large, prospective studies exploring mechanisms could further distinguish the effect of feeding mode from that of nutrients.

New frontiers in translational research: Touchscreens, open science, and the mouse translational research accelerator platform.

Many neurodegenerative and neuropsychiatric diseases and other brain disorders are accompanied by impairments in high-level cognitive functions including memory, attention, motivation, and decision-making. Despite several decades of extensive research, neuroscience is little closer to discovering new treatments. Key impediments include the absence of validated and robust cognitive assessment tools for facilitating translation from animal models to humans. In this review, we describe a state-of-the-art platform poised to overcome these impediments and improve the success of translational research, the Mouse Translational Research Accelerator Platform (MouseTRAP), which is centered on the touchscreen cognitive testing system for rodents. It integrates touchscreen-based tests of high-level cognitive assessment with state-of-the art neurotechnology to record and manipulate molecular and circuit level activity in vivo in animal models during human-relevant cognitive performance. The platform also is integrated with two Open Science platforms designed to facilitate knowledge and data-sharing practices within the rodent touchscreen community, touchscreencognition.org and mousebytes.ca. Touchscreencognition.org includes the Wall, showcasing touchscreen news and publications, the Forum, for community discussion, and Training, which includes courses, videos, SOPs, and symposia. To get started, interested researchers simply create user accounts. We describe the origins of the touchscreen testing system, the novel lines of research it has facilitated, and its increasingly widespread use in translational research, which is attributable in part to knowledge-sharing efforts over the past decade. We then identify the unique features of MouseTRAP that stand to potentially revolutionize translational research, and describe new initiatives to partner with similar platforms such as McGill's M3 platform (m3platform.org).

Lifestyle and Early Achievement in Families (LEAF) study: Design of an ambidirectional cohort study of prenatal marijuana exposure and child development and behaviour.

BACKGROUND: Marijuana is the most-used illicit substance during pregnancy in the USA, but only two cohort studies, begun over 30 years ago, were specifically established to assess the association of pregnancy use with childhood outcomes. They found use to be associated with specific deficits in executive function at 8+ years, but did not focus on these outcomes earlier in life when intervention may be more successful. Two general purpose cohorts found increased aggression in exposed female toddlers and increased behavioural problems and tic disorders in exposed school-age children. OBJECTIVES: The Lifestyle and Early Achievement in Families (LEAF) study assesses the association of in utero marijuana exposure, documented prospectively by biomarker, self-report, and medical records, with executive function and aggression at age 3½-7 years. METHODS: This ambidirectional cohort (historical cohort with continued follow-up) includes women enrolled in the Perinatal Research Repository during prenatal care at Ohio State University Wexner Medical Center and their children, recontacted 3½-7 years post-birth. Children complete 1-2 study visits including cognitive testing, behavioural observation, and maternal and teacher report of behaviour. Family and social environmental factors are assessed. RESULTS: Child follow-up began in September 2016; visits continue through August 2020. There are 362 eligible children; 32% had mothers who used marijuana during pregnancy, 10% of mothers completed college, and 23% did not complete high school. Mean maternal age at study registration in pregnancy was 26.4 years, and 63% of mothers were African American. To date, 268 children have completed at least 1 study visit. CONCLUSIONS: The LEAF Study will document the association of prenatal marijuana exposure with development and behaviour in the current era when marijuana is more potent than when previous cohorts were studied. The results may inform policy and interventions to counsel reproductive-aged women about the risks of use during pregnancy and guide prevention and treatment of adverse effects among children.

Sensory inflow manipulation induces learning-like phenomena in motor behavior.

PURPOSE: Perceptual and goal-directed behaviors may be improved by repetitive sensory stimulations without practice-based training. Focal muscle vibration (f-MV) modulating the spatiotemporal properties of proprioceptive inflow is well-suited to investigate the effectiveness of sensory stimulation in influencing motor outcomes. Thus, in this study, we verified whether optimized f-MV stimulation patterns might affect motor control of upper limb movements. METHODS: To answer this question, we vibrated the slightly tonically contracted anterior deltoid (AD), posterior deltoid (PD), and pectoralis major muscles in different combinations in forty healthy subjects at a frequency of 100 Hz for 10 min in single or repetitive administrations. We evaluated the vibration effect immediately after f-MV application on upper limb targeted movements tasks, and one week later. We assessed target accuracy, movement mean and peak speed, and normalized Jerk using a 3D optoelectronic motion capture system. Besides, we evaluated AD and PD activity during the tasks using wireless electromyography. RESULTS: We found that f-MV may induce increases (p < 0.05) in movement accuracy, mean speed and smoothness, and changes (p < 0.05) in the electromyographic activity. The main effects of f-MV occurred overtime after repetitive vibration of the AD and PD muscles. CONCLUSION: Thus, in healthy subjects, optimized f-MV stimulation patterns might over time affect the motor control of the upper limb movement. This finding implies that f-MV may improve the individual's ability to produce expected motor outcomes and suggests that it may be used to boost motor skills and learning during training and to support functional recovery in rehabilitation.

