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This mixed-methods survey study aims to describe the effects of the COVID-19 pandemic on the mental health of a sample of 571 children and adolescent seeking psychiatric emergency care. The study was conducted from July to October 2020 at a large Midwestern academic center. Among the respondents, there were significant increases in mental health symptoms attributed to the COVID-19 pandemic, including anxiety (71% of respondents), depression (66%), suicidal thoughts or behaviors (45%), and aggression (31%). There were significant differences in reported increases in symptoms by age and gender. In addition, 38% of participants reported that the pandemic led to a change or closure of their health care treatment, including mental health providers, with 22% reporting that reduced treatment access led to their emergency visit. Further research is indicated to assess other, more diverse populations, as well as the longer-term mental health impacts of the pandemic.

This chapter describes all aspects of the evaluation and management of the agitated patient, one of the most common, and challenging, presentations encountered in psychiatric emergency care. Agitated behaviors range from restlessness to overt physical aggression and can escalate rapidly, placing both the patient and staff at risk of harm. Although early recognition and intervention are crucial for success, the wide variety of underlying etiologies of agitation present barriers to optimal care. This chapter will review how tailoring of treatment interventions has developed to more precisely and effectively target the behaviors while always keeping the safety of the patient and staff at the forefront of one’s mind. It will also review the rise of verbal de-escalation as a first line intervention for agitation management, as well as describing principles of pharmacologic management should verbal de-escalation be inadequate. Special population such as those with personality disorders, substance intoxication or withdrawal, and psychosis or mania, will be explored as each may have particularly effective interventions as well pitfalls to avoid. Finally, as a measure of last resort, guidelines around seclusion and/or restraint will be provided.

Background: Suicide is a leading cause of preventable death among adults diagnosed with schizophrenia spectrum disorders. Fewer studies have examined suicide thoughts and behaviors among community ...

The number of youth presenting to Emergency Departments (EDs) with psychiatric chief complaints has almost doubled in the last decade. With pediatric patients, ED brief interventions and discharge recommendations necessitate meaningful parental engagement to optimize youth safety and support. This study examined parent-level factors (stigmatizing attitudes, self-efficacy beliefs, distress symptoms, and illness-related stressors) in relation to parents' behavioral engagement (i.e., participation in and follow-through with best practice discharge recommendations). In this short-term prospective study, participants were 118 parent-youth (aged 11-18) dyads (57% female) recruited from a psychiatric ED. Parents' behavioral engagement was measured with parent- and youth-self report at 2-week follow-up. Parents' self-reported anxious and depressive symptoms, insomnia, stress, and stigmatizing attitudes were not related to engagement 2 weeks later. Higher parental self-efficacy beliefs were significantly associated with greater engagement in standard discharge recommendations. Implications for maximizing parent implementation of clinical recommendations during a youth suicide crisis are discussed.

[Image: see text] Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer’s disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.

To explore utilization patterns and associated clinical factors of school-age children who present to a psychiatric emergency department. This was a 6-year retrospective chart review study of children 5–12 years of age who presented to a psychiatric emergency service from July 2012 to June 2018 ( n = 1654 patients). Demographic variables, clinical diagnoses, lifetime adverse events (physical abuse, sexual abuse, and bullying), and history of self-harm were documented for each visit. We performed a chi square analysis to identify association between demographic and clinical features with key outcomes. Increased service utilization as defined by inpatient psychiatric admission, recurrent visits, or increased length of stay were found in patients who were adopted, presented with suicidal ideation or self-harm behaviors, had a history of abuse, and had a diagnosis of depression or autism. Trends over the course of the study indicated a significantly increased percentage of patients presenting with suicidal ideation, bullying, and self-harm behaviors. The data add to the limited literature regarding school-age children with a psychiatric emergency. Increased emergency service utilization for certain subgroups of children and trends over the course of the study underscore the need for enhanced treatment options for individuals with certain demographic or clinical features, and increased outpatient, intermediate, and inpatient treatment options, as well as preventative care.

Objective: Given increases in mental health utilization among college and university students, this study examines clinical and socio-demographic characteristics in students presenting to psychiatr...

Depression and suicidal ideation have substantially increased among college students, yet many students with clinically significant symptoms do not perceive their distress as warranting mental health services. Personalized feedback (PF) interventions deliver objective data, often electronically, comparing an individual’s reported symptoms or behaviors to a group norm. Several studies have shown promise for PF interventions in the context of mood and depression, yet little is known regarding how, and for whom, mood-focused PF interventions might be best deployed. The primary aim of this study was to examine the sociodemographic, clinical, and treatment-seeking factors associated with reviewing PF reports on emotional distress among college students (N=1,673) screening positive for elevated suicide risk and not receiving mental health treatment. Results indicated that PF engagement was greatest among those with higher depression scores, and those reporting privacy/stigma concerns as barriers to treatment. Sexual minority students were more likely to review their PF than heterosexual students. Taken together, PF interventions may be a useful tool for engaging those with greater clinical acuity, and those hesitant to seek in-person care. Further research is warranted to examine the circumstances in which PF interventions might be used in isolation, or as part of a multi-tiered intervention strategy.

Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2/PTPN11) is one of the key signaling proteins in many oncogenic receptor tyrosine kinase (RTK) pathways. It mediates RAS-driven downstream signaling and activates gene expression for tumorigenesis. Importantly, a critical role of SHP2 has been found during the process of temporal adaptation and ERK re-activation after the treatment of RAS/RAF/MEK/ERK inhibitors, which means that SHP2 could be a promising therapeutic target to shut down the oncogenic RAS pathway, especially in combination with RAS/RAF/MEK/ERK inhibitors. Here we present preclinical data of an allosteric small-molecule SHP2 inhibitor that is highly potent, selective, and brain-permeable. In vitro biochemical and cellular assays showed excellent potency against SHP2 protein. In addition, we confirmed exceptional in vivo activity in mouse xenograft models, and demonstrated combination effects with a KRAS G12C inhibitor. Most importantly, the BBB penetration and anti-tumor activity in brain was confirmed both in vitro and in vivo, supporting the great potential in treating brain-metastasized tumors. In summary, we have successfully discovered and developed a potent and blood-brain barrier permeable SHP2 inhibitor that provides a novel therapeutic option for diverse cancers associated in the RAS pathway. Citation Format: Miyeon Kim, Dongsu Kim, Kyeong Jin Yoon, Yeejin Jeon, Dohyun Park, Mijung Lee, Dahye Jeon, Soyeon Jang, Jinhwan Kim, Eunji Kim, Jihoon Park, Victor Hong, Sang Kyun Lim, Sungpil Choi. Discovery of a potent, selective, and orally available SHP2 inhibitor that can penetrate blood-brain barrier. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4032.

Patients with antisocial personality disorder (ASPD) and borderline personality disorder (BPD) are often suspected of malingering or exaggerating symptoms, though there is no clear evidence that they do so more than other patients. We review the manifestations, etiology, and management of seemingly feigned symptoms in these disorders, particularly related to their presentation in the emergency department (ED). It is dangerous to assume that all patients with ASPD and BPD are intentionally feigning symptoms in the ED. However, when ASPD patients are known to be malingering, the focus should be shifted to addressing the motivation behind malingering and the patient’s true goals, ideally done with a curious rather than confrontational approach. BPD patients also may appear to be malingering or exaggerating symptoms, but their presentation often is more accurately attributed to the lack of ability to mentalize and effectively communicate their needs, as well as emotional hypochondriasis. Education of ED staff, demonstrating genuine concern, and attempting to find a common goal with patients will aid in keeping an objective view of the patient’s distress, minimizing escalation, and optimizing patient outcomes.

Systematic case studies have identified risk factors for targeted violence. The sequence of thinking and behavior on a “pathway to violence” is often discernable, and campus attacks potentially preventable. Threat assessment, described in this chapter, is an evidence-based, information-driven, and collaborative undertaking to address the wide variety of potentially violent scenarios that may occur on campuses. Steps in case assessment and intervention principles are outlined and risk inquiry questions provided.

Reissner’s Mixed Variational Theorem (RMVT) presents both displacements and transverse stresses as primary variables. This property allows the a-priori fulfillment of both interlaminar compatibility and equilibrium with potentially excellent numerical performance. However, the triangular finite element based on RMVT has never been assessed from an energetic perspective. This aspect is investigated in the present contribution for the first time: the functional reconstitution technique is extended to RMVT-based triangular elements (retaining transverse normal stress) and it is demonstrated that the elements exhibit significantly lower errors than the corresponding displacement-based formulation. Moreover, the percentage errors on the approximation of the semi-complementary energy is shown to be invariant with the plate thickness-to-width ratio.

The streaming series 13 Reasons Why generated controversy because of its depiction of teen suicide and concerns about its impact on vulnerable youths. This study examined exposure to and patterns of engagement with the show and the show's perceived impact in a sample of youths presenting to a psychiatric emergency department (ED) with suicide-related concerns in the year after the series' premiere.Participants were 87 parent-youth dyads (youths' mean±SD age=14.6±1.8; 71% of youths were female, 26% male, and 2% gender nonconforming) who completed a battery of questionnaires during their ED visit.Half (49%) of the sample viewed at least one episode of 13 Reasons Why, season 1. Most youths (84%) viewed the show alone and were more likely to discuss their reactions with peers (80%) than with a parent (34%). Over half of youth viewers (51%) believed the series increased their suicide risk to a nonzero degree; having a stronger identification with the lead female character was significantly related to this belief (r=.63, df=41, p0.001). Youths with more depressive symptoms and suicidal ideation were more likely to identify with the lead characters and report negative affect while viewing.To date, this is the first published study examining viewing patterns and reactions to 13 Reasons Why in a high-risk sample. Although further research is needed, the findings suggest a particular vulnerability to the show's themes among youths at risk of suicide and the importance of prevention strategies to ameliorate risk among these viewers.

When clinicians encounter patients with borderline personality disorder (BPD) in the emergency department (ED) setting, challenges include managing acute self-injurious and suicidal behavior, intoxication, anger, interpersonal hypersensitivity, diagnostic confusion, and requests for medication changes. It is imperative to approach the BPD patient in an active, genuinely concerned manner while keeping one’s emotional reactions in check. Determining interpersonal stressors may help the provider expeditiously locate the trigger point for the crisis and can improve the safety risk assessment, which must be guided by the principle of acute-on-chronic risk. Psycho-education about BPD assists the patient in understanding their reactions and provides a useful framework for identifying which interventions are likely to be helpful (psychosocial) or not (medications). Communication with colleagues, the patient’s social supports, and outpatient providers is paramount in reaching the most appropriate disposition.

Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.

Patients with borderline personality disorder (BPD) are high utilizers of psychiatric emergency services and present unique challenges in that setting. Frequently advised to visit an emergency department (ED) if safety is in question, their experiences once there often do not have beneficial effects. Issues specific to patients with BPD in the ED include volatile interactions with staff, repeat visits, concerns about safety (and liability), and disposition. Emergency department staff attitudes toward these patients are frequently negative when compared to patients with other diagnoses, and can detrimentally affect outcomes and perpetuate stigma regarding BPD. These attitudes are often due to lack of education and training about how to understand, approach, and treat the patient with BPD. The limited literature regarding the treatment of BPD in the ED offers few guidelines. This article presents an approach based on Good Psychiatric Management that can reduce negative reactions by ED staff and make ED visits more effective and less harmful. Relevant principles include psychoeducation, the reinforcement of the connection between symptoms and interpersonal stressors, and employment of an active, authentic therapeutic stance. Training ED staff in these principles could lead to attitudinal changes, reduced stigma, and potentially improved outcomes.

Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd × 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.

Background: The ubiquity of smartphones and the development of mental health apps (MHAs) calls for evaluation of consumers’ attitudes towards and usage of MHAs. Due to the increasing demand for mental health services on college campuses, research is especially needed to evaluate MHAs as a potentially viable treatment modality in that setting. Methods: The study team developed survey questions related to MHAs, added these to the Healthy Minds Study, and used Qualtrics as the platform. The participants were 741 students, age 18 and older, from a large Midwest public university. Students could answer a varying number of multiple choice questions based on embedded display logic, and the survey required 20–25 minutes for most participants to complete. Based on embedded display logic in the survey and how questions were answered, students could receive anywhere from 1–20 questions. Questions were primarily categorical (e.g., “Yes”, “Maybe”, “No”), with the remaining questions in free response format. The survey was fielded in April, 2016. Results: 26.1% of respondents were open to using an MHA yet only 7.3% had used an MHA. 9.0% of respondents preferred to use an MHA versus seeing a mental health professional. 13.2% of respondents felt that MHAs do have an evidence base. 23.8% of users felt that MHAs helped with their mental health. Those who reported receiving mental health services within the past 12 months were significantly more open to using MHAs than those who had not received services. Convenience, immediate availability, and confidentiality were common reasons for interest in MHAs. Conclusions: There is interest in, but limited usage, of MHAs among university students, providing evidence of MHAs as a potentially untapped treatment modality for this population. Further research could help assess how best to integrate this technology into the university and college mental health system.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 A resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 A resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.

RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.

Interest has arisen in recent years in the relationship between religious involvement and health outcomes. Although most of the early literature consists of studies with methodological flaws, some recent well-conducted reports show that religious attendance is associated with reduced mortality in selected subgroups and populations.In this study, we investigated the relationship between religious attendance and mortality using the 14,456 participants in the National Institute of Aging-funded 'Established Populations for Epidemiologic Studies of the Elderly'.Our analyses show that after controlling for important prognostic factors, frequent religious attendance was associated with increased survival in the entire cohort [risk ratio (RR) = 0.78, 95% Confidence interval (CI) 0.70-0.88]. However, stratified analyses show that this association exists for only two of the four sites.We conclude that the association between religious attendance and survival is not robust and may depend upon unknown confounders and covariates.

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases.

To evaluate the effects of HSP90 blockade by EC154 on the oncogenic receptor tyrosine kinase macrophage-stimulating 1 receptor (MST1R) in gastric and pancreatic cancer.Impact of EC154 on signaling pathways was investigated by western blotting. Cancer cell migration was evaluated in Boyden chambers. Transcriptional regulation of MST1R was examined by using promoter-luciferase reporter constructs. Effects on MST1R expression, and tumor growth were investigated in in vivo tumor models.MST1R was expressed by cancer cells without evidence of MST1R mutations. EC154 led to an effective inhibition of cancer cell growth, down-regulated MST1R, diminished its promoter activity, and disrupted oncogenic macrophage-stimulating protein 1 (MSP1) signaling. Moreover, pro-migratory activities of cancer cells were dramatically inhibited. In vivo, treatment with EC154 significantly reduced tumor growth, while MST1R expression was down-regulated.Wild-type MST1R is an HSP90 client protein that can be targeted in gastrointestinal cancer using HSP90 inhibitors.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 Å resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 Å resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.

Anthocyanins are the red, blue and purple pigments responsible for the coloration of many plants. These pigments have been the subject of many studies due to their importance as a quality indicator in foods and as an important chemotaxonomic indicator for plants. Early work with anthocyanins employed paper chromatographic methods. More recently, high-performance liquid chromatography has been widely applied to the study of these pigments. The objective of this paper is to review the chromatographic methods that have been employed in the analysis of anthocyanins with emphasis on the more recent developments in high-performance liquid chromatographic analysis of anthocyanins as applied to food quality measurement.

The anthocyanin pigment profiles of commercial black currant, blackberry, black raspberry, elderberry, cherry, plum, grape, bilberry, and red cabbage products were characterized by high-performance liquid chromatography (HPLC)/photodiode array detection. Removal of acylated anthocyanins by alkaline hydrolysis and selective removal of anthocyanins on a reversed-phase cartridge with borate buffer were auxiliary techniques that proved helpful in making peak assignments. Both the retention properties on reversed-phase HPLC and the spectral properties by photodiode array detection were used to characterize the anthocyanins. Other properties including tinctoral strength, total anthocyanin concentration, browning, titratable acidity, and Hunter tristimulus values were also determined for these colorants.

A systematic procedure for separation and characterization of anthocyanins is described. Separation of pigments was achieved by high-performance liquid chromatography (HPLC) on a polymer reversed-phase column. Methods for preparation of an anthocyanin isolate free of other interfering phenolics were developed. Photodiode array detection was employed to determine the UV-visible spectral characteristics of the pigments. Derivatives of delphinidin (delphinidin, petunidin, malvidin) can be distinguished from derivatives of cyanidin (cyanidin, peonidin), which in turn can be distinguished from pelargonidin derivatives on the basis of their different UV-visible spectra. Acylation with cinnamic acids and differentiation between 3- and 3,5-glycosidation can also be determined from the UV-visible spectrum. Auxiliary sample preparation techniques useful for pigment characterization included alkaline hydrolysis of the anthocyanins for determination of acylation. Anthocyanins not containing an o-diphenolic system can be enriched on a C18 reversed-phase cartridge by elution with alkaline borate buffer. With a combination of these techniques, peak assignments for the anthocyanins from sources whose anthocyanin composition is known can be readily made.

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases.

Thirty-one samples of commercial cranberry juice drink and one sample of commercial cranberry juice concentrate were analyzed for nonvolatile acids and anthocyanidin profiles by liquid chromatography (LC). Ultraviolet-visible spectral measurements were used to measure pigment concentration, polymeric color, and percent polymeric color. Nineteen of the 31 samples analyzed were found to be adulterated. The adulterated samples exhibited nonvolatile organic acid profiles indicative of added malic and/or citric acid. Anthocyanidin profiles of the adulterated samples showed the presence of substantial quantities of delphinidin and malvidin, neither of which are present in cranberries in significant amounts. Grape skin extract is believed to be the added colorant.

Eight samples of cranberries (Vaccinium macrocarpon) representing the major varieties and principal commercial growing regions in the United States were processed into juice. Four of the 8 samples were concentrated to 50° Brix. Liquid chromatography (LC) was used to determine nonvolatile organic acid, anthocyanidin pigment, and sugar profiles. Ultraviolet-visible spectral methods were used to determine anthocyanin concentration, polymeric color, and percent polymeric color. Other data presented include stable isotope carbon ratios, degree Brix, pH, and Hunter color parameters. These data are presented to serve as an authentic data base for use in detection of adulterated cranberry juice.