Social-emotional functioning among bias-based bullies, victims, and bully-victims.

Bias-based harassment in U.S. schools is an increasingly significant concern for students' well-being. Although research on bullying broadly defined has indicated that the ways in which youth are involved in bullying (i.e., as bullies, victims, and bully-victims) are differentially associated with functioning, this study adds to extant research by exploring whether similar patterns emerge for bias-based harassment. A nationally representative sample of 639 adolescents, ages 13-17, completed online surveys in 2021 that included measures of bias-based harassment, anxiety, depression, substance use, and school social support. Findings from a multivariate latent variable model indicated that after controlling for demographic variables, compared to individuals not involved in bias-based harassment, students involved as victims, perpetrators, or both victims and perpetrators of bias-based harassment (i.e., bias-based bully-victims) reported more mental health symptoms. Substance use was elevated for bias-based perpetrators and bully-victims, whereas school social support was diminished for bias-based victims and bully-victims. Notably, bias-based bully-victims had the highest levels of anxiety symptoms and substance use, and lowest levels of school social support, among all adolescents. Findings highlight that involvement in bias-based harassment in any capacity is associated with deleterious functioning, with bias-based bully-victims reporting particularly adverse functioning across domains. Bolstering protective factors such as school social support would be a useful component of school practices and prevention programs related to bias-based harassment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Fluidity in Gender Identity and Sexual Orientation Identity in Transgender and Nonbinary Youth.

Changes in sexual orientation identity (SOI) and gender identity (GI) have rarely been studied in transgender and/or nonbinary youth (TNBY), but documenting such changes is important for understanding identity development and gender transition and supporting the needs of TNBY. This study examined the frequency and patterning of changes in GI and SOI across 3 months (T1-T2) and 1.5 years (T1-T4) among 183 TNBY (baseline age 14-17 years; 83.6% White, 16.9% Hispanic/Latinx) who participated in a longitudinal US study. Participants completed online surveys including measures of GI and SOI. The most common gender identity selected at T1 (with or without another gender identity) was nonbinary (56.3%), and more than half (57.4%) of youth identified with a plurisexual identity (e.g., bisexual, pansexual). GI fluidity from T1-T2 was 13.2% and from T1-T4 was 28.9%. It was equally common to move toward a nonbinary gender identity as toward a binary gender identity. SOI fluidity was more common (30.6% from T1-T2; 55.8% from T1-T4) than GI fluidity. Shifts toward plurisexual identities were more common than shifts toward monosexual identities (e.g., straight, gay). Findings highlight the need to assess changes in GI and SOI in research and clinical practice to address the unique needs of TNBY accurately and effectively.

Fentanyl analog structure-activity relationships demonstrate determinants of diverging potencies for antinociception and respiratory depression.

Opioid overdoses, particularly those involving fentanyl-related substances (FRS), present a significant public health challenge in the United States. This structure-activity relationship (SAR) study evaluated the relationship between the chemical structure of seventeen FRS and their in vivo mu-opioid-receptor (MOR) mediated effects. SAR evaluations included fluorine substitutions on the aniline or phenethyl ring and variations in N-acyl chain length. Adult male Swiss Webster mice were administered fluorinated regioisomers of fentanyl, butyrylfentantyl and valerylfentanyl, and compared to MOR standards including morphine, buprenorphine, and fentanyl to determine if they would elicit prototypical opioid-like effects including hyperlocomotion (open-field test), antinociception (warm-water tail-withdrawal test), and hypoventilation (whole-body plethysmography test). To determine if the MOR was the pharmacological mechanism responsible for these effects, naltrexone or naloxone pretreatments were administered to evaluate their actions on FRS-induced antinociception and hypoventilation. There were three main findings. First, FRS elicited hyperlocomotion, antinociception, and hypoventilation in mice to varying degrees, similar to prototypical MOR standards. Second, the rank order of potencies for hypoventilatory effects of FRS were different for each series including FRS with increasing N-acyl chain length (i.e., acetylfentanyl, fentanyl, butyrylfentanyl, valerylfentanyl, hexanoylfentanyl), phenethyl-fluorinated regioisomers (e.g., 2'-fluorofentanyl, 3'-fluorofentanyl, 4'-fluorofentanyl), and aniline-fluorinated regioisomers (e.g., ortho-fluorofentanyl, meta-fluorofentanyl, para-fluorofentanyl). Third, the degree of separation in potencies observed for the antinociceptive and hypoventilatory effects of these drugs did not always follow that which was observed for their antinociceptive and hyperlocomotor effects. This study clarifies the in vivo activities for these FRS and elucidates a SAR for MOR-mediated effects among structural isomers.

Parenting stress and competence among mothers of young children with substance use disorders: The roles of trauma and reflective functioning.

Posttraumatic stress symptoms are prominent in the lives of parents of young children with substance use disorders (SUD). Parenting experiences, particularly stress and competence, impact parenting behaviors and concomitant child growth and development. Factors that promote positive experiences of parenting, such as parental reflective functioning (PRF), and protect the mother and child from negative outcomes are crucial to understand to develop effective therapeutic interventions. The current US study analyzed baseline data from a parenting intervention evaluation to examine how length of substance misuse, PRF, and trauma symptoms were associated with parenting stress and parenting sense of competence among mothers in treatment for SUDs. Measures included the Addiction Severity Index, PTSD Symptom Scale-Self Report, Parental Reflective Functioning Questionnaire, Parenting Stress Index/Short Form, and Parenting Sense of Competence Scale. The sample included 54 predominantly White mothers with SUDs who had young children. Two multivariate regression analyses found that (1) lower parental reflective functioning and higher posttraumatic stress symptoms were associated with higher parenting stress, and (2) only higher posttraumatic stress symptoms were associated with lower levels of parenting sense of competence. Findings underscore the importance of addressing trauma symptoms and PRF when aiming to improve parenting experiences for women with an SUD.

Los síntomas de estrés postraumático son prominentes en las vidas de progenitores de niños pequeños con trastornos de uso de sustancias (SUD). Las experiencias de crianza, particularmente el estrés y la competencia, ejercen un impacto en el comportamiento de crianza y el inherente crecimiento y desarrollo del niño. Los factores que promueven las positivas experiencias de crianza, tales como el funcionamiento con reflexión del progenitor (PRF), y protegen a la madre y al niño de resultados negativos, son cruciales para comprender cómo desarrollar intervenciones terapéuticas eficaces. El presente estudio en Estados Unidos analizó datos de referencia de una evaluación de intervención de crianza para examinar cómo la duración del mal uso de sustancias, PRF y los síntomas de trauma estaban asociados con el estrés de crianza y el sentido de competencia en la crianza entre madres bajo tratamiento por SUD. Entre las medidas se incluyeron el Índice de Severidad de la Adicción, la Escala de Auto Reporte de Síntomas de PTSD, el Cuestionario del Funcionamiento con Reflexión del Progenitor, el Índice de Estrés de Crianza/Forma Abreviada, así como la Escala del Sentido de Competencia en la Crianza. El grupo muestra incluyó 54 madres predominantemente blancas con SUD, que tenían niños pequeños. Dos análisis de regresión multivariados observaron que 1) un más bajo funcionamiento con reflexión del progenitor y unos más altos síntomas de estrés postraumático se asociaban con un más alto estrés de crianza y 2) sólo los más altos síntomas de estrés postraumático se asociaban con niveles más bajos de sentido de competencia en la crianza. Las observaciones subrayan la importancia de hablar sobre los síntomas de trauma y PRF cuando se busca mejorar las experiencias de crianza para mujeres con un SUD.

Les symptômes de stress post-traumatiques sont importants dans les vies de parents de jeunes enfants avec des troubles liés à l'usage d'une substance (TUS) de toxicomanie. Les expériences de parentage, particulièrement le stress et la compétence, ont un impact sur les comportements de parents et la croissance concomitante de l'enfant et son développement. Les facteurs qui promeuvent des expériences positives de parentage, comme le fonctionnement de réflexion parentale (ici abrégé FRP), et protègent la mère et l'enfant de résultats négatifs sont essentiels à comprendre pour développer des interventions thérapeutiques efficaces. Cette étude américaine a analysé les données de base de l'évaluation d'une intervention de parentage pour examiner comment la durée de l'utilisation de substance, le FRP et les symptômes de trauma sont liés au stress de parentage et au sens de compétence de parentage chez les mères étant traitée pour des TUS. Les mesures ont inclus l'Index de Sévérité de Dépendance, l'Échelle d'évaluation des symptômes du TSPT - Déclaration personnelle, le Questionnaire de Fonctionnement de Réflexion Parental, l'Indice de Stress de Parentage/Formulaire Abrégé, et l'Echelle de Sens de Compétence de Parentage. L'échantillon a inclus 54 mères en grande partie blanches ave des TUS qui avaient de jeunes enfants. Deux analyses de régression multivariées ont trouvé que 1) un fonctionnement de réflexion parentage moins élevé et des symptômes de stress post-traumatiques plus élevés étaient liés à un stress de parentage plus élevé et 2) seuls les symptômes de stress post-traumatiques plus élevés étaient liés à des niveaux plus bas de sens de compétence de parentage. Les résultats soulignent l'importance qu'il y a à traiter les symptômes de trauma et le FRP lorsqu'on essaie d'améliorer les expériences de parentage de femmes avec un TUS.

Identifying protective factors for gender diverse adolescents' mental health.

Few studies have disentangled differences in victimization exposures and mental health symptoms among gender diverse subgroups, nor considered the role of potential protective factors in ameliorating the impact of victimization on gender diverse youths' mental health. Here we report findings from a secondary data analysis, in which we address this gap by analyzing cross-sectional survey data (N = 11,264 in the final analytic sample) from a population-based survey of youth in participating school districts in a large Midwestern U.S. county. Relative to cisgender youth with gender conforming expression, transgender youth and cisgender youth with nonconforming gender expression are more likely to experience victimization and severe mental health concerns. Additionally, school-connectedness moderates the association between bias-based harassment and depression for cisgender youth with gender nonconforming expression, and family support/monitoring buffers the association of peer victimization with suicide attempts among transgender youth. Findings highlight the need to better understand factors which may confer protection among gender diverse adolescents, so that in turn appropriate supports across key contexts can be implemented.

Teacher and School Characteristics Associated with the Identification and Referral of Adolescent Depression and Oppositional Defiant Disorders by U.S. Teachers.

Teachers contribute to the process of identifying and referring students for mental health services, however, relatively little is known about how they make those decisions and how decision-making differs across school contexts. This study used a vignette-based method to investigate individual and school contextual factors associated with the likelihood that teachers identify and refer students for mental health services. Teachers were recruited from public middle and high schools across the U.S. using a stratified random sampling strategy. Teachers (N = 462) responded to vignettes by indicating their concern for students, as well as their likelihood of providing mental health referrals. Vignettes varied by problem type (depression, oppositional defiant disorder), problem severity (moderate, severe), and student gender (male, female). Data on school characteristics were extracted from the U.S. Department of Education database. Regression models indicated several significant associations of teacher demographic characteristics and school characteristics with vignette ratings. For example, female teachers were more likely than males to rate vignettes as concerning, and middle school teachers were more likely than high school teachers to indicate they would refer students for mental health services. Teachers in schools with a higher proportion of Black students rated depression vignettes as less serious and indicated they were less likely to refer students for mental health services than teachers in majority white schools. Results suggest school characteristics may contribute to established disparities in mental health service access. Findings have implications for targeting mental health supports in schools. Supplementary Information: The online version contains supplementary material available at 10.1007/s12310-021-09491-1.

Time trends and disparities in anxiety among adolescents, 2012-2018.

PURPOSE: Prior studies have been inconclusive in documenting whether the prevalence of adolescent anxiety is increasing, given sampling and measurement limitations. This study adds new information on recent time trends in anxiety prevalence, specifically investigating trends among previously unexamined sociodemographic subgroups. METHODS: Weighted data of 37,360 youth respondents (51.1% female, 71.8% White, 91.3% heterosexual, 99.2% cisgender) from the 2012-2018 Dane County Youth Assessment, a county-wide survey administered to youth in participating school districts, were analyzed to estimate time trends in anxiety prevalence among the whole sample and by sociodemographic subgroups. RESULTS: The prevalence of youth meeting anxiety-screening criteria increased from 34.1% (95% CI 33.4-34.9) in 2012 to 44% (95% CI 43.2-44.7) in 2018 (OR for trend = 1.07, P for trend < 0.001). The trend remained significant after adjusting for known confounds (AOR for trend = 1.07, P for trend < 0.001). Anxiety increased significantly for several subgroups and widening disparities were documented among females relative to males (P < 0.001), and sexual minority youth relative to heterosexual youth (P = 0.003). In addition, Black youth did not increase at the same swift rate as White youth over the study period (P < 0.001). CONCLUSION: This study reports recent data on anxiety time trends and finds that among a geographically representative sample of adolescents, anxiety prevalence is rising. Findings provide new evidence documenting increased anxiety prevalence among sexual minority youth relative to their peers. Results highlight the need to bolster public health interventions focused on adolescent mental health, with tailored interventions for vulnerable groups.

Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED50 = 0.96 mg/kg) > 3-furanylfentanyl (ED50 = 2.60 mg/kg) > crotonylfentanyl (ED50 = 2.72 mg/kg) > para-methoxyfentanyl (ED50 = 3.31 mg/kg) > buprenorphine (ED50 = 10.8 mg/kg) > isobutyrylfentanyl (ED50 = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED50 = 16.1 mg/kg) > thiophenefentanyl (ED50 = 18.0 mg/kg) > morphine (ED50 = 55.3 mg/kg) > benzodioxolefentanyl (ED50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.

Associations between school-related factors and mental health among transgender and gender diverse youth.

Transgender and gender diverse youth (TGD) report high rates of mental health concerns. However, there is reason to expect that among TGD youth there is variation in mental health experiences related to specific aspects of gender identity. Furthermore, although certain school characteristics are related to improved mental health for sexual minority youth, it is unclear whether the same school characteristics are associated with improved mental health for TGD youth and whether gender identity moderates the associations between school characteristics and mental health. Using baseline data from Project AVANT, a longitudinal study of TGD youth ages 14-18 years in the United States (N = 252), we report on several mental health outcomes (i.e., depression, anxiety, nonsuicidal self-injury, and PTSD), with attention to differences by gender identity. Secondly, we examined associations of three protective school-related factors (i.e., school-connectedness, presence of a Gay-Straight or Gender-Sexuality Alliance [GSA], and state mandated protections for sexual and gender minority students) with TGD youth mental health. TGD youth reported elevated levels of anxious and depressive symptoms, with nonbinary youth assigned female at birth reporting higher mean depressive symptoms relative to transgender females. Among the aggregate sample of TGD youth, 69.9% reported clinically significant anxiety, 57.9% reported clinically significant depression, 56.7% reported nonsuicidal self-injury, and 46.4% met screening criteria for posttraumatic stress disorder. Despite a small effect size, greater school-connectedness was significantly associated with fewer mental health concerns and gender identity moderated the association between school-connectedness and number of anxiety symptoms. Gender identity also moderated the association between presence of a GSA and number of anxious symptoms, depressive symptoms, and clinically significant depression, respectively. No significant associations of state-level protections and mental health outcomes were detected. Findings highlight the importance of improving mental health and fostering GSA-engagement and school-connectedness among TGD youth. Implications for school psychologists are discussed.

School Connectedness Still Matters: The Association of School Connectedness and Mental Health During Remote Learning Due to COVID-19.

School connectedness is consistently associated with adolescent mental health and well-being. We investigated whether student perceptions of school connectedness were associated with anxiety and depressive symptoms, even during remote learning due to COVID-19. In June of 2020, after 13 weeks of remote learning, 320 middle and high school students in one Massachusetts school district completed an online survey that included questions about their perceptions of school connectedness, social connectedness, and symptoms of anxiety and depression. Students were approximately evenly distributed across grades, with 37% in middle school (grades 6-8) and 63% in high school (grades 9-12). School connectedness had a significant negative association with symptoms of anxiety and depression. This association persisted in models controlling for demographic factors and social connectedness. Findings indicate that school connectedness is associated with student mental health, even in the context of remote learning due to COVID-19. Schools engaged in remote learning should consider how to foster school connectedness as a means of supporting youth mental health, particularly given expected increases in the mental health needs of adolescents.

Bilateral Retinal Vasculitis as the First Presentation of Systemic Lupus Erythematosus.

BACKGROUND Systemic lupus erythematosus (SLE) can involve any part of the eye. Keratoconjunctivitis sicca (dry eye) is the most common ocular manifestation, followed by scleritis, episcleritis, and retinitis. Retinal disease affects around 10% of patients with SLE. Mild retinopathy may be asymptomatic. However, severe cases can cause visual loss requiring urgent ophthalmic evaluation. CASE REPORT We present a case of bilateral retinal vasculitis as the presenting manifestation of SLE. A 14-year-old girl with a history of schizophrenia presented to the emergency department (ED) with generalized weakness. Four days before her presentation, she developed itching in her eyes and frontal headaches. In the ED, she reported blurry vision in her left eye only and diffuse arthralgia. The ophthalmic evaluation showed bilateral reduced visual acuity, worse in the left eye. Both eyes had diffuse hemorrhages, white retinal lesions, and blurred optic disc margins. She was diagnosed with panuveitis and retinal vasculitis. The patient was then found to have SLE, diagnosed by the presence of arthralgias, panuveitis, severe bilateral retinal vasculitis, positive ANA and anti-dsDNA, and normocytic anemia. The patient received intravenous methylprednisolone with subsequent oral prednisone upon discharge, hydroxychloroquine, and azathioprine. One year after her presentation, she had significant visual improvement and no other system involvement. CONCLUSIONS Retinal vasculitis, as the presenting symptom of SLE, has been overlooked in large studies. However, the number of case reports documenting this as a presenting symptom, often with minimal or no organ involvement, suggests that upon diagnosis, patients might benefit from a skilled ophthalmic evaluation.

Novel amide and imidazole compounds as potent hematopoietic prostaglandin D2 synthase inhibitors.

In seeking novel and potent small molecule hematopoietic prostaglandin D2 synthase (H-PGDS) inhibitors as potential therapies for PGD2-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole "linker" between the pyrimidine or pyridine "core" ring and the "tail" ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD2 stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.

Victimization and Somatic Problems: The Role of Class Victimization Levels.

BACKGROUND: The link between peer victimization and somatic problems is well-established. What is currently understudied is under what contextual conditions victims' health might be most likely to be compromised. Studies demonstrate that victims suffer from poorer adjustment when they belong to a group in which victimization is less normative (social misfit hypothesis). We examined whether the association between individual victimization and somatic problems was stronger in classrooms with lower class victimization. METHODS: A sample of 1906 adolescents (65% girls; Mage  = 14.4, SD = 1.2) completed a survey about school life quality, peer victimization, and health problems. RESULTS: Multilevel modeling with Bayes estimator indicated modest variation in somatic problems between classrooms. At the individual level, peer victimization was associated with higher reports of somatic problems. This association varied across classroom as a function of class victimization level. Simple slope computation confirmed that the association between peer victimization and somatic complaints became stronger as class victimization levels decreased. CONCLUSIONS: Victims in classrooms with lower levels of victimization are more likely to report somatic problems. Anti-bullying programs should consider the effects of class norms on victims' adjustment and address the possible risks for those who continue to be victimized.

Retrospective perceptions of power imbalance in childhood bullying among college students.

OBJECTIVE: Bullying is characterized by differences in power between targets and aggressors. This study examines how experiences with power dynamics in childhood bullying are associated with symptoms of depression and anxiety in college. PARTICIPANTS: First-year college students (N = 470) at four universities reported on childhood bullying victimization and power imbalance. METHOD: Participants completed an online survey in fall 2012 that assessed childhood bullying victimization and symptoms of depression and anxiety. RESULTS: Students reporting childhood bullying victimization who indicated they were unable to defend themselves had greater symptoms of anxiety and depression than those who reported victimization but indicated they were able to defend themselves. Qualitative analyses explored why students perceived they could not defend themselves, including factors related to themselves and aggressors. CONCLUSION: For college students, feeling unable to defend oneself during childhood bullying victimization may be a focus for intervention and help explain diverse college outcomes associated with bullying victimization.

Improved homology modeling of the human & rat EP4 prostanoid receptors.

BACKGROUND: The EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP. RESULTS: Rank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP4 receptor and ligands including PGE2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models. CONCLUSIONS: This work has generated a set of novel homology models of the rEP4 and hEP4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE1 ≈ PGE2 > 11-deoxy-PGE1 ≈ 11-dexoy-PGE2 > 8-aza-11-deoxy-PGE1. This rank-ordering matches closely with the rEP4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE1 Series EP4 Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE1 Analog (KMN-159) as a Potent EP4 Agonist.

A series of small-molecule full agonists of the prostaglandin E2 type 4 (EP4) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.

All Things in Moderation? Threshold Effects in Adolescent Extracurricular Participation Intensity and Behavioral Problems.

BACKGROUND: School-based extracurricular activity participation is one of the primary avenues for prosocial activity engagement during adolescence. In this study, we test the "overscheduling hypothesis" or whether the negative relationship between structured activity intensity (ie, hours) and adolescent bullying and fighting levels off or declines at moderate to high intensity (ie, threshold effects). METHODS: This study uses the Dane County Youth Survey (N = 14,124) to investigate the relationship between school-based extracurricular activity participation intensity and bullying perpetration and physical fighting and whether there are threshold effects of activity participation intensity. RESULTS: The results indicate that there is a negative relationship between extracurricular activity participation intensity and bullying perpetration and physical fighting and that there are threshold effects in these relationships at 3 to 4 hours per week. Results also suggest that low-income adolescents engage in more fighting than other youth and the negative relationship between activity participation intensity and physical fighting was mainly concentrated among low-income adolescents. CONCLUSIONS: School-based extracurricular activity participation-in moderation (ie, up to 3-4 hours per week)-may provide a positive, supportive context that could be a promising prevention strategy for bullying and fighting. Implications for future research on how school-based extracurricular activity participation intensity benefits adolescent functioning are discussed.

Perceived consequences of hazing exposure during the first year of college: Associations with childhood victimization.

Objective: This study investigates the association between histories of childhood victimization and perceived consequences of college hazing. Participants: First-year college students at four US universities (N = 120). Method: Participants completed Web-based surveys asking about childhood victimization (eg, child maltreatment), peer victimization, and perceived consequences of hazing during college. Results: Results indicated that college students with childhood victimization histories perceived hazing to be negative. In particular, physical dating violence and a greater total number of childhood victimization exposures were related to a higher number of perceived negative consequences. Conclusion: Past victimization exposures confer risk on college students who experience hazing, in that these students are more likely to perceive negative consequences of hazing. Hazing-related policies and outreach efforts should consider these potential negative consequences, and counselors should be aware of the link between past victimization and how hazing might be experienced.