To attend, or not to attend: Examining caregiver intentions and study compliance in a pediatric, randomized controlled trial.

BACKGROUND/AIMS: The Intent to Attend is a brief questionnaire recommended by the National Research Council to address dropout concerns and improve prediction of missing data in clinical trials, although implementation has been very limited. As a formative study in pediatric research, the relationship between caregiver intentions and study compliance was investigated in a 180-day trial of dietary supplementation of preterm toddlers. Treatment effect estimation in the context of missing data was also explored. METHODS: Study compliance (i.e. study completion, supplement adherence, and diary completion) was tracked over three study visits. Baseline questionnaires asked caregivers about intentions concerning study completion via the Intent to Attend, screened for mental health symptoms (depression, trait anxiety), and captured family demographics. Simple and multiple logistic regression models were built to examine associations between caregiver intent and compliance outcomes. The Intent to Attend was also employed as an auxiliary variable to account for missing data within mixed models estimating the treatment effect on the primary outcomes. RESULTS: Of the 316 caregiver-child dyads included, 95% of caregivers with low intentions had a child complete the study, but only 87% of caregivers with high intentions had a child complete the study. Low intentions to complete the study were associated with a more than 60% lower odds of study non-completion, but the confidence interval included the null (odds ratio: 0.36; 95% confidence interval: 0.11, 1.20). No effect measure modification by caregiver mental health, child sex, or annual income was detected. Income was the only significant predictor of study non-completion; the lowest income group was almost four times more likely to be study non-completers compared with the highest income group, even after adjustment for child sex and caregiver mental health (adjusted odds ratio = 3.59, 95% confidence interval: 1.38, 9.31). When using Intent to Attend as an auxiliary variable, similar results were obtained when compared with the original treatment effect estimates on the primary outcomes. CONCLUSION: Contrary to prior adult studies, there is no clear relationship between caregiver intentions and study compliance. Findings elucidate the complexities of caregiver-child interactions during pediatric trial participation.

17 beta-estradiol synthesis modulates cerebellar dependent motor memory formation in adult male rats.

Neurosteroid 17 beta-estradiol (E2) is a steroid synthesized de novo in the nervous system that might influence neuronal activity and behavior. Nevertheless, the impact of E2 on the functioning of those neural systems in which it is slightly synthesized is less questioned. The vestibulo-ocular reflex (VOR) adaptation, may provide an ideal arena for investigating this issue. Indeed, E2 modulates cerebellar parallel fiber-Purkinje cell synaptic plasticity that underlies encoding of VOR adaptation. Moreover, aromatase expression in the cerebellum of adult rodents is maintained at very low levels and localized to Purkinje cells. The significance of age-related maintenance of low levels of aromatase expression in the cerebellum on behavior, however, has yet to be explored. Our aim in this study was to determine whether E2 synthesis exerts an effective and persistent modulation of VOR adaptation in adult male rats. To answer this question, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in VOR adaptation using an oral dose (2.5 mg/kg) of the aromatase inhibitor Letrozole in peri-pubertal and post-pubertal male rats. We found that Letrozole acutely impaired gain increases and decreases in VOR adaptation without altering basal ocular-motor performance and that these effects were similar in peri-pubertal and post-pubertal rats. Thus, in adult male rats neurosteroid E2 effectively modulates VOR adaptation in both of the periods studied. These findings imply that the adult cerebellum uses E2 synthesis for modulating motor memory formation and suggest that low and extremely localized E2 production may play a role in adaptive phenomena.

How landmark suitability shapes recognition memory signals for objects in the medial temporal lobes.

A role of perirhinal cortex (PrC) in recognition memory for objects has been well established. Contributions of parahippocampal cortex (PhC) to this function, while documented, remain less well understood. Here, we used fMRI to examine whether the organization of item-based recognition memory signals across these two structures is shaped by object category, independent of any difference in representing episodic context. Guided by research suggesting that PhC plays a critical role in processing landmarks, we focused on three categories of objects that differ from each other in their landmark suitability as confirmed with behavioral ratings (buildings > trees > aircraft). Participants made item-based recognition-memory decisions for novel and previously studied objects from these categories, which were matched in accuracy. Multi-voxel pattern classification revealed category-specific item-recognition memory signals along the long axis of PrC and PhC, with no sharp functional boundaries between these structures. Memory signals for buildings were observed in the mid to posterior extent of PhC, signals for trees in anterior to posterior segments of PhC, and signals for aircraft in mid to posterior aspects of PrC and the anterior extent of PhC. Notably, item-based memory signals for the category with highest landmark suitability ratings were observed only in those posterior segments of PhC that also allowed for classification of landmark suitability of objects when memory status was held constant. These findings provide new evidence in support of the notion that item-based memory signals for objects are not limited to PrC, and that the organization of these signals along the longitudinal axis that crosses PrC and PhC can be captured with reference to landmark suitability.

Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats.

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber-Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) of the aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites.